# Patent

## Title
Method and apparatus for determining anticoagulant therapy factors

## Abstract

Methods and apparatus are disclosed for determining new anticoagulant therapy factors for monitoring oral anticoagulant therapy to help prevent excessive bleeding or deleterious blood clots that might otherwise occur before, during or after surgery. The inventive methods and apparatus provide an International Normalization Ratio (INR) based on a coagulation reaction with a blood sample of a living being. Embodiments include methods and apparatus for determining an anticoagulant therapy factor without requiring use of a mean normal prothrombin time determination or an ISI, and may be carried out with the patient sample and a coagulation reagent, where the coagulation reagent may be selected from a number of coagulation reagents. One embodiment provides an INRs value which is determined from a prothrombin time (PT or T1) of a patient blood sample and a theoretical end of test time (TEOT), where a theoretical clotting area is used to determine the INRs value according to the expression, INRs=T1*TEOT*MUL, where MUL is a multiplier that takes into account pixel parity and sampling times. The INRs may be used to determine a course of treatment for a patient or other living being without regard to the specific coagulation regent used to generate the coagulation data (e.g., time and optical activity values).

## Background
CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of U.S. application Ser. No. 12/378,456 filed on Feb. 14, 2009 now U.S. Pat. No. 7,901,694, issued on Mar. 8, 2011, the complete disclosures of which are herein incorporated by reference.


BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to analyzing blood for carrying out coagulation studies and other chemistry procedures, including monitoring oral anticoagulant therapy to take into account the platelet count in determining prothrombin times (PT), and providing new Anticoagulant Therapy Factors that are useful in diagnosing and treating individuals in relation to blood conditions.
2. Brief Description of the Related Art
Testing of blood and other body fluids is commonly done in hospitals, labs, clinics and other medical facilities. For example, to prevent excessive bleeding or deleterious blood clots, a patient may receive oral anticoagulant therapy before, during and after surgery. Oral anticoagulant therapy generally involves the use of oral anticoagulants—a class of drugs which inhibit blood clotting. To assure that the oral anticoagulant therapy is properly administered, strict monitoring is accomplished and is more fully described in various medical technical literature, such as the articles entitled “PTs, PR, ISIs and INRs: A Primer on Prothrombin Time Reporting Parts I and II” respectively published November, 1993 and December, 1993 issues of Clinical Hemostasis Review, and herein incorporated by reference.
These technical articles disclose anticoagulant therapy monitoring that takes into account three parameters which are: International Normalized Ratio (INR), International Sensitivity Index (ISI) and prothrombin time (PT), reported in seconds. The prothrombin time (PT) indicates the level of prothrombin and blood factors V, VII, and X in a plasma sample and is a measure of the coagulation response of a patient. Also affecting this response may be plasma coagulation inhibitors, such as, for example, protein C and protein S. Some individuals have deficiencies of protein C and protein S. The INR and ISI parameters are needed so as to take into account various differences in instrumentation, methodologies and in thromboplastins' (Tps) sensitivities used in anticoagulant therapy. In general, thromboplastins (Tps) used in North America are derived from rabbit brain, those previously used in Great Britain from human brain, and those used in Europe from either rabbit brain or bovine brain. The INR and ISI parameters take into account all of these various factors, such as the differences in thromboplastins (Tps), to provide a standardized system for monitoring oral anticoagulant therapy to reduce serious problems related to prior, during and after surgery, such as excessive bleeding or the formation of blood clots.
The ISI itself according to the WHO 1999 guidelines, Publication no. 889-1999, have coefficients of variation ranging from 1.7% to 8.1%. Therefore, if the ISI is used exponentially to determine the INR of a patient, then the coefficients of variation for the INR's must be even greater than those for the ISI range.
As reported in Part I (Calibration of Thromboplastin Reagents and Principles of Prothrombin Time Report) of the above technical article of the Clinical Hemostasis Review, the determination of the INR and ISI parameters are quite involved, and as reported in Part II (Limitation of INR Reporting) of the above technical article of the Clinical Hemostasis Review, the error yielded by the INR and ISI parameters is quite high, such as about up to 10%. The complexity of the interrelationship between the International Normalized Ratio (INR), the International Sensitivity Index (ISI) and the patient's prothrombin time (PT) may be given by the below expression (A),
wherein the quantity




  
    
      
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is commonly referred to as prothrombin ratio (PR):





  
    
      
        
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          R
        
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          ISI
        
      
    
    
      
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The possible error involved with the use of International Normalized Ratio (INR) is also discussed in the technical article entitled “Reliability and Clinical Impact of the Normalization of the Prothrombin Times in Oral Anticoagulant Control” of E. A. Loeliger et al., published in Thrombosis and Hemostasis 1985; 53: 148-154, and herein incorporated by reference. As can be seen in the above expression (B), ISI is an exponent of INR which leads to the possible error involved in the use of INR to be about 10% or possibly even more. A procedure related to the calibration of the ISI is described in a technical article entitled “Failure of the International Normalized Ratio to Generate Consistent Results within a Local Medical Community” of V. L. Ng et al., published in Am. J. Clin. Pathol. 1993; 99: 689-694, and herein incorporated by reference.
The unwanted INR deviations are further discussed in the technical article entitled “Minimum Lyophilized Plasma Requirement for ISI Calibration” of L. Poller et al. published in Am. J. Clin. Pathol. February 1998, Vol. 109, No. 2, 196-204, and herein incorporated by reference. As discussed in this article, the INR deviations became prominent when the number of abnormal samples being tested therein was reduced to fewer than 20 which leads to keeping the population of the samples to at least 20. The paper of L. Poller et al. also discusses the usage of 20 high lyophilized INR plasmas and 7 normal lyophilized plasmas to calibrate the INR. Further, in this article, a deviation of +/−10% from means was discussed as being an acceptable limit of INR deviation. Further still, this article discusses the evaluation techniques of taking into account the prothrombin ratio (PR) and the mean normal prothrombin time (MNPT), i.e., the geometric mean of normal plasma samples.
The discrepancies related to the use of the INR are further studied and described in the technical article of V.L. NG et al. entitled, “Highly Sensitive Thromboplastins Do Not Improve INR Precision,” published in Am. J. Clin. Pathol., 1998; 109, No. 3, 338-346 and herein incorporated by reference. In this article, the clinical significance of INR discordance is examined with the results being tabulated in Table 4 therein and which are analyzed to conclude that the level of discordance for paired values of individual specimens tested with different thromboplastins disadvantageously range from 17% to 29%.
U.S. Pat. No. 5,981,285 issued on Nov. 9, 1999 to Wallace E. Carroll et al., which discloses a “Method and Apparatus for Determining Anticoagulant Therapy Factors” provides an accurate method for taking into account varying prothrombin times (PT) caused by different sensitivities of various thromboplastin formed from rabbit brain, bovine brain or other sources used for anticoagulant therapy. This method does not suffer from the relatively high (10%) error sometimes occurring because of the use of the INR and ISI parameters with the exponents used in their determination.
The lack of existing methods to provide reliable results for physicians to utilize in treatment of patients has been discussed, including in a paper by Davis, Kent D., Danielson, Constance F. M., May, Lawrence S., and Han, Zi-Qin, “Use of Different Thromboplastin Reagents Causes Greater Variability in International Normalized Ratio Results Than Prolonged Room Temperature Storage of Specimens,” Archives of Pathol. and Lab. Medicine, November 1998. The authors observed that a change in the thromboplastin reagent can result in statistically and clinically significant differences in the INR. Considering the current methods for determining anticoagulant therapy factors, there are numerous opportunities for error. For example, it has been reported that patient deaths have occurred at St. Agnes Hospital in Philadelphia, Pa. There the problem did not appear to be the thromboplastin reagent, but rather, was apparently due to a failure to enter the correct ISI in the instrument used to carry out the prothrombin times when the reagent was changed. This resulted in the incorrect INR's being reported. Doses of coumadin were given to already overanticoagulated patients based on the faulty INR error, and it is apparent that patient deaths were caused by excessive bleeding due to coumadin overdoses. In the St. Agnes Hospital, Philadelphia 2001 INR disaster, an incorrect ISI of 1.01 was used instead of 2.028. As has been recommended by Poller, INR studies should be performed at the INR 2.0 and 3.0 levels. 2.0 to 3.0 is the Therapeutic INR Range recommended for most clotting/thrombotic conditions. These two levels will be used in the following calculations:
The PRs at INR 2.0 calculation are:

INR=PRISI; log INR=(ISI)(log PR);

log PR=log INR/ISI;

log PR=log 2.0=0.301; log PR/ISI=0.301/1.01=0.298

PR=1.986

INR=PRISI1.9861.01=2.00

INR=PRISI=1.9862.028=4.02

An INR of 2.00 would have been reported, not the actual 4.02. Warfarin at a reported INR 2.0 level would likely have been administered to an already overanticoagulated patient, but serious consequences may not necessarily have occurred here. Using the erroneous 1.01 ISI with an INR of 3.0 for calculations is drastically different:

log PR=log INR/ISI=0.477/1.01=0.472

PR=2.968

INR=PRISI=2.9681.01=3.00

INRISI=2.9682.028=9.08

This incorrectly reported INR of 3.0 would actually have been 9.08. 9.08 is well above INR=6.0 where excessive bleeding is considered to occur. In addition, the five fatal St. Agnes cases, even at INR=9.08, could have even been administered a routine warfarin dose, since it would have been believed it was intended for patients with an INR of 3.0, not 9.08.
But even in addition to errors where a value is not input correctly, the known methods for determining anticoagulant therapy factors still may be prone to errors, even when the procedure is carried out in accordance with the reagent manufacturer's ISI data. One can see this in that current methods have reported that reagents used to calculate prothrombin times, may, for healthy (i.e., presumed normal) subjects, give rise to results ranging from 9.7 to 12.3 seconds at the 95th % reference interval for a particular reagent, and 10.6 to 12.4 for another. The wide ranges for normal patients illustrates the mean normal prothrombin time differences. When the manufacturer reference data ranges are considered, if indeed 20 presumed normal patients' data may be reported within a broad range, then there is the potential for introduction of this range into the current anticoagulation therapy factor determinations, since they rely on the data for 20 presumed normal patients. Considering the reagent manufacturer expected ranges for expected normal prothrombin times, INR units may vary up to 30%. This error is apparently what physicians must work with when treating patients. A way to remove the potential for this type of error is needed.
This invention relates to the inventions disclosed in U.S. Pat. Nos. 3,905,769 ('769) of Sep. 16, 1975; 5,197,017 ('017) dated Mar. 23, 1993; and 5,502,651 ('651) dated Mar. 26, 1996, all issued to Wallace E. Carroll and R. David Jackson, and all of which are incorporated herein by reference. The present invention provides apparatus and methods for monitoring anticoagulant therapy.
SUMMARY OF THE INVENTION
Methods and apparatus useful for processing coagulation studies, and other chemistry procedures involving blood and blood components. The apparatus and methods may be used to determine anticoagulant therapy factors which are designated herein, in particular, to determine new Anticoagulant Therapy Factors (nATF's) which preferably may replace International Normalized Ratio (INR) in anticoagulation therapy management. Previously, anticoagulation therapy involved the use of International Normalized Ratios (INR's). The International Normalized Ratio (INR) was utilized in order to arrive at an anticoagulant therapy factor (ATF). The INR based ATF was dependent on the prothrombin time (PT), the prothrombin ratio (PR), a fibrinogen transformation rate (FTR), and a maximum acceleration point (MAP) having an associated time to maximum acceleration (TMA).
Methods and apparatus are disclosed for determining a new anticoagulant therapy factor (nATF) for monitoring oral anticoagulant therapy to help prevent excessive bleeding or deleterious blood clots that might otherwise occur before, during or after surgery. In one embodiment, a new anticoagulant therapy factor (nATF) is based upon a determination of the fibrinogen transformation rate (FTR) which, in turn, is dependent on a maximum acceleration point (MAP) for fibrinogen (FBG) conversion. The nATF quantity is also based upon the time to maximum acceleration from the time of reagent injection (TX) into a plasma sample, but does not require the difficulty of obtaining prior art International Normalized Ratio (INR) and International Sensitivity Index (ISI) parameters. The International Normalized Ratio (INR) was created to relate all species' clotting material to human clotting material, and nATF can replace INR in anticoagulant therapy management.
In accordance with other embodiments, methods and apparatus are provided for determining an anticoagulation therapy factor, which do not require the use of a mean normal prothrombin time (MNPT) and ISI data. In other words, the need to obtain and calculate the prothrombin time of 20 presumed normal patients, is not required to determine an anticoagulant therapy factor.
In accordance with the present invention, there is provided apparatus and methods for carrying out coagulation studies and other chemical procedures and analyses.
Another embodiment provides methods and apparatus for determining an anticoagulant therapy factor or INR, such as INRn, from the derivation of clotting curve values in connection with a designated area defined by clotting curve data. One preferred embodiment relates to an area defined by clotting curve data that corresponds with the area of a trapezoid formed along the clotting curve.
Another embodiment provides methods and apparatus for determining an anticoagulant therapy factor or INR, such as INRs, from the derivation of clotting curve values in connection with a designated area defined by clotting curve data that may be utilized to determine an anticoagulant therapy factor. One preferred embodiment relates to an area defined by clotting curve data that corresponds with a clotting area that is derived derived from values represented by the optical activity (such as absorbance values) and time intervals at which that activity occurs. Embodiments used for determining an INRs also may apply a multiplier to an area value to adjust the area, for example, to account for pixel parity and sampling time.
It is another object of the invention to provide a method and apparatus for determining an INR, such as INRs/ATFs, where a transformed INR, INRs, is obtained using various clotting reagents to carry out a clotting reaction of a blood sample where clear fibrinogen in the sample is converted into turbid fibrin to give an optical activity (or absorbance) curve. The traditional INR, an empirically-derived INR, was conceived by Kirkwood in 1983 to standardize the Quick prothrombin time (PT) for oral anticoagulant therapy management, and has two major sources of error: 1. its common denominator, the mean normal prothrombin time (MNPT), and 2. the exponentially-derived ISI exponent. The present methods and devices provide improved alternative INR determinations. According to one embodiment, an INR value, INRs, is determined using a standard curve that is created with fibrinogen standards, such as, for example, using FDA-cleared high and low fibrinogen standards and three fibrinogen/INR controls of levels 1, 2 and 3. The INR (standard) value is obtained for the standards and a hypothetical or theoretical clotting AREA value (A) is calculated for each of the tested thromboplastin standards. The resultant Area and INR values are related to determine a power regression, in which the determination of patient samples using the same thromboplastin reagent as that used for the standards may be carried out by determining the clotting area for the sample, and applying the power regression expression to derive an INRs value for the sample based on the sample's clotting area (A).
The method and apparatus may provide INRs/ATFs coagulation values that may be used to determine a course of treatment for a patient.
These and other advantages are provided by the invention.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a diagram of potentiophotometric apparatus constructed in accordance with one embodiment of the present invention for determining blood chemistry analyses such as coagulation studies, including determination of the new anticoagulant therapy factor (nATF), where the output of the analog/digital (A/D) converter is applied to a computer.
FIG. 2 is a plot of the various phases of the fibrinogen concentration occurring in a typical plasma clotting process.
FIG. 3 is another plot of the various phases of the fibrinogen concentration occurring in a typical plasma clotting process.
FIG. 4 is another plot of the various phases of the fibrinogen concentration occurring in a typical plasma clotting process.
FIG. 5 is another plot of the various phases of the fibrinogen concentration occurring in a typical plasma clotting process illustrating the fibrinogen lag phase.
FIG. 6 is another plot of the various phases of the fibrinogen concentration occurring in a typical plasma clotting process.
FIG. 7 is an illustration showing a preferred embodiment of the area determination and representational clotting area formed based on data from the clotting curve reaction shown in FIG. 6.
FIG. 8 is a figure depicting the clotting area of FIG. 7 with the clotting curve for a reaction of a blood sample containing fibrinogen with a thromboplastin reagent.
FIGS. 9, 10 and 11 illustrate solution curves for clotting reagents, TPC, Innovin and BPT, respectively, based on a power regression.
FIGS. 12, 13 and 14 illustrate curves for clotting reagents, TPC, Innovin and BPT, respectively, for INR determinations, based on a linear regression.



DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to the drawings, wherein the same reference numbers indicate the same elements throughout, there is shown in FIG. 1 a light source 4 which may be a low power gas laser, or other light producing device, producing a beam of light 6 which passes through a sample test tube, such as the container 8, and is received by detection means which is preferably a silicon or selenium generating photocell 10 (photovoltaic cell). Battery 12 acts as a constant voltage DC source. Its negative terminal is connected through switch 14 to one end of variable resistor 16 and its positive terminal is connected directly to the opposite end of variable resistor 16. The combination of battery 12 and variable resistor 16 provides a variable DC voltage source, the variable voltage being derivable between line 18 at the upper terminal of resistor 16 and wiper 20. This variable DC voltage source is connected in series with detection means photocell 10, the positive output of detection means photocell 10 being connected to the wiper 20 of variable resistor 16 so that the voltage produced by the variable voltage DC source opposes the voltage produced by the detection means photocell 10. The negative output of detection means photocell 10 is connected through variable resistor 22 to line 18. Thus, the voltage across variable resistor 22 is the difference between the voltage produced by the variable voltage DC source and the voltage produced by the photovoltaic cell 10. The output of the electrical network is taken between line 18 and wiper 24 of variable resistor 22. Thus, variable resistor 22 acts as a multiplier, multiplying the voltage produced as a result of the aforesaid subtraction by a selective variable depending on the setting of variable resistor 22. The potentiophotometer just described embodies the electrical-analog solution to Beer's Law and its output is expressed directly in the concentration of the substance being measured.
Wiper 24 is illustrated placed at a position to give a suitable output and is not varied during the running of the test. The output between line 18 and wiper 24 is delivered to an A/D converter 26 and digital recorder 28. As is known, the A/D converter 26 and the digital recorder 28 may be combined into one piece of equipment and may, for example, be a device sold commercially by National Instrument of Austin, Tex. as their type Lab-PC+. The signal across variable resistor 22 is an analog signal and hence the portion of the signal between leads 18 and wiper 24, which is applied to the A/D converter 26 and digital recorder 28, is also analog. A computer 30 is connected to the output of the A/D converter 26, is preferably IBM compatible, and is programmed in a manner described hereinafter.
For example, preferably, the detector cell 10 is positioned adjacent an opposite wall of the sample container 8, and the emitter light source 4 positioned adjacent on opposite wall, so the light 6 emitted from the light source 4 passes through the container 8. The light source 4 is preferably selected to produce light 6 which can be absorbed by one or more components which are to be measured.
The apparatus can be used to carry out coagulation studies in accordance with the invention. In accordance with a preferred embodiment of the present invention, the light source 4 may, for example, comprise a light emitting diode (LED) emitting a predetermined wavelength, such as for example, a wavelength of 660 nm, and the detector cell 10 may, for example, comprise a silicon photovoltaic cell detector. Optionally, though not shown, a bar code reader may also be provided to read bar code labels placed on the sample container 8. The bar code reader may produce a signal which can be read by the computer 30 to associate a set of data with a particular sample container 8.
To carry out a coagulation study on blood plasma, the citrated blood is separated from the red blood cell component of the blood. Conventional methods of separation, which include centrifugation, may be employed. Also, the use of a container device such as that disclosed in our issued U.S. Pat. No. 6,706,536, may also be used, and the method disclosed therein for reading the plasma volume relative to the sample volume may also be employed.
Illustrative of an apparatus and method according to one embodiment is a coagulation study which can be carried out therewith. A reagent, such as, for example, Thromboplastin-Calcium (Tp-Ca), is added to the plasma sample which is maintained at about 37° C. by any suitable temperature control device, such as a heated sleeve or compartment (not shown). The reagent addition is done by dispensing an appropriate amount of the reagent into the plasma portion of the blood. The plasma portion may be obtained by any suitable separation technique, such as for example, centrifugation. In one embodiment illustrated herein, the container 8 is vented when reagent is added. The reagent for example, may comprise thromboplastin, which is added in an amount equal to twice the volume of the plasma. The reagent is mixed with the plasma. It is preferable to minimize air bubbles so as not to interfere with the results. The plasma sample to which the reagent has been added is heated to maintain a 37° C. temperature, which, for example, may be done by placing the container holding the plasma and reagent in a heating chamber (not shown).
Readings are taken of the optical activity of the components in the sample container 8.
Reaction kinematics may be studied by observing changes in the optical density of the plasma layer. For example, an amount of reagent, such as Thromboplastin-Calcium (Tp-Ca), may be added to the plasma sample in the container. The plasma sample in the container may comprise a known amount of volume. Alternately, the plasma volume may be ascertained through the method and apparatus described in our U.S. Pat. No. 6,706,536. A controlled amount of Tp-Ca reagent is added to the plasma sample. The amount of reagent added corresponds to the amount of plasma volume. The detector cell 10 and emitter light source 4 are preferably positioned so the absorbance of the plasma sample may be read, including when the reagent is added and the sample volume is thereby increased.
With the detection elements, such as the cell 10 and emitter 4, positioned to read the plasma sample and the reagents added thereto, the reaction analysis of the extended prothrombin time curve can be followed. FIG. 2 shows a graph of a plot of the various phases of the fibrinogen concentration occurring in a typical plasma clotting process. The change in optical density of the plasma level occurs after reagents have been added. The optical density of the plasma sample is monitored, as optically clear fibrinogen converts to turbid fibrin.
The coagulation study of the type described above is used to ascertain the results shown in the graph plotted on FIG. 2. The description of the analysis makes reference to terms, and symbols thereof, having a general description as used herein, all to be further described and all of which are given in Table 1.









TABLE 1





SYMBOL
TERM
GENERAL DESCRIPTION







PT
Prothrombin Time
A period of time calculated from the addition of the




reagent (e.g., thromboplastin-calcium) to a point where




the conversion of fibrinogen to fibrin begins (i.e. the




formation of the first clot).


TMA
Time to Maximum
The time from PT to a point where the rate of conversion



Acceleration
of fibrinogen to fibrin has reached maximum and begins




to slow.


MAP
Maximum Acceleration Point
A point where the fibrinogen conversion achieves




maximum acceleration and begins to decelerate.


EOT
End of Test
Point where there is no appreciable change in the




polymerization of fibrin.


TEOT
Theoretical End Of Test
The time to convert all fibrinogen based on the time to




convert the fibrinogen during the simulated Zero Order




Kinetic rate.


TX (or T2)
Time to Map
Time to reach the Maximum Acceleration Point (MAP)




from point of injection.


MNTX
Mean Normal Time to Map
The mean of the times of at least 20 normal people to




reach then Maximum Acceleration Point (MAP).


FTR
Fibrinogen Transformation
The amount of fibrinogen converted during a particular



Ratio
time period. This is a percentage of the total Fibrinogen.


ATF
Anticoagulation Therapy
The calculated value used to monitor the uses of an



Factor
anticoagulant without a need for an International




Sensitivity Index (ISI) of a thromboplastin.


nATF
new Anticoagulation Therapy
A replacement for the INR to provide a standardized



Factor
system for monitoring oral anticoagulant therapy. (Also




expressed as ATFt and ATFz)


PR
Prothrombin Ratio
A value computed by dividing a sample PT by the




geometric mean of at least 20 normal people (MNPT).


INR
International Normalized
A parameter which takes into account the various factors



Ratio
involved in anticoagulation therapy monitoring to provide




a standardized system for monitoring oral anticoagulant




therapy.


ATFt
Anticoagulation Therapy
Utilizing a calculated Theoretical End Of Test value and



Factor Theoretical
the Natural Log “e” to removed the need for an MNPT.


XR
Time to MAP Ratio
The value computed by dividing a sample “TX” by the




geometric mean of at least 20 normal people “MNTX”.









Prior patents for obtaining an anticoagulant therapy factor (ATF) relied on the International Normalized Ratio (INR) system which was derived in order to improve the consistency of results from one laboratory to another. The INR system utilized the calculation of INR from the equation:

INR=PTpatient/PTgeometric mean)ISI 

wherein the PTpatient is the prothrombin time (PT) as an absolute value in seconds for a patient, PTgeometric mean is the mean, a presumed number of normal patients. The International Sensitivity Index (ISI) is an equalizing number which a reagent manufacturer of thromboplastin specifies. The ISI is a value which is obtained through calibration against a World Health Organization primary reference thromboplastin standard. Local ISI (LSI) values have also been used to provide a further refinement of the manufacturer-assigned ISI of the referenced thromboplastin in order to provide local calibration of the ISI value.

For illustration, the present invention can be employed for accurate determination of a new Anticoagulant Therapy Factor (nATF) from a human blood sample, for use during the monitoring of oral anticoagulant therapy, without the need for an ISI or LSI value, and without the need for an INR value as traditionally determined from the above equation (using a patient's prothrombin time and the prothrombin time from a geometric mean of individuals). As is known in the art, blood clotting Factors I, II, V, VII, VIII, IX and X are associated with platelets (Bounameaux, 1957); and, among these, Factors II, VII, IX and X are less firmly attached, since they are readily removed from the platelets by washing (Betterle, Fabris et al, 1977). The role of these platelet-involved clotting factors in blood coagulation is not, however, defined. The present invention provides a method and apparatus for a new Anticoagulant Therapy Factor (nATF) which may be used for anticoagulant therapy monitoring without the need for INR.
The International Normalized Ratio (INR) is previously discussed in already incorporated reference technical articles entitled “PTs, PRs, ISIS and INRs: A Primer on Prothrombin Time Reporting Part I and II respectively,” published in November, 1993 and December, 1993 issues of Clinical Hemostasis Review. The illustrative example of an analysis which is carried out employing the present invention relies upon the maximum acceleration point (MAP) at which fibrinogen conversion achieves a maximum and from there decelerates, the time to reach the MAP (TX), and the mean normal time to MAP (MNTX), and a fibrinogen transformation rate (FTR), that is, the thrombin activity in which fibrinogen (FBG) is converted to fibrin to cause clotting in blood plasma.
More particularly, during the clotting steps used to determine the clotting process of a plasma specimen of a patient under observation, a thromboplastin (Tp) activates factor VII which, activates factor X, which, in turn, under catalytic action of factor V, activates factor II (sometimes referred to as prothrombin) to cause factor IIa (sometimes referred to as thrombin) that converts fibrinogen (FBG) to fibrin with resultant turbidity activity which is measured, in a manner as to be described hereinafter, when the reaction is undergoing simulated zero-order kinetics.
From the above, it should be noted that the thromboplastin (Tp) does not take part in the reaction where factor IIa (thrombin) converts fibrinogen (FBG) to fibrin which is deterministic of the clotting of the plasma of the patient under consideration. The thromboplastin (Tp) only acts to activate factor VII to start the whole cascade rolling. Note also that differing thromboplastins (Tps) have differing rates of effect on factor VII, so the rates of enzyme factor reactions up to II-IIa (the PT) will vary.
Therefore, the prothrombin times (PTs) vary with the different thromboplastins (Tps) which may have been a factor that mislead authorities to the need of taking into account the International Normalized Ratio (INR) and the International Sensitivity Index (ISI) to compensate for the use of different types of thromboplastins (Tps) during the monitoring of oral anticoagulant therapy. It is further noted, that thromboplastins (Tps) have nothing directly to do with factor IIa converting fibrinogen (FBG) to fibrin, so it does not matter which thromboplastin is used when the fibrinogen transformation is a primary factor.
The thromboplastin (Tp) is needed therefore only to start the reactions that give factor IIa. Once the factor IIa is obtained, fibrinogen (FBG) to fibrin conversion goes on its own independent of the thromboplastin (Tp) used.
In one embodiment, the present method and apparatus has use, for example, in coagulation studies where fibrinogen (FBG) standard solutions and a control solution are employed, wherein the fibrinogen standard solutions act as dormant references to which solutions analyzed with the present invention are compared, whereas the control solution acts as a reagent that is used to control a reaction. The fibrinogen standards include both high and low solutions, whereas the control solution is particularly used to control clotting times and fibrinogens of blood samples. It is only necessary to use fibrinogen standards when PT-derived fibrinogens (FBG's) are determined. In connection with other embodiments of the invention, fibrinogen (FBG) standards are not necessary for the INR determination (such as for example INRz described herein).
Another embodiment provides a method and apparatus for determining an anticoagulation therapy factor which does not require the use of fibrinogen standard solutions. In this embodiment, the apparatus and method may be carried out without the need to ascertain the mean normal prothrombin time (MNPT) of 20 presumed normal patients.
Where a fibrinogen standard solution is utilized, a fibrinogen (FBG) solution of about 10 g/l may be prepared from a cryoprecipitate. The cryoprecipitate may be prepared by freezing plasma, letting the plasma thaw in a refrigerator and then, as known in the art, expressing off the plasma so as to leave behind the residue cryoprecipitate. The gathered cryoprecipitate should contain a substantial amount of both desired fibrinogen (FBG) and factor VIII (antihemophilic globulin), along with other elements that are not of particular concern to the present invention. The 10 g/l fibrinogen (FBG) solution, after further treatment, serves as the source for the high fibrinogen (FBG) standard. A 0.5 g/l fibrinogen (FBG) solution may then be prepared by a 1:20 (10 g/l/20=0.5 g/l) dilution of some of the gathered cryoprecipitate to which may be added an Owren's Veronal Buffer (pH 7.35) (known in the art) or normal saline solution and which, after further treatment, may serve as a source of the low fibrinogen (FBG) standard.
The fibrinogen standard can be created by adding fibrinogen to normal plasma in an empty container. Preferably, the fibrinogen standard is formed from a 1:1 fibrinogen to normal plasma solution. For example, 0.5 ml of fibrinogen and 0.5 ml of plasma can be added together in an empty container. Thromboplastin calcium is then added to the fibrinogen standard. Preferably, twice the amount by volume of thromboplastin is added into the container per volume amount of fibrinogen standard which is present in the container. The reaction is watched with the apparatus 10.
Then, 1 ml of each of the high (10 g/l) and low (0.5 g/l) sources of the fibrinogen standards may be added to 1 ml of normal human plasma (so the cryoprecipitate plasma solution can clot). Through analysis, high and low fibrinogen (FBG) standards are obtained. Preferably, a chemical method to determine fibrinogen (FBG) is used, such as, the Ware method to clot, collect and wash the fibrin clot and the Ratnoff method to dissolve the clot and measure the fibrinogen (FBG) by its tyrosine content. The Ware method is used to obtain the clot and generally involves collecting blood using citrate, oxalate or disodium ethylenediaminetetraacetate as anticoagulant, typically adding 1.0 ml to about 30 ml 0.85% or 0.90% sodium chloride (NaCl) in a flask containing 1 ml M/5 phosphate buffer and 0.5 ml 1% calcium chloride CaCl2, and then adding 0.2 ml (100 units) of a thrombin solution. Preferably, the solution is mixed and allowed to stand at room temperature for fifteen minutes, the fibrin forming in less than one minute forming a solid gel if the fibrinogen concentration is normal. A glass rod may be introduced into the solution and the clot wound around the rod. See Richard J. Henry, M.D., et al., Clinical Chemistry: Principals and Techniques (2nd Edition) 1974, Harper and Row, pp. 458-459, the disclosure of which is incorporated herein by reference. Once the clot is obtained, preferably the Ratnoff method may be utilized to dissolve the clot and measure the fibrinogen (FBG) by its tyrosine content. See “A New Method for the Determination of Fibrinogen in Small Samples of Plasma”, Oscar D. Ratnoff, M. D. et al., J. Lab. Clin. Med., 1951: V. 37 pp. 316-320, the complete disclosure of which is incorporated herein by reference. The Ratnoff method relies on the optical density of the developed color being proportional to the concentration of fibrinogen or tyrosine and sets forth a calibration curve for determining the relationship between optical density and concentration of fibrinogen. The addition of a fibrinogen standard preferably is added to the plasma sample based on the volume of the plasma.
As is known, the addition of the reagent Thromboplastin C serves as a coagulant to cause clotting to occur within a sample of citrated blood under test which may be contained in a container 8. As clotting occurs, the A/D converter 26 of FIG. 1 will count and produce a digital value of voltage at a predetermined period, such as once every 0.05 or 0.01 seconds. As more fully described in the previously incorporated by reference U.S. Pat. No. 5,197,017 ('017), these voltage values are stored and then printed by the recorder as an array of numbers, the printing being from left to right and line by line, top to bottom. There are typically one hundred numbers in the five groups representing voltage values every second and hence, one line represents one-fifth of a second in time (20×0.01 seconds). Individual numbers in the same column are twenty sequential numbers apart. Hence, the time difference between two adjacent numbers in a column is one-fifth of a second. The significance of these recorded values may be more readily appreciated after a general review of the operating principles illustrated in FIG. 2 having a Y axis identified as Fibrinogen Concentration (Optical Density) and an X axis identified in time (seconds).
FIG. 2 illustrates the data point locations of a clotting curve related to a coagulation study which illustrates the activation and conversion of fibrinogen to fibrin. In general, FIG. 2 illustrates a “clot slope” method that may be used in a blood coagulation study carried out for determining a new anticoagulant therapy factor (nATFa). The ATFa represents an anticoagulation therapy factor represented by the expression ATFa=XR(2-nFTR) wherein a maximum acceleration point is obtained, and nFTR=IUX/IUT, where IUX is the change in optical density from a time prior to the MAP time (t<MAP which is tMAP minus some time from MAP) to the optical density at a time after the MAP time (t>MAP which is tMAP plus some time from MAP); and wherein IUT=the change in optical density at the time t1 to the optical density measured at time tEOT, where time tEOT is the end of the test (EOT). The first delta (IUX) represents the fibrinogen (FBG) for MAP (−a number of seconds) to MAP (+a number of seconds) (that is the fibrinogen (FBG) converted from t<MAP to t>MAP on FIG. 2). The (IUT) represents fibrinogen converted from c1 to cEOT (that is the fibrinogen converted from t1 to tEOT, see FIG. 2). The XR for the ATFa expression is XR=TX/MNTX, which is the ratio of time to map (TX) by the mean normal time to map of 20 presumed “normal” patients.
The study which measures the concentration of the fibrinogen (FBG) in the plasma that contributes, to the clotting of the plasma and uses an instrument, such as, for example, the potentiophotometer apparatus illustrated in FIG. 1, to provide an output voltage signal that is directly indicative of the fibrinogen (FBG) concentration in the plasma sample under test, is more fully discussed in the previously incorporated by reference U.S. Pat. No. 5,502,651. The quantities given along the Y-axis of FIG. 2 are values (+ and −) that may be displayed by the digital recorder 28. The “clot slope” method comprises detection of the rate or the slope of the curve associated with the formation of fibrin from fibrinogen. The “clot slope” method takes into account the time to maximum acceleration (TX) which is the point at which fibrinogen conversion achieves a maximum and from there decelerates.
As seen in FIG. 2, at time t0, corresponding to a concentration c0, the thromboplastin/calcium ion reagent is introduced into the blood plasma which causes a disturbance to the composition of the plasma sample which, in turn, causes the optical density of the plasma sample to increase momentarily. After the injection of the reagent (the time of which is known, as to be described, by the computer 30), the digital quantity of the recorder 28 of FIG. 1 rapidly increases and then levels off in a relatively smooth manner and then continues along until the quantity c1 is reached at a time t1. The time which elapses between the injection of thromboplastin at t0 and the instant time t1 of the quantity c1 is the prothrombin time (PT) and is indicated in FIG. 2 by the symbol PT. As shown in FIG. 2, the baseline that develops after the thromboplastin (TP) is introduced or injected into the sample generally is thought to represent the “lag phase” of all of the enzymes preceding prothrombin converting to fibrin. The enzymes types and amounts may vary from person to person, and thus, this would demonstrate the potential for prothrombin times to vary between individuals.
An anticoagulant therapy factor (nATF) is determined. The optical density of a quantity c1 directly corresponds to a specified minimum amount of fibrinogen (FBG) that must be present for a measuring system, such as the circuit arrangement of FIG. 1, to detect in the plasma sample that a clot is being formed, i.e., through the transformation of fibrinogen to fibrin. The quantities shown in FIG. 2 are of optical densities, which may be measured in instrument units, that are directly correlatable to fibrinogen concentration values. The quantity c1, may vary from one clot detection system to another, but for the potentiophotometer system of FIG. 1, this minimum is defined by units of mass having a value of about 0.05 grams/liter (g/l).
Considering the clotting curve of FIG. 2, detection of a first predetermined quantity c1 is illustrated occurring at a corresponding time t1, which is the start of the clotting process. In accordance with one or more embodiments, this process may be monitored with the apparatus of FIG. 1 for determining a new anticoagulant therapy factor (nATF). The time t1 is the beginning point of the fibrinogen formation, that is, it is the point that corresponds to the beginning of the acceleration of the fibrinogen conversion that lasts for a predetermined time, The acceleration of the fibrinogen conversion proceeds from time (t1) and continues until a time tMAP, having a corresponding quantity cMAP. The time tMAP, as well as the quantity cMAP, is of primary importance because it is the point of maximum acceleration of the fibrinogen (FBG) to fibrin conversion and is also the point where deceleration of fibrinogen (FBG) to fibrin conversion begins. Further, the elapsed time from t0 to tMAP is a time to maximum acceleration from reagent injection (TX), shown in FIG. 2. Preferably, the conversion of fibrinogen to fibrin is quantified every 0.1 seconds. The time to maximum acceleration from reagent injection (TX) is defined as the point on the clotting curve time line where this conversion has reached its maximum value for the last time, simulating a zero-order kinetic rate. To facilitate ascertainment of the location point of the last maximum value, the delta value of two points at a fixed interval may be measured until this value begins to decrease. This value is tracked for a period of time, such as for example five seconds, after the first decreasing value has been determined. This facilitates ascertainment of the last point of what may be referred to as a simulated zero-order kinetic rate. Referring to FIG. 3, a zero order kinetic rate is illustrated by the line (L).
As shown in FIG. 2, a quantity cMAP and a corresponding time tMAP define a maximum acceleration point (MAP). Fibrin formation, after a short lag phase before the MAP, occurs for a period of time, in a linear manner. Fibrinogen (FBG) is in excess during this lag phase, and fibrin formation appears linear up to the MAP.
The deceleration of fibrinogen (FBG) to fibrin conversion continues until a quantity cEOT is reached at a time tEOT. The time tEOT is the point where the deceleration of the fibrinogen (FBG) to fibrin conversion corresponds to a value which is less than the required amount of fibrinogen (FBG) that was present in order to start the fibrinogen (FBG) to fibrin conversion process. Thus, because the desired fibrinogen (FBG) to fibrin conversion is no longer in existence, the time tEOT represents the ending point of the fibrinogen (FBG) to fibrin conversion in accordance with the coagulation study exemplified herein, which may be referred to as the end of the test (EOT). The fibrinogen (FBG) to fibrin conversion has a starting point of t1 and an ending point of tEOT. The differential of these times, t1 and tEOT, define a second delta (IUT).
The “clot slope” method that gathers typical data as shown in FIG. 2 has four critical parameters. The first is that the initial delta optical density of substance being analyzed should be greater than about 0.05 g/l in order for the circuit arrangement of FIG. 1 to operate effectively. Second, the acceleration fibrinogen (FBG) to fibrin conversion should be increasing for a minimum period of about 1.5 seconds so as to overcome any false reactions created by bubbles. Third, the total delta optical density (defined by the difference in quantities c1 and cEOT) should be at least three (3) times the instrument value in order to perform a valid test, i.e., (3)*(0.05 g/l)=0.15 g/l. Fourth, the fibrinogen (FBG) to fibrin conversion is defined, in part, by the point (tEOT) where the deceleration of conversion becomes less than the instrument value of about 0.05 g/l that is used to detect the clot point (t1). As with most clot detection systems, a specific amount of fibrinogen needs to be present in order to detect a clot forming. Adhering to the four given critical parameters is an example of how the present apparatus and method may be used to carry out a coagulation study to determine a specific quantity of fibrinogen. In order for that specific amount of fibrinogen to be determined, it is first necessary to detect a clot point (t1). After that clot point (t1) is detected, it logically follows that when the fibrinogen conversion becomes less than the specific amount (about 0.05 g/l for the circuit arrangement of FIG. 1), the end point (tEOT) of the fibrinogen conversion has been reached.
One embodiment of the method and apparatus is illustrated in accordance with the clotting curve shown in FIG. 3. The clotting curve of FIG. 3 illustrates the values ascertained in arriving at a new anticoagulation therapy factor (nATFz). The embodiment illustrates the determination of a new anticoagulation therapy factor (nATFz), expressed by the following formula:

nATFz=XR(2-nFTR)  (1)

This embodiment utilizes a zero order line (L) to obtain a first delta, in particular IUXz, which is a first differential taken along the simulated zero order kinetic line (L), and preferably along the segment between the start of the simulated zero order kinetic (T2S) to the last highest absorbance value (T2) (i.e., preferably, the last highest absorbance value of a simulated zero order kinetic). As previously discussed, the acceleration of the fibrinogen conversion proceeds from a first time, here time (T1) and continues, eventually reaching a time where the last highest delta absorbance value or maximum acceleration point (T2) having a corresponding quantity cT2 is reached. The values for “T” correspond with times, and the values for “c” correspond with quantity, which may be measured in instrument units based on optical density readings (also referred to as optical density or o.d.). The time T2, as well as the quantity cT2, is the point of maximum acceleration of the fibrinogen (FBG) to fibrin conversion and is also the point where deceleration of fibrinogen (FBG) to fibrin conversion begins. In this embodiment, IUXz is the change in optical density preferably from the beginning of the at the time T2S at which the simulated zero order kinetic begins to the optical density at time T2 which is the maximum acceleration point or the last highest delta absorbance value of a simulated zero order kinetic. FIG. 3 shows the differential IUXz taken between a preferred segment of the zero order line. The second delta in particular (IUTz) is the change in optical density at the time T2S to the optical density measured at time T3, where time T3 is the end of the test (EOT).
The (IUXz) represents the fibrinogen (FBG) converted between time T2S and T2. The (IUTz) represents fibrinogen converted from the time T2S to the end of the test or T3.
The maximum acceleration ratio (XR) for this embodiment is calculated to arrive at the new alternate anticoagulation therapy factor (nATFz). The maximum acceleration ratio (XR) is defined as the time to maximum acceleration from reagent injection (TX) divided by the mean normal TX value of a number of presumed normal specimens (MNTX). For example, the mean normal TX value may be derived based on the value of 20 or more presumed normal specimens. The maximum acceleration ratio (XR) may be expressed through the following formula:

XR=TX/MNTX  (2)

The clotting curve of FIG. 3 illustrates the values ascertained in arriving at the new alternate anticoagulation therapy factor (nATFz). The new alternate anticoagulation therapy factor (nATFz) is preferably expressed by the following formula:

nATFz=XR(2-nFTR)  (3)

with FTR being IUXz/IUTz.
The preferred IBM-compatible computer 30 of FIG. 1 stores and manipulates these digital values corresponding to related data of FIG. 3 and is preferably programmed as follows:

    
    
        (a) a sample of blood where the plasma is available, such as, for example, a sample of citrated blood, is obtained and placed in an appropriate container, the computer 30, as well as the recorder 28, sequentially records voltage values for a few seconds before injection of thromboplastin. As previously discussed, thromboplastin (tissue factor) is one of the factors in the human body that causes blood to clot. Prothrombin is another. Fibrinogen is yet another. Before injection of the thromboplastin, the output from the A/D converter 26 is relatively constant. When thromboplastin is injected into the plasma sample in the container, a significant and abrupt change occurs in the recorded voltage values of both the computer 30 and the recorder 28. This abrupt change is recognized by both the recorder 28 and, more importantly, by the computer 30 which uses such recognition to establish To. The computer 30 may be programmed so as to correlate the digital quantities of the A/D converter 26 to the analog output of the detector means photocell 10 which, in turn, is directly correlatable to the fibrinogen (FBG) concentration g/l of the sample of blood discussed with reference to FIG. 3;
        (b) the computer 30 may be programmed to look for a digital quantity representative of a critical quantity c1, and when such occurs, record its instant time T1. (The time span between To and T1 is the prothrombin time (PT), and has an normal duration of about 12 seconds, but may be greater than 30 seconds);
        (c) following the detection of the quantity c1, the computer 30 may be programmed to detect for the acceleration of fibrinogen (FBG) to fibrin conversion. The computer 30 is programmed to detect the maximum acceleration quantity cMAP or CT2 as illustrated in FIG. 3, and its corresponding time of occurrence tMAP, which is T2 in FIG. 3.
        (d) the computer detects a quantity cEOT occurring at time tEOT. Typically, it is important that the rate of fibrin formation increase for at least 1.5 seconds following the occurrence of (T1);
        (e) The computer 30 is programmed to ascertain the value for the time to start (T2S) which corresponds with the time at which the simulated zero order kinetic rate begins.
    
    


(f) following the detection of the acceleration of fibrinogen conversion to detect the start time T2S, the computer 30 is programmed to detect for a deceleration of the fibrinogen conversion, wherein the fibrinogen concentration decreases from a predetermined quantity cMAP to a predetermined quantity cEOT having a value which is about equal but less than the first quantity c1. The computer is programmed to ascertain a first delta (IUTz), by determining the difference between the quantity cT2S and the quantity cEOT; and a second delta (IUXz) by determining the difference between the quantity cT2S and the quantity c2 (or cMAP).

    
    
        (g) the computer 30 manipulates the collected data of (a); (b); (c); (d); (e) and (f) above, to determine the new fibrinogen transfer rate (nFTR). The nFTR may be arrived at based on the principle that if a required amount (e.g., 0.05 g/l) of fibrinogen concentration c1 is first necessary to detect a clot point (T1); then when the fibrinogen concentration (cEOT) becomes less than the required amount c1, which occurs at time (TEOT), the fibrinogen end point has been reached. More particularly, the required fibrinogen concentration c1 is the starting point of fibrinogen conversion of the clotting process and the less than required fibrinogen concentration cEOT is the end point of the fibrinogen conversion of the clotting process.
        (h) The computer now has the information needed to determine the new fibrinogen transfer rate (nFTRz) which is expressed by the following formula:

nFTRz=IUXz/IUTz  (4)

        (i) data collected is manipulated by the computer 30 to calculate the maximum acceleration ratio (XR), which is expressed as TX divided by the mean normal TX value of at least 20 presumed normal specimens (MNTX):

XR=TX/MNTX  (2)

The MNTX value may be ascertained and stored in the computer for reference.

        (j) the computer 30 now has the information needed to determine the nATFz, (also referred to as INRz) which typically is expressed as:

nATFz or INRz=XR(2-nFTR)  (3)

    
    


where, in the exponent, the value 2 is the logarithm of the total fibrinogen, which, as expressed in terms of the optical density, is 100% transmittance, the log of 100 being 2.
The new anticoagulation therapy factor (nATFz) does not require an ISI value, as was previously used to determine anticoagulation therapy factors. The new anticoagulation therapy factor (nATFz) uses for its ascertainment the values extracted from the clotting curve (see FIG. 3), in particular (nFTRz) (determined based on IUXz and IUTz), and (TX). In carrying out coagulation studies, the new anticoagulant therapy factor (nATFz) may replace INR in anticoagulant therapy management.
The apparatus and method for obtaining a new anticoagulant therapy factor, (nATFz), may be accomplished without encountering the complications involved with obtaining the prior art quantities International Normalized Ratio (INR) and International Sensitivity Index (ISI).
The new anticoagulant therapy factor (nATFz or ATF) preferably is a replacement for the International Normalized Ratio (INR), hence it may be referred to as INRz. Existing medical literature, instrumentation, and methodologies are closely linked to the International Normalized Ratio (INR). The nATFz was compared for correlation with the INR by comparative testing, to INR quantities, even with the understanding that the INR determination may have an error of about ten (10) % which needs to be taken into account to explain certain inconsistencies.
Table 2, below, includes anticoagulant therapy factors obtained from patients at two different hospitals. The ATFz values were obtained, with GATFz representing one geographic location where patients were located and MATFz being another location. The ATFz was obtained as the new anticoagulant therapy factor, and as illustrated in Tables 4 and 5, below, compares favorably to results obtained for INR determinations.
Another alternate embodiment for determining a new anticoagulant therapy factor (ATFt) is provided. The alternate embodiment for determining ATFt eliminates the need for determining a mean normal prothrombin time (MNPT) (or MNXT) and ISI, saving considerable time and costs, and removing potential sources of error, as the MNPT (the expected value of MNPT's depending on the varying 20 presumed normals population) and ISI (generally provided by the manufacturer of the reagent—such as, for example, the thromboplastin, etc.) are not required for the determination of the ATFt. An alternate embodiment for determining ATFt is illustrated in accordance with the clotting curve shown in
FIG. 4. The clotting curve of FIG. 4 illustrates values ascertained in arriving at the alternate new anticoagulation therapy factor (nATFt). The alternate new anticoagulation therapy factor (nATFt) is preferably expressed by the following formula:

nATFt=Value 1*Value 2  (4)

The alternate embodiment utilizes the zero order line (L) to obtain a first delta, in particular IUXz, which is a first differential taken along the simulated zero order kinetic line (L), and preferably along the segment between the start of the simulated zero order kinetic (T2S) to the last highest absorbance value (T2) (i.e., preferably, the last highest absorbance value of a simulated zero order kinetic). As previously discussed, the acceleration of the fibrinogen conversion proceeds from a first time, here time (T1) and continues, eventually reaching a time where the last highest delta absorbance value or maximum acceleration point (T2) having a corresponding quantity cT2 is reached. The time T2, as well as the quantity cT2, is the point of maximum acceleration of the fibrinogen (FBG) to fibrin conversion and also is the point where deceleration of fibrinogen (FBG) to fibrin conversion begins. As illustrated on the clotting chart in FIG. 4, IUXz represents a change in optical density (o.d.) preferably from the beginning of the at the time T2S at which the simulated zero order kinetic begins to the optical density at time T2 which is the maximum acceleration point or the last highest delta absorbance value of a simulated zero order kinetic. The value IUXz is generally expressed in instrument units (corresponding to absorbance or percent transmittance) and may generally be referred to as optical density or o.d. FIG. 4 shows the differential IUXz taken between a preferred segment of the zero order line. The second delta in particular (IUTz) represents a change in optical density at a time T2S to the optical density measured at a time T3, where time T3 is the end of the test (EOT).
The (IUXz) represents the fibrinogen (FBG) converted between time T2S and T2. The (IUTz) represents fibrinogen converted from the time T2S to the end of the test or T3.
The first value V1 corresponds to the value determined for the theoretical end of test (TEOT), which, as illustrated in the clotting curve representation in FIG. 4, is where the zero order kinetic line (L) crosses the line y=T3. The value TEOT is the elapsed time to convert the total instrument units (TIU) at the zero order kinetic rate, which is representative of the fibrinogen in the sample undergoing the conversion to fibrin. In other words, the expression for the first value (V1), or TEOT, is:

V1=TEOT=ZTM/IUXz*IUTz  (5)

where ZTM is the time between Tmap (i.e., T2 shown on FIG. 4) and T2S. ZTM may be generally represented by the following expression:

ZTM=T2−T2S  (6)

A second value, V2, also referred to as a multiplier, is determined based on the value T2S. In the expression for the ATFt, the second value, V2, may be obtained by taking the value of the time (T2S) corresponding to a second time (t2) or the maximum acceleration point (Tmap), and scaling this value. It is illustrated in this embodiment that the multiplier is derived from the natural log base “e”, which is 2.71828, scaled to provide an appropriately decimaled value. The scaling number used in the example set forth for this embodiment is 100. The second value (V2) may be expressed by the following relationship:

V2=T2S/100e  (7)

where T2S is the maximum acceleration point for the sample, and 100e is the value 100 multiplied by the natural log base “e” (2.71828) or 271.828. The new anticoagulation therapy factor according to the alternate embodiment may be expressed as follows:

nATFt=[(T2−T2S)/IUXz*IUTz]*[T2S/M]  (8)

where M represents a multiplier. In the present example, the multiplier M, corresponds to the value 271.828 (which is 100 times the natural log base “e”).

An alternate embodiment of an anticoagulant therapy factor, ATFt2, which does not require the ascertainment of a mean normal prothrombin time (MNPT) or use of an ISI value, is derived using the expression (5), wherein the IUTz is replaced by the expression (IUTz+IULz). In this alternate expression the method is carried out to ascertain the values for Value1 and Value2, in the manner described herein, with Value 1 being obtained through expression (5.1):

V1=TEOT=ZTM/IUXz*(IUTz+IULz)  (5.1)

where IULz is time to convert the lag phase fibrinogen (FBG) measured along the ordinate between T1 and T2S. In expression 5.1, the theoretical end of test (TEOT) is set to include the time to convert the fibrinogen (FBG) in the lag phase of the clotting curve. FIG. 5 illustrates the fibrinogen lag phase and the TEOT obtained from the line L2, and shows the IULz. ATFt2 is expressed by the following:

nATFt2=[(T2−T2S)/IUXz*(IUTz+IULz)]*[T2S/M]  (8.1)

The apparatus may comprise a computer which is programmed to record, store and process data. The zero order rate may be determined by ascertaining data from analyzing the sample, and optical density properties. One example of how this may be accomplished is using two arrays, a data array and a sub array. A data array may be ascertained by collecting data over a time interval. In one embodiment, for example, the data array may comprise a sequential list of optical densities, taken of a sample by an optical analytical instrument, such as, for example, a spectrophotometer, for a frequency of time. In the example, the frequency of sample data is taken every 100th of a second. In this embodiment, a computer is programmed to record the optical density of the sample, every 100th of a second. Two values, NOW and THEN, for the data array are provided for ascertaining the Prothrombin Time (PT) (which is the time point T1), maximum acceleration point (MAP), and end of test point (EOT). Two time definitions may be specified, one being the interval between NOW and THEN on the clotting curve, which may be 2.72 seconds ( 272/100th of a second), the second being the size of the filter used for signal averaging. NOW is the sum of the last 20 optical densities and THEN is the sum of the 10 prior data points 2.72 seconds prior to NOW. A graphical illustration is provided in FIG. 5. As illustrated in FIG. 5, four values are defined: SUM(NOW), SUM(THEN), AVERAGE(NOW) and AVERAGE(THEN). The average is the sum divided by the filter value.
The sub array may be defined as a sequential list of delta absorbance units. This may begin at T1, the prothrombin time (PT), and continue until the last highest delta absorbance (delta A) has been detected, then continues an additional five (5) seconds to insure the last delta A has been found. A determination of T2S may be accomplished by locating within the sub array, the first occurrence of when the sub array delta value is greater than or equal to 80% of the highest delta absorbance units. The first derivative is ascertained by computing the difference between (NOW) and (THEN). The PT is ascertained by determining the point prior to the positive difference between AVERAGE(THEN) and AVERAGE(NOW) for a period of 2.72 seconds or 272 ticks. The MAP is the point where the last highest difference between SUM(THEN) and SUM(NOW) has occurred. The computer may be programmed to store this delta A value in the sub array. The EOT may be ascertained by determining the point prior to where the difference between SUM(THEN) and SUM(NOW) is less than one.
Table 2 illustrates examples of samples, identified by ID numbers, along with corresponding data which compares the ATF values obtained for an ATF determined through the prior method, using ISI and INR values (represented as ATFa), an ATF determined through the use of a zero order kinetic reaction using the MNTX (nATFz), and an ATF determined without using the MNXT or ISI (nATFt). The data in table 2 represents universal laboratory data from combined locations for the patients listed. The data is based on analysis of absorbance data, storage of the data by the computer, such as, for example, with a storage device, like a hard drive, and retrieving the data and processing the data. The data, in the example represented in Table 2 was processed using the definitions and NOW and THEN intervals.
















TABLE 2





ID
AINR
GINR
GatfA
GatfZ
GatfT
MINR
MatfA
MatfZ
MatfT







U0047
2.10
1.70
1.76
1.74
1.62
2.00
2.08
1.78
1.68


U0048
1.80
1.80
1.84
1.83
1.72
1.90
1.96
1.85
1.82


U0050
1.80
1.70
1.77
1.80
1.68
1.90
2.00
1.80
1.70


U0056
1.60
1.50
1.54
1.54
1.40
1.80
1.83
1.61
1.48


U0058
3.20
2.80
2.93
2.92
2.93
3.30
3.38
3.10
3.29


U0060
2.20
2.10
2.15
2.17
2.11
2.20
2.21
2.26
2.27


U0062
2.80
2.60
2.69
2.72
2.69
3.00
3.19
2.86
2.91


U0415
0.90
0.90
0.88
0.94
0.74
0.90
0.95
0.97
0.83


U0432
1.80
1.50
1.53
1.42
1.24
1.40
1.39
1.46
1.33


U0436
2.40
2.40
2.57
2.24
1.99
2.40
2.41
2.28
2.17


U0438
3.90
3.70
4.25
3.26
3.21
3.80
4.22
3.40
3.55


U0439
2.30
2.20
2.27
1.94
1.75
2.30
2.32
2.07
2.02


U0440
5.80
4.80
5.41
4.33
4.50
4.60
4.84
4.55
5.18


U0441
4.50
4.90
5.58
5.01
4.86
4.40
4.71
4.64
5.35


U0442
1.80
1.70
1.79
1.65
1.48
1.80
1.84
1.64
1.52


U0800
2.00
2.00
2.02
1.78
1.64
2.10
2.11
2.12
2.09


U0843
1.40
1.40
1.43
1.42
1.22
1.40
1.47
1.44
1.31


U0848
1.30
1.40
1.41
1.31
1.13
1.30
1.37
1.34
1.23


U0849
2.40
2.30
2.44
1.94
1.77
2.30
2.38
1.98
1.93


U0855
1.30
1.30
1.29
1.35
1.17
1.20
1.24
1.36
1.22


U0860
1.00
1.00
0.99
1.00
0.77
1.00
0.97
1.00
0.85


U0861
2.80
2.90
2.98
2.70
2.58
3.00
2.99
2.88
3.00


U0863
1.70
1.70
1.70
1.76
1.65
1.70
1.77
1.83
1.79


U0867
3.20
2.90
3.19
2.64
2.38
3.00
3.10
2.85
2.83


U0875
2.20
2.00
2.16
1.80
1.60
2.00
2.02
1.81
1.71


U1198
2.20
2.10
2.17
2.07
1.91
2.00
1.98
2.22
2.22


U1199
2.80
3.30
3.57
2.79
2.76
3.20
3.21
2.99
3.28


U1201
1.90
1.90
1.95
1.76
1.62
1.80
1.84
1.82
1.80


U1202
1.30
1.30
1.35
1.31
1.16
1.40
1.39
1.35
1.20


U1205
1.60
1.80
1.90
1.71
1.53
1.90
1.90
1.80
1.67


U1207
1.90
1.90
1.96
1.68
1.49
1.90
1.87
1.78
1.61


U1218
3.00
2.60
2.86
2.57
2.56
2.80
3.07
2.90
3.08


U1225
2.20
2.30
2.34
2.01
1.83
2.60
2.40
2.21
2.16


U1230
1.30
1.40
1.45
1.47
1.32
1.40
1.45
1.50
1.45


U1575
1.40
1.30
1.30
1.53
1.41
1.40
1.44
1.49
1.35


U1576
2.20
2.10
2.11
2.10
2.02
2.30
2.32
2.19
2.17


U1579
1.50
1.70
1.72
1.64
1.49
1.80
1.81
1.61
1.44


U1581
1.70
1.70
1.74
1.85
1.81
1.70
1.77
1.74
1.73


U1599
2.00
1.70
1.78
2.01
1.96
2.00
2.14
2.04
1.93


U1600
3.50
3.30
3.39
3.58
3.63
3.90
4.21
3.37
3.64


U1649
0.90
0.80
0.80
0.94
0.76
0.90
0.89
0.89
0.74


U3050
2.70
2.80
3.08
2.34
2.17
2.30
2.34
2.05
2.02


U3077
1.30
1.40
1.44
1.34
1.17
1.30
1.28
1.31
1.16


U3083
1.60
1.60
1.58
1.47
1.31
1.60
1.68
1.48
1.37


U3395
2.70
3.20
3.51
2.80
2.70
2.80
2.90
2.38
2.32


U3398
1.50
1.70
1.77
1.60
1.47
1.60
1.65
1.61
1.47


U3408
1.10
1.20
1.18
1.13
0.92
1.10
1.03
1.09
0.94


U3453
1.10
1.20
1.24
1.19
0.97
1.20
1.18
1.11
1.00


U3456
1.10
1.00
0.96
0.99
0.81
1.00
0.98
1.04
0.90


U3457
2.20
2.30
2.38
2.03
1.94
2.10
2.28
1.94
1.86


U3459
2.90
2.60
2.81
2.40
2.22
2.40
2.53
2.11
2.04


U3724
2.70
2.40
2.47
2.16
1.95
2.60
2.72
2.31
2.25


U4471
1.50
1.60
1.67
1.63
1.43
1.70
1.71
1.71
1.62


U4737
2.90
2.60
2.79
2.42
2.26
2.70
2.87
2.51
2.42


U4752
1.40
1.50
1.55
1.47
1.26
1.50
1.48
1.46
1.33


U4757
2.00
2.10
2.09
1.95
1.77
2.00
2.02
2.00
1.92


U4767
2.60
2.40
2.52
2.16
1.95
2.60
2.56
2.33
2.27


U4772
2.50
2.70
2.78
2.59
2.58
2.80
2.84
2.55
2.56


U4801
1.30
1.40
1.41
1.33
1.13
1.50
1.49
1.41
1.22


U5133
0.90
0.90
0.91
0.92
0.74
1.00
0.97
0.97
0.78


U5158
5.50
5.10
5.90
5.34
5.64
6.00
6.57
6.50
7.00


U5169
2.60
2.90
3.16
3.14
3.09
3.20
3.35
3.35
3.67


U5173
1.10
1.20
1.17
1.19
1.02
1.20
1.21
1.16
1.03


U5175
1.70
1.80
1.86
1.85
1.67
1.90
1.92
1.82
1.70


U5178
2.30
2.20
2.28
2.02
1.79
2.60
2.85
2.03
2.01


U5183
2.90
2.60
2.83
2.43
2.23
3.60
3.86
2.88
3.01


U5190
2.80
2.70
2.82
2.85
2.70
3.20
3.36
3.00
3.15


U5193
3.10
3.00
3.13
2.93
2.81
3.60
3.73
3.33
3.30


U5565
2.70
3.20
3.34
3.16
3.04
3.50
3.48
3.31
3.50


U5589
1.60
1.80
1.86
1.69
1.52
1.90
1.96
1.64
1.44


U5591
2.00
2.20
2.33
2.16
1.98
2.30
2.28
2.19
2.24


U5592
1.10
1.20
1.23
1.26
1.09
1.40
1.35
1.49
1.37


U5593
1.70
1.80
1.89
1.76
1.55
1.80
1.85
1.76
1.70


U5594
2.30
2.60
2.79
2.84
2:81
2.80
2.84
2.85
2.96


U5597
3.30
3.30
3.64
3.25
2.96
4.10
4.03
3.85
4.08


U5992
1.40
1.40
1.42
1.45
1.29
1.30
1.37
1.37
1.30


U5993
1.00
0.90
0.94
1.03
0.84
1.00
0.98
1.03
0.84


U6017
1.00
0.90
0.95
0.99
0.77
0.90
0.89
0.97
0.79


U6047
2.30
2.30
2.36
2.17
1.97
2.20
2.28
2.23
2.22


U6056
1.00
1.00
1.01
1.03
0.87
1.00
1.01
1.02
0.85


U6060
1.90
2.10
2.17
2.10
1.94
2.30
2.00
2.16
2.12


U6065
3.10
2.80
2.93
2.77
2.60
3.00
3.13
2.74
2.76


U6928
1.20
1.20
1.17
1.34
1.17
1.20
1.24
1.22
1.05


U6929
1.20
1.20
1.20
1.23
1.06
1.20
1.19
1.15
0.98


U6936
2.40
2.50
2.45
3.02
3.15
2.60
2.61
2.51
2.60


U6938
2.10
2.10
2.12
2.30
2.22
2.30
2.26
2.25
2.21


U6951
1.50
1.50
1.51
1.59
1.42
1.60
1.66
1.49
1.36


U6972
2.40
2.40
2.47
2.57
2.49
2.80
2.84
2.54
2.51


U6977
1.30
1.30
1.34
1.35
1.19
1.30
1.37
1.23
1.08


U6987
5.10
4.50
4.43
5.29
5.42
5.70
5.44
6.16
6.82


U7316
1.20
1.10
1.15
1.28
1.14
1.30
1.28
1.26
1.11


U7317
2.00
1.60
1.68
1.66
1.56
1.90
1.90
1.68
1.56


U7318
2.80
2.70
2.86
2.71
2.57
3.30
3.40
2.70
2.72


U7320
2.00
1.90
1.92
2.17
2.13
2.00
2.06
2.12
2.13


U7321
1.50
1.40
1.38
1.59
1.50
1.60
1.60
1.61
1.51


U7322
1.80
1.70
1.72
1.63
1.46
1.70
1.76
1.55
1.42


U7324
1.30
1.20
1.25
1.33
1.17
1.40
1.40
1.30
1.13


U7440
2.60
3.00
2.98
2.90
2.89
3.00
3.01
3.05
3.37


U7443
2.00
2.00
2.03
1.87
1.73
2.10
2.17
1.90
1.79


U7458
1.40
1.40
1.43
1.38
1.20
1.40
1.40
1.40
1.26


U7465
9.70
7.40
8.12
6.47
7.80
7.10
7.54
7.06
7.63


U7469
1.10
1.10
1.11
1.11
0.86
1.20
1.14
1.10
0.90


U7470
3.20
3.40
3.65
3.27
3.12
3.60
3.67
3.62
3.70


U7707
2.20
2.20
2.27
2.34
2.28
2.30
2.29
2.23
2.22


U7708
1.60
1.60
1.60
1.73
1.61
1.70
1.73
1.71
1.62


U7710
2.30
2.50
2.64
2.71
2.73
2.70
2.85
2.75
2.96


U7713
1.40
1.60
1.59
1.57
1.50
1.60
1.64
1.58
1.48


U7724
2.40
2.40
2.47
2.62
2.65
2.70
2.73
2.75
2.84


U7727
1.70
1.70
1.73
1.78
1.68
1.90
1.90
1.91
1.86


U7738
2.40
2.30
2.45
2.27
2.21
2.40
2.54
2.29
2.32


U7794
1.90
1.80
1.91
1.72
1.58
1.70
1.78
1.71
1.55


U8080
3.10
3.60
3.63
3.41
3.54
3.30
3.33
3.18
3.34


U8087
1.90
1.90
1.95
1.80
1.62
1.90
1.91
1.79
1.74


U8092
1.70
1.70
1.76
1.67
1.49
1.90
1.93
1.67
1.57


U8210
2.60
2.90
3.04
2.72
2.63
2.70
2.77
2.54
2.56


U8221
3.20
3.70
3.99
3.42
3.35
3.50
3.47
3.24
3.46


U8555
2.60
2.40
2.54
2.56
2.52
2.90
3.09
2.57
2.56


U8558
2.30
2.20
2.26
2.16
2.15
2.30
2.33
2.31
2.35


U8559
1.60
1.40
1.45
1.42
1.24
1.60
1.65
1.45
1.28


U8563
2.20
2.30
2.30
2.32
2.30
2.40
2.43
2.34
2.42


U8570
1.20
1.20
1.20
1.34
1.23
1.20
1.21
1.35
1.25


U8575
0.90
0.80
0.84
0.96
0.80
0.90
0.89
0.95
0.78


U9031
2.10
2.40
2.33
2.42
2.42
2.60
2.38
2.34
2.35


U9032
1.70
1.70
1.75
1.78
1.58
1.90
1.93
1.68
1.53


U9034
3.00
2.90
2.82
3.79
3.97
3.40
3.37
3.49
3.80


U9039
2.70
3.00
3.17
2.99
3.03
3.20
3.20
3.12
3.27


U9040
1.40
1.40
1.44
1.36
1.20
1.40
1.39
1.33
1.15


U9049
3.50
3.30
3.46
3.33
3.45
3.60
3.77
3.33
3.72


U9055
2.40
2.10
2.14
2.15
2.04
2.40
2.39
2.15
2.13









A statistical comparison of the above data from Table 2 is presented below in Tables 4 and 5. The value AINR in Table 2 represents the INR value obtained pursuant to the World Health Organization (WHO), using expressions (A) and (B) above. GINR and MINR correspond to INR values used to determine the comparison data set forth in Tables 4 and 5.
The determination of the new anticoagulant therapy factor (ATFt) may be carried out with a computer. According to one example, the gathering, storing, and manipulation of the data generally illustrated in FIG. 4, may be accomplished by computer 30 of FIG. 1 that receives digital voltage values converted, by the A/D converter 26, from analog voltage quantities of the photocell 10 detection means.
In accordance with one embodiment, the IBM-compatible computer 30 of FIG. 1 stores and manipulates these digital values corresponding to related data of FIG. 4 and may be programmed as follows:

    
    
        (a) a sample of blood where the plasma is available, such as, for example, a sample of citrated blood, is obtained and placed in an appropriate container, the computer 30, as well as the recorder 28, sequentially records voltage values for a few seconds before injection of thromboplastin. As previously discussed, thromboplastin (tissue factor) is one of the factors in the human body that causes blood to clot. Prothrombin is another. Fibrinogen is yet another. Before injection of the thromboplastin, the output from the A/D converter 26 is relatively constant. When thromboplastin is injected into the plasma sample in the container, a significant and abrupt change occurs in the recorded voltage values of both the computer 30 and the recorder 28. This abrupt change is recognized by both the recorder 28 and, more importantly, by the computer 30 which uses such recognition to establish To. The computer 30 may be programmed so as to correlate the digital quantities of the A/D converter 26 to the analog output of the detector means photocell 10 which, in turn, is directly correlatable to the fibrinogen (FBG) concentration g/l of the sample of blood discussed with reference to FIG. 3;
        (b) the computer 30 may be programmed to look for a digital quantity representative of a critical quantity c1, and when such occurs, record its instant time T1. (The time span between To and T1 is the prothrombin time (PT), and has an normal duration of about 12 seconds, but may be greater than 30 seconds);
        (c) following the detection of the quantity c1, the computer 30 may be programmed to detect for the acceleration of fibrinogen (FBG) to fibrin conversion. The computer 30 is programmed to detect the maximum acceleration quantity cMAP or cT2 as illustrated in FIG. 3, and its corresponding time of occurrence tMAP, which is T2 in FIG. 3.
        (d) the computer detects a quantity cEOT occurring at time tEOT. Typically, it is important that the rate of fibrin formation increase for at least 1.5 seconds following the occurrence of (T1); the computer determines a theoretical end of test (TEOT) based on the determination of the zero order kinetic rate. The computer may be programmed to determine the zero order rate, which is expressed as a Line (L) in FIG. 4. The TEOT may be determined by the corresponding time value (TEOT) along the line L which corresponds with the quantity cEOT (i.e., that quantity corresponding to the time, T3).
        (e) following the detection of the maximum acceleration quantity cT2 (also representing cMAP) and the time T2 (also representing tMAP) both of which define the maximum acceleration point (MAP), and the TEOT, the computer is programmed to determine a new fibrinogen transformation rate (nFTR) covering a predetermined range starting prior to the maximum acceleration point (MAP) and ending after the maximum acceleration point (MAP). The elapsed time from T0 to T2 (which is tMAP) is the time to maximum acceleration (TMA), shown in FIG. 4, and is represented by TX (i.e., time to MAP);
        The new fibrinogen transformation rate (nFTR) has an upwardly rising (increasing quantities) slope prior to the maximum acceleration point (MAP) and, conversely, has a downwardly falling (decreasing quantities) slope after the maximum acceleration point (MAP).
        The computer 30 is programmed to ascertain the value for the time to start (T2S) which corresponds with the time at which the simulated zero order kinetic rate begins.
        (f) following the detection of the acceleration of fibrinogen conversion to detect the start time T2S, the computer 30 is programmed to detect for a deceleration of the fibrinogen conversion, wherein the fibrinogen concentration decreases from a predetermined quantity cMAP to a predetermined quantity cEOT having a value which is about equal but less than the first quantity c1. The computer is programmed to ascertain a first delta (IUTz), by determining the difference between the quantity cT2S and the quantity cEOT; and a second delta (IUXz) by determining the difference between the quantity cT2S and the quantity c2(or CMAP); the computer also determines the value ZTM by determining the difference between the time T2 (which is Tmap) and the time T2S;
    
    


(g) the computer 30 manipulates the collected data of (a); (b); (c); (d), (e) and (f) above, to determine the new fibrinogen transfer rate (nFTR). The nFTR may be arrived at based on the principle that if a required amount (e.g., 0.05 g/l) of fibrinogen concentration c1 is first necessary to detect a clot point (t1); then when the fibrinogen concentration (cEOT) becomes less than the required amount c1, which occurs at time (tEOT), the fibrinogen end point has been reached. More particularly, the required fibrinogen concentration c1 is the starting point of fibrinogen conversion of the clotting process and the less than required fibrinogen concentration cEOT is the end point of the fibrinogen conversion of the clotting process.

    
    
        (h) the duration of the fibrinogen conversion of the clotting process of the present invention is defined by the zero order time period between TEOT and T2S and is generally indicated in FIG. 3 as IUTz. The difference between the corresponding concentrations cT2S and cT2 is used to define a delta IUXz. The computer now has the information needed to determine the TEOT, which is expressed by the following formula:

TEOT=ZTM/IUXz*IUTz  (5)

The value TEOT may be assigned VALUE 1;

    
    


(i) data collected is manipulated by the computer 30 to calculate a second value, VALUE 2, using T2S and a multiplier M (which in this example, in expression 7 below, is a fraction). The computer may be programmed to use as a multiplier a value based on the natural log base “e” (which is 2.71828), scaled by a scaling value. Here, the scaling value is 100, and the multiplier may be expressed as follows:

M=100e  (9)

    
    
        VALUE 2 is determined using the information which the computer has ascertained and stored, by the following expression:

VALUE 2=T2S/100e  (7)

The data may be ascertained and stored in the computer for reference.

        (j) the computer 30 now has the information needed to determine the nATFt, which typically is expressed as:

nATFt=VALUE 1*VALUE 2  (4)

    
    


The computer 30 may be used to manipulate and derive the quantities of expression (4) to determine a new anticoagulant therapy factor nATFt utilizing known programming routines and techniques. The data collected by a computer 30 may be used to manipulate and derive the new anticoagulant therapy factor (nATFt) of expression (4). Similarly, one skilled in the art, using known mathematical techniques may derive the theoretical end of test TEOT of expression (5) and the second value VALUE 2 of expression (7) which, in turn, are used to determine the new anticoagulant therapy (nATFt) of expression (4). In the nATFt determination, the determination is based on the patient's own sample, and does not rely on the determination of normal prothrombin times for the reagent used (e.g., thromboplastin, innovin or the like). With the nATFt, no longer does the accuracy of the quantities determined depend, in whole or part, on the number of specimens used, that is, the number of stable (or presumed stable) patients.
The new anticoagulation therapy factor (nATFt) does not require an ISI value, as was previously used to determine anticoagulation therapy factors. The new anticoagulation therapy factor (nATFt) uses for its ascertainment the values extracted from the clotting curve (see FIG. 4), in particular T2S, Tmap, TEOT, cT2S, cmap and ceot. In determining the new anticoagulant therapy factor (nATFt), the ISI is not required, nor is the MNPT, or the need to obtain and calculate the prothrombin times (PT's) for 20 presumed normal patients. In carrying out coagulation studies, the new anticoagulant therapy factor (nATFt) may replace INR in anticoagulant therapy management. In addition, using the sample from the patient, the computer 30 has knowledge of the values obtained for the fibrinogen reaction, to ascertain the (nATFt).
It should now be appreciated that the present invention provides an apparatus and method for obtaining a new anticoagulant therapy factor (nATF) without encountering the complications involved with obtaining the prior art quantities International Normalized Ratio (INR) and International Sensitivity Index (ISI).
The new anticoagulant therapy factor (nATFt) preferably is a replacement for the International Normalized Ratio (INR). Existing medical literature, instrumentation, and methodologies are closely linked to the International Normalized Ratio (INR). The nATFt was compared for correlation with the INR by comparative testing, to INR quantities, even with the understanding that the INR determination may have an error of about +/−15%, at a 95% confidence interval, which needs to be taken into account to explain certain inconsistencies.
The hereinbefore description of the new anticoagulant therapy factor (nATFt) does correlate at least as well as, and preferably better than, studies carried out using the International Normalized Ratio (INR). For some comparisons, see the tables below, and in particular Table 4 and Table 5.
Table 3 (Part A) and Table 3 (Part B) provide corresponding data for a coagulation study. In Table 3 (Part A and B), the following references are used:












Column
Label
Definition







A
ID
Sample ID


B
OD@T2S
OD at the start of Zero Order Kinetic


C
OD@Map
OD at the Maximum Acceleration Point




(MAP)


D
OD@Eot
OD at the END OF TEST (Eot)


E
ΔT2SMap
Delta of Column B and C creating the IUXz


F
ΔT2SEot
Delta of Column B and D creating the IUTz


G
FTR od
Ratio of Column E divided by F




The FTR od is subtracted from 2 creating the




Exponent that replaces the ISI


H
Time@T2S
Time at the start of Zero Order Kinetics


I
Time@Map
Time at the Maximum Acceleration Point




(MAP)


J
Time@TEot
Time at the Theoretical End of Test (TEOT)


K
ΔT2SMap
Delta of Column H and I creating the IUXz




(and ZTM)


L
ΔT2STEot
Delta of Column H and J creating the IUTz


M
FTR Time
Ration of Column K divided by L
















TABLE 3







(Part A)












ID
OD@T2S
OD@Map
OD@Eot
ΔT2SMap
ΔT2SEot















A001
3719
3707
3664
12
55


A002
3713
3704
3686
9
27


A003
3729
3720
3705
9
24


A004
3708
3696
3663
12
45


A005
3727
3715
3700
12
27


A007
3725
3718
3698
7
27


A008
3714
3693
3646
21
68


A009
3727
3716
3697
11
30


A010
3727
3714
3701
13
26


A011
3690
3676
3647
14
43


A012
3728
3716
3695
12
33


A013
3715
3690
3641
25
74


A014
3717
3708
3694
9
23


A015
3726
3718
3706
8
20


A016
3722
3715
3678
7
44


A017
3720
3707
3681
13
39


A018
3723
3709
3697
14
26


A019
3716
3695
3653
21
63


A020
3727
3716
3698
11
29


A021
3727
3720
3694
7
33


A022
3717
3700
3667
17
50


A023
3719
3706
3663
13
56


A024
3717
3702
3661
15
56


A025
3731
3727
3716
4
15


A026
3717
3705
3673
12
44


A027
3714
3698
3667
16
47


A028
3713
3696
3651
17
62


A029
3712
3691
3647
21
65


A030
3716
3695
3635
21
81


A031
3715
3704
3687
11
28


A032
3716
3710
3675
6
41


A033
3718
3704
3671
14
47


A034
3721
3705
3674
16
47


A035
3723
3715
3699
8
24


A036
3722
3710
3681
12
41


A037
3715
3700
3669
15
46


A038
3722
3707
3686
15
36


A039
3721
3712
3698
9
23


A040
3720
3706
3664
14
56


A041
3711
3695
3638
16
73


A042
3722
3709
3687
13
35


A044
3723
3709
3683
14
40


A045
3712
3697
3647
15
65


A047
3716
3697
3668
19
48


A048
3720
3708
3682
12
38


A049
3725
3711
3690
14
35


A050
3724
3712
3685
12
39


A051
3705
3688
3634
17
71


A052
3725
3714
3687
11
38


A053
3724
3717
3696
7
28


A054
3715
3701
3679
14
36


A055
3718
3684
3627
34
91


A056
3710
3689
3624
21
86


A057
3709
3701
3683
8
26


A058
3725
3710
3669
15
56


A059
3722
3712
3696
10
26


A060
3719
3712
3698
7
21


A061
3720
3708
3680
12
40


A062
3719
3701
3651
18
68


A063
3728
3715
3697
13
31


A064
3718
3707
3685
11
33


A065
3721
3704
3680
17
41


A066
3727
3717
3707
10
20


A067
3708
3689
3641
19
67


A068
3726
3712
3686
14
40


A069
3719
3715
3695
4
24


A070
3716
3705
3671
11
45


A071
3714
3696
3660
18
54


A072
3713
3693
3646
20
67


A073
3707
3686
3639
21
68


A074
3699
3684
3665
15
34


A075
3734
3730
3726
4
8


A076
3719
3704
3665
15
54


A077
3718
3694
3634
24
84


A078
3723
3707
3684
16
39


A080
3729
3712
3637
17
92


A081
3710
3694
3626
16
84


A082
3716
3703
3654
13
62


A083
3720
3710
3686
10
34


A084
3731
3721
3667
10
64


A085
3727
3704
3675
23
52


A086
3717
3699
3650
18
67


A087
3715
3694
3654
21
61


A088
3704
3681
3630
23
74


A089
3723
3714
3687
9
36


A090
3714
3685
3588
29
126


A091
3724
3710
3659
14
65


A092
3696
3657
3582
39
114


A093
3730
3716
3693
14
37


A094
3720
3708
3676
12
44


A095
3710
3689
3638
21
72


A096
3725
3717
3700
8
25


A097
3721
3713
3692
8
29


A098
3716
3696
3659
20
57


A099
3720
3712
3685
8
35


A100
3709
3685
3625
24
84


A101
3727
3715
3690
12
37


A102
3722
3708
3661
14
61


A103
3714
3693
3640
21
74


A104
3719
3705
3682
14
37


A105
3725
3706
3660
19
65


A107
3720
3707
3660
13
60


A108
3731
3723
3709
8
22


A109
3727
3711
3689
16
38


A110
3719
3693
3635
26
84


A111
3723
3701
3667
22
56


A112
3714
3695
3614
19
100


A113
3717
3702
3664
15
53


A114
3711
3687
3655
24
56


A115
3716
3697
3652
19
64


A116
3726
3717
3698
9
28


A117
3710
3688
3630
22
80


A118
3729
3721
3699
8
30


A119
3729
3716
3679
13
50


A120
3722
3713
3688
9
34


A121
3730
3722
3704
8
26


A122
3713
3688
3650
25
63


A123
3729
3721
3704
8
25


A124
3721
3712
3696
9
25


A125
3683
3668
3600
15
83


A126
3736
3723
3714
13
22


A127
3715
3703
3640
12
75


A128
3723
3714
3682
9
41


A129
3728
3715
3677
13
51


A130
3715
3700
3656
15
59


A131
3723
3711
3690
12
33


A132
3720
3700
3665
20
55


A133
3728
3706
3673
22
55


A134
3725
3696
3667
29
58


A135
3717
3703
3676
14
41


A136
3725
3712
3659
13
66


A137
3712
3691
3662
21
50


A138
3714
3691
3641
23
73


A139
3717
3700
3642
17
75


A140
3710
3690
3642
20
68


A141
3715
3698
3661
17
54


A142
3729
3719
3706
10
23


A143
3726
3709
3693
17
33


A144
3709
3693
3641
16
68


A145
3704
3688
3639
16
65


A146
3718
3706
3664
12
54


A147
3713
3698
3661
15
52


A148
3714
3701
3646
13
68


A149
3711
3692
3653
19
58


A150
3701
3678
3608
23
93


A151
3701
3668
3587
33
114


A152
3717
3706
3683
11
34


A153
3691
3669
3596
22
95


A154
3706
3690
3645
16
61


A155
3724
3703
3667
21
57


A156
3717
3711
3688
6
29


A157
3717
3702
3678
15
39


A158
3723
3715
3689
8
34


A159
3714
3696
3652
18
62


A160
3717
3690
3655
27
62


A161
3720
3713
3676
7
44


A162
3722
3706
3653
16
69


A163
3725
3715
3683
10
42


A164
3721
3712
3685
9
36


A165
3707
3693
3636
14
71


A166
3704
3683
3631
21
73


A167
3718
3712
3690
6
28


A168
3722
3700
3669
22
53


A169
3705
3694
3624
11
81


A170
3717
3704
3680
13
37


A171
3721
3699
3666
22
55


A172
3726
3719
3691
7
35


A173
3718
3708
3680
10
38


A174
3707
3692
3648
15
59


A175
3689
3671
3642
18
47


A176
3724
3711
3671
13
53


A177
3721
3710
3689
11
32


A178
3716
3700
3655
16
61


A179
3717
3707
3672
10
45


A180
3718
3706
3686
12
32


A181
3722
3703
3676
19
46


A182
3716
3706
3667
10
49


A183
3711
3703
3689
8
22


A184
3717
3705
3661
12
56


A185
3711
3694
3639
17
72


A186
3721
3675
3620
46
101


A187
3715
3704
3668
11
47


A188
3717
3703
3672
14
45


A189
3709
3689
3658
20
51


A190
3718
3709
3688
9
30


A191
3725
3717
3696
8
29


A192
3722
3714
3691
8
31


A193
3727
3718
3685
9
42


A194
3720
3710
3688
10
32


A195
3691
3667
3589
24
102


A196
3718
3707
3673
11
45


A197
3706
3692
3637
14
69


A198
3717
3707
3692
10
25


A199
3720
3705
3684
15
36


A200
3718
3709
3686
9
32


A201
3725
3713
3681
12
44


A202
3723
3713
3694
10
29


A203
3715
3704
3670
11
45


A204
3723
3713
3697
10
26


A205
3717
3706
3674
11
43


A207
3710
3702
3668
8
42


A208
3722
3708
3680
14
42


A209
3725
3709
3682
16
43


A210
3724
3714
3688
10
36


A211
3712
3694
3637
18
75


A212
3727
3711
3689
16
38


A213
3724
3705
3652
19
72


A214
3727
3715
3687
12
40


A215
3715
3703
3668
12
47


A216
3722
3707
3667
15
55


A217
3716
3695
3630
21
86


A218
3699
3665
3583
34
116


A219
3727
3716
3699
11
28


A220
3717
3704
3674
13
43


A222
3713
3704
3684
9
29


A223
3724
3715
3695
9
29


A224
3718
3703
3676
15
42


A225
3721
3707
3683
14
38
















TABLE 3







(Part B)















ID
FTR od
Time@T2S
Time@Map
Time@TEot
ΔT2SMap
ΔT2STEot
FTR time
FTR od


















A001
0.218
2211
2366
2921
155
710
0.218
0.218


A002
0.333
2279
2464
2834
185
555
0.333
0.333


A003
0.375
2329
2523
2846
194
517
0.375
0.375


A004
0.267
1975
2107
2470
132
495
0.267
0.267


A005
0.444
2166
2387
2663
221
497
0.444
0.444


A007
0.259
1838
1931
2197
93
359
0.259
0.259


A008
0.309
2160
2369
2837
209
677
0.309
0.309


A009
0.367
2391
2598
2956
207
565
0.367
0.367


A010
0.500
1716
1925
2134
209
418
0.500
0.500


A011
0.326
1788
1935
2240
147
452
0.326
0.326


A012
0.364
2233
2428
2769
195
536
0.364
0.364


A013
0.338
2409
2667
3173
258
764
0.338
0.338


A014
0.391
1701
1836
2046
135
345
0.391
0.391


A015
0.400
1715
1877
2120
162
405
0.400
0.400


A016
0.159
2233
2336
2880
103
647
0.159
0.159


A017
0.333
1728
1882
2190
154
462
0.333
0.333


A018
0.538
1862
2175
2443
313
581
0.538
0.538


A019
0.333
1756
1927
2269
171
513
0.333
0.333


A020
0.379
2535
2761
3131
226
596
0.379
0.379


A021
0.212
2151
2283
2773
132
622
0.212
0.212


A022
0.340
1900
2089
2456
189
556
0.340
0.340


A023
0.232
2251
2384
2824
133
573
0.232
0.232


A024
0.268
2522
2676
3097
154
575
0.268
0.268


A025
0.267
1708
1775
1959
67
251
0.267
0.267


A026
0.273
1611
1730
2047
119
436
0.273
0.273


A027
0.340
1537
1689
1984
152
447
0.340
0.340


A028
0.274
1780
1927
2316
147
536
0.274
0.274


A029
0.323
1839
2023
2409
184
570
0.323
0.323


A030
0.259
2051
2245
2799
194
748
0.259
0.259


A031
0.393
2107
2321
2652
214
545
0.393
0.393


A032
0.146
2584
2678
3226
94
642
0.146
0.146


A033
0.298
2251
2426
2839
175
588
0.298
0.298


A034
0.340
1909
2107
2491
198
582
0.340
0.340


A035
0.333
3037
3305
3841
268
804
0.333
0.333


A036
0.293
2211
2417
2915
206
704
0.293
0.293


A037
0.326
2173
2335
2670
162
497
0.326
0.326


A038
0.417
1543
1713
1951
170
408
0.417
0.417


A039
0.391
1572
1721
1953
149
381
0.391
0.391


A040
0.250
1959
2119
2599
160
640
0.250
0.250


A041
0.219
1993
2144
2682
151
689
0.219
0.219


A042
0.371
2660
2929
3384
269
724
0.371
0.371


A044
0.350
2657
2858
3231
201
574
0.350
0.350


A045
0.231
2175
2325
2825
150
650
0.231
0.231


A047
0.396
2197
2458
2856
261
659
0.396
0.396


A048
0.316
2535
2783
3320
248
785
0.316
0.316


A049
0.400
2004
2256
2634
252
630
0.400
0.400


A050
0.308
2193
2403
2876
210
683
0.308
0.308


A051
0.239
1745
1867
2255
122
510
0.239
0.239


A052
0.289
2073
2247
2674
174
601
0.289
0.289


A053
0.250
2239
2353
2695
114
456
0.250
0.250


A054
0.389
1816
2005
2302
189
486
0.389
0.389


A055
0.374
3127
3668
4575
541
1448
0.374
0.374


A056
0.244
2538
2728
3316
190
778
0.244
0.244


A057
0.308
2125
2263
2574
138
449
0.308
0.308


A058
0.268
4120
4529
5647
409
1527
0.268
0.268


A059
0.385
2164
2358
2668
194
504
0.385
0.385


A060
0.333
2325
2494
2832
169
507
0.333
0.333


A061
0.300
2006
2205
2669
199
663
0.300
0.300


A062
0.265
3718
4058
5002
340
1284
0.265
0.265


A063
0.419
2231
2584
3073
353
842
0.419
0.419


A064
0.333
1926
2076
2376
150
450
0.333
0.333


A065
0.415
2225
2494
2874
269
649
0.415
0.415


A066
0.500
1761
1968
2175
207
414
0.500
0.500


A067
0.284
1701
1852
2233
151
532
0.284
0.284


A068
0.350
1979
2215
2653
236
674
0.350
0.350


A069
0.167
1935
1998
2313
63
378
0.167
0.167


A070
0.244
1939
2063
2446
124
507
0.244
0.244


A071
0.333
1762
1950
2326
188
564
0.333
0.333


A072
0.299
1723
1912
2356
189
633
0.299
0.299


A073
0.309
1614
1774
2132
160
518
0.309
0.309


A074
0.441
1698
1884
2120
186
422
0.441
0.441


A075
0.500
1489
1620
1751
131
262
0.500
0.500


A076
0.278
1529
1684
2087
155
558
0.278
0.278


A077
0.286
2845
3154
3927
309
1082
0.286
0.286


A078
0.410
1867
2081
2389
214
522
0.410
0.410


A080
0.185
3548
3924
5583
376
2035
0.185
0.185


A081
0.190
2698
2853
3512
155
814
0.190
0.190


A082
0.210
1625
1744
2193
119
568
0.210
0.210


A083
0.294
1583
1692
1954
109
371
0.294
0.294


A084
0.156
3394
3647
5013
253
1619
0.156
0.156


A085
0.442
2416
2867
3436
451
1020
0.442
0.442


A086
0.269
2111
2293
2788
182
677
0.269
0.269


A087
0.344
1740
1924
2274
184
534
0.344
0.344


A088
0.311
1715
1881
2249
166
534
0.311
0.311


A089
0.250
1876
1981
2296
105
420
0.250
0.250


A090
0.230
3411
3775
4993
364
1582
0.230
0.230


A091
0.215
3897
4201
5308
304
1411
0.215
0.215


A092
0.342
1906
2151
2622
245
716
0.342
0.342


A093
0.378
2821
3197
3815
376
994
0.378
0.378


A094
0.273
2447
2600
3008
153
561
0.273
0.273


A095
0.292
1573
1726
2098
153
525
0.292
0.292


A096
0.320
1784
1913
2187
129
403
0.320
0.320


A097
0.276
1374
1479
1755
105
381
0.276
0.276


A098
0.351
1480
1655
1979
175
499
0.351
0.351


A099
0.229
1679
1770
2077
91
398
0.229
0.229


A100
0.286
1538
1705
2123
167
585
0.286
0.286


A101
0.324
2137
2344
2775
207
638
0.324
0.324


A102
0.230
2473
2657
3275
184
802
0.230
0.230


A103
0.284
1868
2069
2576
201
708
0.284
0.284


A104
0.378
2344
2732
3369
388
1025
0.378
0.378


A105
0.292
2427
2750
3532
323
1105
0.292
0.292


A107
0.217
2140
2305
2902
165
762
0.217
0.217


A108
0.364
1876
2034
2311
158
435
0.364
0.364


A109
0.421
1900
2206
2627
306
727
0.421
0.421


A110
0.310
2621
3048
4001
427
1380
0.310
0.310


A111
0.393
2064
2409
2942
345
878
0.393
0.393


A112
0.190
2000
2165
2868
165
868
0.190
0.190


A113
0.283
1699
1872
2310
173
611
0.283
0.283


A114
0.429
1838
2101
2452
263
614
0.429
0.429


A115
0.297
2091
2281
2731
190
640
0.297
0.297


A116
0.321
1571
1707
1994
136
423
0.321
0.321


A117
0.275
1691
1874
2356
183
665
0.275
0.275


A118
0.267
1835
1969
2338
134
503
0.267
0.267


A119
0.260
2118
2320
2895
202
777
0.260
0.260


A120
0.265
1833
1960
2313
127
480
0.265
0.265


A121
0.308
1825
1992
2368
167
543
0.308
0.308


A122
0.397
1674
1931
2322
257
648
0.397
0.397


A123
0.320
1669
1824
2153
155
484
0.320
0.320


A124
0.360
1627
1766
2013
139
386
0.360
0.360


A125
0.181
1485
1591
2072
106
587
0.181
0.181


A126
0.591
2476
2969
3310
493
834
0.591
0.591


A127
0.160
1935
2040
2591
105
656
0.160
0.160


A128
0.220
2485
2627
3132
142
647
0.220
0.220


A129
0.255
3083
3385
4268
302
1185
0.255
0.255


A130
0.254
3137
3330
3896
193
759
0.254
0.254


A131
0.364
1729
1930
2282
201
553
0.364
0.364


A132
0.364
2288
2601
3149
313
861
0.364
0.364


A133
0.400
2132
2531
3130
399
998
0.400
0.400


A134
0.500
3654
4285
4916
631
1262
0.500
0.500


A135
0.341
1511
1652
1924
141
413
0.341
0.341


A136
0.197
2697
2874
3596
177
899
0.197
0.197


A137
0.420
1797
1980
2233
183
436
0.420
0.420


A138
0.315
1931
2137
2585
206
654
0.315
0.315


A139
0.227
1905
2069
2629
164
724
0.227
0.227


A140
0.294
1483
1623
1959
140
476
0.294
0.294


A141
0.315
1872
2044
2418
172
546
0.315
0.315


A142
0.435
2390
2573
2811
183
421
0.435
0.435


A143
0.515
2047
2421
2773
374
726
0.515
0.515


A144
0.235
2017
2143
2553
126
536
0.235
0.235


A145
0.246
1492
1602
1939
110
447
0.246
0.246


A146
0.222
1899
2068
2660
169
761
0.222
0.222


A147
0.288
1608
1738
2059
130
451
0.288
0.288


A148
0.191
1967
2090
2610
123
643
0.191
0.191


A149
0.328
1581
1718
1999
137
418
0.328
0.328


A150
0.247
1558
1690
2092
132
534
0.247
0.247


A151
0.289
2177
2402
2954
225
777
0.289
0.289


A152
0.324
1876
2006
2278
130
402
0.324
0.324


A153
0.232
1713
1859
2343
146
630
0.232
0.232


A154
0.262
1887
2053
2520
166
633
0.262
0.262


A155
0.368
2906
3327
4049
421
1143
0.368
0.368


A156
0.207
2191
2291
2674
100
483
0.207
0.207


A157
0.385
1886
2065
2351
179
465
0.385
0.385


A158
0.235
2424
2551
2964
127
540
0.235
0.235


A159
0.290
2678
2973
3694
295
1016
0.290
0.290


A160
0.435
2160
2489
2915
329
755
0.435
0.435


A161
0.159
1674
1762
2227
88
553
0.159
0.159


A162
0.232
3480
3835
5011
355
1531
0.232
0.232


A163
0.238
2505
2697
3311
192
806
0.238
0.238


A164
0.250
2535
2718
3267
183
732
0.250
0.250


A165
0.197
2072
2189
2665
117
593
0.197
0.197


A166
0.288
1883
2051
2467
168
584
0.288
0.288


A167
0.214
2228
2321
2662
93
434
0.214
0.214


A168
0.415
2366
2847
3525
481
1159
0.415
0.415


A169
0.136
2543
2661
3412
118
869
0.136
0.136


A170
0.351
1456
1589
1835
133
379
0.351
0.351


A171
0.400
2463
2761
3208
298
745
0.400
0.400


A172
0.200
1944
2070
2574
126
630
0.200
0.200


A173
0.263
1505
1600
1866
95
361
0.263
0.263


A174
0.254
1687
1816
2194
129
507
0.254
0.254


A175
0.383
1681
1821
2047
140
366
0.383
0.383


A176
0.245
2344
2544
3159
200
815
0.245
0.245


A177
0.344
1596
1733
1995
137
399
0.344
0.344


A178
0.262
2019
2183
2644
164
625
0.262
0.262


A179
0.222
2056
2181
2619
125
563
0.222
0.222


A180
0.375
1891
2096
2438
205
547
0.375
0.375


A181
0.413
2575
2959
3505
384
930
0.413
0.413


A182
0.204
1828
1930
2328
102
500
0.204
0.204


A183
0.364
1523
1644
1856
121
333
0.364
0.364


A184
0.214
2049
2187
2693
138
644
0.214
0.214


A185
0.236
2417
2606
3217
189
800
0.236
0.236


A186
0.455
2223
2909
3729
686
1506
0.455
0.455


A187
0.234
1654
1755
2086
101
432
0.234
0.234


A188
0.311
2229
2460
2972
231
743
0.311
0.311


A189
0.392
2320
2588
3003
268
683
0.392
0.392


A190
0.300
2473
2670
3130
197
657
0.300
0.300


A191
0.276
1782
1907
2235
125
453
0.276
0.276


A192
0.258
2127
2255
2623
128
496
0.258
0.258


A193
0.214
1788
1920
2404
132
616
0.214
0.214


A194
0.313
1930
2107
2496
177
566
0.313
0.313


A195
0.235
1581
1710
2129
129
548
0.235
0.235


A196
0.244
1821
1958
2381
137
560
0.244
0.244


A197
0.203
1743
1835
2196
92
453
0.203
0.203


A198
0.400
1696
1912
2236
216
540
0.400
0.400


A199
0.417
1498
1665
1899
167
401
0.417
0.417


A200
0.281
1441
1554
1843
113
402
0.281
0.281


A201
0.273
2036
2205
2656
169
620
0.273
0.273


A202
0.345
1898
2080
2426
182
528
0.345
0.345


A203
0.244
1768
1880
2226
112
458
0.244
0.244


A204
0.385
1642
1820
2105
178
463
0.385
0.385


A205
0.256
1851
1983
2367
132
516
0.256
0.256


A207
0.190
2173
2299
2835
126
662
0.190
0.190


A208
0.333
2277
2531
3039
254
762
0.333
0.333


A209
0.372
1721
1937
2302
216
581
0.372
0.372


A210
0.278
1907
2066
2479
159
572
0.278
0.278


A211
0.240
2153
2306
2791
153
638
0.240
0.240


A212
0.421
2143
2458
2891
315
748
0.421
0.421


A213
0.264
2057
2332
3099
275
1042
0.264
0.264


A214
0.300
2116
2363
2939
247
823
0.300
0.300


A215
0.255
1982
2118
2515
136
533
0.255
0.255


A216
0.273
2799
3061
3760
262
961
0.273
0.273


A217
0.244
2021
2237
2906
216
885
0.244
0.244


A218
0.293
2319
2571
3179
252
860
0.293
0.293


A219
0.393
2098
2309
2635
211
537
0.393
0.393


A220
0.302
1803
1943
2266
140
463
0.302
0.302


A222
0.310
1705
1876
2256
171
551
0.310
0.310


A223
0.310
1593
1732
2041
139
448
0.310
0.310


A224
0.357
1649
1811
2103
162
454
0.357
0.357


A225
0.368
1655
1824
2114
169
459
0.368
0.368









Comparative Results of nATFt's and nATFz's
Results between patients in two different geographic locations (i.e., two different hospitals) were compared for correlation with each other. This comparison is expressed in Table 4 below, and includes a comparison of INR values calculated by the WHO method for each respective location, with GInr representing one location for these traditionally WHO determined values, and MInr representing values based on data obtained at the other location. The values identified as ATFz and ATFt, such as, GATFt and MATFt, and GATFz and MATFz, represent anticoagulant therapy factors derived from the expressions (1) through (9) above.
The ATFa represents an anticoagulation therapy factor derived from our method and apparatus for the expression ATFa=XR(2-nFTR) wherein a maximum acceleration point is obtained, and nFTR=IUX/IUT, where IUX is the change in optical density from a time prior to the MAP time (t<MAP which is tMAP minus some time from MAP) to the optical density at a time after the MAP time (t>MAP which is tMAP plus some time from MAP); and wherein IUT=the change in optical density at the time t1 to the optical density measured at time tEOT, where time tEOT is the end of the test (EOT). The (IUX) represents the fibrinogen (FBG) for MAP (−a number of seconds) to MAP (+a number of seconds) (that is the fibrinogen (FBG) converted from t<MAP to t>MAP on FIG. 2) The (IUT) represents fibrinogen converted from c1 to cEOT (that is the fibrinogen converted from t1 to tEOT, see FIG. 2). The XR for the ATFa expression is XR=TX/MNTX, which is the ratio of time to map (TX) by the mean normal time to map of 20 presumed “normal” patients.







TABLE 4







COMPARATIVE RESULTS FOR ATFt and ATFz














Comparison
n
r
m
b
Std. Error
Ng
Lassen

















GInr vs.
129
0.996
0.891
0.148
0.082
6/129 =
delta <= 0.4 5@96.1%


GATFa





4.7% mismatches
delta <= 0.7 2@98.4%


GInr vs.
129
0.975
1.014
−0.016
0.215
15/129 =
delta <= 0.4 9@93%


GATFz





11.6% mismatches
delta <= 0.7 3@97.7%


GInr vs.
129
0.971
0.895
0.332
0.232
26/129 =
delta <= 0.4 18@86.0%


GATFt





20.2% mismatches
delta <= 0.7 2@98.4%


MInr vs.
129
0.996
0.943
0.082
0.094
18/129 =
delta <= 0.4 15@88.4%


MATFa





14.0% mismatches
delta <= 0.7 5@96.1%


MInr vs.
129
0.985
0.993
−0.058
0.177
2/129 =
delta <= 0.4 0@100%


MATFz





1.6% mismatches
delta <= 0.7 0@100%


MInr vs.
129
0.981
0.851
0.420
0.200
8/129 =
delta <= 0.4 6@95.3


MATFt





6.2% mismatches
delta <= 0.7 2@98.4%









A comparison of combined location data is shown in Table 5, below. The sample size was 217.







TABLE 5







STATISTICAL SUMMARY OF MHTL DATA














Comparison
n
r
m
b
Std. Error
Ng
Lassen





Inr vs
217
0.984
1.006
0.011
0.215
30/217 =
delta <= 0.4 16@92.6%


ATFa





13.8% mismatches
delta <= 0.7 1@99.5%


Inr vs.
217
0.984
1.002
0.120
0.214
26/217 =
delta <= 0.4 18@91.7%


ATFz





12.0% mismatched
delta <= 0.7 3@98.6%


Inr vs.
217
0.984
0.900
0.482
1.218
45/217 =
delta <= 0.4 43@80.2%


ATFt





20.7% mismatches
delta <= 0.7 6@97.2%









Comparative results were also calculated for the ATFt which includes the lag phase fibrinogen, in accordance with the IULz, using the expression (5.1) for the TEOT value. Table 6 below provides the values for the ATFz, ATFt, and the ATFt2 (which is obtained from expression 5.1 using the IULz).












TABLE 6






ID
INR
INRz
ATFt
ATFt2








A001
3.1
2.9
2.4
2.6



A002
3.3
2.9
2.4
2.6



A003
3.3
2.9
2.4
2.6



A004
2.1
2.3
1.8
2.0



A005
2.9
2.6
2.1
2.3



A007
2.1
2.0
1.5
1.6



A008
2.8
2.8
2.3
2.5



A009
3.4
3.1
2.6
2.8



A010
1.9
1.8
1.3
1.5



A011
2.1
1.9
1.5
1.6



A012
3.2
2.8
2.3
2.5



A013
3.5
3.3
2.8
3.0



A014
1.8
1.7
1.3
1.4



A015
1.9
1.8
1.3
1.5



A016
3.2
2.9
2.4
2.6



A017
1.8
1.9
1.4
1.6



A018
2.2
2.1
1.7
1.8



A019
1.8
1.9
1.5
1.6



A020
3.5
3.4
2.9
3.2



A021
2.8
2.7
2.2
2.4



A022
2.2
2.2
1.7
1.9



A023
3.2
2.9
2.3
2.5



A024
3.7
3.5
2.9
3.1



A025
1.8
1.7
1.2
1.4



A026
1.6
1.6
1.2
1.4



A027
1.5
1.5
1.1
1.3



A028
1.9
2.0
1.5
1.7



A029
2.1
2.1
1.6
1.8



A030
2.6
2.6
2.1
2.3



A031
2.7
2.5
2.1
2.3



A032
4.1
3.8
3.1
3.3



A033
2.9
2.9
2.4
2.6



A034
2.2
2.2
1.7
1.9



A035
4.9
4.7
4.3
4.7



A036
3.2
2.9
2.4
2.6



A037
2.5
2.7
2.1
2.4



A038
1.6
1.6
1.1
1.2



A039
1.4
1.6
1.1
1.3



A040
2.4
2.4
1.9
2.1



A041
2.3
2.4
2.0
2.2



A042
4.1
3.8
3.3
3.6



A044
4.2
3.7
3.2
3.4



A045
2.7
2.8
2.3
2.5



A047
2.8
2.8
2.3
2.5



A048
3.9
3.6
3.1
3.3



A049
2.6
2.4
1.9
2.1



A050
2.8
2.8
2.3
2.5



A051
1.9
1.9
1.4
1.6



A052
2.8
2.6
2.0
2.2



A053
3.0
2.8
2.2
2.4



A054
2.1
2.0
1.5
1.7



A055
5.6
5.4
5.3
5.6



A056
3.6
3.7
3.1
3.4



A057
2.8
2.6
2.0
2.2



A058
8.5
8.7
8.6
9.1



A059
2.9
2.6
2.1
2.3



A060
3.5
3.0
2.4
2.6



A061
2.4
2.5
2.0
2.1



A062
7.0
7.2
6.8
7.3



A063
3.0
3.0
2.5
2.7



A064
2.2
2.2
1.7
1.9



A065
2.6
2.8
2.4
2.6



A066
2.0
1.9
1.4
1.6



A067
1.8
1.8
1.4
1.6



A068
2.6
2.4
1.9
2.1



A069
2.4
2.2
1.6
1.8



A070
2.4
2.3
1.7
1.9



A071
1.9
2.0
1.5
1.7



A072
1.8
1.9
1.5
1.6



A073
1.5
1.7
1.3
1.4



A074
1.7
1.8
1.3
1.5



A075
1.6
1.4
1.0
1.1



A076
1.4
1.6
1.2
1.3



A077
4.5
4.6
4.1
4.4



A078
2.2
2.1
1.6
1.8



A080
7.3
7.4
7.3
7.6



A081
3.8
4.2
3.5
3.8



A082
1.6
1.7
1.3
1.5



A083
1.6
1.6
1.1
1.3



A084
6.7
6.7
6.3
6.6



A085
3.3
3.4
3.1
3.3



A086
2.8
2.7
2.2
2.4



A087
1.8
1.9
1.5
1.6



A088
1.7
1.9
1.4
1.6



A089
2.3
2.1
1.6
1.7



A090
6.3
6.6
6.3
6.7



A091
7.6
8.1
7.6
8.1



A092
1.9
2.3
1.8
2.0



A093
4.9
4.3
4.0
4.2



A094
3.2
3.3
2.7
2.9



A095
1.5
1.6
1.2
1.4



A096
2.3
1.9
1.4
1.6



A097
1.3
1.3
0.9
1.0



A098
1.4
1.5
1.1
1.2



A099
1.8
1.7
1.3
1.4



A100
1.4
1.6
1.2
1.3



A101
2.7
2.7
2.2
2.4



A102
3.8
3.6
3.0
3.2



A103
2.0
2.2
1.8
1.9



A104
3.2
3.3
2.9
3.2



A105
3.7
3.6
3.2
3.4



A107
2.9
2.8
2.3
2.5



A108
2.1
2.1
1.6
1.8



A109
2.2
2.3
1.8
2.0



A110
3.9
4.2
3.9
4.1



A111
2.5
2.7
2.2
2.4



A112
2.5
2.5
2.1
2.3



A113
1.9
1.9
1.4
1.6



A114
2.1
2.1
1.7
1.8



A115
2.4
2.6
2.1
2.3



A116
1.7
1.6
1.2
1.3



A117
1.6
1.9
1.5
1.6



A118
2.1
2.1
1.6
1.7



A119
3.0
2.7
2.3
2.4



A120
2.1
2.0
1.6
1.7



A121
2.2
2.1
1.6
1.7



A122
1.7
1.9
1.4
1.6



A123
1.8
1.8
1.3
1.5



A124
1.8
1.7
1.2
1.3



A125
1.4
1.4
1.1
1.3



A126
3.7
3.2
3.0
3.3



A127
2.4
2.3
1.8
2.0



A128
3.8
3.5
2.9
3.1



A129
5.3
5.3
4.8
5.3



A130
4.7
5.2
4.5
4.9



A131
1.7
1.9
1.5
1.6



A132
2.8
3.1
2.7
2.9



A133
2.6
2.9
2.5
2.7



A134
6.6
6.0
6.6
7.1



A135
1.5
1.5
1.1
1.2



A136
4.3
4.2
3.6
3.8



A137
1.9
1.9
1.5
1.6



A138
2.0
2.3
1.8
2.0



A139
2.1
2.3
1.8
2.0



A140
1.3
1.5
1.1
1.2



A141
2.2
2.1
1.7
1.8



A142
3.4
2.9
2.5
2.7



A143
2.5
2.5
2.1
2.3



A144
2.5
2.4
1.9
2.1



A145
1.4
1.4
1.1
1.2



A146
2.3
2.3
1.9
2.0



A147
1.7
1.6
1.2
1.4



A148
2.3
2.4
1.9
2.1



A149
1.6
1.6
1.2
1.3



A150
1.6
1.6
1.2
1.3



A151
2.8
2.9
2.4
2.6



A152
2.2
2.1
1.6
1.7



A153
1.8
1.9
1.5
1.6



A154
2.2
2.2
1.7
1.9



A155
4.8
4.6
4.3
4.7



A156
2.9
2.8
2.2
2.4



A157
2.1
2.1
1.6
1.8



A158
3.6
3.3
2.6
2.8



A159
3.9
4.1
3.6
3.9



A160
2.7
2.8
2.3
2.5



A161
1.7
1.8
1.4
1.5



A162
6.6
6.8
6.4
6.9



A163
3.9
3.6
3.1
3.3



A164
4.0
3.6
3.0
3.3



A165
2.7
2.6
2.0
2.2



A166
2.2
2.2
1.7
1.9



A167
2.9
2.8
2.2
2.4



A168
3.6
3.5
3.1
3.3



A169
4.1
3.8
3.2
3.4



A170
1.4
1.4
1.0
1.1



A171
3.4
3.3
2.9
3.1



A172
2.5
2.3
1.8
2.0



A173
1.6
1.4
1.0
1.1



A174
1.8
1.8
1.4
1.5



A175
1.8
1.7
1.3
1.4



A176
3.4
3.3
2.7
2.9



A177
1.7
1.6
1.2
1.3



A178
2.3
2.5
2.0
2.1



A179
2.6
2.5
2.0
2.2



A180
2.3
2.2
1.7
1.9



A181
3.5
3.7
3.3
3.6



A182
2.1
2.0
1.6
1.7



A183
1.5
1.5
1.0
1.2



A184
2.6
2.5
2.0
2.2



A185
3.3
3.4
2.9
3.1



A186
3.1
3.5
3.1
3.3



A187
1.8
1.7
1.3
1.4



A188
3.1
2.9
2.4
2.6



A189
3.0
3.0
2.6
2.8



A190
3.6
3.4
2.8
3.1



A191
2.0
1.9
1.5
1.6



A192
2.7
2.6
2.1
2.3



A193
2.1
2.0
1.6
1.7



A194
2.2
2.3
1.8
2.0



A195
1.4
1.6
1.2
1.4



A196
2.0
2.1
1.6
1.8



A197
1.8
1.9
1.4
1.5



A198
2.0
1.9
1.4
1.5



A199
1.5
1.5
1.0
1.2



A200
1.4
1.4
1.0
1.1



A201
2.6
2.5
2.0
2.2



A202
2.5
2.2
1.7
1.9



A203
2.0
1.9
1.4
1.6



A204
1.8
1.7
1.3
1.4



A205
1.9
2.1
1.6
1.8



A207
2.7
2.8
2.3
2.5



A208
3.0
3.0
2.5
2.8



A209
1.9
1.9
1.5
1.6



A210
2.4
2.2
1.7
1.9



A211
2.9
2.7
2.2
2.4



A212
2.8
2.7
2.3
2.5



A213
2.7
2.8
2.3
2.5



A214
2.8
2.8
2.3
2.5



A215
2.5
2.3
1.8
2.0



A216
4.1
4.4
3.9
4.2



A217
2.3
2.6
2.2
2.3



A218
2.9
3.2
2.7
3.0



A219
2.7
2.5
2.0
2.2



A220
2.0
2.0
1.5
1.7



A222
2.0
1.9
1.4
1.6



A223
1.7
1.6
1.2
1.4



A224
1.6
1.7
1.3
1.4



A225
1.8
1.7
1.3
1.4









Table 7 represents a comparison of the data from Table 6.












TABLE 7






“r”
“m”
“b”
StdErr
StdDev





















INR








vs
INRz
0.988
0.988
0.059
0.190
1.201



ATFt
0.984
0.966
0.568
0.215
1.238



ATFt2
0.983
0.913
0.504
0.219
1.257


ATFt








vs
ATFt2
1.000
0.946
−0.068
0.022
1.264









Table 8 provides comparative data for the anticoagulant therapy factors, similar to Table 2, but using the ATFt2 method from expressions (4) and (5.1) for corresponding GINRt2 and MINRt2 values.
















TABLE 8





ID
AINR
GINR
GINRa
GINRz
GINRt2
MINR
MINRa
MINRz
MINRt2
























U0800
2.0
2.0
2.0
2.0
1.7
2.1
2.1
2.2
2.1


U7440
2.6
3.0
3.0
2.9
2.9
3.0
3.0
2.8
3.4


U7443
2.0
2.0
2.0
2.0
1.8
2.1
2.2
2.1
1.8


U7458
1.4
1.4
1.4
1.4
1.2
1.4
1.4
1.3
1.3


U7465
9.7
7.4
8.1
6.6
7.9
7.1
7.5
8.1
7.8


U7469
1.1
1.1
1.1
1.1
0.9
1.2
1.1
1.1
1.0


U7470
3.2
3.4
3.6
3.4
3.2
3.6
3.7
3.8
3.8


U8080
3.1
3.6
3.6
3.3
3.6
3.3
3.3
3.5
3.4


U8087
1.9
1.9
1.9
1.8
1.6
1.9
1.9
1.9
1.7


U8092
1.7
1.7
1.8
1.7
1.6
1.9
1.9
1.9
1.6


U3050
2.7
2.8
3.1
2.6
2.2
2.3
2.3
2.3
2.0


U3077
1.3
1.4
1.4
1.4
1.1
1.3
1.3
1.3
1.2


U3083
1.6
1.6
1.6
1.6
1.3
1.6
1.7
1.6
1.4


U8210
2.6
2.9
3.0
2.8
2.7
2.7
2.8
2.8
2.6


U8221
3.2
3.7
4.0
3.7
3.4
3.5
3.5
3.3
3.6


U3408
1.1
1.2
1.2
1.2
0.9
1.1
1.0
1.0
0.9


U3453
1.1
1.2
1.2
1.2
1.0
1.2
1.2
1.2
1.0


U3457
2.2
2.3
2.4
2.2
1.9
2.1
2.3
2.2
1.8


U3395
2.7
3.2
3.5
3.2
2.7
2.8
2.9
2.5
2.3


U3398
1.5
1.7
1.8
1.8
1.5
1.6
1.6
1.6
1.5


U3456
1.1
1.0
1.0
1.0
0.8
1.0
1.0
1.0
0.9


U3459
2.9
2.6
2.8
2.6
2.2
2.4
2.5
2.5
2.0


U0415
0.9
0.9
0.9
0.9
0.8
0.9
1.0
1.0
0.8


U0432
1.8
1.5
1.5
1.5
1.3
1.4
1.4
1.4
1.3


U0436
2.4
2.4
2.6
2.3
2.1
2.4
2.4
2.4
2.2


U0438
3.9
3.7
4.2
3.7
3.2
3.8
4.2
3.9
3.6


U0439
2.3
2.2
2.3
2.1
1.8
2.3
2.3
2.2
2.0


U0440
5.8
4.8
5.4
5.2
4.4
4.6
4.8
4.3
5.2


U0441
4.5
4.9
5.6
6.0
5.0
4.4
4.7
4.7
5.4


U0442
1.8
1.7
1.8
1.7
1.5
1.8
1.8
1.8
1.6


U3724
2.7
2.4
2.5
2.4
2.0
2.6
2.7
2.6
2.3


U0849
2.4
2.3
2.4
2.1
1.8
2.3
2.4
2.2
2.0


U0860
1.0
1.0
1.0
1.0
0.8
1.0
1.0
1.0
0.9


U0861
2.8
2.9
3.0
2.8
2.6
3.0
3.0
2.9
3.0


U0863
1.7
1.7
1.7
1.7
1.7
1.7
1.8
1.8
1.8


U0875
2.2
2.0
2.2
2.1
1.6
2.0
2.0
2.0
1.7


U0843
1.4
1.4
1.4
1.4
1.2
1.4
1.5
1.5
1.3


U0848
1.3
1.4
1.4
1.4
1.2
1.3
1.4
1.4
1.2


U0855
1.3
1.3
1.3
1.3
1.2
1.2
1.2
1.2
1.3


U0867
3.2
2.9
3.2
2.8
2.5
3.0
3.1
3.0
2.9


U1201
1.9
1.9
2.0
1.9
1.7
1.8
1.8
1.9
1.8


U1202
1.3
1.3
1.3
1.3
1.2
1.4
1.4
1.4
1.2


U1205
1.6
1.8
1.9
1.8
1.6
1.9
1.9
1.8
1.7


U1207
1.9
1.9
2.0
1.8
1.5
1.9
1.9
1.7
1.7


U1230
1.3
1.4
1.5
1.4
1.3
1.4
1.5
1.5
1.5


U1198
2.2
2.1
2.2
2.1
1.9
2.0
2.0
2.0
2.3


U1199
2.8
3.3
3.6
3.1
2.8
3.2
3.2
2.8
3.3


U1218
3.0
2.6
2.9
2.9
2.7
2.8
3.1
3.1
3.2


U1225
2.2
2.3
2.3
2.1
1.9
2.6
2.4
2.2
2.2


U1575
1.4
1.3
1.3
1.3
1.4
1.4
1.4
1.4
1.4


U1579
1.5
1.7
1.7
1.7
1.5
1.8
1.8
1.7
1.5


U1649
0.9
0.8
0.8
0.8
0.8
0.9
0.9
0.9
0.8


U1576
2.2
2.1
2.1
2.1
2.1
2.3
2.3
2.3
2.2


U1581
1.7
1.7
1.7
1.8
1.9
1.7
1.8
1.8
1.7


U1599
2.0
1.7
1.8
1.8
2.0
2.0
2.1
2.1
2.0


U1600
3.5
3.2
3.4
3.4
3.7
3.9
4.2
3.5
3.7


U4471
1.5
1.6
1.7
1.6
1.5
1.7
1.7
1.7
1.7


U4757
2.0
2.1
2.1
2.0
1.8
2.0
2.0
2.1
2.0


U4767
2.6
2.4
2.5
2.6
2.0
2.6
2.6
2.5
2.3


U4772
2.5
2.7
2.8
2.5
2.6
2.8
2.8
2.9
2.5


U4801
1.3
1.4
1.4
1.4
1.2
1.5
1.5
1.4
1.2


U4737
2.9
2.6
2.8
2.7
2.3
2.7
2.9
2.8
2.5


U4752
1.4
1.5
1.6
1.5
1.3
1.5
1.5
1.5
1.4


U5133
0.9
0.9
0.9
0.9
0.7
1.0
1.0
1.0
0.8


U5173
1.1
1.2
1.2
1.2
1.1
1.2
1.2
1.2
1.0


U5175
1.7
1.8
1.9
1.8
1.7
1.9
1.9
1.9
1.7


U5178
2.3
2.2
2.3
2.1
1.9
2.6
2.9
2.8
2.0


U5183
2.9
2.6
2.8
2.6
2.3
3.6
3.9
3.7
3.0


U5158
5.5
5.1
5.9
5.7
5.8
6.0
6.6
7.1
7.0


U5169
2.6
2.9
3.2
3.2
3.2
3.2
3.4
3.6
3.7


U5190
2.8
2.7
2.8
2.9
2.8
3.2
3.4
3.5
3.2


U5193
3.1
3.0
3.1
3.0
2.9
3.6
3.7
3.7
3.4


U5589
1.6
1.8
1.9
1.8
1.6
1.9
2.0
1.8
1.5


U5592
1.1
1.2
1.2
1.2
1.1
1.4
1.3
1.3
1.4


U5593
1.7
1.8
1.9
1.8
1.6
1.8
1.9
1.8
1.7


U5565
2.7
3.2
3.3
3.3
3.1
3.5
3.5
3.6
3.5


U5591
2.0
2.2
2.3
2.3
2.1
2.3
2.3
2.1
2.3


U5594
2.3
2.6
2.8
2.8
2.8
2.8
2.8
3.0
3.0


U5597
3.3
3.3
3.6
3.6
3.1
4.1
4.0
4.3
4.0


U5993
1.0
0.9
0.9
0.9
0.8
1.0
1.0
1.0
0.8


U6017
1.0
0.9
1.0
1.0
0.8
0.9
0.9
0.9
0.8


U6056
1.0
1.0
1.0
1.0
0.9
1.0
1.0
1.0
0.9


U5992
1.4
1.4
1.4
1.4
1.3
1.3
1.4
1.4
1.3


U6047
2.3
2.3
2.4
2.3
2.0
2.2
2.3
2.3
2.2


U6060
1.9
2.1
2.2
2.2
2.0
2.3
2.0
2.0
2.1


U6065
3.1
2.8
2.9
2.8
2.7
3.0
3.1
2.9
2.8


U6928
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.1


U6929
1.2
1.2
1.2
1.2
1.1
1.2
1.2
1.2
1.0


U6951
1.5
1.5
1.5
1.5
1.5
1.6
1.7
1.6
1.4


U6977
1.3
1.3
1.3
1.3
1.2
1.3
1.4
1.4
1.1


U6936
2.4
2.5
2.4
2.6
3.2
2.6
2.6
2.7
2.6


U6938
2.1
2.1
2.1
2.2
2.3
2.3
2.3
2.3
2.3


U6972
2.4
2.4
2.5
2.4
2.5
2.8
2.8
2.8
2.5


U6987
5.1
4.5
4.4
5.0
5.5
5.7
5.4
5.7
7.0


U7316
1.2
1.1
1.1
1.1
1.1
1.3
1.3
1.3
1.1


U7321
1.5
1.4
1.4
1.4
1.5
1.6
1.6
1.6
1.5


U7324
1.3
1.2
1.3
1.2
1.2
1.4
1.4
1.4
1.2


U7317
2.0
1.6
1.7
1.7
1.6
1.9
1.9
1.8
1.6


U7318
2.8
2.7
2.9
2.9
2.6
3.3
3.4
3.3
2.7


U7320
2.0
1.9
1.9
1.9
2.2
2.0
2.1
2.1
2.2


U7322
1.8
1.7
1.7
1.7
1.5
1.7
1.8
1.7
1.4


U7708
1.6
1.6
1.6
1.6
1.6
1.7
1.7
1.7
1.7


U7713
1.4
1.6
1.6
1.6
1.5
1.6
1.6
1.6
1.5


U7727
1.7
1.7
1.7
1.8
1.7
1.9
1.9
1.9
1.9


U7794
1.9
1.8
1.9
1.8
1.6
1.7
1.8
1.7
1.6


U7707
2.2
2.2
2.3
2.3
2.3
2.3
2.3
2.3
2.2


U7710
2.3
2.5
2.6
2.7
2.8
2.7
2.9
3.0
3.0


U7724
2.4
2.4
2.5
2.6
2.7
2.7
2.7
2.8
2.9


U7738
2.4
2.3
2.4
2.5
2.2
2.4
2.5
2.6
2.3


U8559
1.6
1.4
1.4
1.4
1.3
1.6
1.7
1.6
1.3


U8570
1.2
1.2
1.2
1.2
1.3
1.2
1.2
1.2
1.3


U8575
0.9
0.8
0.8
0.8
0.8
0.9
0.9
0.9
0.8


U8555
2.6
2.4
2.5
2.6
2.6
2.9
3.1
3.0
2.6


U8558
2.3
2.2
2.3
2.3
2.2
2.3
2.3
2.4
2.4


U8563
2.2
2.3
2.3
2.4
2.3
2.4
2.4
2.5
2.5


U9031
2.1
2.4
2.3
2.3
2.5
2.6
2.4
2.3
2.4


U9032
1.7
1.7
1.7
1.7
1.6
1.9
1.9
1.7
1.5


U9040
1.4
1.4
1.4
1.4
1.2
1.4
1.4
1.3
1.1


U9034
3.0
2.9
2.8
3.0
4.0
3.4
3.4
3.5
3.8


U9039
2.7
3.0
3.2
3.1
3.1
3.2
3.2
3.2
3.3


U9049
3.5
3.3
3.5
3.5
3.5
3.6
3.8
3.6
3.7


U9055
2.4
2.1
2.1
2.2
2.1
2.4
2.4
2.4
2.1


U0048
1.8
1.8
1.8
1.8
1.7
1.9
2.0
2.0
1.8


U0050
1.8
1.7
1.8
1.8
1.7
1.9
2.0
2.0
1.7


U0056
1.6
1.5
1.5
1.5
1.4
1.8
1.8
1.7
1.5


U0047
2.1
1.7
1.8
1.8
1.6
2.0
2.1
2.0
1.7


U0058
3.2
2.8
2.9
3.0
3.0
3.3
3.4
3.2
3.3


U0060
2.2
2.1
2.1
2.2
2.1
2.2
2.2
2.2
2.3


U0062
2.8
2.6
2.7
2.8
2.7
3.0
3.2
3.2
2.9
















TABLE 9







COMPARATIVE RESULTS














Comparison









on
n
r
m
b
Std. Error
Ng
Lassen





GInr vs
129
0.997
0.879
0.163
0.079
7/129 =
Delta <= 0.4 | 5 @ 96.1%


GATFa





5.4%
Delta <= 0.7 | 2 @ 98.4%


GInr vs
129
0.986
0.948
0.078
0.162
3/129 =
Delta <= 0.4 | 4 @ 96.9%


GATFz





2.3%
Delta <= 0.7 | 2 @ 98.4%


GInr vs
129
0.974
0.935
0.413
0.221
20/129 =
Delta <= 0.4 | 16 @ 87.6%


GATFt2





15.5%
Delta <= 0.7 | 4 @ 96.9%


MInr vs
129
0.996
0.921
0.122
0.092
9/129 =
Delta <= 0.4 | 2 @ 98.4%


MATFa





7.0%
Delta <= 0.7 | 0 @ 100.0%


MInr vs
129
0.989
0.908
0.190
0.155
7/129 =
Delta <= 0.4 | 4 @ 96.9%


MATFz





5.4%
Delta <= 0.7 | 2 @ 98.4%


MInr vs
129
0.983
0.893
0.491
0.193
8/129 =
Delta <= 0.4 | 13 @ 89.9%


MATFt2





6.2%
Delta <= 0.7 | 4 @ 96.9%









Table 9 provides comparative data for the ATFa, ATFz and ATFt2 and INR values calculated by the WHO method for each respective location, with GInr representing one location for these traditionally WHO determined values, and MInr representing values based on data obtained at the other location. The values identified as ATFz and ATFt2, such as, GATFt2 and MATFt2, and GATFz and MATFz, represent anticoagulant therapy factors derived from the expressions (1) through (9) above, inclusive of expressions (5.1) and (8.1).
Further comparative results are provided in Table 10 to illustrate the effect of prothrombin time (PT) on INR values. Table 10 provides a comparison based on data from Table 3, and provides INR values for PT's of PT=PT (under the heading “INR”), PT=PT+0.5 (under the heading “+0.5”), PT=PT+1.0 (under the heading “+1.0”), PT=PT+1.5 (under the heading “+1.5”), and PT=+2.0 (under the heading “+2.0”). The new anticoagulation therapy factor (ATFt2) was compared with the WHO method for determining ATF. The WHO method utilizes the mean prothrombin time of 20 presumed normal patients. The thromboplastin reagents list MNPT “expected ranges” listed in the accompanying thromboplastin-reagent (Tp) brochures. These brochures acknowledge that MNPT differences are inevitable because of variations in the 20 “normal donor” populations. Geometric, rather than arithmetic mean calculation limits MNPT variation somewhat, but simulated 0.5 second incremented increases over a total 2.5 second range, show ever-increasing INR differences notably at higher INR levels. To exemplify this, Table 10 shows these changes with Thromboplastin C Plus (which has a manufacturer's reported ISI=1.74 and MNPT=9.89 seconds) in POTENS+.














TABLE 10






ID
PT
INR
+0.5
+1.0
+1.5
+2.0























WEC
9.8
1.0
0.9
0.8
0.8
0.7



A095
12.5
1.5
1.4
1.3
1.2
1.1



A191
14.8
2.0
1.9
1.7
1.6
1.5



A112
16.9
2.5
2.3
2.2
2.0
1.8



A208
18.6
3.0
2.8
2.5
2.3
2.2



A020
20.3
3.5
3.2
3.0
2.7
2.5



A164
21.9
4.0
3.7
3.4
3.1
2.9



A093
24.5
4.9
4.5
4.1
3.8
3.5



A055
26.5
5.6
5.1
4.7
4.4
4.0



A090
28.5
6.3
5.8
5.3
4.9
4.6



R091
32.2
7.8
7.2
6.6
6.1
5.7



A058
33.8
8.5
7.8
7.2
6.6
6.2









Since the in-house determined MNPT would continue with that Tp lot, intralaboratory results would be relatively unaffected. However, between laboratory INR agreements, or interlab results, are compromised. As a denominator, considering the expression used to derive the MNPT, such as expression (B), above, MNPT is, of course, less problematic for INRs than the exponent, ISI. Comparative results, showing interlab results, are provided in Table 11. ATFt is seen to be numerically equal to WHO/INRs determined in both analytical instruments, namely, the MDA-Electra 9000C and the POTENS+. Identical computer bits derived in POTENS+ from the absorbances creating the thrombin-fibrinogen-fibrin clotting curve are used for the POTENS+WHO/INR and ATFt (NO ISI, NO MNPT) determinations. MNPT is, of course, still necessary for the WHO method. For ATFt, Zero Order Kinetics Line's slope is extended in both directions to intersect with the Tp-plasma baseline and the absorbance at total fibrin formation. The sum of this interval and the time from the Tp injection to the beginning of Zero Order Kinetics (T2S) is Value 1. Value 2 is T2S/100e. “e” is the Natural Logarithm, base 2.71828. ATFt=(Value 1)*(Value 2), in accordance with expression (4) herein (and the expression (8.1) for ATFt2).
Table 11 provides statistical comparisons for results obtained using two POTENS+ coagulometers (one designated as GINR and another designated as MINR), and using a Bio Merieux MDA-180 coagulometer (designated as AINR). The POTENS+, WHO/INRs, INRzs, and ATFts and the MDA-180 (AINR) WHO/INRs are compared. Statistical data and Bland-Altman plot data demonstrate that the new anticoagulant therapy factor ATFt may replace WHO/INR and provide results which are within the parameters of traditional therapeutic or reference ranges.















TABLE 11






“r”
“m”
“b”
StdErr
StdDev
mY
mX
My/mX
























AINR











vs
GINR
0.937
0.872
0.290
0.388
1.148
2.169
2.155
1.007



GATFz
0.941
1.119
−0.208
0.378
1.022
2.169
2.124
1.021



GATFt2
0.951
1.003
0.146
0.343
1.081
2.169
2.016
1.076



MINR
0.950
1.018
−0.126
0.349
1.070
2.169
2.253
0.963



MATFz
0.943
1.020
−0.040
0.371
1.065
2.169
2.167
1.001



MATFt2
0.937
0.872
0.290
0.388
1.148
2.169
2.155
1.007


MINR











vs
GINR
0.971
1.036
0.039
0.247
1.001
2.253
2.136
1.055


MINRz











vs
GINRz
0.984
1.082
−0.132
0.186
0.978
2.167
2.124
1.020


MINRt2











vs
GINRt2
0.979
1.110
−0.083
0.242
1.123
2.155
2.016
1.069









The linear regression analysis expression y=mx+b, when solved for the slope, m, is expressed as (y−b)/x. This is biased, so the expression is y/x is when b is equal to zero. The comparison in Table 11, above, provides comparative data for mean y (mY) and mean x (mX) values, including the slope mY/mX. The use of mY/mX is used to provide comparative results.
In another embodiment, an article may be provided to derive an anticoagulant therapy factor (ATF). The article may comprise stored instructions on a storage media which can be read and processed with a processor. For example, the computer may be provided with a stored set of instructions, or chip, which is programmed to determine a new ATF for the spectral data obtained from the coagulation activity of a sample. For example, the computer chip may be preprogrammed with a set of instructions for cooperating with the output of a photodetection device, such as, the device shown and described in FIG. 1, which provides electrical data to said computer processor and/or storage device as a function of the optical density for a sample being analyzed. The chip may be employed in, or used with, an apparatus having input means and storage means for storing data. The set of instructions on the chip includes instructions for carrying out the steps of determining one or more anticoagulant therapy factors based on the expressions (1) through (9), inclusive of expressions (5.1) and (8.1).
According to alternate embodiments, methods for determining an anticoagulant therapy factor are provided to derive an INR. The customary classical INR (also referred to herein as INRm) has been the laboratory standard of care for monitoring oral anticoagulant therapies, such as, for example, coumarin therapy, for 25 years. However, the classical INR (INRm) which is discussed in the background, above, is cumbersome, and suffers from exponential inaccuracies. According to an alternate embodiment, the exponent-derived INRm (that is, the manufacturer's INR) may be supplantable by carrying out a clotting reaction and recording absorbance values over time intervals. The alternate INR (INRn) may be determined by computing the representative area of a trapezoid formed within the clotting curve absorbance, as determined by the absorbance values for the clotting reaction of a patient sample. According to preferred embodiments, the trapezoidal area is provided to approximate area under the clotting curve. According to this embodiment, the ISI and MNPT are eliminated. The sample of a person's blood or blood component is obtained and reacted with the coagulant, such as thromboplastin C, and the corresponding time and absorbance values for the clotting reaction of the sample are recorded.
The INRn may be used to determine and regulate treatment for a patient, including administration of anticoagulant therapy, and other blood therapy applications. According to one embodiment of the method, obtaining values for an area in connection with a blood clotting analysis is used to derive a corresponding INR value (INRn) (e.g., a value that may be used as the INR value is used). For example, according to a preferred embodiment, an Area T, which may be made up of two sides S1 and S2, an upper base S3 and a lower base S4, may be derived to generate an INR value, INRn. An INRn value may be derived from clotting curve data, wherein one or more locations along the clotting curve may be used to determine values corresponding to a designated area, as in accordance with preferred embodiments, may be represented by a trapezoidal area, such as that area represented by Area T. According to a preferred embodiment, the area is a two dimensional planar location, and, for example, may comprise a designated area located in a quadrant of an ordinate and abscissa corresponding with clotting curve time and absorbance values. The clotting curve and absorbance values, preferably, may be obtained with the use of a photodetection apparatus, and a computer that records the electrical output of the detection components. For example, a linear-output photo-optical coagulometer may be used to obtain optically responsive signal data from the sample, as the clotting reaction takes place. This reaction and absorbance data collection may be conducted as described herein in conjunction with the use of a coagulometer, such as the instrument illustrated in FIG. 1, or other suitable absorbance measuring device. Preferred devices are described herein and may be configured with the instructions to provide the INRn.
As illustrated in connection with FIG. 6, a clotting curve is shown. An Area T is identified in the first quadrant where the clotting curve of a coagulation reaction is illustrated. The Area T derivation may be used to derive a corresponding INRn value for the patient sample that generated the information represented by the clotting curve. The INRn values obtained by the method and apparatus are useful in determining the treatment course for an individual, based on the INRn value.
According to a preferred embodiment, the INRn may be expressed with the following formulae:

INRn=(Area T)*MUL  (10)

The MUL is a multiplier that is based on two relationships that are addressed by the multiplier. MUL relates the sampling rate of the instrument and the pixel parity of the x-y axis. The instrument used to measure the optical changes in the sample generates values, and preferably, the values, or signals are taken at a particular frequency. For example, a preferred sampling rate for the clotting curve reaction of a patient blood or blood component sample may be a number of optical absorbance values in a particular time interval. A preferred rate, for example, may be 100 optical absorbance values (or samples) per second, expressed 100/second. The sample rate preferably is used to derive a multiplier component, MUL. Also used to derive the multiplier component is the parity value, which is a multiplier utilized to create x-y pixel parity for the clotting curve information (that is shown expressed on the clotting curve graph, see FIG. 6). According to the example illustrated, the sampling rate used was 100 values per second. The pixel parity multiplier was 0.535. The multiplier, according to this example, is 0.535 (pixel parity value)/100 (the number of samples reflected in a second). The multiplier, or MUL, according to a preferred embodiment, was 0.00535.
In order to derive the INRn, the clotting curve is considered, and the theoretical or hypothetical zero order kinetic line, or line L as it is referred to and appears on the Figures, provides an (x,y) coordinate of (TEOT, 0), where the time value at which the clotting reaction, if theorized from the slope or line taken between the point where the maximum acceleration of the conversion rate of fibrinogen transformation begins (T2S) and the end of the maximum conversion (which is the last highest delta value of conversion rate), which is T2 or Tmap. The value, TEOT, is a time value, and generally, for example, may be expressed in seconds. As illustrated, the right side S2, may be designated to correspond with the line formed between the point (t1, c1) and TEOT. According to an alternate embodiment, the slope of the line L may corresponds with the slope of the side S2 of trapezoidal Area T. For example, according to some embodiments, the line L may form the side S2 of the trapezoid whose area is illustrated as Area T.
As shown in the preferred embodiments illustrated in FIGS. 6 and 7, a segment of the line from TEOT and the point on the clotting curve T1, forms the trapezoid side S2.
With the multiplier MUL, the INRn may be derived according to the following expression:

INRn=((T1+TEOT)/2)*0.00535*T2  (11)

As illustrated in FIG. 7, the lower base, S4, of the trapezoid TP, is the time value of the theoretical or hypothetical end of the coagulation test, TEOT. The time value component TEOT includes the time value of T2 plus the time value (Tiut) to convert the remainder of the fibrinogen in the sample that is considered to provide active optical activity (by the theoretical time value of the end of the test, TEOT). Both the Teot and TSot are values that are determined from the absorbance readings for a sample in a coagulation reaction. Dividing the difference in Instrument Units (IU) @ T2S to IU @ T2 (which is IUX) by the time it takes this conversion T2S to T2 (which may be represented by the time interval, Tiux) gives the maximum transformation rate for a specific sample. Using this specific test rate (IUX/Tiux), it is determined how long it would take to convert the fibrinogen from T2S to T3 (end of test) and add this value to T2S. This gives the TEot. Another value listed in the data Table 14 is the TSot which is the hypothetical start of test. The TSot is similar to the TEot, the hypothetical end of test. (The TEot, according to some embodiments, also may be referred to herein as a theoretical end of test.) The time that it takes to convert the IU@T1 to IU@T2S (which may be expressed as the difference between T1 and T2S (the value Tcon)) may be determined using the same rate of change. The TSot is determined by subtracting the time (Tcon) from T2S to give the TSot. The TSot may come before or after T1 and the TEot will always come before T3.
Referring again to FIG. 7, an upper base, S3, is indicated to correspond with the time of the start of the clot formation when the coagulation reaction is carried out. The start time of the clotting is represented by the time, T1, as shown in FIG. 6. With the upper and lower bases, S3 and S4, respectively, being ascertained through the clotting reaction times, they may be averaged (e.g., divided by 2). The S3,S4 average may be used to derive a trapezoidal area, such as, for example, Area T, represented by the clotting absorbance signal data. The altitude S1 (or height) of the trapezoidal area, Area T, is derived by the value of the point of time (T1) where the beginning of the conversion of fibrinogen to fibrin for the patient sample is determined. That point is represented as time value T1 on FIGS. 6 and 7. The height component of the trapezoid represented by Area T is designated to correspond with the side S1. The height component is assigned the value T1*MUL (T1 multiplied by the multiplier).
The INRn may be determined for a patient sample by determining (i) when the clot formation begins, which is represented by the time value T1, (ii) when the clotting commences a maximum conversion rate (of conversion of fibrinogen to fibrin in the patient sample), which is represented by the time value T2, and (iii) the end of the maximum conversion rate, represented by the time value T3 (the end of the maximum conversion rate). Therefore, according to embodiments of the present method and apparatus, a new INR determination that, through the transformation of information (e.g., signals corresponding to optical activity of a clotting reaction), may be derived by (i) determining the start of the clotting when a reagent (such as, for example, thromboplastin C) is reacted with a blood or blood component sample of a person (by determining the length of time from the introduction of the reagent and sample to the time clotting begins, which is T1), (ii) determining the start of the maximum acceleration rate of conversion for the clotting reaction that began at time T1) which is represented by the time T2, and (ii) determining the value of the end of the maximum conversion rate for the clotting reaction, which is represented by the value T3.
The present method and apparatus may be used to derive an INR, INRn, which does not utilize exponential components, and therefore, is not subject to exponential inaccuracies that have previously been experienced in connection with traditional INR determinations. The INRn value may be used to monitor a patient's blood or blood components for administration of oral anticoagulant therapy, such as, for example, coumarin, and other treatment agents, including those discussed herein. The present method and apparatus preferably, according to a preferred embodiment, where INRn is derived (and may be used for treatment administration of anticoagulant therapy).
The clotting curve illustrates a representation of absorbance values for a clotting reaction where substantially optically clear fibrinogen converts to turbid fibrin, hence reducing the absorbance unit values, as indicated on the abscissa. The point of intersection of the line L with the x-axis, or the time axis, preferably, may be derived using the value T2S and adding to that time value, the time required to convert additional fibrinogen in the sample, which is the time value corresponding with the absorbance value IUT (in instrument units). The TEOT value may be derived from the intercept that the slope of the line L defined by T2S and T2 makes with the x-axis. However, as described herein, the x axis would, in theory, be where y=0, and accordingly, since some signal may be detected (and hence not zero), the trapezoidal lower base S4 (FIGS. 6 and 7) may be represented along y=Ceot, between times T0 and TEot. According to a preferred embodiment, the TEOT value may be derived by the following determination:

TEOT=T2S+(ZTM/IUX*IUT)  (12)

where ZTM is the time (in seconds) to convert the fibrinogen corresponding to the time interval between T2S and T2, or in other words, the time to convert the IUX absorbance value (the IUX being the difference between instrument units (or IU) at T2S (IU@T2S) and instrument units at T2 (IU@T2)). The IUT value is the difference between instrument units (or IU) at T2S (IU@T2S) and instrument units at T3 (IU@T3).

A method was carried out using the Dade Behring Thromboplastin C Plus (Dade TPC+) as the reagent. The number of patient samples that were reacted and used to obtain the following data was 218. The WHO INR (the World Health Organization INR is the average of INR values from five different thromboplastins. The INRm is the manufacturer's INR. INRz is the INR that is derived using the exponent (2-FTR) instead of the ISI (as described herein (see formulae (1), (2), (3), (3.1), above). INRn (uses no ISI and no MNPT values for its determination) and is the calculation for the INR in accordance with the alternate embodiment described herein and represented by the formula INRn=((T1+TEOT)/2)*0.00535*T2, which is formula (II), above.
Coagulation reactions were carried out for a number of individuals, using the blood samples from the individuals, prepared as indicated herein in connection with clotting reactions, where a clotting reagent is added to the blood sample, and preferably a blood plasma sample. The absorbance values (measured in instrument units) were obtained for the sample throughout the coagulation reaction using a linear-output photo-optical coagulometer, POTENS+. The clotting agent used was thromboplastin reagent (Tp) which was injected into citrated human blood plasma. The clotting curve absorbance values were tracked as optically-clear fibrinogen (Fg) (also referred to as FBG herein) converts into turbid fibrin. The table below provides the values of the absorbance and time data that was obtained. By extending the slope L derived by the slope of the curve where the maximum conversion rate of fibrinogen occurs, a trapezoid is formed whose area may be derived and used to provide a value, INRn, which is essentially equal to the traditionally obtained INR values.







TABLE 12







Comparative Summary











INK WHO

LASSEN




(INRw)
NG
Agreement
Poller
Highest












Versus
Discordant
<=0.4
<=0.7
Diff >10%
Percent
















vs. INRM
13.8%
85.3%
95.9%
9/218
4.1%
18.3%


vs. INRZ
10.1%
89.4%
96.3%
7/218
3.2%
15.2%


vs. INRN
9.2%
88.5%
96.3%
12/218
5.5%
14.8%









Table 12 provides comparative data for INRm, INRz and INRn values compared with INR values calculated by the INR WHO method (which is also represented as INRw). The INR obtained using the WHO method (INRw) was compared with each of the alternate INR determinations, including INRm (using the manufacturer's INR), INRz, using the expressions of the above formulae (1), (2), (3), (3.1), as discussed herein, and INRn, using the expressions of the above formulae (10), (11), (12).
Further details of the comparative data are provided in Table 13 to illustrate values for each of the INR WHO comparisons.







TABLE 13





COMPARATIVE SUMMARY DETAILS using


DADE TPC + Thromboplastin















WHO INR vs INRm Specimens


Using NG algorithm


Number of mismatches 30/218 = 13.8%










Range
<2.0
13(13, 0)/79 
16.5%


Range
  2.0 to 3.0
12(10, 2)/91 
13.2%


Range
>3.0 to 4.5
5(4, 1)/37
13.5%


Range
>4.5
0(0, 0)/11
0.0%







Lassen values


Samples: 218 delta <= 0.4 32@ 85.3% delta <= 0.7 9@ 95.9%


WHO INR vs INRz Specimens


Using NG algorithm


Number of mismatches 22/218 = 10.1%










Range
<2.0
11(11, 0)/79 
13.9%


Range
  2.0 to 3.0
5(4, 1)/91
5.5%


Range
>3.0 to 4.5
5(2, 3)/37
13.5%


Range
>4.5
1(0, 1)/11
9.1%







LASSEN values


Samples: 218 delta <= 0.4 23@ 89.4% delta <= 0.7 8@ 96.3%


INRw vs. INRn Specimens


Using NG algorithm


Number of mismatches 20/218 = 9.2%










Range
<2.0
1(1, 0)/79
1.3%


Range
  2.0 to 3.0
13(4, 9)/91 
14.3%


Range
>3.0 to 4.5
6(4, 2)/37
16.2%


Range
>4.5
0(0, 0)/11
0.0%







LASSEN values


Samples: 218 delta <= 0.4 25@ 88.5% delta <= 0.7 8@ 96.3%









The sample data upon which the above data summaries were based, is provided in Table 14. Table 14 provides corresponding data for a coagulation study. In Tables 14 and 15, the following references are used, and may be further identified by reference to FIG. 8:

    
    
        ID—Sample ID
        T0—Time of thromboplastin reagent injection
        T1—Start of the clot formation
        T2S—Start of maximum conversion rate
        T2—End of maximum conversion rate. (Last highest delta value of conversion rate.)
        T3—(T4−T2s)
        T4—Hypothetical End Of Test (HEOT)
        IU—Instrument unit
        IUT—Delta IU between IU@T2S and IU@T3
        RTX—Delta IU between IU@T2S and IU@T2
        IUA—Altitude component value of the trapezoidal area (in instrument units) (c1-ceot)
        IUL—Length component value of the trapezoidal area (in instrument units)
        ZTM—Time in seconds to convert the IUX (T2-T2S)
        TEOT—Hypothetical End Of Test. (Time at T2S plus the time to convert IUT.)
        TSot—Hypothetical Start Of Test
        Fg—Fibrinogen concentration of the blood sample (in g/l)
        c1—Absorbance value (in instrument units) at time of the start of the clot formation (T1)
        cT2S—Absorbance value (in instrument units) at the time of the start of maximum conversion rate (T2S)
        c2—Absorbance value (in instrument units) at time of the end of maximum conversion rate (T2). (Last highest delta value of conversion rate.)
        ceot—Absorbance value (in instrument units) at time TEOT
    
    



















TABLE 14





ID
WHO
INRm
INRz
INRn
T1
T2S
T2
T3
TSot
TEot







A001
3.00
3.08
2.55
2.38
18.89
22.04
23.89
49.55
19.66
29.44


A002
2.88
3.32
2.56
2.19
19.71
23.00
24.42
37.75
20.87
27.61


A003
2.78
3.33
2.55
2.41
19.75
23.10
25.48
37.55
20.94
28.51


A004
2.08
2.03
2.03
1.66
14.85
19.66
21.62
37.55
16.89
24.96


A005
2.30
2.87
2.31
2.04
18.11
21.69
23.83
37.55
19.36
26.75


A007
1.85
2.03
1.78
1.45
14.86
18.19
20.18
33.95
15.87
22.83


A008
2.83
2.62
2.42
2.17
17.22
21.59
23.63
41.95
18.97
28.20


A009
2.70
3.38
2.65
2.47
19.91
23.91
26.43
37.87
21.39
29.31


A010
1.65
1.88
1.61
1.24
14.22
17.16
19.27
30.15
14.73
21.38


A011
1.83
2.09
1.71
1.34
15.10
17.90
19.32
33.75
15.57
22.26


A012
2.68
3.17
2.47
2.03
19.21
22.40
23.94
36.95
19.78
27.33


A013
3.30
3.44
2.92
2.86
20.13
24.09
26.68
50.15
21.60
31.76


A014
1.60
1.78
1.55
1.12
13.76
17.01
18.35
30.15
14.78
20.43


A015
1.70
1.88
1.60
1.20
14.23
17.15
18.96
28.30
14.74
21.17


A016
2.73
3.02
2.53
2.14
18.68
22.33
23.35
45.75
19.91
27.94


A017
1.70
1.78
1.63
1.24
13.76
17.29
18.86
31.35
14.82
21.66


A018
2.18
2.17
1.91
1.60
15.44
18.77
21.23
34.55
16.09
24.36


A019
1.85
1.82
1.71
1.41
13.97
17.58
19.30
36.75
15.29
22.74


A020
3.80
3.52
2.93
2.75
20.40
25.35
28.02
42.75
22.47
31.31


A021
2.63
2.83
2.39
2.08
17.98
21.51
23.37
37.35
18.91
27.65


A022
2.08
2.18
1.92
1.59
15.46
19.01
20.55
36.75
16.65
24.14


A023
3.20
3.11
2.55
2.20
18.98
22.51
23.92
43.35
20.09
28.15


A024
3.03
3.39
3.05
2.81
19.94
25.22
27.22
45.28
22.66
31.44


A025
1.73
1.84
1.51
1.06
14.03
16.98
18.01
27.40
15.09
19.73


A026
1.45
1.60
1.45
1.11
12.94
15.96
17.58
31.69
13.53
20.52


A027
1.45
1.48
1.36
1.05
12.41
15.34
16.91
33.35
13.12
19.77


A028
1.90
1.93
1.73
1.41
14.41
17.80
19.22
39.15
15.38
22.98


A029
2.20
2.06
1.85
1.59
14.99
18.36
20.31
40.55
16.07
23.96


A030
2.50
2.61
2.25
2.05
17.17
20.52
22.08
48.75
18.18
27.54


A031
2.43
2.75
2.25
1.95
17.69
21.07
23.20
35.84
18.55
26.49


A032
3.63
3.83
3.33
2.88
21.40
25.84
26.78
48.15
23.33
32.26


A033
2.65
2.94
2.52
2.22
18.39
22.44
24.46
41.95
19.79
28.37


A034
2.08
2.24
1.96
1.69
15.71
19.14
20.89
38.95
16.92
24.62


A035
4.00
4.87
3.71
4.36
24.58
29.96
34.33
47.75
27.15
38.08


A036
2.98
3.19
2.51
2.47
19.26
21.94
24.50
43.55
19.89
29.11


A037
2.20
2.50
2.32
1.97
16.73
21.61
23.71
36.95
18.96
26.80


A038
1.45
1.57
1.35
0.99
12.82
15.48
16.81
29.69
13.15
19.36


A039
1.50
1.46
1.39
0.99
12.27
15.70
17.37
28.67
13.27
19.34


A040
2.28
2.39
2.06
1.79
16.33
19.59
21.24
39.75
17.17
25.75


A041
2.18
2.30
2.14
1.88
15.95
19.93
21.44
45.15
17.29
26.82


A042
3.40
4.07
3.36
3.15
22.16
26.65
29.21
49.35
23.45
33.90


A044
3.38
4.31
3.31
2.90
22.90
26.85
28.41
41.15
24.38
31.92


A045
2.60
2.70
2.44
2.26
17.52
21.56
24.20
45.75
18.92
28.64


A047
2.45
2.81
2.46
2.24
17.90
21.99
24.21
41.55
19.51
28.26


A048
3.38
3.82
3.13
3.15
21.35
25.34
28.49
46.15
22.61
33.32


A049
2.28
2.68
2.15
1.99
17.42
20.04
22.56
39.55
17.88
26.34


A050
2.70
2.80
2.49
2.17
17.86
22.06
24.08
40.75
19.20
28.46


A051
1.88
1.91
1.64
1.32
14.35
17.45
18.41
35.55
15.19
22.32


A052
2.55
2.82
2.31
2.05
17.94
20.98
22.93
40.35
18.50
27.36


A053
2.88
3.06
2.48
2.09
18.82
22.39
24.07
38.75
19.78
27.62


A054
1.90
2.07
1.78
1.48
15.04
18.09
20.21
33.15
15.84
22.99


A055
6.58
5.56
4.81
5.66
26.51
31.27
36.08
70.15
28.32
45.39


A056
3.48
3.58
3.19
3.09
20.60
25.34
27.68
53.15
22.73
33.17


A057
2.58
2.85
2.23
1.87
18.05
21.05
22.66
35.15
18.72
25.88


A058
7.40
8.47
7.73
8.65
33.76
41.78
45.33
79.97
37.98
55.47


A059
2.25
2.93
2.27
1.99
18.34
21.38
23.74
34.15
18.82
26.69


A060
2.43
3.15
2.54
2.21
19.12
23.19
25.32
36.55
20.59
28.16


A061
2.25
2.49
2.17
1.97
16.70
20.05
22.25
38.35
17.68
26.82


A062
6.35
6.20
6.43
6.80
28.21
37.32
40.28
78.95
33.62
49.72


A063
2.65
3.04
2.63
2.61
18.75
22.31
25.84
42.15
19.59
30.73


A064
2.05
2.21
1.92
1.55
15.59
19.19
21.08
32.55
16.76
23.78


A065
2.28
2.65
2.47
2.22
17.32
22.25
24.96
39.75
19.39
28.42


A066
1.83
1.99
1.67
1.24
14.69
17.83
19.19
30.15
15.50
21.52


A067
1.78
1.75
1.62
1.30
13.63
17.02
18.52
36.75
14.49
22.31


A068
2.68
2.65
2.13
1.90
17.30
19.97
21.86
37.35
17.76
26.11


A069
2.10
2.41
1.92
1.41
16.41
19.35
20.15
31.95
16.95
23.19


A070
1.65
2.38
1.97
1.58
16.29
19.40
20.80
37.55
16.92
24.25


A071
1.73
1.89
1.73
1.44
14.25
17.63
19.53
39.50
15.23
23.03


A072
1.60
1.82
1.69
1.45
13.97
17.27
18.98
43.55
14.80
23.54


A073
1.48
1.49
1.50
1.21
12.46
16.14
17.82
37.75
13.77
21.33


A074
1.65
1.71
1.59
1.26
13.44
16.86
19.03
33.35
14.56
21.33


A075
1.58
1.57
1.21
0.75
12.80
14.89
15.87
23.28
13.18
16.85


A076
1.45
1.44
1.37
1.11
12.18
15.39
16.78
37.55
13.01
20.65


A077
4.63
4.64
4.03
4.26
23.88
28.45
31.55
64.71
25.61
39.30


A078
2.05
2.16
1.88
1.64
15.41
18.55
20.89
35.71
16.35
24.06


A080
6.13
7.35
6.42
8.00
31.12
35.48
40.50
86.95
32.86
55.56


A081
3.55
3.76
3.63
3.30
21.18
26.98
28.55
57.95
23.84
35.22


A082
1.53
1.54
1.55
1.29
12.69
16.24
18.15
43.55
13.76
22.16


A083
1.60
1.60
1.38
0.98
12.97
15.82
16.98
28.23
13.50
19.41


A084
6.98
6.67
5.72
6.91
29.43
33.64
38.19
76.55
30.96
51.04


A085
3.10
3.27
3.01
3.29
19.55
24.14
29.21
48.15
21.22
34.28


A086
2.45
2.85
2.35
2.11
18.07
21.11
22.84
46.95
18.57
27.93


A087
1.93
1.84
1.69
1.40
14.06
17.40
19.24
37.00
15.03
22.74


A088
1.78
1.71
1.64
1.35
13.44
17.15
18.79
37.95
14.80
22.43


A089
2.18
2.28
1.83
1.44
15.90
18.76
20.00
33.95
16.62
22.82


A090
5.93
6.31
5.59
6.68
28.51
33.63
38.36
84.35
30.64
49.81


A091
8.23
7.68
6.96
7.83
31.91
38.95
42.75
74.75
35.15
53.48


A092
2.00
1.91
2.03
1.81
14.36
19.10
21.48
50.15
16.41
26.06


A093
4.30
4.86
3.81
4.26
24.53
28.21
31.94
53.15
25.81
38.07


A094
2.53
3.17
2.94
2.41
19.18
24.61
25.77
42.95
22.06
29.60


A095
1.43
1.50
1.43
1.15
12.48
15.73
17.24
37.76
13.36
20.91


A096
1.80
2.12
1.69
1.29
15.22
17.85
19.14
30.95
15.59
21.88


A097
1.40
1.32
1.11
0.76
11.59
13.74
14.88
27.05
11.21
17.41


A098
1.45
1.40
1.32
1.04
11.98
14.78
16.59
34.95
12.54
19.69


A099
1.53
1.81
1.52
1.17
13.93
16.63
18.24
30.15
14.48
20.60


A100
1.40
1.41
1.40
1.18
12.06
15.39
17.01
39.15
13.23
21.06


A101
2.45
2.76
2.39
2.26
17.71
21.22
24.16
42.97
18.67
28.47


A102
3.83
3.79
3.13
2.90
21.28
24.77
25.93
56.17
22.32
32.50


A103
2.15
2.03
1.94
1.74
14.84
18.67
20.63
45.75
16.35
25.35


A104
3.10
3.21
2.96
3.01
19.32
23.44
27.32
50.53
20.39
33.69


A105
3.85
3.69
3.15
3.34
20.93
24.28
26.92
63.15
22.14
35.01


A107
2.53
2.84
2.42
2.36
18.01
21.27
23.85
50.16
19.06
28.89


A108
1.95
2.08
1.85
1.55
15.06
18.37
20.98
32.12
15.76
23.83


A109
2.28
2.27
2.06
1.85
15.86
19.19
22.04
38.31
16.53
26.22


A110
3.83
3.91
3.72
4.05
21.65
26.20
29.96
67.75
23.26
39.93


A111
2.90
2.52
2.39
2.35
16.84
20.64
24.09
45.11
18.13
29.42


A112
2.30
2.39
2.22
2.13
16.33
20.00
22.03
56.41
17.63
28.46


A113
1.80
1.87
1.65
1.41
14.17
16.98
18.78
38.35
14.73
22.94


A114
1.90
2.10
1.87
1.65
15.13
18.38
20.51
43.35
16.14
24.34


A115
2.10
2.38
2.30
2.03
16.26
20.91
22.84
47.35
18.27
27.41


A116
1.78
1.73
1.40
1.07
13.53
15.66
17.28
29.70
13.64
19.58


A117
1.65
1.62
1.65
1.45
13.04
16.91
18.76
49.15
14.58
23.34


A118
1.98
2.18
1.80
1.46
15.46
18.36
19.65
35.35
16.10
23.20


A119
2.65
2.98
2.43
2.32
18.53
21.29
23.20
48.14
19.06
29.09


A120
1.85
2.11
1.79
1.48
15.18
18.33
19.61
34.35
16.20
23.17


A121
2.05
2.21
1.82
1.58
15.60
18.24
20.28
36.04
16.20
23.54


A122
1.55
1.76
1.64
1.42
13.70
16.76
18.82
42.35
14.50
22.94


A123
1.70
1.81
1.55
1.25
13.91
16.51
18.38
31.51
14.27
21.37


A124
1.63
1.80
1.46
1.08
13.85
16.27
17.67
29.01
13.94
20.16


A125
1.50
1.39
1.26
1.04
11.93
14.86
15.88
37.95
12.41
20.50


A126
3.25
3.70
2.97
3.02
20.99
25.08
28.61
41.35
22.26
32.49


A127
2.20
2.38
2.05
1.83
16.28
19.39
20.92
51.15
16.81
26.47


A128
3.38
3.89
3.06
2.64
21.58
24.88
26.01
47.86
22.48
30.67


A129
4.35
5.25
4.67
4.77
25.65
30.83
33.84
60.80
27.13
42.64


A130
4.05
4.66
4.55
4.16
23.94
31.39
33.06
58.52
28.41
38.43


A131
1.63
1.72
1.68
1.42
13.49
17.05
19.42
34.86
14.68
22.81


A132
2.43
2.65
2.75
2.62
17.33
22.89
26.55
47.95
19.39
31.64


A133
2.65
2.64
2.56
2.63
17.27
21.32
25.37
48.11
18.85
31.00


A134
6.33
6.48
6.27
6.27
28.95
36.89
39.54
62.23
32.81
48.31


A135
1.40
1.49
1.32
0.97
12.42
15.07
16.62
30.63
12.59
19.31


A136
4.38
4.33
3.63
3.63
22.96
26.93
29.17
62.05
24.27
36.17


A137
1.58
1.96
1.73
1.33
14.56
18.09
19.56
35.32
15.80
22.09


A138
2.18
1.99
2.04
1.74
14.69
19.49
21.15
46.15
16.78
25.69


A139
2.05
2.12
1.97
1.78
15.24
19.05
20.42
48.75
16.77
25.90


A140
1.35
1.34
1.28
1.01
11.72
14.83
16.21
38.35
12.55
19.52


A141
2.05
2.22
1.87
1.52
15.65
18.77
20.00
34.32
16.40
23.78


A142
3.10
3.36
2.60
2.24
19.86
23.90
25.80
37.58
21.43
28.27


A143
2.08
2.56
2.23
2.08
16.97
20.55
23.80
37.75
17.91
27.25


A144
2.20
2.44
2.12
1.76
16.53
20.17
21.49
41.68
17.76
25.45


A145
1.28
1.38
1.28
0.99
11.91
14.81
16.17
36.48
12.38
19.53


A146
2.48
2.26
1.98
1.80
15.81
18.99
20.67
49.55
16.66
25.97


A147
1.48
1.64
1.45
1.10
13.14
16.08
17.38
34.14
13.57
20.59


A148
2.18
2.38
2.07
1.79
16.28
19.67
21.10
46.95
17.00
26.15


A149
1.33
1.52
1.41
1.05
12.57
15.82
17.19
34.20
13.23
20.16


A150
1.45
1.55
1.40
1.14
12.72
15.57
16.97
39.21
13.27
20.78


A151
2.83
2.80
2.52
2.42
17.89
21.77
24.31
56.93
19.30
29.60


A152
1.85
2.19
1.82
1.34
15.50
18.79
20.08
33.19
16.21
22.66


A153
1.73
1.77
1.64
1.41
13.75
17.14
18.49
46.91
14.70
23.25


A154
2.30
2.29
1.97
1.75
15.94
18.86
20.90
41.84
16.50
25.41


A155
4.98
4.80
3.87
4.77
24.37
29.06
35.08
53.55
26.05
40.50


A156
2.80
2.77
2.40
1.89
17.76
21.91
23.03
40.00
19.35
26.55


A157
2.03
2.22
1.87
1.52
15.64
18.86
20.65
36.62
16.47
23.51


A158
3.43
3.64
2.84
2.55
20.79
24.24
25.84
44.53
22.00
29.68


A159
3.78
3.94
3.60
3.72
21.74
26.43
29.76
61.35
23.28
37.47


A160
2.58
2.74
2.47
2.40
17.64
21.60
24.95
44.35
18.99
29.29


A161
1.68
1.66
1.60
1.31
13.24
16.74
18.54
35.95
14.17
22.40


A162
7.33
6.56
5.90
6.52
29.16
34.82
38.19
74.78
31.45
49.35


A163
3.90
3.90
3.15
3.04
21.62
25.10
27.09
49.55
22.75
32.70


A164
3.45
3.79
3.19
2.83
21.28
25.53
26.93
47.44
23.08
31.66


A165
2.63
2.60
2.25
1.96
17.13
20.69
22.34
43.75
18.17
26.86


A166
2.05
2.19
1.91
1.62
15.52
18.84
20.12
42.98
16.44
24.60


A167
2.65
3.00
2.45
1.91
18.61
22.28
23.38
36.00
19.77
26.68


A168
3.60
3.61
3.03
3.20
20.68
23.69
25.98
51.55
21.61
34.72


A169
3.78
4.13
3.34
3.14
22.35
25.61
26.64
60.89
23.24
33.75


A170
1.30
1.37
1.24
0.88
11.84
14.56
16.01
30.00
12.18
18.39


A171
3.18
3.41
2.94
3.02
20.01
24.48
27.83
47.95
21.97
32.30


A172
2.58
2.58
1.99
1.71
17.06
19.43
20.73
39.75
17.41
24.63


A173
1.48
1.51
1.30
0.95
12.55
15.03
16.46
28.97
12.78
18.91


A174
1.88
1.84
1.60
1.31
14.04
16.86
18.51
36.75
14.60
21.98


A175
1.60
1.84
1.52
1.13
14.02
16.78
18.20
29.70
14.61
20.37


A176
3.08
3.33
2.82
2.72
19.75
23.45
25.14
50.35
21.34
30.91


A177
1.58
1.73
1.42
1.05
13.56
15.96
17.33
31.35
13.59
19.95


A178
2.53
2.34
2.16
1.89
16.13
20.20
21.83
43.07
17.75
26.41


A179
2.33
2.51
2.18
1.86
16.78
20.38
22.02
39.95
17.86
26.18


A180
2.18
2.26
1.88
1.59
15.79
18.80
20.33
36.32
16.66
23.85


A181
3.68
3.49
3.21
3.44
20.29
25.17
29.85
51.67
21.98
35.38


A182
2.05
2.10
1.78
1.44
15.15
18.28
19.30
39.14
15.93
23.28


A183
1.53
1.55
1.30
0.91
12.70
15.24
16.46
28.49
12.95
18.59


A184
2.48
2.58
2.22
1.96
17.06
20.49
21.89
47.65
18.04
27.02


A185
3.05
3.28
2.96
2.87
19.59
24.06
26.64
54.15
21.37
32.25


A186
3.10
3.12
3.09
3.58
19.01
22.19
29.51
65.55
19.65
37.28


A187
1.75
1.83
1.51
1.18
13.99
16.52
17.86
34.85
14.22
21.02


A188
2.93
3.12
2.56
2.46
19.01
22.29
24.63
36.67
20.11
29.31


A189
2.93
2.98
2.68
2.47
18.52
23.20
25.87
44.13
20.26
30.01


A190
3.25
3.59
3.00
2.75
20.62
24.60
26.72
44.63
21.77
31.67


A191
2.05
2.04
1.71
1.39
14.91
17.82
19.08
34.18
15.77
22.39


A192
2.28
2.49
2.25
1.81
16.69
21.28
22.69
39.02
18.88
25.65


A193
1.95
2.11
1.84
1.64
15.20
17.86
20.52
39.35
15.51
24.43


A194
2.18
2.27
1.98
1.72
15.83
19.27
21.44
36.83
16.93
24.78


A195
1.45
1.37
1.46
1.17
11.86
15.76
17.48
34.90
13.23
21.30


A196
1.95
1.99
1.82
1.56
14.68
18.04
20.23
42.94
15.59
23.97


A197
1.63
1.78
1.62
1.28
13.76
17.46
18.33
41.41
15.35
21.69


A198
1.85
1.92
1.66
1.43
14.39
16.92
19.77
31.95
14.88
22.21


A199
1.40
1.49
1.32
0.94
12.42
15.08
16.68
28.38
12.57
19.08


A200
1.35
1.38
1.21
0.88
11.92
14.39
15.64
30.32
12.02
18.39


A201
2.40
2.56
2.19
1.96
16.97
20.37
22.05
42.55
18.13
26.53


A202
2.20
2.39
1.93
1.59
16.31
18.99
20.82
37.23
16.43
24.30


A203
1.80
2.07
1.67
1.28
15.04
17.69
18.76
36.37
15.26
22.07


A204
1.73
1.80
1.50
1.14
13.85
16.41
17.97
30.75
14.07
20.62


A205
1.85
1.87
1.84
1.46
14.19
18.51
20.05
39.13
15.79
23.60


A207
2.65
2.75
2.42
2.11
17.69
21.70
23.07
45.74
19.37
27.59


A208
3.05
3.04
2.63
2.62
18.75
22.27
25.50
45.50
19.80
30.63


A209
1.70
1.84
1.69
1.44
14.06
17.22
19.31
37.35
15.00
22.84


A210
2.35
2.37
1.95
1.58
16.23
19.23
20.54
39.33
16.76
24.32


A211
2.50
2.68
2.40
2.12
17.44
21.54
23.03
47.55
19.14
27.75


A212
2.88
2.77
2.44
2.18
17.78
21.82
23.45
43.47
19.54
27.85


A213
2.53
2.74
2.40
2.41
17.65
20.57
23.19
56.75
18.23
30.50


A214
2.60
2.80
2.44
2.38
17.86
21.07
24.24
44.75
18.53
29.52


A215
2.40
2.47
2.06
1.70
16.63
19.82
21.16
41.43
17.36
25.07


A216
4.48
4.13
3.86
3.78
22.33
27.99
30.59
58.40
24.70
37.52


A217
2.23
2.33
2.26
2.19
16.10
20.21
22.30
63.13
17.82
28.77


A218
2.95
2.94
2.82
2.70
18.38
23.22
25.69
59.95
20.39
31.65


A219
2.38
2.71
2.17
2.01
17.55
20.69
23.43
36.97
18.50
26.17


A220
1.90
2.05
1.74
1.34
14.92
18.06
19.41
34.75
15.57
22.53


A222
1.83
1.89
1.63
1.36
14.27
17.07
18.81
33.95
14.98
22.12


A223
1.73
1.74
1.41
1.05
13.60
16.00
17.00
31.79
13.57
20.14


A224
1.73
1.62
1.52
1.15
13.03
16.52
18.07
31.77
14.04
20.86


A225
1.68
1.81
1.52
1.18
13.93
16.59
17.97
32.58
14.29
20.96
















TABLE 15







Table 15 provides additional data for the coagulation study of the samples in Table 14.

















ID
Fg
c1
ct2s
C2
Ceot
IUL
IUX
IUT
IUA
Ztm




















A001
388
3738
3720
3706
3664
18
14
56
74
1.85


A002
226
3724
3712
3704
3686
12
8
26
38
1.42


A003
213
3740
3730
3719
3705
10
11
25
35
2.38


A004
370
3733
3709
3692
3663
24
17
46
70
1.96


A005
226
3738
3726
3715
3700
12
11
26
38
2.14


A007
244
3740
3726
3714
3698
14
12
28
42
1.99


A008
482
3741
3714
3693
3646
27
21
68
95
2.04


A009
253
3741
3727
3713
3697
14
14
30
44
2.52


A010
240
3742
3727
3714
3701
15
13
26
41
2.11


A011
352
3713
3690
3676
3647
23
14
43
66
1.42


A012
276
3744
3727
3717
3695
17
10
32
49
1.54


A013
496
3739
3715
3690
3641
24
25
74
98
2.59


A014
226
3732
3717
3708
3694
15
9
23
38
1.34


A015
199
3738
3726
3717
3706
12
9
20
32
1.81


A016
340
3741
3722
3714
3678
19
8
44
63
1.02


A017
331
3742
3720
3706
3681
22
14
39
61
1.57


A018
218
3734
3722
3711
3697
12
11
25
37
2.46


A019
472
3744
3716
3695
3653
28
21
63
91
1.72


A020
246
3741
3727
3714
3698
14
13
29
43
2.67


A021
265
3741
3727
3717
3694
14
10
33
47
1.86


A022
387
3740
3717
3702
3667
23
15
50
73
1.54


A023
420
3743
3719
3705
3663
24
14
56
80
1.41


A024
415
3740
3717
3699
3661
23
18
56
79
2.00


A025
171
3743
3732
3726
3716
11
6
16
27
1.03


A026
363
3742
3718
3702
3673
24
16
45
69
1.62


A027
377
3739
3715
3698
3667
24
17
48
72
1.57


A028
463
3742
3713
3696
3651
29
17
62
91
1.42


A029
472
3740
3713
3690
3647
27
23
66
93
1.95


A030
540
3743
3716
3698
3635
27
18
81
108
1.56


A031
236
3728
3715
3704
3687
13
11
28
41
2.13


A032
309
3732
3716
3710
3675
16
6
41
57
0.94


A033
358
3739
3718
3702
3671
21
16
47
68
2.02


A034
349
3740
3721
3706
3674
19
15
47
66
1.75


A035
209
3734
3725
3711
3699
9
14
26
35
4.37


A036
295
3735
3723
3708
3681
12
15
42
54
2.56


A037
372
3740
3716
3697
3669
24
19
47
71
2.10


A038
304
3742
3721
3709
3686
21
12
35
56
1.33


A039
232
3738
3722
3711
3698
16
11
24
40
1.67


A040
404
3742
3720
3705
3664
22
15
56
78
1.65


A041
493
3739
3711
3695
3638
28
16
73
101
1.51


A042
261
3736
3721
3709
3687
15
12
34
49
2.56


A044
301
3741
3722
3710
3683
19
12
39
58
1.56


A045
453
3739
3714
3689
3647
25
25
67
92
2.64


A047
341
3735
3716
3699
3668
19
17
48
67
2.22


A048
270
3733
3720
3705
3682
13
15
38
51
3.15


A049
252
3737
3725
3711
3690
12
14
35
47
2.52


A050
288
3740
3723
3711
3685
17
12
38
55
2.02


A051
514
3738
3705
3691
3634
33
14
71
104
0.96


A052
276
3737
3723
3712
3687
14
11
36
50
1.95


A053
241
3738
3724
3715
3696
14
9
28
42
1.68


A054
294
3733
3716
3700
3679
17
16
37
54
2.12


A055
540
3737
3718
3687
3627
19
31
91
110
4.81


A056
566
3740
3711
3685
3624
29
26
87
116
2.34


A057
232
3723
3710
3701
3683
13
9
27
40
1.61


A058
360
3738
3723
3709
3669
15
14
54
69
3.55


A059
232
3736
3723
3711
3696
13
12
27
40
2.36


A060
197
3730
3719
3710
3698
11
9
21
32
2.13


A061
294
3734
3720
3707
3680
14
13
40
54
2.20


A062
439
3738
3718
3702
3651
20
16
67
87
2.96


A063
237
3738
3728
3715
3697
10
13
31
41
3.53


A064
285
3737
3719
3705
3685
18
14
34
52
1.89


A065
320
3740
3721
3703
3680
19
18
41
60
2.71


A066
186
3738
3726
3719
3707
12
7
19
31
1.36


A067
494
3740
3708
3689
3641
32
19
67
99
1.50


A068
286
3739
3725
3713
3686
14
12
39
53
1.89


A069
223
3734
3719
3714
3695
15
5
24
39
0.80


A070
354
3739
3716
3703
3671
23
13
45
68
1.40


A071
399
3738
3714
3695
3660
24
19
54
78
1.90


A072
463
3738
3712
3694
3646
26
18
66
92
1.71


A073
494
3738
3707
3685
3639
31
22
68
99
1.68


A074
286
3718
3700
3683
3665
18
17
35
53
2.17


A075
114
3741
3734
3730
3726
7
4
8
15
0.98


A076
385
3742
3718
3704
3665
24
14
53
77
1.39


A077
508
3740
3718
3694
3634
22
24
84
106
3.10


A078
296
3740
3724
3707
3684
16
17
40
56
2.34


A080
499
3741
3729
3706
3637
12
23
92
104
5.02


A081
550
3742
3710
3694
3626
32
16
84
116
1.57


A082
431
3742
3716
3696
3654
26
20
62
88
1.91


A083
296
3742
3720
3709
3686
22
11
34
56
1.16


A084
376
3742
3732
3715
3667
10
17
65
75
4.55


A085
342
3742
3727
3701
3675
15
26
52
67
5.07


A086
448
3742
3717
3700
3650
25
17
67
92
1.73


A087
431
3742
3715
3694
3654
27
21
61
88
1.84


A088
512
3737
3704
3681
3630
33
23
74
107
1.64


A089
292
3742
3723
3712
3687
19
11
36
55
1.24


A090
711
3742
3718
3680
3588
24
38
130
154
4.73


A091
393
3741
3724
3707
3659
17
17
65
82
3.80


A092
711
3740
3696
3657
3582
44
39
114
158
2.38


A093
243
3739
3730
3716
3693
9
14
37
46
3.73


A094
322
3741
3719
3709
3676
22
10
43
65
1.16


A095
490
3743
3710
3689
3638
33
21
72
105
1.51


A096
214
3739
3725
3717
3700
14
8
25
39
1.29


A097
256
3741
3721
3712
3692
20
9
29
49
1.14


A098
398
3742
3716
3695
3659
26
21
57
83
1.81


A099
289
3742
3722
3707
3685
20
15
37
57
1.61


A100
536
3741
3709
3685
3625
32
24
84
116
1.62


A101
269
3740
3727
3712
3690
13
15
37
50
2.94


A102
397
3740
3721
3712
3661
19
9
60
79
1.16


A103
495
3741
3715
3693
3640
26
22
75
101
1.96


A104
260
3730
3719
3705
3682
11
14
37
48
3.88


A105
393
3738
3725
3709
3660
13
16
65
78
2.64


A107
402
3740
3722
3701
3660
18
21
62
80
2.58


A108
198
3743
3732
3721
3709
11
11
23
34
2.61


A109
273
3740
3726
3711
3689
14
15
37
51
2.85


A110
499
3737
3719
3696
3635
18
23
84
102
3.76


A111
366
3739
3723
3701
3667
16
22
56
72
3.45


A112
614
3742
3714
3690
3614
28
24
100
128
2.03


A113
371
3737
3717
3701
3664
20
16
53
73
1.80


A114
388
3732
3711
3691
3655
21
20
56
77
2.13


A115
446
3742
3716
3697
3652
26
19
64
90
1.93


A116
230
3742
3727
3715
3698
15
12
29
44
1.62


A117
499
3739
3710
3687
3630
29
23
80
109
1.85


A118
230
3743
3729
3721
3699
14
8
30
44
1.29


A119
308
3742
3728
3716
3679
14
12
49
63
1.91


A120
250
3737
3722
3713
3688
15
9
34
49
1.28


A121
196
3740
3730
3720
3704
10
10
26
36
2.04


A122
404
3736
3713
3692
3650
23
21
63
86
2.06


A123
205
3742
3730
3720
3704
12
10
26
38
1.87


A124
213
3736
3721
3712
3696
15
9
25
40
1.40


A125
541
3719
3683
3668
3600
36
15
83
119
1.02


A126
177
3743
3735
3725
3714
8
10
21
29
3.53


A127
482
3741
3714
3698
3640
27
16
74
101
1.53


A128
300
3740
3723
3715
3682
17
8
41
58
1.13


A129
338
3744
3728
3715
3677
16
13
51
67
3.01


A130
410
3740
3715
3701
3656
25
14
59
84
1.67


A131
258
3738
3724
3710
3690
14
14
34
48
2.37


A132
381
3742
3720
3697
3665
22
23
55
77
3.66


A133
347
3742
3728
3705
3673
14
23
55
69
4.05


A134
376
3743
3723
3710
3667
20
13
56
76
2.65


A135
330
3741
3717
3702
3676
24
15
41
65
1.55


A136
414
3744
3725
3709
3659
19
16
66
85
2.24


A137
381
3739
3711
3693
3662
28
18
49
77
1.47


A138
487
3743
3712
3693
3641
31
19
71
102
1.66


A139
478
3742
3717
3702
3642
25
15
75
100
1.37


A140
482
3743
3710
3690
3642
33
20
68
101
1.38


A141
373
3739
3714
3701
3661
25
13
53
78
1.23


A142
197
3742
3729
3719
3706
13
10
23
36
1.90


A143
239
3739
3726
3710
3693
13
16
33
46
3.25


A144
460
3740
3709
3692
3641
31
17
68
99
1.32


A145
465
3739
3705
3686
3639
34
19
66
100
1.36


A146
347
3736
3718
3705
3664
18
13
54
72
1.68


A147
385
3742
3713
3698
3661
29
15
52
81
1.30


A148
448
3742
3714
3699
3646
28
15
68
96
1.43


A149
427
3744
3710
3692
3653
34
18
57
91
1.37


A150
607
3742
3701
3676
3608
41
25
93
134
1.40


A151
698
3737
3701
3664
3587
36
37
114
150
2.54


A152
293
3738
3716
3705
3683
22
11
33
55
1.29


A153
626
3729
3691
3670
3596
38
21
95
133
1.35


A154
412
3728
3706
3687
3645
22
19
61
83
2.04


A155
365
3739
3724
3694
3667
15
30
57
72
6.02


A156
250
3733
3717
3710
3688
16
7
29
45
1.12


A157
310
3737
3717
3702
3678
20
15
39
59
1.79


A158
263
3737
3723
3713
3689
14
10
34
48
1.60


A159
404
3733
3715
3696
3652
18
19
63
81
3.33


A160
412
3738
3717
3690
3655
21
27
62
83
3.35


A161
331
3740
3720
3706
3676
20
14
44
64
1.80


A162
421
3738
3722
3706
3653
16
16
69
85
3.37


A163
293
3738
3725
3714
3683
13
11
42
55
1.99


A164
267
3734
3720
3712
3685
14
8
35
49
1.40


A165
485
3736
3707
3688
3636
29
19
71
100
1.65


A166
486
3733
3703
3687
3631
30
16
72
102
1.28


A167
235
3734
3718
3711
3690
16
7
28
44
1.10


A168
317
3732
3722
3711
3669
10
11
53
63
2.29


A169
486
3726
3703
3693
3624
23
10
79
102
1.03


A170
304
3740
3717
3703
3680
23
14
37
60
1.45


A171
365
3740
3722
3698
3666
18
24
56
74
3.35


A172
261
3741
3727
3718
3691
14
9
36
50
1.30


A173
304
3740
3718
3704
3680
22
14
38
60
1.43


A174
412
3733
3707
3688
3648
26
19
59
85
1.65


A175
378
3719
3690
3671
3642
29
19
48
77
1.42


A176
337
3739
3724
3712
3671
15
12
53
68
1.69


A177
267
3740
3721
3710
3689
19
11
32
51
1.37


A178
408
3740
3716
3700
3655
24
16
61
85
1.63


A179
329
3738
3718
3705
3672
20
13
46
66
1.64


A180
250
3733
3719
3709
3686
14
10
33
47
1.53


A181
317
3739
3724
3702
3676
15
22
48
63
4.68


A182
354
3739
3716
3706
3667
23
10
49
72
1.02


A183
209
3726
3711
3703
3689
15
8
22
37
1.22


A184
375
3738
3717
3705
3661
21
12
56
77
1.40


A185
458
3736
3712
3689
3639
24
23
73
97
2.58


A186
545
3738
3721
3672
3620
17
49
101
118
7.32


A187
350
3739
3715
3701
3668
24
14
47
71
1.34


A188
300
3731
3717
3702
3672
14
15
45
59
2.34


A189
358
3731
3709
3689
3658
22
20
51
73
2.67


A190
230
3730
3718
3709
3688
12
9
30
42
2.12


A191
234
3738
3725
3717
3696
13
8
29
42
1.26


A192
261
3739
3722
3712
3691
17
10
31
48
1.41


A193
301
3742
3727
3710
3685
15
17
42
57
2.66


A194
257
3735
3721
3708
3688
14
13
33
47
2.17


A195
716
3739
3692
3660
3589
47
32
103
150
1.72


A196
337
3738
3719
3702
3673
19
17
46
65
2.19


A197
502
3739
3705
3691
3637
34
14
68
102
0.87


A198
208
3728
3718
3704
3692
10
14
26
36
2.85


A199
301
3741
3719
3705
3684
22
14
35
57
1.60


A200
274
3737
3718
3708
3686
19
10
32
51
1.25


A201
319
3741
3725
3713
3681
16
12
44
60
1.68


A202
243
3737
3723
3713
3694
14
10
29
43
1.83


A203
364
3740
3715
3704
3670
25
11
45
70
1.07


A204
239
3739
3724
3714
3697
15
10
27
42
1.56


A205
346
3740
3717
3704
3674
23
13
43
66
1.54


A207
319
3728
3711
3701
3668
17
10
43
60
1.37


A208
306
3737
3724
3707
3680
13
17
44
57
3.23


A209
319
3742
3725
3709
3682
17
16
43
60
2.09


A210
283
3740
3723
3714
3688
17
9
35
52
1.31


A211
515
3741
3712
3694
3637
29
18
75
104
1.49


A212
279
3740
3726
3716
3689
14
10
37
51
1.63


A213
448
3741
3724
3705
3652
17
19
72
89
2.62


A214
283
3739
3727
3712
3687
12
15
40
52
3.17


A215
359
3737
3715
3703
3668
22
12
47
69
1.34


A216
389
3741
3722
3707
3667
19
15
55
74
2.60


A217
560
3740
3716
3695
3630
24
21
86
110
2.09


A218
773
3738
3699
3665
3583
39
34
116
155
2.47


A219
238
3741
3729
3714
3699
12
15
30
42
2.74


A220
356
3741
3717
3704
3674
24
13
43
67
1.35


A222
233
3725
3713
3703
3684
12
10
29
41
1.74


A223
257
3741
3724
3717
3695
17
7
29
46
1.00


A224
351
3742
3718
3703
3676
24
15
42
66
1.55


A225
314
3741
3721
3709
3683
20
12
38
58
1.38









Though the sample ID's in Tables 14 and 15 range from A001 to A225, gaps in sample numbers indicate occurrences where a sample was not able to be tested because it was beyond three standard deviations.










TABLE 16






R2
mY




















INRw






vs
TPC INRm
0.9482
1.0506x




TPC INRz
0.9482
1.0389x




TPC INRn
0.9401
1.048x



INRw






vs
INRm
−0.0908
−0.0186x




INRz
−0.0966
−0.0144X




INRn
0.0327
−0.0065x









The linear regression analysis expression y=m×+b, when solved for the slope, m, is expressed as (y−b)/x. This is biased, so the expression is y/x is when b is equal to zero. Statistical data and plots demonstrate that the INRn may replace prior WHO INR and provide results which are within the parameters of traditional therapeutic or reference ranges.
In accordance with one embodiment, the IBM-compatible computer 30 of FIG. 1 stores and manipulates these digital values corresponding to the clotting curve represented in FIG. 6 and the related data provided in Tables 14 and 15. According to a preferred embodiment, the computer may be programmed as follows:

    
    
        (k) a sample of blood where the plasma is available, such as, for example, a sample of citrated blood, is obtained and placed in an appropriate container, the computer 30, as well as the recorder 28, sequentially records voltage values for a few seconds before injection of the reagent (thromboplastin calcium combined). As previously discussed, thromboplastin (tissue factor) is one of the factors in the human body that causes blood to clot. Prothrombin is another. Fibrinogen is yet another. Before injection of the thromboplastin, the output from the A/D converter 26 is relatively constant. When thromboplastin is injected into the plasma sample in the container, a significant and abrupt change occurs in the recorded voltage values of both the computer 30 and the recorder 28. This abrupt change is recognized by both the recorder 28 and, more importantly, by the computer 30 which uses such recognition to establish To. The computer 30 may be programmed so as to correlate the digital quantities of the A/D converter 26 to the analog output of the detector means photocell 10 which, in turn, is directly correlatable to the fibrinogen (FBG) concentration g/l of the sample of blood discussed herein and represented by the clotting curve shown in FIG. 6;
        (l) the computer 30 may be programmed to look for a digital quantity representative of a critical quantity F1, and when such occurs, record its instant time T1. (The time span between To and T1 is the prothrombin time (PT), and has an normal duration of about 12 seconds, but may be greater than 30 seconds);
        (m) following the detection of the quantity c1, the computer 30 may be programmed to detect for the acceleration of fibrinogen (FBG) to fibrin conversion. The computer 30 is programmed to detect the maximum acceleration quantity cMAP or cT2 as illustrated in FIG. 6, and its corresponding time of occurrence tMAP, which is T2 in FIG. 6.
        (d) The computer detects a quantity cEOT occurring at time tEOT. Typically, it is important that the rate of fibrin formation increase for at least 1.5 seconds following the occurrence of (T1); the computer determines a theoretical end of test (TEOT) based on the determination of the zero order kinetic rate. The computer may be programmed to determine the zero order rate, which is expressed as a Line (L) in FIG. 6. The TEOT may be determined by the corresponding time value (TEOT) along the line L which corresponds with the quantity cEOT (i.e., that corresponds with the value for T3);
        (e) The computer 30 is programmed to ascertain the value for the time to start (T2S) which corresponds with the time at which the simulated zero order kinetic rate begins.
        (f) Following the detection of the acceleration of fibrinogen conversion to detect the start time T2S, the computer 30 is programmed to detect for a deceleration of the fibrinogen conversion, wherein the fibrinogen concentration decreases from a predetermined quantity cMAP to a predetermined quantity cEOT having a value which is about equal but less than the first quantity c1. The computer is programmed to ascertain a first delta (IUTz), by determining the difference between the quantity cT2S and the quantity cEOT; and a second delta (IUXz) by determining the difference between the quantity cT2S and the quantity c2 (or CMAP); the computer also determines the value ZTM by determining the difference between the time T2 (which is Tmap) and the time T2S;
        (g) the computer 30 manipulates the collected data of (a); (b); (c); (d), (e) and (f) above, to determine the new fibrinogen transfer rate (nFTR). The nFTR may be arrived at based on the principle that if a required amount (e.g., 0.05 g/l) of fibrinogen concentration c1 is first necessary to detect a clot point (t1); then when the fibrinogen concentration (cEOT) becomes less than the required amount c1, which occurs at time (tEOT), the fibrinogen end point has been reached. More particularly, the required fibrinogen concentration c1 is the starting point of fibrinogen conversion of the clotting process and the less than required fibrinogen concentration CEOT is the end point of the fibrinogen conversion of the clotting process.
        (h) the duration of the fibrinogen conversion of the clotting process of the present invention is defined by the zero order time period between TEOT and T2S and is generally indicated in FIG. 6 as IUTz. The difference between the corresponding concentrations cT2S and cT2 is used to define a delta IUXz. The computer now has the information needed to determine the TEOT, which is expressed by the following formula:

TEOT=T2S+(ZTM/IUX*IUT)  (12)

        The TEOT is determined and the data collected is manipulated by the computer 30 to determine a new INR, referred to as INRn:

INRn=((T1+TEot)/2)*0.00535*T2S  (11)

        Using the multiplier MUL (which in this example, as discussed herein and according to expression 10 above, preferably is 0.00535).
    
    


The computer 30 may be used to manipulate and derive the quantities of expression (11) to determine a new INR (INRn) utilizing known programming routines and techniques. The data collected by a computer 30 may be used to manipulate and derive INRn of expression (11). Similarly, one skilled in the art, using known mathematical techniques may derive the theoretical end of test TEOT of expression (5), and using the TEOT value in expression (11), in turn, may determine the new INR, INRn of expression (12). In the INRn determination, the determination is based on the patient's own sample, and does not rely on the determination of normal prothrombin times for the reagent used (e.g., thromboplastin, innovin or the like). With the INRn determination method, no longer does the accuracy of the quantities determined depend, in whole or part, on the number of specimens used, that is, the number of stable (or presumed stable) patients.
The new anticoagulation therapy value (INRn) does not require an ISI value, as was previously used to determine anticoagulation therapy factors. The new anticoagulation therapy value INRn uses for its ascertainment the values extracted from the clotting curve (see FIG. 6), in particular T2S, Tmap, TEOT, c1, cT2s, ct2 and ceot. In determining the new INRn, the ISI is not required, nor is the MNPT, or the need to obtain and calculate the prothrombin times (PT's) for 20 presumed normal patients. In carrying out coagulation studies, the new anticoagulant therapy factor INRn may replace the INR traditionally used in anticoagulant therapy management (such as INR WHO and INRm). In addition, using the sample from the patient, the computer 30 has knowledge of the values obtained for the fibrinogen reaction, to ascertain the INRn.
Theoretical Clotting Area INRs Determination
An alternate embodiment for determining an anticoagulant therapy factor is provided and is based on determinations made during the clotting reaction of fibrinogen for a sample of a patient's blood. This alternate embodiment utilizes a theoretical clotting area. According to the illustration in FIG. 6, a clotting curve is shown where optical activity in instrument units is plotted against time (in seconds). Time values are indicated on the x axis, and optical activity values, such as absorbance values are indicated on the y axis. The optical activity values are measured with an instrument that detects changes in the optical activity (e.g., absorbance), and are recorded with their corresponding time values in order to derive a corresponding anticoagulant therapy factor value, ATFs or INRs. The INRs value is a value determined for the patient sample that generated the information represented by the clotting curve. The ATFs/INRs values obtained are useful in determining the treatment course for an individual, in particular where the individual has a blood disorder.
According to a preferred embodiment, the alternate embodiment determines an ATF value that utilizes the clotting curve information represented by the graph illustrated in FIG. 6. The clotting curve represents the optical activity for the coagulant reaction where the fibrinogen in the sample and a clotting agent are combined and the fibrinogen is transformed to fibrin. As illustrated in FIG. 8, the clotting curve defines an area below it and there also is a portion of the clotting area that is above the clotting curve. The alternate method is used for determining the INR for the sample, where the INR is an anticoagulant therapy factor and is represented by ATFs or INRs. The theoretical clotting area is derived to determine the INRs, and, according to the preferred alternate embodiment, utilizes an area defined by the time measurements at which certain functions of the clotting reaction occur. Preferably, an instrument is programmed with instructions for implementing processing of the signals based on the photodetection output of a photocell, such as, for example, the photocell of a spectrophotometer. The instrument described and shown in connection with FIG. 1 herein may be utilized to carry out the ATFs/INRs determination. Alternately, according to preferred embodiments, the spectrometric devices shown and described in connection with our copending application Ser. No. 12/932,824, filed on Mar. 7, 2011, may be used in connection with the method disclosed herein for determining the theoretical clotting area (A), shown in FIG. 7 being represented by area (A1) and area (A2), using the formulas set forth in expression (13), below.
Optical activity is determined for times corresponding with the time that the reagent is combined with the sample containing fibrinogen (To), and the time that represents the theoretical end of the test (TEOT). FIG. 6 illustrates a graph of the clotting curve and shows To, which is where the clotting agent, such as TPC or other clotting agent, is combined with the sample. The TEOT is also identified on FIG. 6. Preferably, the times T1 and TEOT are measured from the time To. The area (A) corresponds with the INRs. The INRs preferably is derived by utilizing a parity parameter to bring the time values in parity with the optical density measurements (such as absorbance values) that are recorded at the corresponding times. The TEOT may be determined as set forth herein in connection with the embodiments discussed herein, such as, for example, where the zero order kinetic line L is determined, and where the TEOT is derived. For example, in order to determine the TEOT, preferably, the slope of maximum acceleration on the clotting curve that corresponds with the maximum rate of formation of fibrin during the reaction of the fibrinogen in the sample with a clotting agent is determined. One preferred method for determining the slope is by determining the maximum acceleration point (identified as T2 or Tmap on FIG. 6). The determination of Tmap may be done as described herein in connection with the other embodiments. A preferred method involves sampling optical activity values (e.g., such as absorbance values) of the sample and clotting agent as the clotting reaction takes place to determine the last highest delta of an increasing rate of fibrinogen transformation. The slope is illustrated represented by the line L in FIG. 6, and the line L intersects c=Ceot, which provides a value for the TEOT.
According to a preferred embodiment, the ATFs or INRs may be expressed with the following formulae:

Area=T1*TEOT  (13)

ATFs=INRs=T1*TEOT*MUL  (14)

The MUL is a multiplier that is based on two relationships that are addressed by the multiplier. MUL relates the sampling rate of the instrument and the pixel parity of the x-y axis. The instrument used to measure the optical changes in the sample generates values, and preferably, the values, or signals are taken at a particular frequency. For example, a preferred sampling rate for the clotting curve reaction of a patient blood or blood component sample may be a number of optical absorbance values in a particular time interval. A preferred rate, for example, may be 100 optical absorbance values (or samples) per second, expressed 100/second. The sample rate preferably is used to derive a multiplier component, MUL. Also used to derive the multiplier component is the parity value, which is a multiplier utilized to create x-y pixel parity for the clotting curve information (that is shown expressed on the clotting curve graph, see FIG. 6). According to the example illustrated, the sampling rate used was 100 values per second. The pixel parity multiplier was 0.535. The multiplier, according to this example, is 0.535 (pixel parity value)/100 (the number of samples reflected in a second). The multiplier, or MUL, according to a preferred embodiment, was 0.00535.
In order to derive the ATFs, the clotting curve is considered, and the theoretical or hypothetical zero order kinetic line, or line L as it is referred to and appears on the Figures, provides an (x,y) coordinate of (TEOT, 0), where the time value at which the clotting reaction, if theorized from the slope or line taken between the point where the maximum acceleration of the conversion rate of fibrinogen transformation begins (T2S) and the end of the maximum conversion (which, according to preferred embodiments, may be determined as the last highest delta value of conversion rate), which is T2 or Tmap. The value, TEOT, is a time value, and generally, for example, may be expressed in seconds.
The INRs value preferably is determined using a clotting agent that reacts with the fibrinogen in the sample to provide a clotting reaction, such as the clotting reactions represented by the graph in FIG. 6. The clotting agents may be those discussed herein.
ATFs/INRs EXAMPLES
In accordance with the embodiment discussed above in connection with expression (14), the ATFs/INRs was determined for a number of patient samples. INRs/ATFs derivations were carried out using the data for the patient samples contained in Table 17. The INRs was determined as discussed herein by determining the PT for a sample, which is the value T1 (the time from the addition of the reagent to the time of the first clot, e.g., between T0 and T1 on FIG. 6). The clotting begins (at T1) and accelerates where the maximum conversion rate is determined at T2 (the maximum acceleration point or map). The coagulation reaction continues until reaching the end of test time, which is represented by time T3. The time T2S on the graph of FIG. 6 represents the beginning of the maximum acceleration of the clotting rate. The slope of the zero order kinetic reaction is represented by the line L. The theoretical end of the test TEOT may be determined by the point at which the line L crosses the line y=Ceot (see FIG. 6).
Based on carrying out the clotting reaction and detecting changes in the optical activity of the sample, the determination of the ATFs/INRs may be accomplished. Preferably, an instrument that has means for measuring the optical activity of the sample as the sample undergoes the coagulation reaction. According to preferred embodiments, a spectrophotometer such as, for example, the apparatus shown in FIG. 1 and described herein, may be used to provide optical activity data. According to alternate embodiments, a photocell and light source may be configured and arranged to provide information corresponding with the optical activity of a sample. For example, the light source, such as an LED light or other source, may be used to provide a beam that passes through the sample tube. According to a preferred embodiment, the light beam may be configurable by providing a variable power supply to operate the light source, as described in our co-pending patent application Ser. No. 12/932,824, filed on Mar. 7, 2011, the complete disclosure of which is herein incorporated by reference. The optical path output may be adjusted, e.g., increased or decreased, through the regulation of the light source power supply adjustment. A photocell preferably may be arranged to receive the light beam. The photocell preferably may be provided in an electric circuit that may be operated with a computer. The computer may be configured with a program that records the signals from the photocell over the time of the coagulation reaction. Preferably, the photocell output is part of a circuit. The circuit also may utilize a variable resistor and the variable resistor may be controlled though a computer. For example, if it is desirable to have the voltage from the voltage source varied, the computer may be operated with inputs from a keyboard or other input device to control the resistance. The negative output of the photocell also may be connected in the circuit though a variable resistor that may be controlled using the computer. According to one embodiment, the computer is programmed with software to implement the changes in the voltage so that the voltage is set to a level that will provide a baseline for the sample, and the computer may implement a routine that derives a voltage that will provide an appropriate scale for the optical activity measurements. The voltage setting may also be determined by blanking, where a blank of the sample container with water (or other material), or may be set to a baseline by determining the voltage corresponding to the optical activity of the sample itself, before the clotting agent addition. According to some embodiments, the reference voltage may be utilized by the computer, so that instructions are implemented to subtract the reference or baseline voltage from subsequent readings. In addition, the data from the photocell may be digitized so that the voltage readings may then be stored and manipulated.
Results for the coagulation studies on the data in Table 17, below, were carried out using Thromboplastin C as a reagent.
Table 17 shows data for samples corresponding to a sample ID A001 through A225, with some gaps in the sample numbers. Gaps in sample numbers indicate occurrences where a sample was not able to be tested because they were beyond three standard deviations. The INR values were determined based on the coagulation data for the sample. Each sample was reacted in a coagulation reaction with a clotting agent, which, for determination of the values in Table 17, was Thromboplastin C. The start of the recording of optical density values is represented by the start time (T0) (see FIG. 6) which corresponds with the time of the Thromboplastin C reagent addition to the sample. The prothrombin time (PT) or (T1), identified as (T1) in FIG. 6, was recorded, which is a time when the optical activity changes (after the addition of the reagent has been added at time To). The time to start (T2S) of the clotting reaction was determined and recorded, and the maximum acceleration point (MAP) was determined and the time corresponding therewith (Tmap) was recorded. The instrument unit value of the maximum acceleration point (Cmap) at the time of maximum acceleration (Tmap) was recorded. In Table 17, time value (T3) represents the end of test time where the fibrinogen transformation to fibrin in the sample has completed. The time (EtTm) represents the time of the end of the recording, which is later than the end of test time (T3), and which may be used to verify that the fibrinogen transformation has completed. Instrument unit value CT3 corresponding to the time T3, and the instrument unit value EtV1 corresponding with the time value EtTm, also are provided in Table 17. The instrument units corresponding with the time T1 (or prothrombin time PT) are provided in Table 17 as the value CT1. The instrument unit value StV1 is a value determined using the MAP and by proceeding from the MAP and reverting to a point along the baseline of the clotting curve before the acceleration of the fibrinogen transformation takes place. The StV1 value may be used as a check for the PT, and corresponds with the time value StTm (which is a value that approximates the PT). The FTR is also reported in Table 17 and represents the fibrinogen transformation rate, which was derived using the expression TUX/IUT, which was determined for the reported INRz values in Table 17. The Area represents the area determined in accordance with expression T1*TEOT. The Area is multiplied by the multiplier MUL (which in this example was 1/187 or 0.00535) in order to determine the INRs. The INRs values in Table 17 represent the Area*MUL. The values To, T1, Tmap and T2S preferably are determined as described herein and are recorded, and the corresponding associated instrument unit values CT0, CT1, CMAP and CT2S, respectively are determined and recorded. A computer was provided with software containing instructions for obtaining the information from the coagulation reaction, including optical activity during the time of the coagulation reaction. The software also included instructions for recording and storing the data. Preferably, readings were taken every 1/100th of a second, or 100 readings every second. The time values were recorded, and the corresponding optical activity values (in instrument units) at those respective times also were recorded. The data was stored and the software included instructions to manipulate the data to determine an anticoagulant therapy factor, which, using the data provided in Table 17, is identified as INRs, a new International Normalization Ratio (INR), based on the formula (14), INRs=T1*TEOT*MUL. According to one embodiment, the multiplier value (MUL) was utilized based on the pixel parity and sampling rate, which for the values in Table 17, was 1/187, or 0.00535.







TABLE 17





SAMPLE DATA FOR ATF/INR DETERMINATIONS INCLUDING THE INRs


DETERMINATION




























PT







ID
INRm
INRz
INRs
(T1)
T2S
Tmap
T3
StTm
EtTm





A001
2.97
2.98
2.91
18.49
22.38
23.58
49.55
18.88
49.64


A002
3.17
3.02
2.85
19.19
23.33
24.43
37.75
18.30
37.84


A003
3.36
3.03
3.06
19.84
23.48
25.27
37.55
19.70
37.64


A004
2.05
2.36
2.00
14.94
20.11
21.62
37.55
14.61
37.64


A005
2.87
2.66
2.60
18.11
21.95
23.92
37.55
18.35
37.64


A007
2.04
2.05
1.79
14.89
18.64
19.38
33.95
14.67
34.04


A008
2.61
2.82
2.56
17.16
21.95
23.23
41.95
17.21
42.04


A009
3.16
3.27
3.02
19.17
24.26
25.55
37.95
19.90
38.04


A010
1.78
1.84
1.55
13.78
17.55
18.73
30.15
14.21
30.24


A011
2.09
1.98
1.81
15.10
18.19
19.36
33.75
14.88
33.84


A012
3.19
2.86
2.84
19.26
22.55
24.01
36.95
19.25
37.04


A013
3.47
3.46
3.41
20.21
24.55
26.05
50.15
19.86
50.24


A014
1.78
1.79
1.52
13.76
17.28
18.41
30.15
13.75
30.24


A015
1.86
1.86
1.62
14.11
17.64
18.79
30.15
14.22
30.24


A016
3.04
2.93
2.82
18.73
22.43
23.36
45.75
18.67
45.84


A017
1.80
1.88
1.62
13.85
17.55
18.77
31.35
13.87
31.44


A018
2.07
2.18
1.95
15.02
19.07
21.01
34.55
14.86
34.64


A019
1.84
1.97
1.72
14.05
17.90
19.09
36.75
13.76
36.84


A020
3.55
3.74
3.43
20.49
25.69
26.49
42.75
20.26
42.84


A021
2.85
2.78
2.70
18.07
21.87
23.38
37.35
17.52
37.44


A022
2.11
2.24
1.99
15.20
19.28
20.62
36.75
15.45
36.84


A023
3.09
2.96
2.85
18.92
22.72
23.92
43.35
18.32
43.44


A024
3.33
3.58
3.34
19.75
25.57
27.26
45.35
19.93
45.44


A025
1.84
1.80
1.53
14.03
17.39
17.81
27.45
13.61
30.24


A026
1.56
1.67
1.42
12.78
16.34
17.30
31.75
12.93
31.84


A027
1.48
1.54
1.33
12.41
15.50
16.58
33.35
12.40
33.44


A028
1.91
1.99
1.78
14.34
18.03
19.04
39.15
14.40
39.24


A029
2.05
2.14
1.92
14.92
18.70
20.26
40.55
14.67
40.64


A030
2.57
2.63
2.56
17.00
20.76
21.99
48.75
17.16
48.84


A031
2.60
2.65
2.45
17.14
21.51
22.95
39.55
17.68
39.64


A032
3.85
3.89
3.72
21.46
26.04
26.82
48.15
21.39
48.24


A033
2.94
2.97
2.82
18.39
22.75
24.33
41.95
16.58
42.04


A034
2.21
2.28
2.06
15.58
19.48
20.80
38.95
14.71
39.04


A035
4.87
4.53
5.04
24.58
30.42
33.72
47.75
23.26
47.84


A036
3.11
2.96
2.89
18.99
22.41
23.18
43.55
19.25
43.64


A037
2.41
2.79
2.36
16.38
21.97
23.02
36.95
16.40
37.04


A038
1.59
1.54
1.32
12.91
15.72
16.63
29.75
12.59
31.24


A039
1.46
1.59
1.30
12.27
15.92
17.25
30.15
11.79
30.24


A040
2.36
2.38
2.24
16.21
19.86
21.29
39.75
16.33
39.84


A041
2.32
2.48
2.35
16.03
20.04
21.48
45.15
15.94
45.24


A042
4.07
4.33
3.99
22.17
27.49
28.09
49.35
22.16
49.44


A044
4.34
3.88
3.96
22.99
27.07
28.46
41.15
21.20
41.24


A045
2.70
2.83
2.64
17.52
22.01
23.58
45.75
17.51
45.84


A047
2.82
2.93
2.73
17.95
22.50
23.94
41.55
17.89
41.64


A048
3.84
3.78
3.81
21.44
26.02
27.87
46.15
21.47
46.24


A049
2.70
2.50
2.50
17.51
20.34
22.01
39.55
17.10
39.64


A050
2.74
2.87
2.68
17.66
22.31
24.13
40.75
17.08
40.84


A051
1.92
1.92
1.75
14.37
17.72
18.46
35.55
14.28
35.64


A052
2.77
2.65
2.59
17.76
21.28
22.94
40.35
17.32
40.44


A053
3.09
2.87
2.72
18.91
22.60
23.56
38.75
18.53
38.84


A054
2.10
2.06
1.88
15.13
18.40
20.12
33.15
14.39
33.24


A055
5.39
6.00
6.30
26.05
32.30
34.28
70.15
26.51
70.24


A056
3.52
3.79
3.63
20.40
25.80
27.34
53.15
19.89
53.24


A057
2.87
2.66
2.50
18.14
21.61
22.66
35.15
17.79
35.24


A058
8.49
9.07
10.19
33.82
41.85
45.34
81.95
30.69
82.04


A059
2.72
2.77
2.51
17.57
21.95
22.95
34.15
17.56
34.24


A060
3.12
3.04
2.82
19.02
23.49
24.54
36.55
19.11
36.64


A061
2.49
2.47
2.38
16.70
20.20
21.50
38.35
16.45
38.44


A062
6.14
7.67
7.45
28.07
37.69
39.90
78.95
27.67
79.04


A063
3.05
3.17
3.10
18.78
23.35
25.84
42.15
17.95
42.24


A064
2.23
2.26
2.04
15.68
19.48
20.73
32.55
15.37
32.64


A065
2.68
2.89
2.68
17.41
22.34
24.26
39.75
17.10
39.84


A066
1.99
1.93
1.70
14.69
18.11
19.28
30.15
14.68
30.24


A067
1.65
1.84
1.57
13.19
17.29
18.12
36.75
13.66
36.84


A068
2.51
2.44
2.36
16.78
20.05
21.86
37.35
17.29
37.44


A069
2.41
2.24
2.08
16.39
19.46
20.21
31.95
16.40
32.04


A070
2.39
2.28
2.12
16.31
19.58
20.66
37.55
15.39
37.64


A071
1.89
2.02
1.79
14.28
18.01
19.61
39.55
13.49
39.64


A072
1.82
1.96
1.78
13.94
17.61
18.83
43.55
13.22
43.64


A073
1.41
1.71
1.39
12.06
16.39
17.72
37.75
12.45
37.84


A074
1.63
1.83
1.51
13.11
17.32
18.89
33.35
13.43
33.44


A075
1.53
1.39
1.17
12.64
15.17
15.71
26.34
12.93
30.24


A076
1.44
1.57
1.38
12.18
15.54
16.73
37.55
12.17
37.64


A077
4.64
4.85
5.01
23.88
29.00
30.64
68.15
23.18
68.24


A078
2.12
2.18
1.99
15.23
18.93
20.51
37.15
15.40
37.24


A080
7.27
7.76
9.23
30.92
36.28
38.50
86.95
31.11
87.04


A081
3.61
4.27
3.95
20.69
27.25
28.59
57.95
21.17
58.04


A082
1.54
1.73
1.51
12.68
16.57
17.53
43.55
12.68
43.64


A083
1.60
1.59
1.36
12.97
16.00
17.04
30.15
12.42
30.24


A084
6.70
6.86
8.06
29.52
34.53
37.73
76.55
29.27
76.64


A085
3.29
3.59
3.59
19.62
25.14
28.43
48.15
19.66
48.24


A086
2.69
2.73
2.61
17.47
21.37
22.39
46.95
17.59
47.04


A087
1.84
1.93
1.72
14.06
17.60
18.99
40.75
13.75
40.84


A088
1.71
1.88
1.62
13.44
17.39
18.49
37.95
13.43
38.04


A089
2.19
2.12
1.92
15.52
18.89
20.02
33.95
15.29
34.04


A090
6.13
6.70
7.51
28.05
34.40
37.78
84.35
27.31
84.44


A091
7.71
8.68
9.20
31.99
39.58
41.64
74.75
31.38
74.84


A092
1.91
2.33
1.99
14.36
19.42
21.08
50.15
14.35
50.24


A093
4.80
5.00
5.01
24.37
29.39
30.21
53.15
22.78
53.24


A094
3.13
3.39
2.98
19.07
24.84
25.77
42.95
18.28
43.04


A095
1.50
1.62
1.41
12.48
15.95
17.00
39.55
12.47
39.64


A096
2.12
1.93
1.80
15.22
17.92
19.14
30.95
15.21
31.04


A097
1.33
1.27
1.11
11.67
13.92
14.89
27.63
11.58
30.24


A098
1.41
1.46
1.27
12.07
15.00
16.05
34.95
11.71
35.04


A099
1.76
1.78
1.53
13.67
17.04
18.11
30.15
13.92
30.24


A100
1.40
1.61
1.37
12.02
15.71
17.08
41.95
11.28
42.04


A101
2.76
2.82
2.73
17.71
21.79
23.55
44.75
17.13
44.84


A102
3.63
3.64
3.61
20.75
24.96
25.99
57.95
21.27
58.04


A103
1.96
2.27
2.00
14.58
19.13
20.70
45.75
14.83
45.84


A104
3.14
3.37
3.47
19.10
23.49
27.37
51.95
19.31
52.04


A105
3.69
3.76
3.98
20.93
24.99
26.57
63.15
20.92
63.24


A107
2.81
2.81
2.76
17.90
21.63
23.09
50.20
18.00
52.04


A108
2.05
2.16
1.91
14.93
18.93
20.43
33.55
15.05
33.64


A109
2.26
2.35
2.23
15.82
19.44
21.64
42.15
15.85
42.24


A110
3.90
4.43
4.64
21.61
27.03
29.19
67.75
21.64
67.84


A111
2.55
2.79
2.69
16.92
21.24
24.12
45.75
16.61
45.84


A112
2.27
2.55
2.41
15.85
20.28
21.63
56.43
16.32
58.04


A113
1.85
1.89
1.75
14.10
17.12
18.76
38.35
13.67
38.44


A114
1.96
2.18
1.92
14.58
18.82
20.19
43.35
15.12
43.44


A115
2.29
2.72
2.36
15.93
21.39
22.90
47.35
16.25
47.44


A116
1.73
1.61
1.49
13.53
15.90
17.10
29.98
13.14
31.84


A117
1.59
1.85
1.61
12.93
17.12
18.16
49.15
13.03
49.24


A118
2.18
2.08
1.94
15.49
18.54
19.71
35.35
15.03
35.44


A119
2.98
2.82
2.92
18.53
21.48
23.28
50.95
18.52
51.04


A120
2.11
2.11
1.88
15.18
18.76
19.62
34.35
15.17
34.44


A121
2.05
2.15
1.94
14.95
18.74
20.36
36.55
15.59
36.64


A122
1.76
1.89
1.68
13.70
17.19
18.82
42.35
13.28
42.44


A123
1.79
1.80
1.63
13.80
16.78
18.26
31.54
13.15
33.04


A124
1.77
1.68
1.51
13.73
16.44
17.50
29.07
13.84
29.64


A125
1.39
1.46
1.33
11.93
15.07
15.92
37.95
11.92
38.04


A126
3.63
3.59
3.66
20.75
25.11
27.37
41.35
20.98
41.44


A127
2.36
2.35
2.28
16.20
19.63
20.54
51.15
16.27
51.24


A128
3.89
3.62
3.57
21.59
25.16
26.03
49.55
20.87
49.64


A129
5.13
5.86
6.00
25.32
32.20
34.47
66.15
25.65
66.24


A130
4.66
5.39
4.95
23.94
31.73
33.07
60.35
21.93
60.44


A131
1.72
1.93
1.68
13.49
17.47
19.10
35.95
13.48
36.04


A132
2.56
3.27
2.86
16.97
24.01
26.61
47.95
17.32
48.04


A133
2.64
3.08
2.90
17.27
22.41
24.52
50.65
17.26
53.04


A134
6.30
7.84
7.59
28.48
37.77
39.63
64.95
27.67
65.04


A135
1.48
1.49
1.30
12.40
15.36
16.23
31.15
12.41
31.24


A136
4.20
4.28
4.38
22.57
27.22
28.75
63.10
22.95
64.24


A137
1.96
1.99
1.74
14.56
18.25
19.56
36.95
13.58
37.04


A138
2.00
2.36
2.04
14.73
19.67
21.19
46.15
14.74
46.24


A139
2.07
2.31
2.11
15.03
19.36
20.51
48.75
15.23
48.84


A140
1.29
1.48
1.22
11.44
14.99
16.28
38.35
11.71
38.44


A141
2.17
2.20
2.02
15.45
19.06
20.07
36.35
15.64
36.44


A142
3.32
3.24
2.97
19.71
24.36
25.31
37.79
18.26
39.04


A143
2.56
2.56
2.48
16.97
20.91
23.81
37.75
16.96
37.84


A144
2.44
2.46
2.23
16.53
20.45
21.49
42.81
16.73
43.04


A145
1.38
1.46
1.25
11.91
15.09
16.05
37.55
11.90
37.64


A146
2.16
2.27
2.18
15.38
19.19
20.18
49.55
15.80
49.64


A147
1.59
1.67
1.43
12.92
16.29
17.43
34.55
13.13
34.64


A148
2.40
2.39
2.27
16.37
19.88
20.88
46.95
16.03
47.04


A149
1.53
1.60
1.36
12.61
16.04
16.93
34.35
12.78
34.44


A150
1.55
1.60
1.43
12.72
15.86
16.84
39.95
12.71
40.04


A151
2.80
2.90
2.82
17.89
21.97
23.44
58.75
17.88
58.84


A152
2.19
2.13
1.91
15.51
19.02
20.16
33.45
14.86
33.84


A153
1.71
1.90
1.69
13.46
17.34
18.52
47.55
13.74
47.64


A154
2.28
2.26
2.17
15.88
19.06
20.58
44.75
15.41
44.84


A155
4.59
4.84
5.08
23.75
30.13
33.35
53.55
23.45
53.64


A156
2.79
2.80
2.55
17.85
22.10
23.06
40.95
17.43
41.04


A157
2.24
2.20
2.03
15.72
19.16
19.88
37.15
15.16
37.24


A158
3.56
3.42
3.35
20.52
24.45
25.53
46.55
18.40
46.64


A159
3.94
4.21
4.31
21.74
27.09
29.76
61.35
21.51
61.44


A160
2.67
2.89
2.69
17.39
22.14
24.02
44.35
16.75
44.44


A161
1.66
1.82
1.58
13.24
16.83
18.59
35.95
13.23
36.04


A162
6.47
7.15
7.82
28.92
35.32
37.56
79.75
27.09
79.84


A163
3.83
3.67
3.80
21.40
25.31
27.09
49.55
20.91
49.64


A164
3.65
3.82
3.59
20.81
25.84
26.79
49.35
21.27
49.44


A165
2.62
2.60
2.43
17.20
20.99
21.95
43.75
17.57
43.84


A166
2.19
2.23
2.06
15.52
19.13
20.18
43.03
14.58
43.84


A167
2.78
2.90
2.55
17.80
22.39
22.99
38.15
17.95
38.24


A168
3.64
3.53
3.73
20.77
24.33
25.44
51.55
21.00
51.64


A169
4.13
3.91
4.13
22.35
25.76
26.76
62.15
22.34
62.24


A170
1.39
1.41
1.18
11.93
14.85
15.90
31.79
11.60
32.44


A171
3.35
3.54
3.40
19.81
25.06
26.96
47.95
20.00
48.04


A172
2.46
2.33
2.24
16.58
19.67
20.50
39.75
17.05
39.84


A173
1.51
1.47
1.32
12.55
15.25
16.08
30.75
12.73
30.84


A174
1.84
1.81
1.67
14.04
17.00
18.10
36.75
14.03
36.84


A175
1.77
1.76
1.51
13.71
17.05
17.83
34.84
13.32
36.24


A176
3.33
3.38
3.31
19.75
24.04
25.23
50.35
19.28
50.44


A177
1.74
1.64
1.48
13.59
16.19
17.28
31.35
13.34
31.44


A178
2.37
2.55
2.36
16.22
20.52
21.78
43.11
15.39
43.64


A179
2.45
2.51
2.28
16.56
20.69
21.85
39.95
16.07
40.04


A180
2.17
2.21
2.03
15.43
19.03
20.41
37.55
15.78
37.64


A181
3.41
3.78
3.76
20.01
26.08
29.59
52.35
20.28
52.44


A182
2.10
2.09
1.95
15.15
18.53
19.35
39.18
14.47
41.04


A183
1.56
1.50
1.28
12.79
15.54
16.46
28.95
12.54
29.04


A184
2.58
2.59
2.51
17.06
20.69
21.95
47.68
16.69
48.04


A185
3.26
3.45
3.35
19.52
24.32
25.97
54.15
18.41
54.24


A186
3.12
3.52
3.80
19.01
22.67
29.11
65.55
18.00
65.64


A187
1.81
1.72
1.54
13.91
16.79
17.57
35.55
13.22
35.64


A188
3.01
3.09
2.95
18.64
22.95
24.40
36.72
19.00
38.64


A189
2.98
3.13
3.02
18.53
23.48
25.90
45.95
18.52
46.04


A190
3.38
3.69
3.46
19.91
25.18
26.54
44.68
20.61
45.44


A191
2.04
2.00
1.82
14.91
18.05
19.10
34.53
14.33
36.24


A192
2.43
2.62
2.23
16.46
21.45
22.35
39.47
17.58
40.44


A193
2.13
2.08
1.97
15.26
18.27
19.60
39.35
15.16
39.44


A194
2.29
2.33
2.16
15.92
19.61
21.10
38.55
15.27
40.04


A195
1.39
1.64
1.35
11.95
16.03
17.12
35.10
11.80
36.84


A196
1.99
2.09
1.89
14.68
18.44
19.71
43.95
14.67
44.04


A197
1.78
1.88
1.59
13.76
17.64
18.37
42.35
12.74
42.44


A198
1.93
1.89
1.79
14.44
17.62
18.13
31.95
14.30
32.04


A199
1.42
1.49
1.25
12.11
15.28
16.33
29.55
12.41
29.64


A200
1.40
1.39
1.23
12.01
14.60
15.62
31.95
11.84
32.04


A201
2.58
2.58
2.48
17.06
20.72
21.83
42.55
16.56
42.64


A202
2.27
2.31
2.15
15.86
19.48
20.57
37.28
16.30
38.44


A203
2.01
1.95
1.77
14.76
17.89
18.82
37.23
15.04
37.44


A204
1.81
1.66
1.49
13.91
16.54
17.20
30.75
13.52
30.84


A205
1.87
2.11
1.78
14.19
18.71
19.73
39.55
14.18
39.64


A207
2.73
2.84
2.68
17.60
21.88
23.14
46.15
16.83
46.24


A208
3.05
3.12
3.12
18.76
22.85
24.53
50.15
18.16
50.24


A209
1.85
1.91
1.70
14.09
17.71
18.33
37.35
13.70
37.44


A210
2.29
2.27
2.14
15.92
19.31
20.63
40.95
14.20
41.04


A211
2.68
2.81
2.59
17.41
21.86
23.03
47.55
17.43
47.64


A212
2.80
2.95
2.75
17.87
22.38
23.51
45.15
17.50
45.24


A213
2.67
2.73
2.82
17.38
20.91
22.53
56.75
17.64
56.84


A214
2.70
2.80
2.77
17.51
21.33
23.66
44.75
17.85
44.84


A215
2.47
2.40
2.29
16.63
19.96
21.23
42.55
16.62
42.64


A216
4.15
4.64
4.61
22.42
28.51
30.54
61.15
21.19
61.24


A217
2.33
2.66
2.52
16.10
20.76
22.01
65.15
16.09
65.24


A218
2.82
3.30
3.06
17.96
23.54
25.10
59.95
18.37
60.04


A219
2.74
2.60
2.53
17.64
21.10
22.86
38.75
17.21
38.84


A220
1.93
2.01
1.75
14.43
18.21
19.42
34.75
14.91
34.84


A222
1.89
1.87
1.73
14.27
17.25
18.42
33.95
13.97
34.04


A223
1.74
1.65
1.52
13.60
16.25
17.09
33.55
13.59
33.64


A224
1.64
1.76
1.49
13.12
16.79
18.12
32.95
12.71
33.04


A225
1.82
1.72
1.55
13.94
16.85
17.40
33.15
13.93
33.24

























CTmap =







ID
TSOT
TEOT
CT1
CT2S
EtZo
CT3
StV1
EtV1
FTR
AREA





A001
19.58
29.45
3738
3717
3708
3664
3739
3663
0.167
544.53


A002
20.76
27.73
3724
3710
3704
3686
3726
3686
0.250
532.14


A003
20.80
28.85
3740
3728
3720
3704
3741
3704
0.333
572.38


A004
16.86
24.99
3733
3705
3692
3663
3734
3664
0.317
373.35


A005
19.39
26.88
3738
3725
3715
3700
3739
3700
0.400
486.80


A007
16.27
22.49
3739
3723
3718
3697
3741
3698
0.200
334.88


A008
19.21
27.89
3741
3711
3697
3646
3742
3646
0.215
478.59


A009
21.31
29.42
3741
3725
3718
3697
3742
3697
0.250
563.98


A010
15.04
21.09
3742
3725
3717
3701
3743
3701
0.333
290.62


A011
15.42
22.44
3713
3687
3676
3647
3715
3648
0.282
338.84


A012
19.79
27.58
3743
3726
3717
3695
3744
3695
0.290
531.19


A013
21.85
31.55
3738
3711
3696
3641
3740
3641
0.214
637.63


A014
14.54
20.67
3732
3715
3708
3694
3733
3694
0.333
284.42


A015
14.96
21.47
3738
3724
3718
3704
3739
3705
0.316
302.94


A016
19.77
28.14
3741
3721
3714
3678
3742
3679
0.167
527.06


A017
14.50
21.94
3742
3717
3707
3681
3742
3681
0.278
303.87


A018
16.27
24.24
3734
3721
3712
3697
3735
3697
0.375
364.08


A019
15.18
22.92
3744
3712
3698
3653
3745
3654
0.241
322.03


A020
22.49
31.29
3741
3725
3721
3697
3742
3698
0.148
641.13


A021
18.85
27.91
3741
3725
3717
3693
3742
3694
0.258
504.33


A022
16.38
24.53
3740
3714
3702
3667
3741
3667
0.255
372.86


A023
20.12
28.12
3743
3717
3705
3663
3745
3663
0.222
532.03


A024
22.64
31.65
3740
3714
3699
3660
3741
3660
0.278
625.09


A025
14.45
20.33
3743
3729
3727
3715
3745
3715
0.143
285.23


A026
13.35
20.82
3742
3714
3705
3672
3743
3672
0.214
266.08


A027
12.95
20.02
3739
3713
3702
3667
3740
3667
0.239
248.45


A028
15.42
23.16
3742
3711
3699
3650
3743
3651
0.200
332.11


A029
16.01
24.07
3740
3709
3691
3647
3742
3647
0.290
359.12


A030
17.92
28.14
3743
3713
3700
3635
3744
3635
0.167
478.38


A031
18.81
26.73
3728
3713
3705
3684
3729
3685
0.286
458.15


A032
23.39
32.44
3732
3715
3710
3674
3733
3675
0.125
696.16


A033
19.59
28.68
3739
3715
3703
3670
3741
3670
0.267
527.43


A034
16.84
24.76
3740
3718
3707
3674
3742
3674
0.250
385.76


A035
26.79
38.34
3734
3723
3713
3699
3736
3699
0.417
942.40


A036
20.10
28.42
3735
3720
3715
3681
3736
3681
0.128
539.70


A037
18.70
26.99
3740
3712
3703
3669
3741
3669
0.209
442.10


A038
13.39
19.06
3742
3719
3710
3686
3743
3685
0.265
246.06


A039
12.93
19.74
3738
3720
3712
3697
3740
3698
0.364
242.21


A040
17.33
25.80
3741
3718
3705
3664
3742
3664
0.241
418.22


A041
16.95
27.45
3739
3709
3695
3637
3740
3638
0.197
440.02


A042
23.89
33.69
3735
3717
3714
3686
3736
3687
0.100
746.91


A044
24.15
32.21
3741
3720
3710
3683
3743
3683
0.270
740.51


A045
19.16
28.19
3739
3710
3694
3647
3740
3647
0.254
493.89


A047
19.49
28.39
3735
3712
3701
3667
3736
3667
0.244
509.60


A048
22.73
33.21
3733
3717
3708
3682
3733
3682
0.257
712.02


A049
17.74
26.65
3737
3723
3714
3689
3738
3689
0.265
466.64


A050
19.50
28.43
3739
3722
3711
3685
3741
3685
0.297
502.07


A051
14.98
22.75
3738
3701
3691
3633
3740
3634
0.149
326.92


A052
18.79
27.26
3737
3722
3712
3686
3739
3687
0.286
484.14


A053
20.20
26.92
3738
3723
3717
3696
3739
3697
0.231
509.06


A054
15.53
23.27
3733
3713
3701
3679
3734
3679
0.353
352.08


A055
28.64
45.25
3736
3712
3699
3627
3737
3627
0.153
1178.76


A056
22.72
33.23
3740
3706
3689
3624
3741
3625
0.210
677.89


A057
18.81
25.81
3723
3707
3701
3683
3724
3682
0.240
468.19


A058
37.55
56.35
3738
3722
3709
3668
3740
3667
0.236
1905.76


A059
18.75
26.75
3736
3720
3715
3696
3737
3696
0.208
470.00


A060
20.97
27.69
3730
3718
3713
3698
3731
3698
0.250
526.66


A061
17.76
26.70
3734
3719
3711
3679
3736
3680
0.205
445.89


A062
33.45
49.66
3739
3716
3704
3651
3740
3651
0.185
1393.96


A063
19.75
30.82
3737
3724
3715
3697
3739
3696
0.321
578.80


A064
16.20
24.32
3737
3716
3708
3685
3738
3685
0.258
381.34


A065
19.14
28.74
3740
3720
3708
3680
3741
3680
0.300
500.36


A066
15.57
21.62
3738
3725
3719
3707
3739
3707
0.333
317.60


A067
14.72
22.19
3739
3705
3694
3640
3740
3640
0.169
292.69


A068
17.58
26.30
3739
3724
3713
3686
3740
3686
0.289
441.31


A069
16.46
23.77
3734
3718
3714
3695
3735
3695
0.174
389.59


A070
16.99
24.33
3738
3714
3704
3670
3740
3670
0.227
396.82


A071
15.13
23.45
3737
3710
3695
3659
3739
3659
0.294
334.87


A072
14.56
23.91
3738
3708
3696
3646
3740
3646
0.194
333.31


A073
13.65
21.48
3738
3703
3686
3638
3739
3639
0.266
259.05


A074
14.44
21.51
3718
3696
3684
3664
3719
3665
0.387
282.00


A075
13.01
17.33
3741
3733
3731
3725
3742
3725
0.250
219.05


A076
12.73
21.17
3742
3716
3705
3664
3743
3665
0.216
257.85


A077
25.72
39.22
3740
3714
3701
3633
3742
3633
0.160
936.57


A078
16.20
24.39
3740
3721
3710
3683
3741
3683
0.289
371.46


A080
32.73
55.82
3741
3725
3715
3637
3742
3637
0.114
1725.95


A081
23.64
35.70
3742
3707
3694
3625
3743
3626
0.160
738.63


A082
13.69
22.23
3742
3712
3702
3653
3743
3654
0.172
281.88


A083
13.61
19.54
3742
3719
3709
3685
3744
3685
0.294
253.43


A084
31.06
51.06
3742
3729
3717
3667
3743
3667
0.194
1507.29


A085
21.27
34.24
3742
3722
3705
3675
3743
3676
0.370
671.79


A086
18.51
27.90
3742
3714
3704
3650
3743
3650
0.156
487.41


A087
15.08
22.90
3742
3713
3697
3652
3744
3652
0.262
321.97


A088
14.68
22.52
3737
3700
3685
3630
3738
3630
0.214
302.67


A089
16.25
23.16
3742
3721
3712
3687
3744
3687
0.265
359.44


A090
30.77
50.05
3741
3712
3685
3587
3743
3588
0.218
1403.90


A091
35.00
53.77
3741
3721
3712
3659
3742
3659
0.145
1720.10


A092
16.52
25.88
3740
3691
3663
3582
3741
3582
0.257
371.64


A093
25.56
38.41
3739
3725
3722
3692
3741
3693
0.094
936.05


A094
22.46
29.18
3741
3718
3709
3676
3743
3677
0.220
556.46


A095
13.25
21.13
3743
3707
3693
3638
3744
3637
0.200
263.70


A096
15.31
22.10
3739
3724
3717
3700
3740
3701
0.304
336.36


A097
10.87
17.80
3741
3719
3712
3691
3742
3691
0.250
207.73


A098
12.46
19.72
3742
3713
3701
3659
3743
3659
0.222
238.02


A099
14.19
20.96
3742
3718
3709
3685
3743
3685
0.273
286.52


A100
13.18
21.26
3741
3704
3684
3623
3743
3624
0.250
255.55


A101
18.66
28.83
3740
3724
3715
3688
3742
3689
0.257
510.58


A102
22.38
32.56
3740
3720
3712
3661
3741
3661
0.136
675.62


A103
16.27
25.59
3741
3710
3693
3640
3742
3640
0.243
373.10


A104
20.44
34.02
3730
3719
3705
3681
3731
3681
0.368
649.78


A105
21.83
35.52
3738
3720
3711
3660
3739
3660
0.150
743.43


A107
19.07
28.81
3740
3719
3707
3660
3741
3660
0.203
515.70


A108
15.43
23.93
3743
3729
3723
3709
3744
3709
0.300
357.27


A109
16.69
26.41
3740
3725
3713
3687
3741
3688
0.324
417.81


A110
23.21
40.16
3737
3714
3701
3635
3738
3634
0.163
867.86


A111
18.04
29.72
3739
3719
3701
3666
3740
3666
0.340
502.86


A112
17.66
28.46
3742
3711
3695
3614
3743
3614
0.165
451.09


A113
14.66
23.21
3737
3716
3702
3664
3739
3664
0.269
327.26


A114
15.85
24.64
3732
3706
3694
3655
3733
3655
0.235
359.25


A115
18.05
27.75
3742
3711
3697
3652
3743
3652
0.237
442.06


A116
12.81
20.53
3742
3724
3717
3697
3744
3697
0.259
277.77


A117
14.56
23.28
3739
3707
3694
3630
3740
3630
0.169
301.01


A118
16.20
23.39
3742
3728
3721
3699
3744
3699
0.241
362.31


A119
19.03
29.50
3742
3727
3716
3678
3743
3678
0.224
546.64


A120
16.18
23.20
3737
3719
3713
3688
3738
3688
0.194
352.18


A121
15.73
24.29
3740
3727
3720
3703
3741
3703
0.292
363.14


A122
14.60
22.94
3736
3709
3692
3649
3738
3650
0.288
314.28


A123
13.82
22.07
3742
3728
3721
3703
3744
3703
0.280
304.57


A124
13.44
20.50
3736
3719
3713
3696
3737
3696
0.261
281.47


A125
12.31
20.81
3719
3680
3668
3599
3720
3599
0.148
248.26


A126
22.10
33.02
3743
3735
3729
3714
3744
3714
0.286
685.17


A127
16.99
26.27
3741
3712
3702
3639
3742
3639
0.137
425.57


A128
22.55
30.96
3739
3721
3715
3681
3741
3681
0.150
668.43


A129
26.90
44.31
3743
3722
3713
3674
3744
3674
0.188
1121.93


A130
28.32
38.67
3740
3712
3701
3655
3742
3656
0.196
925.76


A131
14.39
23.27
3738
3721
3712
3689
3739
3690
0.290
313.91


A132
19.73
31.50
3742
3714
3697
3665
3743
3665
0.347
534.56


A133
18.89
31.38
3742
3722
3710
3671
3743
3670
0.231
541.93


A134
31.96
49.86
3743
3718
3710
3666
3744
3666
0.154
1420.01


A135
12.42
19.60
3741
3714
3706
3675
3742
3676
0.211
243.04


A136
24.30
36.26
3744
3723
3712
3658
3745
3658
0.169
818.39


A137
15.54
22.35
3739
3708
3693
3661
3741
3661
0.319
325.42


A138
16.81
25.84
3742
3710
3693
3641
3743
3641
0.246
380.62


A139
16.68
26.26
3742
3714
3702
3642
3743
3642
0.167
394.69


A140
12.26
19.92
3743
3707
3690
3642
3744
3642
0.262
227.88


A141
16.23
24.41
3739
3711
3701
3658
3740
3658
0.189
377.13


A142
21.32
28.16
3742
3726
3721
3706
3744
3705
0.238
555.03


A143
17.80
27.33
3739
3724
3710
3693
3740
3693
0.452
463.79


A144
17.92
25.28
3740
3706
3692
3641
3741
3641
0.215
417.88


A145
12.28
19.67
3739
3701
3688
3639
3740
3639
0.210
234.27


A146
16.36
26.54
3736
3716
3709
3664
3737
3664
0.135
408.19


A147
13.57
20.67
3742
3711
3698
3661
3743
3661
0.260
267.06


A148
17.15
25.88
3742
3712
3701
3646
3743
3646
0.167
423.66


A149
13.37
20.12
3743
3707
3695
3652
3744
3653
0.222
253.71


A150
13.21
20.99
3742
3696
3679
3607
3743
3607
0.191
266.99


A151
19.36
29.45
3737
3698
3676
3586
3738
3586
0.196
526.86


A152
16.11
23.07
3737
3714
3705
3682
3739
3682
0.281
357.82


A153
14.65
23.44
3729
3688
3670
3595
3730
3595
0.194
315.50


A154
16.56
25.57
3727
3704
3690
3644
3729
3643
0.230
406.05


A155
26.34
39.98
3739
3719
3702
3667
3741
3667
0.327
949.53


A156
19.38
26.74
3733
3716
3710
3687
3734
3687
0.207
477.31


A157
15.85
24.20
3736
3713
3708
3678
3738
3678
0.143
380.42


A158
21.57
30.57
3737
3721
3715
3687
3739
3688
0.182
627.30


A159
23.59
37.10
3733
3712
3696
3652
3735
3652
0.267
806.55


A160
19.20
28.96
3738
3713
3697
3655
3740
3655
0.276
503.61


A161
14.32
22.36
3740
3720
3706
3676
3741
3677
0.326
296.05


A162
30.84
50.55
3739
3719
3709
3651
3740
3651
0.147
1461.91


A163
22.34
33.22
3738
3723
3714
3683
3740
3684
0.231
710.91


A164
22.80
32.30
3734
3718
3713
3684
3735
3684
0.147
672.16


A165
18.51
26.43
3735
3704
3692
3636
3736
3636
0.176
454.60


A166
16.46
24.78
3733
3700
3687
3630
3735
3629
0.183
384.59


A167
19.69
26.74
3735
3717
3713
3688
3736
3688
0.138
475.97


A168
22.11
33.58
3731
3719
3713
3669
3733
3670
0.122
697.46


A169
23.09
34.54
3726
3702
3693
3623
3727
3623
0.114
771.97


A170
12.12
18.53
3740
3714
3704
3679
3741
3679
0.286
221.06


A171
22.07
32.12
3740
3718
3704
3666
3741
3666
0.269
636.30


A172
17.01
25.31
3741
3725
3720
3691
3742
3691
0.147
419.64


A173
12.29
19.64
3740
3715
3708
3678
3741
3679
0.194
246.48


A174
14.43
22.23
3733
3705
3693
3648
3734
3648
0.211
312.11


A175
14.48
20.64
3719
3686
3676
3640
3721
3640
0.217
282.97


A176
21.21
31.33
3739
3720
3712
3671
3741
3671
0.163
618.77


A177
13.47
20.41
3739
3719
3711
3688
3741
3689
0.267
277.37


A178
17.31
27.16
3740
3712
3701
3654
3741
3653
0.186
440.54


A179
18.02
25.79
3739
3716
3706
3672
3740
3673
0.233
427.08


A180
16.27
24.55
3733
3717
3709
3685
3734
3685
0.250
378.81


A181
22.16
35.16
3739
3720
3703
3676
3740
3676
0.386
703.55


A182
15.48
24.04
3739
3713
3706
3666
3741
3666
0.149
364.21


A183
12.93
18.76
3726
3709
3703
3688
3727
3688
0.286
239.94


A184
17.79
27.49
3738
3715
3705
3661
3740
3661
0.185
468.98


A185
21.46
32.13
3736
3710
3695
3639
3738
3639
0.211
627.18


A186
19.67
37.35
3738
3718
3675
3620
3740
3620
0.439
710.02


A187
14.45
20.69
3739
3712
3703
3667
3741
3667
0.200
287.80


A188
20.05
29.56
3731
3713
3704
3672
3732
3670
0.209
551.00


A189
20.06
30.46
3730
3706
3689
3657
3731
3657
0.347
564.42


A190
21.10
32.52
3730
3715
3710
3688
3731
3686
0.172
647.47


A191
15.43
22.77
3738
3723
3717
3696
3740
3694
0.207
339.50


A192
19.14
25.31
3739
3721
3714
3691
3740
3690
0.226
416.60


A193
15.91
24.18
3741
3725
3716
3685
3743
3685
0.225
368.99


A194
16.44
25.38
3735
3718
3710
3687
3736
3687
0.258
404.05


A195
13.38
21.17
3739
3688
3667
3589
3740
3590
0.214
252.98


A196
15.65
24.03
3738
3716
3706
3672
3739
3673
0.233
352.76


A197
15.45
21.66
3739
3703
3691
3637
3741
3638
0.185
298.04


A198
14.30
23.23
3727
3714
3712
3692
3729
3692
0.091
335.44


A199
12.48
19.25
3741
3717
3708
3683
3742
3683
0.265
233.12


A200
11.54
19.12
3737
3716
3709
3685
3738
3686
0.233
229.63


A201
17.87
27.22
3740
3722
3715
3681
3742
3681
0.171
464.37


A202
15.77
25.37
3737
3720
3715
3693
3738
3692
0.179
402.37


A203
15.20
22.44
3739
3713
3704
3669
3740
3669
0.205
331.21


A204
14.56
19.97
3738
3723
3718
3697
3740
3697
0.192
277.78


A205
15.88
23.47
3740
3715
3706
3673
3741
3673
0.214
333.04


A207
18.89
28.50
3728
3709
3701
3667
3730
3667
0.190
501.60


A208
20.05
31.06
3736
3721
3712
3677
3738
3678
0.209
582.69


A209
15.23
22.55
3741
3721
3716
3682
3743
3682
0.128
317.73


A210
16.17
25.09
3741
3722
3714
3687
3742
3687
0.229
399.43


A211
19.10
27.79
3741
3708
3694
3637
3742
3637
0.197
483.82


A212
18.99
28.78
3740
3722
3716
3688
3741
3688
0.176
514.30


A213
18.35
30.36
3741
3722
3710
3652
3742
3653
0.174
527.66


A214
18.58
29.59
3739
3726
3715
3687
3740
3687
0.282
518.12


A215
16.91
25.80
3737
3713
3703
3667
3738
3667
0.217
429.05


A216
24.63
38.48
3740
3719
3708
3665
3742
3665
0.204
862.72


A217
17.63
29.30
3740
3710
3698
3628
3741
3628
0.146
471.73


A218
20.27
31.86
3738
3694
3673
3582
3739
3583
0.189
572.21


A219
18.17
26.77
3741
3726
3717
3697
3742
3697
0.310
472.22


A220
15.35
22.72
3741
3715
3704
3674
3742
3674
0.268
327.85


A222
14.71
22.71
3725
3712
3706
3684
3727
3684
0.214
324.07


A223
13.06
20.95
3741
3722
3717
3694
3742
3695
0.185
284.92


A224
13.80
21.22
3742
3715
3703
3675
3743
3675
0.300
278.41


A225
14.43
20.81
3740
3718
3713
3682
3741
3682
0.139
290.09









By determining the prothrombin time (T1) and the theoretical end of the test (TEOT), the INRs may be determined. The instrument pixel parity and sampling rate multiplier preferably is applied to the product of T1 and TEOT to provide the resultant INRs.
INRs A001 ID Example
An example of the determination of the INRs is provided using expression (14) and the reported data in Table 17. The TPC derived values of Table 17 for the sample ID A001, included the value PT or T1, where T1 or PT=18.49. The value of TEOT was determined and reported in Table 17, and for A001, is TEOT=29.45. Taking the product of T1 and TEOT, the value is 544.53, which is reported in Table 17 as the Area, which is a theoretical area determined according to the expression (13) above. Referring to FIG. 7, the theoretical area A is shown corresponding to a first area portion A1, representing the square of the value T1, (i.e., T12), and a second area portion A2 representing the rectangular area of the product of T1 and (TEOT−T1). Since the expression A1 plus A2, which is represented by T12+T1*(TEOT−T1) is simplified to T1*TEOT, the Area (A) represented by the combined areas A1 and A2, may be determined by the expression A=T1*TEOT. From the determination of the Area, the INRs may be obtained. According to one embodiment, the INRs is determined using the formula of expression (14) above. The time values and instrument unit values were taken into account for the pixel parity and sampling rate. A multiplier (MUL) ( 1/187 or 0.00535) that takes into account the pixel parity was applied to the area by multiplying the multiplier (MUL) and the area to obtain the INRs. As shown in relation to the clotting curve in FIG. 8, the area included in the preferred INR determination, where INRs is derived, includes area portions above and below the clotting curve.
Comparative Results
Comparative INR values also were determined using the values obtained in Table 17. Table 17, in addition to reporting the INRs values (using expression (14)), also includes the reporting of INRm and INRz values, for comparative purposes. The comparative results between the INR values derived from the data reported in Table 17 are presented in Table 18.







TABLE 18







COMPARATIVE RESULTS FOR INRs VERSUS INRm and INRz












Ng
Lassen
1 = Pass 2 = Fail
Poller

















TPC

MisMatch
<=0.4
<=0.7
MisMatch
<=0.4
<=0.7
±10%
Total
Pcnt





INRs
INRm
10.60%
87.20%
94.00%
1
1
1
9
218
4.10%


INRs
INRz
10.60%
87.20%
94.00%
1
1
1
9
218
4.10%









The above data represented in Table 18 shows comparisons for INR/ATF determinations made to compare INRs (obtained using the formula in expression (14) above) with: (1) INR values obtained using the World Health Organization method which is represented by INRm, uses the ISI of the manufacturer and is determined by INRm=(PT/Mnpt)^ISI and (2) INRz which is determined by: INRz=(Map/Mnxt)^2-FTR). In each comparison case in Table 18, the reagent used to obtain the data was Thromboplastin C.
As a result of the comparisons set forth in Table 18, the hereinbefore description of the new anticoagulant therapy factor (ATFs/INRs) does correlate at least as well as, and preferably better than, studies carried out using the International Normalized Ratio (INR) and International Sensitivity Index (ISI) for the INR values obtained using the World Health Organization (WHO) values, represented in Table 18 as INRm, and studies carried out using INR/ATF determinations using methods where the mean normal prothrombin time of a number of individuals having presumed normal coagulation functions must be determined, as with INRz. The inventive method represented by the formula in expression (14) and expressed herein as INRs and/or ATFs is an improvement over the prior methods.
Power Regression Determination and Comparisons
According to an alternate embodiment, the Area is determined as discussed herein using expression (13), and a multiplier is applied with the use of a power regression. The results in Table 17 include values for an Area for each respective sample. The PT or T1 is the prothrombin time, which is the point where the conversion of fibrinogen to fibrin begins to decay after achieving the maximum rate. This, as discussed herein, is referred to as the maximum acceleration point (MAP). As described herein, the MAP is used to determine the mean normal maximum time (MNXT) (or MNPT as it is sometimes also referred to). The MNXT is used to derive the INRm, which is the WHO INR determination, where the mean of a number of presumed normal coagulation patients is used. According to the following expression, the INRm, the WHO INR, is:

INRm=(XT/MNXT)ISI 

According to preferred embodiments, the present invention provides an area determination which represents a hypothetical or theoretical clotting area. The clotting area has two sides, as shown in FIG. 7. Using each sample's maximum fibrinogen conversion rate, the time to convert all of the fibrinogen to fibrin in a sample using this rate is determined. This time to convert the fibrinogen to fibrin in the sample defines a hypothetical or theoretical end of test (TEOT) (or HEOT as it also may be referred to). The TEOT is designated as the height of the area. The other side of the area is the time required to convert sufficient prothrombin to thrombin, thus beginning the conversion of fibrinogen to fibrin. The time required for the conversion of prothrombin to thrombin is represented by the value T1 (or PT) and is designated as the length of the area. In this area determination, the two sides are not parallel. The value TEOT and the value T1 are defining two sides of an event creating the hypothetical clotting area. The one side represents the length (T1) and the other side represents the height (TEOT). This relationship is illustrated in FIG. 7. This is expressed by the equation of expression (13): Area=T1*TEOT.
According to further embodiments of the invention, an expression is derived to enable the use of a power progression expression to determine the INRs for a sample. The INRs may be related to the INRm (WHO determined INR value) by utilization of a power regression that relates the clotting area (A) with the INRs of the sample. The relationship of the INRm values determined for fibrinogen standards may be used to provide an expression or formula from which determinations of an INRs for patient samples may be done by determining the clotting area for the patient sample. Preferably, the patient sample clotting area determination is made using the same thromboplastin, and more preferably, the same batch of thromboplastin, and the same instrument, so that the patient samples may be reacted in a coagulation reaction with a coagulation reagent, and the clotting area (A) determined, and an INRs for the patient sample determined using the power regression obtained with the fibrinogen standard samples (for the thromboplastin reagent and the instrument).
According to a preferred method, a number of fibrinogen standards are run and the respective area for each fibrinogen standard is determined. From these determinations, an expression was derived for determining the INRs value using the thromboplastin for which the fibrinogen standard determinations were made. One preferred method involves utilizing five fibrinogen standards, a high fibrinogen standard, a low fibrinogen standard and three fibrinogen/INR control levels 1, 2 and 3. For each of the five samples, an Area value and an INR value are calculated and plotted. According to exemplary embodiments, three thromboplastins (e.g., TPC, BPT and Innovin) were used to provide three power regressions.
Each level has an INR value, and replacing the prothrombin time ratio (PR) with the values for an INR based on the following relationship in expression (15):

INR=(MAP/MNXT)ISI  (15)

where MAP is the point in time that is where maximum rate of conversion of fibrinogen to fibrin occurs, where MNXT is the mean normal maximum time, and where ISI is an exponent that is the ISI (international sensitivity index) of the manufacturer for the clotting reagent used (e.g., thromboplastin).

A solution curve for each thromboplastin using the five levels of standards and controls was created. The Area is plotted on the “x” axis and the INR is plotted on the “y” axis. To solve for “y”, and because the INR value uses an exponent, the solution should solve for an exponent. The power regression is implemented to provide a result that relates the INRs to an INRm for a particular thromboplastin, such as, for example, TPC thromboplastin (and for a particular batch of thromboplastin. The use of “y”=INR and “x”=Area provides relationships for determining INRs based on the INR(standard) for coagulation determinations carried out with a clotting reagent (e.g., thromboplastin), where according to a preferred embodiment, the INR(standard) (which is an INR obtained for the fibrinogen standard samples) is determined in accordance with expression (15). For example, according to one example, five levels were obtained, and, for TPC, the INR was y=0.0174×0.8117, for INN the INR was y=0.1333×0.4329, and for BTP was y=0.005×1.0179. Using these expressions, the INRm or “y” as it is designated in the previous expressions, may be determined based on the area determined for the sample according to expression (14), where Area=T1*TEOT*MUL. The INRs may therefore be substituted in the expression as “x”, and a corresponding INRm may be determined by solving for “y”. The use of this method provides a way to determine the correlation of the INRs with the WHO determined INRm.
A linear regression and Pearson's R results were determined, and for TPC was y=0.9688 and R2=0.9834, for INN was y=0.9332 and R2=0.984, and for BPT was y=0.911 and R2=0.99.
As discussed herein, the INR is calculated by a standard method, where the INR is the international normalized ratio and the ISI is the international sensitivity index. The prothrombin ratio (PR) is a sample's prothrombin time divided by a mean normal prothrombin time (MNPT) created by using 20-plus presumed normal samples. INR=Prothrombin Ratio^ISI. The method for determining an INRs value for a patient blood sample was carried out as follows. A standard curve was created with fibrinogen standards, and, preferably, as in this example, using FDA-cleared high and low fibrinogen standards and three fibrinogen/INR controls of levels 1, 2 and 3. For each of these 5 samples, a hypothetical or theoretical clotting AREA value (A) and an INR value were calculated and plotted for each of the tested thromboplastins. The clotting area (A) was determined by obtaining values for the time and optical activity as discussed herein. A spectrophotometric device was used, and the output of the spectrophotometric device was provided to a computer. The computer was programmed with software, and the software included instructions to record, store and manipulate the time and absorbance data to provide the INR, area and INRs values.
First, the fibrinogen sample was reacted by introducing by injection a clotting reagent into the sample, while the sample was in position on the spectrophotometer device so that time and optical dentisy values could be obtained for the sample and recorded, as the fibrinogen transformation to fibrin was occurring. A determination was made to record the occurrence of the prothrombin time (T1). The time and absorbance values continued to be recorded. A maximum acceleration point (MAP) was determined for the rate of fibrinogen conversion. This is the point where the conversion of fibrinogen to fibrin begins to decay after achieving a maximum rate. This is called the maximum acceleration point (MAP) and is used to determine a mean normal maximum time (MNXT). Next was to define the hypothetical or theoretical clotting area (A). By using each fibrinogen standard sample's maximum fibrinogen conversion rate, we determined the conversion time by calculating the time to convert all of the fibrinogen to fibrin in a sample using this rate. This time defines a hypothetical or theoretical end of test (TEOT) and is designated as the height of the clotting area (A). The other side is the time required to convert sufficient prothrombin to thrombin (which is represented as the time value T1 in FIGS. 6, 7 and 8), thus beginning the conversion of fibrinogen to fibrin. This time is represented and referred to as the prothrombin time (T1) and is designated the length of the area (A). According to a preferred embodiment, these two sides are not parallel lines, but rather, are defining two sides of an event creating a hypothetical or theoretical clotting area (A). The clotting area is expressed by the equation: AREA=T1*HEOT. Each of the abovementioned fibrinogen standard levels has an INR value, and replacing the standard prothrombin time ratio (PR) element in the original INR expression with values relating to the time to convert the fibrinogen in the sample to fibrin using the rate of maximum acceleration and the mean normal maximum time, the equation ISI becomes expression (15): INR=(MAP/MNXT)^ISI 
The method illustrated according to this example utilizes the Area of the fibrinogen standard samples and the INR(standard) values determined for the fibrinogen standard samples to derive an equation, which comprises a power regression. The INR area method was compared and related to the reference INR(standard) values obtained using the method of expression (15). A solution curve for each thromboplastin (which in this example included TPC, BPT and Innovin) using the 5 levels of fibrinogen standards and controls was created. The AREA is plotted on the ‘x’ axis and the INR area method is plotted on the ‘y’ axis. To solve for ‘y’, and because the INR value uses an exponent, the solution is to solve for an exponent. A solution that related the INRs derivation to the standards and controls was developed in the form of a power regression. The solution curve, where INR on the ‘y’ axis and AREA on the ‘x’ axis, was as follows: for TPC: y=0.0174×0.8117, for INN: y=0.1333×0.4329 and for BTP: y=0.005×1.0179. Examples of plots illustrating the solution curves for these clotting reagents are shown in FIGS. 9-11.
Applying these solutions to the three thromboplastins tested using the same 218 samples (which were used to provide the data in Table 17, above) gave a linear regression and Pearson's R results of: TPC: y=0.9688 and R2=0.9834, INN: y=0.9332 and R2=0.984 and BTP: y=0.911 with R2=0.99.
According to preferred embodiments, the INRs determination made using the power regression embodiments may be implemented utilizing the computer in the manner described herein in connection with determinations made of the zero order kinetic reactions and determinations of the time and optical activity values. According to one embodiment, the method includes determining an INR value for known fibrinogen standard samples by conducting a clotting reaction for the reaction of each known fibrinogen standard sample and a clotting reagent, and, for each known fibrinogen sample, determining the time to maximum acceleration (XT) for each standard fibrinogen sample, determining the maximum rate of acceleration (MNXT) by determining a slope corresponding with the maximum acceleration rate of transformation of fibrinogen to fibrin during the clotting reaction of the standard fibrinogen sample, and determining the INR value for the fibrinogen standard sample by the expression INR(standard)=(XT/MNXT)ISI, wherein ISI is an exponent and is the manufacturer's ISI value for the clotting reagent used to carry out the clotting reaction. The method preferably includes deriving the INRs for a patient sample by determining an expression based on the INR values obtained for each fibrinogen standard sample, including determining, from said clotting area (A) for each standard fibrinogen sample and the INR value for each standard fibrinogen sample, a power regression expression, wherein y=m*A^e, where y is the INRs, m is a constant, A is the clotting area, and e is another constant which is an exponent, and wherein obtaining the INRs for a patient sample comprises determining the clotting area A for the patient sample, raising the area A to the exponent e, and multiplying the value (the e power of A) by the constant m to obtain the INRs. The power regression constants m and e are obtained using the INR(standard) value and the clotting area A determined for each fibrinogen standard sample according to the expression INR(standard)=m*A^e. In this manner, the INRs of a patient sample may be derived using the power regression expression, and substituting for the A value the clotting area of the patient sample (from conducting a clotting reaction with the thromboplastin) and solving the expression for the INRs.
The present methods, including, in particular, the INRs determination, provide resultant INR values (INRs value) for a patient blood sample (or blood component sample) which may be used to determine treatments for a patient, such as, for example, blood therapy treatments. The methods herein may include administering to a living being, such as, for example, a patient, a course of treatment. The course of treatment, for example, may involve a treatment agent for regulating the clotting activity of blood and administering that blood treatment agent to the patient. The INR value, (INRs), corresponds with the clotting activity of the blood of the living being and therefore provides a reference for the amount of treatment agent to be administered. The INRs may be determined for the patient at intervals, and administering the treatement may be done at intervals. For example, the treatment agent may comprise an anticoagulant, such as, coumadin or warfarin.
The present invention provides apparatus and methods for obtaining an new anticoagulant therapy value, INRs, without encountering the complications involved with obtaining the prior art quantities International Normalized Ratio (INR) and International Sensitivity Index (ISI). Preferred embodiments utilize a determination based on the time of commencement of the fibrinogen transformation, which is the prothrombin time (T1 or PT) and a time of the hypothetical or theoretical end of test (TEOT). These values are used to derive a hypothetical clotting area. The hypothetical clotting area determinations, when compared with WHO determined INR values are consistent.
The new International Normalized Ratio (INRs) preferably is a replacement for the International Normalized Ratio (INR) such as that of the WHO, or the manufacturers of the clotting reagent that may provide an ISI for use with their particular clotting reagent. Embodiments of the invention may determine an INRs value, which preferably is derived by determining a clotting area. According to one embodiment, the clotting area is adjusted with a multiplier to provide an INRs value. Another embodiment utilizes fibrinogen standard solutions, and provides a power regression obtained from the standards that relates the clotting area of the standard samples, so that an expression may be used to determine patient INRs values based on the clotting area determined for those patient samples.
Existing medical literature, instrumentation and methodologies are closely linked to the International Normalized Ratio (INR). The new INRs was compared for correlation with the INR by comparative testing, to INR quantities of INRm and INRz, even with the understanding that the INR determination may have an error of about +/−15%, at a 95% confidence interval, which needs to be taken into account to explain certain inconsistencies. The hereinbefore description of the new INRs does correlate at least as well as, and preferably better than, studies carried out using the traditional methods and determinations involving International Normalized Ratio (INR).
While the invention has been described with reference to specific embodiments, the description is illustrative and is not to be construed as limiting the scope of the invention. The sample container used to contain the sample may comprise a vial, or cuvette, including, for example, the sample container disclosed in our U.S. Pat. No. 6,706,536. For example, although described in connection with body fluids of a human, the present invention has applicability to veterinary procedures, as well, where fluids are to be measured or analyzed. Various modifications and changes may occur to those skilled in the art without departing from the spirit and scope of the invention described herein and as defined by the appended claims

## Claims

1. A method for determining a coagulation parameter for a blood or blood component of a living being, comprising:
reacting a sample of blood or a blood component containing fibrinogen with a clotting agent that transforms fibrinogen to fibrin by combining said blood sample with said clotting agent;
recording, with recording means for making optical measurements, time and optical density values for the sample that correspond with the optical activity of fibrinogen activity during the reaction with the clotting agent, wherein optical density values plotted at their respective corresponding times over the course of the reaction represent a clotting curve;
determining the time at which the sample and the clotting agent combined therewith begin to form a change in clotting activity, wherein (T1) represents the time at which the sample and the clotting agent combined therewith begin to form a change in clotting activity, and wherein (c1) represents an optical density value of the sample at the time (T1) where the sample and the clotting agent combined therewith begin to form a change in clotting activity;
determining a slope corresponding with a maximum acceleration rate of transformation of fibrinogen to fibrin during the clotting reaction;
determining an end of test time (TEOT) corresponding with an optical density value (cEOT) that is indicative of a substantial completion of the reaction of the fibrinogen of the sample and the clotting agent to transform the fibrinogen in the sample to fibrin, wherein said time (TEOT) corresponds with the time at which a line of said slope that represents the rate of maximum acceleration of the clotting activity based on the optical activity of the clotting reaction intersects said optical density value at c=(cEOT);
determining a value for an anticoagulant therapy factor (INRs) for the sample, wherein INRs corresponds with a clotting area (A) represented by the time (T1) at which the sample and the clotting agent combined therewith begin to form a change in clotting activity and the time corresponding with the end of test time (TEOT);
wherein the clotting area (A) is defined by two sides wherein one side defining said clotting area (A) is represented by the value (T1) and wherein the other side defining said clotting area is represented by the value (TEOT),
and wherein the determination of the INRs value is based on the correspondence of a clotting area defined by taking the product of (T1) and (TEOT), and multiplying the said product by a multiplier (MUL), wherein said multiplier (MUL) represents a value based on a sampling rate and a pixel parity value, and wherein said multiplier (MUL) is expressed by the pixel parity value divided by the sampling rate, and wherein said INRs value is expressed by the following relationship: INRs=(T1*TEOT)*MUL, where (MUL) is a multiplier that relates the sampling rate at which time and optical activity measurements are recorded with the pixel parity of the x-y-axis of the clotting curve.

2. The method of claim 1, wherein said clotting area (A) comprises at least a portion that is beneath said clotting curve for said reaction, and at least a portion that is above said clotting curve for said reaction.

3. The method of claim 1, wherein said slope that represents the maximum acceleration of the clotting activity based on the optical activity of the clotting reaction and that intersects said optical density value (cEOT) is defined by a slope of the line between points along the clotting curve, (T2S) and (Tmap), where T2S is the time the maximum acceleration of the conversion rate of fibrinogen transformation begins and Tmap is a time to maximum acceleration of the clotting reaction.

4. The method of claim 1, wherein recording, with recording means for making optical measurements, time and optical density values for the sample during the reaction with the clotting agent includes developing a series of analog electrical voltage signals having voltage amplitudes proportional to an optical density of a clotting component of said sample.

5. The method of claim 4, wherein the clotting component comprises fibrinogen.

6. The method of claim 4, wherein the recording means comprises an instrument, and wherein the multiplier (MUL) relates the sampling rate of the instrument and a pixel parity of the x-y axis of the clotting curve, wherein they axis represents optical density and wherein the x axis represents time.

7. The method of claim 6, wherein the multiplier (MUL) is 1/187 or about 0.00535.

8. The method of claim 1, wherein determining the INRs includes determining a pixel parity value for said recording means for making optical measurements and converting said optical density values and said time values to a scale based on the pixel parity for the said recording means.

9. The method of claim 8, wherein converting said optical density values and said time values to a scale based on the pixel parity for the said recording means comprises converting one or more of the group of said optical density values and the group of time values to a scale based on the pixel parity for the said recording means.

10. The method of claim 1, including recording an optical activity value (CTMAP) at a time of maximum acceleration (Tmap) of the clotting reaction and at a time T2S, wherein (T2S) represents the time at which the maximum acceleration of the conversion rate of fibrinogen transformation begins, and wherein said slope that represents the maximum acceleration of the clotting activity based on the optical activity of the clotting reaction and that intersects said optical density value at c=cEOT is defined by a slope of the line between points along the clotting curve, (T2S) and (Tmap).

11. The method of claim 1, wherein a sampling rate at which time and optical density values are recorded is about 100 values per second.

12. The method of claim 1, further comprising determining a time to maximum acceleration (Tmap) of the clotting reaction for the transformation from fibrinogen to fibrin in the sample, and wherein said determining of Tmap comprises determining a last highest delta value of conversion rate from the time the maximum acceleration of the conversion rate of fibrinogen transformation begins at a time value (T2S).

13. The method of claim 12, wherein the last highest delta value of the conversion rate is obtained by measuring the delta value of two points at a fixed interval and recording said measurements, wherein each conversion rate comprises one value corresponding to time and a second value corresponding to optical density.

14. The method of claim 1, wherein a rate of optical activity increases for at least about 1.5 seconds following the commencement of the reaction between the fibrinogen in the sample and the clotting agent.

15. The method of claim 1, wherein said clotting area (A) is defined by a first area portion (A1) represented by a square of (T1) and a second area portion (A2) represented by a rectangular area portion defined by the product of (T1) and (TEOT), said clotting area comprising the first portion in a location represented under the clotting curve and between the optical density c=cEOT, and the second portion above the clotting curve.

16. The method of claim 1, wherein the value (T1) represents the time differential between (i) the time at which the sample and the clotting agent are combined (To) and (ii) the time the clotting agent and sample begin to form a change in clotting activity (T1); and
wherein the time value (TEOT) represents the time differential between (i) a time (To) at which the sample and clotting agent are combined and (ii) a time value corresponding with the intersection of (a) a line having the aforesaid slope that represents the rate of maximum acceleration of the clotting activity and (b) an optical activity value representing the end of the reaction, wherein the optical activity value representing the end of the reaction is defined by the line y=CEOT.

17. An apparatus for determining an anticoagulant therapy factor (INRs) according to the method of claim 1, said apparatus having a processor and a computer chip preprogrammed with a set of instructions for cooperating with an output of a photodetection device which provides electrical data to said processor as a function of the optical density for a sample being analyzed, said apparatus having input means and storage means for storing data, said set of instructions including instructions for implementing steps to obtain time and optical activity data from the clotting activity of the sample based on the optical activity of the sample during a reaction period, the instructions including implementing the steps of claim 1 to record values for optical measurements, time and optical activity during the clotting reaction and to determine one or more anticoagulant therapy factors (INRs) for the sample.

18. The method of claim 1, wherein the method includes adjusting the clotting area (A) according to a power regression that relates the clotting area (A) to a known standard to determine an INRs for the sample.

19. The method of claim 18, including determining the clotting area (A) for a plurality of fibrinogen standard samples whose fibrinogen concentrations are known.

20. The method of claim 19, wherein said fibrinogen standard samples include at least one high fibrinogen standard and at least one low fibrinogen standard.

21. The method of claim 20, wherein said fibrinogen standards include at least a plurality of fibrinogen standards between said high fibrinogen standard and said low fibrinogen standard.

22. The method of claim 19, wherein the method includes determining an INR value for said known fibrinogen standard samples by conducting a clotting reaction using each fibrinogen standard sample and a clotting reagent, and, for each fibrinogen sample, determining a time to maximum acceleration (XT) for each standard fibrinogen sample, determining a maximum rate of acceleration (MNXT) by determining a slope corresponding with a maximum acceleration rate of transformation of fibrinogen to fibrin during the clotting reaction of the standard fibrinogen sample, and determining the INR value for the fibrinogen standard sample by the expression INR(standard)=(XT/MNXT)ISI, wherein ISI is an exponent and is a manufacturer's ISI value for the clotting reagent used to carry out the clotting reaction.

23. The method of claim 22, including deriving the INRs for a patient sample by determining an expression based on the INR values obtained for each fibrinogen standard sample, including determining, from said clotting area (A) for each standard fibrinogen sample and the INR value for each standard fibrinogen sample, a power regression expression wherein y=m*A^e, where y is the INRs, m is a constant, A is the clotting area, and e is another constant which is an exponent, and wherein obtaining the INRs for a patient sample comprises determining the clotting area A for the patient sample, raising the area A to the exponent e, and multiplying the value by the constant m to obtain the INRs.

24. The method of claim 23, wherein the power regression constants m and e are obtained using the INR(standard) value and the clotting area A determined for each fibrinogen standard sample according to the expression INR(standard)=m*A^e.

25. A method for determining a coagulation parameter for a blood or blood component of a living being, comprising:
reacting a sample of blood or a blood component containing fibrinogen with a clotting agent that transforms fibrinogen to fibrin by combining said blood sample with said clotting agent;
recording, with recording means for making optical measurements, time and optical density values for the sample that correspond with the optical activity of fibrinogen activity during the reaction with the clotting agent, wherein optical density values plotted at their respective corresponding times over the course of the reaction represent a clotting curve;
determining the time at which the sample and the clotting agent combined therewith begin to form a change in clotting activity, wherein (T1) represents the time at which the sample and the clotting agent combined therewith begin to form a change in clotting activity, and wherein (c1) represents an optical density value of the sample at the time (T1) where the sample and the clotting agent combined therewith begin to form a change in clotting activity;
determining a slope corresponding with a maximum acceleration rate of transformation of fibrinogen to fibrin during the clotting reaction;
determining an end of test time (TEOT) corresponding with an optical density value (cEOT) that is indicative of a substantial completion of the reaction of the fibrinogen of the sample and the clotting agent to transform the fibrinogen in the sample to fibrin, wherein said time (TEOT) corresponds with the time at which a line of said slope that represents the rate of maximum acceleration of the clotting activity based on the optical activity of the clotting reaction intersects said optical density value at c=(cEOT);
determining a value for an anticoagulant therapy factor (INRs) for the sample, wherein INRs corresponds with a clotting area (A) represented by the time (T1) at which the sample and the clotting agent combined therewith begin to form a change in clotting activity and the time corresponding with the end of test time (TEOT);
wherein the clotting area (A) is defined by two sides wherein one side defining said clotting area (A) is represented by the value (T1) and wherein the other side defining said clotting area is represented by the value (TEOT),
wherein said clotting area is a scaled area, and wherein said scaled area defining said INRs is derived by determining a pixel parity value for said recording means for making optical measurements and converting said optical density values and said time values to a scale based on the pixel parity for the said recording means.

26. The method of claim 25, wherein said pixel parity value is a multiplier (MUL), and wherein said multiplier (MUL) is a multiplier that relates the sampling rate at which time and optical activity measurements are recorded with the pixel parity of the x-y axis of the clotting curve.

27. The method of claim 26, wherein said multiplier (MUL) represents a value based on the sampling rate and the pixel parity values, and is expressed by the pixel parity value divided by the sampling rate.

28. The method of claim 27, wherein the multiplier (MUL) is 1/187 or about 0.00535 and is defined by a pixel parity value of 0.535 and a sampling rate of 100 samples per second, using the expression pixel parity/sampling rate.

29. The method of claim 25, wherein said determination of an INRs value is expressed by the following relationship: INRs=(T1*TEOT)*MUL, wherein (MUL) represents a scaling value.

30. The method of claim 29, wherein the scaling value (MUL) is based on a value that corresponds with a parity of fibrinogen transformation per unit of time.

31. The method of claim 25, wherein said determination of an INRs value is expressed by the following relationship: INRs=T1*TEOT*MUL, and wherein the INRs is determined by scaling the clotting area (A), wherein scaling includes adjusting the product of (T1) and (TEOT) by a multiplier, (MUL), wherein the multiplier (MUL) is a value that relates a sampling rate at which time and optical activity measurements are recorded with a pixel parity of the x-y axis of the clotting curve.

32. The method of claim 25, wherein the method includes adjusting the clotting area (A) according to a power regression that relates the clotting area (A) to a known standard to determine an INRs for the sample.

33. The method of claim 32, including determining the clotting area (A) for a plurality of fibrinogen standard samples whose fibrinogen concentrations are known.

34. The method of claim 33, wherein said fibrinogen standard samples include at least one high fibrinogen standard and at least one low fibrinogen standard.

35. The method of claim 34, wherein said fibrinogen standards include at least a plurality of fibrinogen standards between said high fibrinogen standard and said low fibrinogen standard.

36. The method of claim 33, wherein the method includes determining an INR value for said known fibrinogen standard samples by conducting a clotting reaction using each fibrinogen standard sample and a clotting reagent, and, for each fibrinogen sample, determining a time to maximum acceleration (XT) for each standard fibrinogen sample, determining a maximum rate of acceleration (MNXT) by determining a slope corresponding with a maximum acceleration rate of transformation of fibrinogen to fibrin during the clotting reaction of the standard fibrinogen sample, and determining the INR value for the fibrinogen standard sample by the expression INR(standard)=(XT/MNXT)ISI, wherein ISI is an exponent and is a manufacturer's ISI value for the clotting reagent used to carry out the clotting reaction.

37. The method of claim 36, including deriving the INRs for a patient sample by determining an expression based on the INR values obtained for each fibrinogen standard sample, including determining, from said clotting area (A) for each standard fibrinogen sample and the INR value for each standard fibrinogen sample, a power regression expression wherein y=m*A^e, where y is the INRs, m is a constant, A is the clotting area, and e is another constant which is an exponent, and wherein obtaining the INRs for a patient sample comprises determining the clotting are A for the patient sample, raising the area A to the exponent e, and multiplying the value by the constant m to obtain the INRs.

38. The method of claim 37, wherein the power regression constants m and e are obtained using the INR(standard) value and the clotting area A determined for each fibrinogen standard sample according to the expression INR(standard)=m*A^e.

39. A method of treating a living being who has a blood disorder by determining a coagulation parameter for a blood or blood component of a living being and administering a treatment based on the coagulation parameter, wherein the method includes:
monitoring anticoagulant therapy for said living being, comprising determining an anticoagulant therapy factor (INRs) for the patient by:
reacting a sample of blood or a blood component containing fibrinogen with a clotting agent that transforms fibrinogen to fibrin by combining said blood sample with said clotting agent;
recording, with recording means for making optical measurements, time and optical density values for the sample that correspond with the optical activity of fibrinogen activity during the reaction with the clotting agent, wherein optical density values plotted at their respective corresponding times over the course of the reaction represent a clotting curve;
determining the time at which the sample and the clotting agent combined therewith begin to form a change in clotting activity, wherein (T1) represents the time at which the sample and the clotting agent combined therewith begin to form a change in clotting activity, and wherein (c1) represents an optical density value of the sample at the time (T1) where the sample and the clotting agent combined therewith begin to form a change in clotting activity;
determining a slope corresponding with a maximum acceleration rate of transformation of fibrinogen to fibrin during the clotting reaction;
determining an end of test time (TEOT) corresponding with an optical density value (cEOT) that is indicative of a substantial completion of the reaction of the fibrinogen of the sample and the clotting agent to transform the fibrinogen in the sample to fibrin, wherein said time (TEOT) corresponds with the time at which a line of said slope that represents the rate of maximum acceleration of the clotting activity based on the optical activity of the clotting reaction intersects said optical density value at c=(cEOT);
determining a value for an anticoagulant therapy factor (INRs) for the sample, wherein INRs corresponds with a clotting area (A) represented by the time (T1) at which the sample and the clotting agent combined therewith begin to form a change in clotting activity and the time corresponding with the end of test time (TEOT);
wherein the clotting area (A) is defined by two sides wherein one side defining said clotting area (A) is represented by the value (T1) and wherein the other side defining said clotting area is represented by the value (TEOT); and wherein the determination of the INRs value is based on the correspondence of a clotting area defined by taking the product of (T1) and (TEOT), and multiplying the said product by a multiplier (MUL), wherein said multiplier (MUL) represents a value based on a sampling rate and a pixel parity value, and wherein said multiplier (MUL) is expressed by the pixel parity value divided by the sampling rate, and wherein said INRs value is expressed by the following relationship: INRs=(T1*TEOT)*MUL, where (MUL) is a multiplier that relates the sampling rate at which time and optical activity measurements are recorded with the pixel parity of the x-y-axis of the clotting curve; and
administering to the living being a course of treatment, wherein said course of treatment involves at least one treatment agent for regulating the clotting activity of blood that is administered to said living being, wherein said INR value, (INRs), corresponds with the clotting activity of said blood of said living being and comprises a reference for the amount of treatment agent to be administered to said living being.

40. The method of claim 39, wherein said steps of monitoring and administering are done at intervals over the course of treatment.

41. The method of claim 39, wherein the treatment agent comprises an anticoagulant.

42. The method of claim 39, wherein the treatment agent comprises coumadin.

43. The method of claim 39, wherein the treatment agent comprises warfarin.

44. An apparatus for determining a new anticoagulant therapy factor (INRs) comprising:
a. means including a light source, a test tube, a photocell, a battery, and a variable resistor all for developing an analog electric voltage signal having an amplitude proportional to an optical density of a liquid sample containing fibrinogen;
b. means including an A/D converter and a computer both cooperating for converting and recording the developed analog signal into a series of digital voltage signal values;
c. means for injecting a coagulant into a body fluid sample, thereby producing an abrupt change in the optical density of the body fluid sample, said abrupt change producing a change in the amplitude of the electrical analog signals, which, in turn, produces an abrupt change in the value of said digital voltage signals, the value of said digital voltage signals being directly indicative of fibrinogen concentration in the body fluid sample;
d. means, including a computer, with computer readable media that is programmed with instructions for implementing monitoring of said voltage digital signal values corresponding with the optical density of the body fluid sample and representing the coagulant activity and for processing the digital signal values;
e. means, including said computer, for recording an instant time (T1) at a start of a zero order kinetic rate of conversion of fibrinogen to fibrin for a reaction of a reagent which reacts with fibrinogen present in the body fluid sample to convert the fibrinogen to fibrin, and a value corresponding to the start time (T1);
f. means, including said computer, for recording a time to maximum acceleration (Tmap) for the rate of conversion of fibrinogen to fibrin for the body fluid sample;
g. means, including said computer, for monitoring voltage digital signal values at times (T1) and the time to maximum acceleration (Tmap) for respective fibrinogen concentration quantities (CT1) and (CTmap) based on the respective optical densities of the sample at those times and the corresponding digital voltage signals;
h. means, including said computer, for determining a slope that represents a rate of maximum acceleration of the clotting activity based on the optical activity of the clotting reaction and for determining an end of test time (TEOT) corresponding with an optical density value (cEOT) that is indicative of a substantial completion of the reaction of the fibrinogen of the sample and the clotting agent, wherein said time (TEOT) corresponds with the time at which a line of said slope that represents the rate of maximum acceleration of the clotting activity based on the optical activity of the clotting reaction intersects said optical density value at c=(cEOT);
i. means, including said computer, for determining an anticoagulant therapy factor value (INRn) for the sample, based on the correspondence of a clotting area defined by taking the product of (T1) and (TEOT), and multiplying the said product by a multiplier (MUL), wherein said multiplier (MUL) represents a value based on a sampling rate and a pixel parity value, and wherein said multiplier (MUL) is expressed by the pixel parity value divided by the sampling rate, and wherein said INRs value is expressed by the following relationship: INRs=(T1*TEOT)*MUL, where (MUL) is a multiplier that relates the sampling rate at which time and optical activity measurements are recorded with the pixel parity of the x-y axis of the clotting curve.

45. The apparatus of claim 44, wherein said (INRs) is determined by assigning the (MUL) a value of 1/187 or about 0.00535.