Patent Publication Number: US-2018031539-A1

Title: Method for determining severity of hemophilia, blood specimen analyzer and computer readable medium

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application claims priority from prior Japanese Patent Application No. 2016-148459, filed on Jul. 28, 2016, entitled “METHOD FOR DETERMINING SEVERITY OF HEMOPHILIA AND BLOOD SPECIMEN ANALYZER”, the entire contents of which are incorporated herein by reference. 
     TECHNICAL FIELD 
     The present invention relates to a method for determining severity of hemophilia and a blood specimen analyzer. 
     BACKGROUND 
     Hemophilia is a hemorrhagic disease caused by congenital defect or dysfunction of coagulation factor VIII (FVIII) or coagulation factor IX (FIX). Hemophilia is called hemophilia A when it is caused by FVIII. Hemophilia is called hemophilia B when it is caused by FIX. In hemophilic patients, bleeding symptoms are found in deep tissues such as intraarticular tissues or intramuscular tissues, and intracranial hemorrhage also occurs in severe cases. 
     The severity of hemophilia is classified based on FVIII activity or FIX activity in the blood. Specifically, patients with an activity of less than 1% are classified as severe, patients with an activity of 1% or more and less than 5% are classified as moderate, and patients with an activity of 5% or more and less than 40% are classified as mild, based on FVIII activity or FIX activity of healthy subjects as 100%. Patients with severe hemophilia exhibit bleeding symptoms at a frequency significantly higher than patients with moderate and mild cases. However, in recent years, it has been understood that, among patients with severe hemophilia, there is a difference in clinical severity and in occurrence probability of inhibitors to be described later, between patients with a particularly low FVIII activity (less than 0.2%; Very-Severe Haemophilia A; VS-HA) and other patients (0.2% or more and less than 1%; Modestly-Severe Haemophilia A; MS-HA). 
     In order to prevent bleeding symptoms in patients with severe hemophilia, a replacement therapy that gives administration of a coagulation factor preparation to patients is useful. However, antibodies (inhibitors) against such coagulation factors may occur in 10 to 15% of patients with hemophilia A and 1 to 3% in patients with hemophilia B. In patients with an inhibitor value of less than 5 BU (Bethesda unit), the inhibitor may transiently disappear. On the other hand, in patients with an inhibitor value of 5 BU or more, inhibitors tend to remain in the blood. For such patients, it is difficult to manage hemostasis with a coagulation factor preparation. Thus, it is forced to change the treatment policy by switching to immune tolerance therapy, administration of bypass preparation, or the like. Patients with inhibitors can be more severe than VS-HA patients. Therefore, from the viewpoint of selecting an appropriate treatment policy, it is important to detect the appearance of the inhibitor with high accuracy at an early stage. 
     A method for examining the presence or absence of the inhibitor by a blood test is known. For example, Matsumoto et al., A putative inhibitory mechanism in the tenase complex responsible for loss of coagulation function in acquired hemophilia A patients with anti-C2 autoantibodies, Thorombosis and Haemostasis 107.2/2012 describes that a plasma specimen of a moderate hemophilia A patient (Moderate type HA, 2.1±0.9 IU/dl) and a plasma specimen of a hemophilia A patient in which the antibody has appeared (Type 2) are distinguished using the minimum value mini (|min1|: maximum absolute value) of a first derivative curve of a coagulation curve. 
     SUMMARY OF THE INVENTION 
     The scope of the present invention is defined solely by the appended claims, and is not affected to any degree by the statements within this summary. 
     A first aspect of the present invention is to provide a method for determining severity of hemophilia, the method including the steps of: coagulating a blood specimen to acquire a coagulation waveform; acquiring an average change rate of a coagulation rate from the coagulation waveform; and acquiring information regarding the severity of hemophilia in the blood specimen based on the average change rate of the coagulation rate. 
     A second aspect of the present invention is to provide a blood specimen analyzer including a measurement sample preparing unit for preparing a measurement sample including a blood specimen and a coagulation time measuring reagent, an information acquisition unit for acquiring a coagulation waveform from the prepared measurement sample, and a control unit, wherein the control unit controls the measurement sample preparing unit so as to prepare the measurement sample from the blood specimen and the coagulation time measuring reagent, acquires an average change rate of a coagulation rate based on the coagulation waveform, and outputs information on severity of hemophilia based on the average change rate of the coagulation rate. 
     A third aspect of the present invention is to provide a computer readable medium storing a program causing a computer to execute process, the process comprising: coagulating a blood specimen to acquire a coagulation waveform; acquiring an average change rate of a coagulation rate from the coagulation waveform; and outputting information on severity of hemophilia based on the average change rate of the coagulation rate. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1A  is an example of a coagulation waveform obtained by measuring transmittance of a normal plasma specimen; 
         FIG. 1B  is an example of a waveform of rate obtained by primarily differentiating the coagulation waveform in  FIG. 1A ; 
         FIG. 2  is an example of a waveform of coagulation acceleration obtained by secondarily differentiating a coagulation waveform; 
         FIG. 3  is an example of a possible approximation by a method of the present embodiment; 
         FIG. 4  is a perspective view showing the configuration of an appearance of a blood specimen analyzer; 
         FIG. 5  is a plan view of an inside of a measurement unit of the blood specimen analyzer when viewed from above; 
         FIG. 6  is a diagram showing the configuration of the measurement unit of the blood specimen analyzer; 
         FIG. 7  is a diagram showing the configuration of a lamp unit provided in the measurement device; 
         FIG. 8A  is a diagram showing the configuration of a detection unit provided in the measurement device; 
         FIG. 8B  is a diagram showing the configuration of the detection unit provided in the measurement device; 
         FIG. 8C  is a diagram showing the configuration of the detection unit provided in the measurement device; 
         FIG. 8D  is a diagram showing the configuration of the detection unit provided in the measurement device; 
         FIG. 9  is a diagram showing the functional configuration of a control device of the blood specimen analyzer; 
         FIG. 10  is a diagram showing the hardware configuration of a control device of the blood specimen analyzer; 
         FIG. 11  is a flowchart showing measurement processing of a blood specimen by the blood specimen analyzer; 
         FIG. 12  is a flowchart showing analysis processing of a blood specimen by the blood specimen analyzer; 
         FIG. 13  is a view showing an example of a screen for displaying an analysis result by the blood specimen analyzer; 
         FIG. 14  is a diagram showing a discrimination result using parameters of the present embodiment; and 
         FIG. 15  is a diagram showing a discrimination result using conventional parameters. 
     
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     A method of determining the severity of hemophilia includes a step of coagulating a blood specimen to acquire a coagulation waveform. 
     Examples of the blood specimen include whole blood and plasma, and the blood specimen is preferably plasma. The blood specimen is preferably a blood specimen derived from a patient suspected of being a VS-HA patient. A known anticoagulant commonly used for coagulation test may be added to the blood specimen. Examples of the anticoagulant include trisodium citrate. Prior to preparation of a measurement sample, the blood specimen may be heated to a temperature suitable for coagulation reaction (for example, 36° C. or more and 38° C. or less) in advance. 
     The method for coagulating the blood specimen is not particularly limited, and can be performed by a method known to those skilled in the art. For example, it can be performed by contacting a blood specimen with a coagulation time measuring reagent to prepare a measurement sample, and coagulating the blood specimen in the measurement sample. 
     The coagulation time measuring reagent should be any reagent for measuring coagulation time based on the measurement principle known in the art. Examples of the reagent include reagents for measuring at least one of activated partial thromboplastin time, prothrombin time, diluted prothrombin time, diluted activated partial thromboplastin time, kaolin clotting time, diluted Russell viper venom time, thrombin time, and diluted thrombin time. The coagulation time measuring reagent is preferably a reagent for measuring activated partial thromboplastin time. Commercially available coagulation time measuring reagents and reagent kits may be used. 
     It is preferable that the coagulation time measuring reagent contains a coagulation system activator. The coagulation system activator should be any substance that activates any coagulation factor involved in the coagulation system. Examples of the coagulation system activator include ellagic acid, silica, kaolin, celite, tissue factor, thrombin, viper venom, and the like. Ellagic acid may be in a state of forming a chelate with a metal ion. The tissue factor may be a tissue factor derived from rabbit brain or human placenta, or may be a recombinant tissue factor. Examples of the viper venom include Russell viper venom, Texturing viper venom, Ecarin viper venom, and the like. These coagulation system activators may be used alone or in combination of two or more kinds thereof. Usually, commercially available coagulation time measuring reagents and reagent kits contain any coagulation system activator, depending on the kind of coagulation time to be measured. 
     The final concentration of the coagulation system activator in the measurement sample can be appropriately determined according to the kind of the coagulation system activator. When the coagulation system activator is ellagic acid, the final concentration of ellagic acid in the measurement sample is usually 3.5 μM or more and 150 μM or less, and preferably 10 μM or more and 50 μM or less. When the coagulation system activator is a tissue factor, the final concentration of the tissue factor in the measurement sample is usually 0.4 μg/mL or more and 0.7 μg/mL or less, and preferably 0.5 μg/mL or more and 0.6 μg/mL or less. 
     Since a phospholipid promotes coagulation reaction, the coagulation time measuring reagent may further contain a phospholipid. Examples of the phospholipid include phosphatidylethanolamine (PE), phosphatidylcholine (PC) and phosphatidylserine (PS). In the present embodiment, one, preferably two, more preferably all kinds of phospholipids selected from PE, PC and PS can be added to the coagulation time measuring reagent. The phospholipid may be a naturally occurring phospholipid or a synthetic phospholipid. Among them, synthetic phospholipids or naturally occurring phospholipids purified to have a purity of 99% or more are preferred. The fatty acid side chains of PE, PC and PS are not particularly limited, and examples thereof include palmitic acid, oleic acid, stearic acid, and the like. Among them, oleic acid is preferable. In the present embodiment, the phospholipid is preferably in the form of a liquid in which the phospholipid is dissolved in a suitable solvent. 
     The final concentration of the phospholipid in the measurement sample can be appropriately determined depending on the kind of the phospholipid. When the phospholipid is PE, the final concentration of the phospholipid in the measurement sample is usually 1 μg/mL or more and 150 μg/mL or less, and preferably 5 μg/mL or more and 50 μg/mL or less. When the phospholipid is PC, the final concentration of the phospholipid in the measurement sample is usually 1 μg/mL or more and 100 μg/mL or less, and preferably 5 μg/mL or more and 80 μg/mL or less. When the phospholipid is PS, the final concentration of the phospholipid in the measurement sample is usually 0.1 μg/mL or more and 50 μg/mL or less, and preferably 1 μg/mL or more and 10 μg/mL or less. When using two or more kinds of the phospholipids, the total concentration of each of the phospholipid in the measurement sample is usually 5 μg/mL or more and 400 μg/mL or less, and preferably 20 μg/mL or more and 100 μg/mL or less. 
     The coagulation time measuring reagent preferably contains a phospholipid and a coagulation system activator. Examples of the coagulation time measuring reagent containing a phospholipid and a coagulation system activator include an activated partial thromboplastin time (APTT) measuring reagent. In this case, the coagulation system activator is preferably a substance that activates a contact factor of the intrinsic coagulation pathway, such as ellagic acid, silica, kaolin and celite. 
     Calcium ions are required to initiate blood coagulation in the measurement sample. In the present embodiment, calcium ions are provided to the measurement sample by using an aqueous solution containing calcium ions for preparation of the measurement sample. As the aqueous solution containing calcium ions, an aqueous solution of a calcium salt is preferable, and examples thereof include an aqueous calcium chloride solution, an aqueous calcium lactate solution, and the like. The calcium ion content in the measurement sample may be an amount sufficient to cause coagulation, and for example, it is usually 2 mM or more and 20 mM or less, and preferably 4 mM or more and 10 mM or less, in terms of calcium chloride concentration. Hereinafter, the aqueous solution containing calcium ions is also called a “calcium solution”. 
     Since coagulation starts when a calcium solution is added, it is preferable to add the calcium solution last in the preparation of the measurement sample. The preparation procedure of the measurement sample is as follows. The measurement sample can be prepared by, firstly, mixing a blood specimen with a coagulation time measuring reagent and then mixing the resulting mixture with a calcium solution. Alternatively, firstly, a measurement sample may be prepared by mixing a blood specimen with a coagulation time measuring reagent and then mixing the resulting mixture with a calcium solution. When using a commercially available prothrombin time (PT) measuring reagent, the reagent contains a tissue factor and calcium ions, and thus a measurement sample can be prepared by mixing a blood specimen with a PT measuring reagent. By which procedure to prepare the measurement sample may be determined according to the coagulation time measuring reagent to be used. 
     In this embodiment, the mixture may be incubated under conditions suitable for coagulation reaction before adding the calcium solution. Examples of the suitable conditions include conditions for incubating at a temperature of 35° C. or more and 40° C. or less for a time period of 2 minutes or more and 5 minutes or less. The preparation of the measurement sample may be carried out by a manual method or may be carried out by a fully automatic measurement device. Examples of the device include the CS series of a fully automated blood coagulation measurement device (Sysmex Corporation), and the like. 
     When using the coagulation time measuring reagent containing a phospholipid and a coagulation system activator, it is preferable to prepare a measurement sample as follows. First, a blood specimen is mixed with the coagulation time measuring reagent containing a phospholipid and a coagulation system activator. Next, the resulting mixture is mixed with a calcium solution. 
     In the method of the present embodiment, a coagulation waveform is acquired using the measurement sample prepared as described above. A coagulation waveform is a waveform representing a change with time in the optical characteristics and the like of a blood specimen caused accompanying the progress of coagulation of the blood specimen. In the present embodiment, the coagulation waveform may be acquired by an optical measurement method. An example of the optical measurement method includes a method of acquiring optical information such as transmittance by irradiating the measurement sample with light. The measurement may be performed by a fully automatic measurement device. For example, the CS series of a fully automated blood coagulation measurement device (Sysmex Corporation) can measure optical information such as transmittance. 
     The acquisition of the optical information is carried out continuously or intermittently from the start point to the completion of coagulation. Based on the optical information measured continuously or intermittently in the process of coagulation, it is possible to acquire parameters related to the differentiation of coagulation waveform to be described later at any time point or time in the process. The start point refers to a time point at which acquisition of data of each plot constituting the coagulation waveform is started, in order to acquire the average change rate of a coagulation rate to be described later. The start point is not particularly limited as long as it does not hinder the acquisition of the average change rate of the coagulation rate; however, it is preferable to set the start point before the time point when the coagulation rate becomes the maximum. For example, the start point can be set to the measurement starting point of coagulation time (point a in  FIGS. 1A and 1B ) or the starting point of coagulation (point b in  FIGS. 1A and 1B ), or a time point indicated by the numerical value obtained by adding or subtracting an arbitrary coefficient to or from the numerical value indicating the time point. The start point is preferably set to the measurement starting point of coagulation time. 
     The measurement time may be determined from the range of usually 5 seconds or more and 1800 seconds or less, and preferably 10 seconds or more and 600 seconds or less. In the method of the present embodiment, when normal plasma (plasma obtained from a healthy subject) is used as a blood specimen, coagulation is usually completed within 30 seconds from the time of preparation of the measurement sample. 
     The coagulation waveform is preferably acquired from optical information obtained by irradiating the measurement sample with light. Examples of the optical information include the amount of scattered light, transmittance and absorbance measured continuously or intermittently, and the like. In this case, the coagulation waveform is a waveform representing a change with time in the amount of scattered light, transmittance or absorbance. The light to be irradiated to the measurement sample may be light which is usually used for measuring coagulation time, and is for example, light having a wavelength of around 660 nm, and preferably, light having a wavelength of 660 nm. A light source is not particularly limited, and examples thereof include a light emitting diode, a halogen lamp, and the like. The coagulation waveform acquired in the present embodiment includes the coagulation waveform curve itself and the data of each plot constituting the coagulation waveform. Examples of the data of each plot constituting the coagulation waveform include the time from the start point and the measurement value of the optical specification of the measurement sample at the time point. 
     An example of the coagulation waveform obtained by the method of the present embodiment will be described with reference to  FIG. 1A . In the coagulation waveform shown in  FIG. 1A , a point a is the measurement starting point of coagulation time, a point b is the point of fibrin precipitation (starting point of coagulation), and a point c is the end point of coagulation. In a general coagulation time measuring method, the time to precipitate fibrin is defined as coagulation time. In  FIG. 1A , the time between a and b represents coagulation time. Since coagulation proceeds by the action of the coagulation time measuring reagent, the transmittance of the measurement sample decreases as shown in a to c in  FIG. 1A . 
     The method for determining the severity of hemophilia includes the step of acquiring an average change rate of the coagulation rate from the coagulation waveform. 
     The average change rate of the coagulation rate is not particularly limited as long as it reflects the average change rate of the coagulation rate with respect to the time from the start point. For example, the average change rate of the coagulation rate may be an approximate value reflecting the average change rate of the coagulation rate. In the present embodiment, a curve obtained by differentiation of the coagulation waveform, parameters related to differentiation, and the like are acquired, and the average change rate of the coagulation rate is acquired using them. 
     The curve obtained by differentiation of the coagulation waveform is preferably a primary differential curve (waveform of rate) obtained by primarily differentiating the coagulation waveform. With reference to  FIG. 1B , the waveform of rate will be described. When the coagulation waveform of  FIG. 1A  is primarily differentiated, a waveform showing the rate of coagulation shown in  FIG. 1B  is obtained. In  FIG. 1B , the waveform is represented so that the coagulation rate (rate between a and c) is a positive value; however, it may be represented so that the coagulation rate is a negative value. That is, a waveform in which the plus or minus of the vertical axis is inverted from the waveform in  FIG. 1B  may be acquired. Points a to c in  FIG. 1B  correspond to the points a to c in  FIG. 1A . In  FIG. 1B , the point c that represents the end point of coagulation is a point at which the increased rate is zero. 
     It is preferable that the curve obtained by differentiation of the coagulation waveform is not a secondary differential curve obtained by differentiating the coagulation waveform twice. This is because a second derivative curve easily includes noise, and shows a non-uniform waveform (for example,  FIG. 2 ), so that accurate information may not be obtained in the microdetermination of coagulation factors. It is assumed that a curve obtained by differentiating the coagulation waveform three or more times easily includes noise as well. Therefore, it is particularly preferable that the curve obtained by differentiation of the coagulation waveform is a primary differential curve. 
     The parameters related to differentiation of the coagulation waveform are not particularly limited as long as they are values indicating at least one such as a coagulation rate that is obtained by differentiating the coagulation waveform at least once. Examples of the parameters related to differentiation of the coagulation waveform include a coagulation rate (the slope of the coagulation waveform), the maximum coagulation rate (the maximum value of the slope of the coagulation waveform) (|min1|), a time until the coagulation rate becomes the maximum (time to |min1|), a time until the coagulation rate becomes a times (0&lt;a&lt;1) the maximum (time to a x |min1|), an average change rate of the coagulation rate, a time until coagulation acceleration (the slope of the waveform of the rate) becomes the maximum (time to |min2|), a time until coagulation acceleration becomes a times (0&lt;a&lt;1) the maximum (time to a ×|min2|) and their approximate values, and the like. The number of the parameters related to differentiation of the coagulation waveform may be one, or two or more. The parameters related to differentiation of the coagulation waveform may be a value obtained by combination of two or more parameters, and examples of the value include the sum, difference, product and ratio of at least two of the parameters exemplified above, and the like. 
     The average change rate of the coagulation rate is calculated based on the waveform of rate obtained by differentiating the coagulation waveform. An example of the average change rate of the coagulation rate includes a magnitude of the slope of a straight line connecting two points on the waveform of rate. The two points on the waveform of rate are selected from an arbitrary point on the waveform of rate and a peripheral point close to the arbitrary point. Both of these two points are preferably selected from the range of (0, f(0)) to (time to |min1|, |min1|) with representation of arbitrary points on the waveform of rate as (time, coagulation rate)=(x, f(x)). Time x=0 is a start point. More preferably, the average change rate of the coagulation rate is the magnitude of the slope of a straight line connecting the point (time to |min1|, |min1|) and the point (time to |min2|, f(time to |min2|)). Each of time to |min1|, f(time to |min1|), time to |min2|, and f(time to |min2|) can be represented by their approximate values. Since f(time to |min2|) can be approximated as ½×|min1|, ½×|min1| can be used as f(time to |min2|). The time (time to ½×|min1|) until the coagulation rate becomes ½×|min1|can be approximated as time to |min2|. Therefore, as the point (time to |min2|, f(time to |min2|)), for example, the point (time to |min2|, ½×|min1|), the point (time to ½×|min1|, ½×|min1|) or the like can be used. 
     With reference to  FIG. 3 , an example of a possible approximation by the method of the present embodiment will be described in detail. The waveform in the lower left diagram in  FIG. 3  is a waveform of rate derived from a blood specimen of a healthy person, and the upper right diagram in  FIG. 3  is the waveform of rate derived from a hemophilia A patient. In  FIG. 3 , the broken line of a represents a straight line parallel to the vertical axis passing through the point (time to |min1|, 0), and the intersection of the straight line and the waveform of rate corresponds to the point (time to |min1|, |min1|). On the other hand, the broken line of b represents a straight line parallel to the vertical axis passing through the point (time to |min2|, 0), and the intersection of the straight line and the waveform of rate corresponds to the point (time to |min2|, f(time to |min2|)). Since f(time to |min2|) can be approximated by ½×|min1|, the average change rate of the coagulation rate is calculated as a magnitude of the slope of a straight line connecting two points, the point (time to |min1|, |min1|) and the point (time to |min2|, ½×|min1|). The triangle shown in  FIG. 3  is a conceptual diagram of the approximation. 
     Though not shown in  FIG. 3 , the above approximation can be similarly applied to patients with severe hemophilia, especially MS-HA patients and VS-HA patients as well as hemophilia patients (HA-inh) having the antibody. 
     In another viewpoint, the average change rate of the coagulation rate is preferably calculated using the maximum coagulation rate (|min1|) and the time until the coagulation rate becomes the maximum (time to |min1|), and is more preferably calculated further using the time until the coagulation acceleration becomes the maximum (time to |min2|). 
     In a particularly preferred embodiment, the average change rate of the coagulation rate is calculated by the following Expression 1. 
       [Mathematical Expression 1] 
       (½×|min1|)/(time to |min1|−time to |min2|)  Expression 1
 
     Using Expression 1 above, it is possible to calculate the average change rate of the coagulation rate by using only those which can be easily acquired among the parameters related to differentiation. This is based on the fact empirically found by the present inventors that the time until the coagulation rate becomes ½×|min1| (time to ½×|min1|) can be approximated by time to |min2|, when the average change rate of the coagulation rate is calculated by using a blood specimen of a severe hemophilia patient, a blood specimen of a hemophilia patient in which the antibody has appeared, and a blood specimen of a healthy person. From this viewpoint, according to the method of the present embodiment, it can also be said that the time until the coagulation acceleration becomes the maximum is the time before the coagulation rate becomes the maximum and until the coagulation rate becomes ½ of the maximum coagulation rate. 
     The method for determining the severity of hemophilia includes the step of determining the severity of hemophilia in the blood specimen based on the average change rate of the coagulation rate. 
     Hemophilia may be either hemophilia A or hemophilia B, and is preferably hemophilia A. 
     In the present embodiment, when the average change rate of the coagulation rate is equal to or less than the reference value, it is determined that there is a high possibility of the antibody against a coagulation factor having appeared in the blood specimen, and when the average change rate exceeds the reference value, it is determined that there is not a high possibility of the antibody against a coagulation factor having appeared in the blood specimen. The phrase “the antibody has appeared” means that the antibody is present in the blood at least at a detectable level, and may mean the state in which the blood antibody level is 5 BU or more. Such a determination result can be data that supports a doctor to diagnose that inhibitors have appeared in the blood of a hemophilia patient. When the antibody has appeared as above, it can be considered that hemophilia is more severe than VS-HA patients. In contrast, when the average change rate of the coagulation rate exceeds the reference value, no inhibitor has appeared in the blood of a hemophilia patient, but it can be data that supports a doctor to diagnose the patient as severe. 
     In severe hemophilia, especially VS-HA with a factor VIII activity of less than 0.2 IU/dl, and in hemophilia in which the antibody has appeared, the coagulation time is markedly prolonged in the APTT test in both hemophilia cases, and both hemophilia cases are below the quantitation limit in the quantitative examination of coagulation factor. Thus, it is difficult to simply detect inhibitors by such a general test. On the other hand, when inhibitors occur in hemophilia patients, it is difficult to manage hemostasis with factor VIII preparations commonly used in replacement therapy. Thus, it is necessary to consider immune tolerance therapy or administration of bypass preparation, and it is important to detect inhibitor expression in the choice of treatment at an early stage, with high specificity and high reliability. According to the method of the present embodiment, as described above, VS-HA with a factor VIII activity of less than 0.2 IU/dl can be discriminated from hemophilia in which the antibody has appeared. Thus, it is possible to select a treatment policy suitable for each patient. This is an unexpected result from the prior art. The case of hemophilia B is also the same only by replacing factor VIII with factor IX. 
     The reference value is not particularly limited, and can be appropriately set in advance by a person skilled in the art. For example, a coagulation waveform is acquired in advance using each of a blood specimen from a severe hemophilia A patient group and a blood specimen from a hemophilia patient group in which the antibody has appeared, and the value of Expression 1 above is obtained based on the obtained coagulation waveform. Then, it is possible to set a value that can most accurately classify the severe hemophilia patient group, particularly a VS-HA patient group, and the hemophilia patient group in which the antibody has appeared. 
     [2. Blood Specimen Analyzer] 
     An example of a blood specimen analyzer will be described below with reference to the drawings. However, the present embodiment is not limited to this example. As shown in  FIG. 4 , a blood specimen analyzer  10  includes a measurement device  50  for preparing and measuring a measurement sample; a control device  40  for analyzing measurement data acquired by the measurement device  50  and providing an instruction to the measurement device  50 . The measurement device  50  includes a measurement unit  20  for acquiring optical information from the measurement sample and a specimen transporting section  30  arranged in front of the measurement unit  20 . 
     The measurement unit  20  is provided with lids  20   a  and  20   b,  a cover  20   c,  and a power button  20   d.  A user can open the lid  20   a  and replace a reagent container  103  placed in reagent tables  11  and  12  (see  FIG. 5 ) with a new reagent container  103 , or a user can newly add another reagent container  103 . To the reagent container  103  is attached a barcode label  103   a  printed with a barcode including the kind of the reagent to be accommodated and a reagent ID made up of serial number provided to the reagent. 
     The user can open the lid  20   b  and replace a lamp unit  27  (see  FIG. 5 ). The user can also open the cover  20   c  and replace a piercer  17   a  (see  FIG. 5 ). The specimen transporting section  30  transports a specimen container  101  supported by a specimen rack  102  to an aspiration position by the piercer  17   a.  The specimen container  101  is hermetically sealed by a rubber lid  101   a.    
     When using the blood specimen analyzer  10 , the user first presses the power button  20   d  of the measurement unit  20  to activate the measurement unit  20 , and the user presses a power button  439  of the control device  40  to activate the control device  40 . When the control device  40  is activated, a log-on screen is displayed on a display unit  41 . The user inputs the user name and the password on the log-on screen to log on to the control device  40 , and the user starts using the blood specimen analyzer  10 . 
     (Configuration of Measurement Device) 
     The configuration of the measurement device  50  will be described below. As shown in  FIG. 5 , the measurement unit  20  includes reagent tables  11  and  12 , a cuvette table  13 , a barcode reader  14 , a cuvette supply section  15 , a catcher  16 , a specimen dispensing arm  17 , a reagent dispensing arm  18 , an urgent specimen setting section  19 , an optical fiber  21 , a detecting section  22 , a cuvette transfer section  23 , a warming section  24 , a disposal port  25 , a fluid section  26 , and a lamp unit  27 . 
     (Measurement Sample Preparing Unit) 
     The measurement sample preparing unit includes the reagent tables  11  and  12 , the cuvette table  13 , the barcode reader  14 , the cuvette supply section  15 , the catcher  16 , the specimen dispensing arm  17 , the reagent dispensing arm  18 , the urgent specimen setting section  19 , the cuvette transfer section  23 , the warming section  24 , the waste port  25 , the fluid section  26 , and the specimen transporting section  30 . Each of the reagent tables  11  and  12  and the cuvette table  13  has an annular shape. Each of the reagent tables  11  and  12  and the cuvette table  13  is configured rotatably. Each of the reagent tables  11  and  12  corresponds to a reagent storing section, onto which a reagent container  103  is placed. The barcode of the reagent container  103  placed on the reagent tables  11  and  12  is read by the barcode reader  14 . Information (kind of reagent, reagent ID) read from the barcode is input to the control device  40  and stored in a hard disk  434  (see  FIG. 9 ). 
     In the blood specimen analyzer of the present embodiment, a reagent container  103 , in which a coagulation time measuring reagent, a calcium solution or the like is each accommodated, is placed on the reagent tables  11  and/or  12 . Also, a reagent container  103 , in which normal plasma is accommodated as a control specimen, may be placed on the reagent tables  11  and/or  12 . 
     The cuvette table  13  is formed with a support portion  13   a  composed of a plurality of holes capable of supporting a cuvette  104 . A new cuvette  104  introduced into the cuvette supply section  15  by the user is sequentially transferred by the cuvette supply section  15 , and the cuvette  104  is placed on the support portion  13   a  of the cuvette table  13  by the catcher  16 . 
     A stepping motor is connected to each of the specimen dispensing arm  17  and the reagent dispensing arm  18  so as to be able to move up and down and rotatably. A piercer  17   a  of which a tip is sharply formed is provided at the tip of the sample dispensing arm  17 , so that the lid  101   a  of the specimen container  101  can be punctured. A pipette  18   a  is provided at the tip of the reagent dispensing arm  18 . The tip of the pipette  18   a  is formed flat unlike the piercer  17   a.  An electrostatic capacitance type liquid level detection sensor  213  (see  FIG. 6 ) is connected to the pipette  18   a.    
     When the specimen container  101  is transported to a predetermined position by the specimen transporting unit  30  (see  FIG. 4 ), the piercer  17   a  is positioned just above the specimen container  101  by the rotational movement of the specimen dispensing arm  17 . Then, the specimen dispensing arm  17  is moved downward, the piercer  17   a  penetrates the lid  101   a  of the specimen container  101 , and the blood specimen accommodated in the specimen container  101  is aspirated by the piercer  17   a.  When an urgent blood specimen is set in the urgent specimen setting section  19 , the piercer  17   a  intervenes in the specimen supplied from the specimen transporting section  3  and aspirates the urgent blood specimen. The blood specimen aspirated by the piercer  17   a  is discharged into an empty cuvette  104  on the cuvette table  13 . 
     The cuvette  104  into which the blood specimen has been discharged is transferred from the support portion  13   a  of the cuvette table  13  to a support portion  24   a  of the warming section  24  by a catcher  23   a  of the cuvette transfer section  23 . The warming section  24  warms the blood specimen accommodated in the cuvette  104  placed in the support portion  24   a  at a predetermined temperature (for example, 36 to 38° C.) for a certain period of time. When the warming of the blood specimen by the warming section  24  is finished, the cuvette  104  is again gripped by the catcher  23   a.  Then, the cuvette  104  is positioned at a predetermined position while being gripped by the catcher  23   a,  and in this state, the reagent aspirated by the pipette  18   a  is discharged into the cuvette  104 . 
     In the dispensing of the reagent by the pipette  18   a,  first, the reagent tables  11  and  12  are rotated, and the reagent container  103  that accommodates the reagent corresponding to the measurement item is transported to an aspiration position by the pipette  18   a.  Then, after the position of the pipette  18   a  in the vertical direction is positioned at the origin position, the pipette  18   a  is lowered until the lower end of the pipette  18   a  comes into contact with the liquid level of the reagent by the liquid level detection sensor  213 . When the lower end of the pipette  18   a  comes into contact with the liquid level of the reagent, the pipette  18   a  is further lowered to an extent that a necessary amount of the reagent can be aspirated. Then, the lowering of the pipette  18   a  is stopped, and the reagent is aspirated by the pipette  18   a.  The reagent aspirated by the pipette  18   a  is discharged into the cuvette  104  gripped by the catcher  23   a.  Then, the blood specimen and the reagent in the cuvette  104  are agitated by the vibrating function of the catcher  23   a.  Thus, the measurement sample is prepared. Thereafter, the cuvette  104  that accommodates the measurement sample is transferred to a support portion  22   a  of the detecting section  22  by the catcher  23   a.    
     (Information Acquisition Unit) 
     The information acquisition unit includes the optical fiber  21 , the detecting section  22 , and the lamp unit  27 . The lamp unit  27  supplies light having plural kinds of wavelengths used for detection of an optical signal by the detecting section  22 . An example of the configuration of the lamp unit  27  will be described with reference to  FIG. 7 . The lamp unit  27  corresponds to a light source. The lamp unit  27  includes a halogen lamp  27   a,  a lamp case  27   b,  condenser lenses  27   c  to  27   e,  a disk-shaped filter section  27   f,  a motor  27   g,  a light transmission type sensor  27   h,  and an optical fiber coupler  27   i.    
     With reference to  FIG. 5 , light from the lamp unit  27  is supplied to the detecting section  22  via the optical fiber  21 . A plurality of hole-shaped support portions  22   a  are provided in the detecting section  22 , and a cuvette  104  can be inserted into each of the support portions  22   a.  The end part of the optical fiber  21  is attached to each of the support portions  22   a,  and the cuvette  104  supported by the support portion  22   a  can be irradiated with light from the optical fiber  21 . The detecting section  22  irradiates the cuvette  104  with light supplied from the lamp unit  27  via the optical fiber  21 . The detecting section  22  detects the light amount of light to be transmitted through the cuvette  104  (or scattered light from the cuvette  104 ). 
       FIGS. 8A to 8D  show an example of one configuration of the plurality of support portions  22   a  arranged in the detecting section  22 , and the other support portions  22   a  have the same configuration. With reference to  FIG. 8A , the detecting section  22  is formed with a circular hole  22   b  into which the tip of the optical fiber  21  is inserted. The detecting section  22  is further formed with a circular communication hole  22   c  for communicating the hole  22   b  with the support portion  22   a.  The diameter of the hole  22   b  is larger than the diameter of the communication hole  22   c.  A lens  22   d  for condensing light from the optical fiber  21  is arranged at the end of the hole  22   b.  On the inner wall surface of the support portion  22   a,  a hole  22   f  is formed at a position facing the communication hole  22   c.  A photodetector  22   g  is arranged at the back of the hole  22   f.  The photodetector  22   g  corresponds to a light receiving portion. The photodetector  22   g  outputs an electric signal corresponding to the amount of received light. The light transmitted through the lens  22   d  is condensed on the light receiving surface of the photodetector  22   g,  through the communication hole  22   c,  the support portion  22   a,  and the hole  22   f.  The optical fiber  21  is prevented from falling off by a plate spring  22   e  in a state in which the end part of the optical fiber  21  is inserted into the hole  22   b.    
     With reference to  FIG. 8B , when the cuvette  104  is supported by the support portion  22   a,  the light condensed by the lens  22   d  is transmitted through the cuvette  104  and the sample accommodated in the cuvette  104 , and the transmitted light enters the photodetector  22   g.  As the blood coagulation reaction progresses in the sample, the turbidity of the sample increases. Along with this, the amount of light to be transmitted through the sample (the amount of transmitted light) decreases, and the level of the detection signal of the photodetector  22   g  decreases. 
     With reference to  FIG. 8C , the configuration of the detecting section  22  when scattered light is used will be described. On the inner side surface of the support portion  22   a,  a hole  22   h  is provided at a position which is the same height as the communication hole  22   c.  A photodetector  22   i  is arranged at the back of the hole  22   h . When the cuvette  104  is inserted into the support portion  22   a  and light is emitted from the optical fiber  21 , the light scattered by the measurement sample in the cuvette  104  is irradiated to the photodetector  22   i  via the hole  22   h.  In this example, the detection signal from the photodetector  22   i  indicates the intensity of scattered light by the measurement sample. As shown in  FIG. 8D , both the light to be transmitted through the measurement sample and the light to be scattered by the measurement sample may be detected. 
     As described above, the detecting section  22  irradiates the cuvette  104  with light supplied from the lamp unit  27 . The detecting section  22  acquires optical information from the measurement sample. The acquired optical information is transmitted to the control device  40 . The control device  40  performs analysis based on the optical information. The control device  40  displays the analysis result on a display unit  41 . 
     After completion of the measurement, the cuvette  104  that has become unnecessary is transported by the cuvette table  13 . The transported cuvette  104  is discarded to the disposal port  25  by the catcher  16 . During the measurement operation, the piercer  17   a  and the pipette  18   a  are appropriately washed with a liquid such as a cleaning liquid supplied from the fluid section  26 . 
     The hardware configuration of the measurement device will be described below. As shown in  FIG. 6 , the measurement unit  20  includes a control section  200 , a stepping motor section  211 , a rotary encoder section  212 , a liquid level detection sensor  213 , a sensor section  214 , a mechanism section  215 , an optical information acquisition section  216 , and a barcode reader  14 . 
     With reference to  FIG. 6 , the control section  200  includes a CPU  201 , a memory  202 , a communication interface  203 , and an I/O interface  204 . The CPU  201  executes a computer program stored in the memory  202 . The memory  202  is composed of a ROM, a RAM, a hard disk, and the like. The CPU  201  drives the specimen transporting section  30  via the communication interface  203 . The CPU  201  also transmits and receives instruction signals and data with the control device  40 . The CPU  201  controls each section in the measurement unit  20  via the I/O interface  204 . The CPU  201  also receives signals output from each section. 
     The stepping motor section  211  includes stepping motors for driving the reagent tables  11  and  12 , the cuvette table  13 , the catcher  16 , the specimen dispensing arm  17 , the reagent dispensing arm  18 , and the cuvette transfer section  23 , respectively. The rotary encoder section  212  includes a rotary encoder that outputs a pulse signal corresponding to the amount of rotational displacement of each stepping motor included in the stepping motor unit  211 . 
     The liquid level detection sensor  213  is connected to the pipette  18   a  provided at the tip of the reagent dispensing arm  18 . The liquid level detection sensor  213  detects that the lower end of the pipette  18   a  has come into contact with the liquid level of the reagent. The sensor section  214  includes a sensor for detecting that the vertical position of the pipette  18   a  is positioned at the origin position and a sensor for detecting that the power button  20   d  is pressed. The mechanism section  215  includes a mechanism for driving the cuvette supply section  15 , the urgent specimen setting section  19 , the warming section  24  and the fluid section  26 , and an air pressure source which supplies pressure to the piercer  17   a  and the pipette  18   a  so that dispensing operation by the piercer  17   a  and the pipette  18   a  can be performed. With reference to  FIG. 5 , the optical information acquisition section  216  includes at least the lamp unit  27 , the optical fiber  21 , and the detecting section  22 . 
     (Control Unit) 
     The configuration of the control device  40  (control unit) will be described below. As shown in  FIG. 4 , the control device  40  includes the display unit  41 , an input unit  42 , and a computer body  43 . When the user inputs a measurement start instruction of a blood specimen via the input unit  42 , the control device  40  transmits the measurement start instruction to the measurement unit  20  to start the measurement. The control device  40  receives optical information from the measurement unit  20 . Then, a processor of the control device  40  calculates, based on the optical information, a primary differential curve of a coagulation waveform, parameters related to differentiation, and the like. The processor of the control device  40  may also calculate coagulation time based on the optical information. Then, the processor of the control device  40  executes a computer program for analyzing the blood specimen. 
     Accordingly, the control device  40  also functions as a computer system for analyzing the blood specimen. 
     As to the functional configuration of the control device  40 , as shown in  FIG. 9 , the control device  40  includes an acquisition unit  401 , a storage unit  402 , a calculation unit  403 , a determination unit  404 , and an output unit  405 . The acquisition unit  401  is communicably connected to the measurement unit  20  via a network. The output unit  405  is communicably connected to the display unit  41 . 
     The acquisition unit  401  acquires the optical information transmitted from the measurement unit  20 . The storage unit  402  stores an expression for calculating values of various parameters related to differentiation of the coagulation waveform, a normal range corresponding to the various parameters, a predetermined reference value, and the like. The storage unit  402  may store an expression for calculating the coagulation time. Using the information acquired by the acquisition unit  401 , the calculation unit  403  calculates the values of the various parameters according to the expression stored in the storage unit  402 . The determination unit  404  determines whether or not the values of the parameters calculated by the calculation unit  403  deviates from the normal range corresponding to the parameters stored in the storage unit  402 . The output unit  405  outputs the values of the parameters calculated by the calculation unit  403  as reference information regarding the blood specimen. 
     As shown in  FIG. 10 , the computer body  43  of the control device  40  includes a CPU  431 , a ROM  432 , a RAM  433 , a hard disk  434 , a readout device  435 , an input/output interface  436 , a communication interface  437 , an image output interface  438 , and a power button  439 . The CPU  431 , the ROM  432 , the RAM  433 , the hard disk  434 , the readout device  435 , the input/output interface  436 , the communication interface  437 , the image output interface  438 , and the power button  439  are communicably connected by a bus  440 . 
     The CPU  431  executes a computer program stored in the ROM  432  and a computer program loaded in the RAM  433 . Each of the above-described functional blocks is realized by the CPU  431  executing an application program. Thus, the computer system functions as a terminal of the blood specimen analyzer. 
     The ROM  432  includes a mask ROM, PROM, EPROM, EEPROM, and the like. In the ROM  432 , a computer program executed by the CPU  431  and data used for the computer program are recorded. 
     The RAM  433  includes SRAM, DRAM, and the like. The RAM  433  is used for reading out the computer program recorded in the ROM  432  and the hard disk  434 . The RAM  433  is also used as a work area of the CPU  431  when executing these computer programs. 
     The hard disk  434  has installed therein an operating system, a computer program such as an application program (a computer program for analyzing a blood specimen) to be executed by the CPU  431 , data used for executing the computer program, and setting contents of the control device  40 . 
     The readout device  435  includes a flexible disk drive, a CD-ROM drive, a DVD ROM drive, and the like. The readout device  435  can read out a computer program or data recorded on a portable recording medium  441  such as a CD or a DVD. 
     The input/output interface  436  includes, for example, a serial interface such as USB, IEEE 1394 or RS-232C, a parallel interface such as SCSI, IDE or IEEE 1284, and an analog interface including a D/A converter, an A/D converter and the like. The input unit  42  such as a keyboard and a mouse is connected to the input/output interface  436 . The user inputs an instruction via the input unit  42 , and the input/output interface  436  receives a signal input via the input unit  42 . 
     The communication interface  437  is, for example, an Ethernet (registered trademark) interface or the like. The control device  40  can transmit print data to a printer through the communication interface  437 . The communication interface  437  is connected to the measurement unit  20 , and the CPU  431  transmits and receives an instruction signal and data with the measurement unit  20  via the communication interface  437 . 
     The image output interface  438  is connected to the display unit  41  including an LCD, a CRT, and the like. The image output interface  438  outputs a video signal corresponding to image data to the display unit  41 , and the display unit  41  displays an image based on the video signal output from the image output interface  438 . 
     With reference to  FIG. 6 , during the measurement operation, the CPU  201  of the measurement unit  20  temporarily stores in the memory  202  the data (optical information) obtained by digitizing the detection signal output from the detecting section  22  (see  FIG. 5 ). The storage area of the memory  202  is divided into areas for each support portion  22   a.  In each area, the data (optical information) are sequentially stored which are acquired when the cuvette  104  supported by the corresponding support portion  22   a  is irradiated with light having a predetermined wavelength. Thus, the data is sequentially stored in the memory  202  over a predetermined measurement time. When the measurement time elapses, the CPU  201  stops storing the data in the memory  202 , and the CPU  201  transmits the stored data to the control device  40  via the communication interface  203 . The control device  40  processes and analyzes the received data. The control device  40  displays the analysis result on the display unit  41 . 
     (Processing Procedure of Blood Specimen Analyzer) 
     The processing in the measurement unit  20  is mainly performed under the control of the CPU  201  of the measurement unit  20 , and the processing in the control device  40  is mainly performed under the control of the CPU  431  of the control device  40 . When receiving a measurement start instruction input by the user from the control device  40 , the measurement unit  20  starts measurement processing. With reference to  FIG. 11 , when the measurement processing is started, the measurement unit  20  aspirates a predetermined amount of a blood specimen from the specimen container  101  transported by the specimen transporting section, and the measurement unit  20  dispenses the aspirated blood specimen into an empty cuvette  104  on the cuvette table  13 . When also measuring normal plasma as a control sample, the measurement unit  20  aspirates a predetermined amount of the normal plasma from a reagent container  103  containing the normal plasma accommodated in the reagent accommodation section, and the measurement unit  20  dispenses the aspirated blood specimen into an empty cuvette  104 . The measurement unit  20  transfers the cuvette  104  into which the specimen is dispensed to the warming section  24 . The measurement unit  20  warms the plasma in the cuvette  104  to a predetermined temperature (for example, 37° C.). Thereafter, the measurement unit  20  adds a coagulation time measuring reagent and a calcium solution to the cuvette  104  to prepare a measurement sample (step S 11 ). 
     The measurement unit  20  transfers the cuvette  104  to which various reagents are added to the detecting section  22 . The measurement unit  20  irradiates the cuvette  104  with light to measure the measurement sample (step S 12 ). The measurement unit  20  starts measuring the time from the start point, preferably the time from the time point when the calcium solution is added to the cuvette  104 . In this measurement, data (the amount of scattered light or the amount of transmitted light) based on the light with a wavelength of 660 nm is sequentially stored in the memory  202  during the measurement time. At this time, the data is stored in the memory  202  in a state associated with the elapsed time from the start point, preferably the elapsed time from the time point of adding the calcium solution. Then, when the measurement time elapses, the measurement unit  20  stops the measurement, and the measurement unit  20  transmits the measurement result (data) stored in the memory  202  to the control device  40  (step S 13 ). Accordingly, when the control device  40  receives the measurement result (data) from the measurement unit  20  (step S 21 : YES), the control device  40  executes analysis processing on the received measurement result (step S 22 ). That is, the control device  40  calculates, regarding the measurement sample, parameters related to differentiation of a coagulation waveform from the coagulation waveform. The control device  40  may calculate the coagulation time of the measurement sample, the coagulation waveform, the waveform of rate, and the like. After performing the analysis processing, the control device  40  executes display processing of the analysis result (step S 23 ). 
     (Processing Procedure for Acquiring Average Change Rate of Coagulation Rate and Output of Information on Severity of Hemophilia) 
     With reference to  FIG. 12 , an example of the processing flow for acquiring the average change rate of the coagulation rate will be described. However, the present embodiment is not limited to this example. 
     In step S 101 , the acquisition unit  401  of the control device  40  acquires optical information (scattered light intensity, transmittance or absorbance) based on the data (the amount of scattered light or the amount of transmitted light) received from the measurement unit  20 . In step S 102 , the calculation unit  403  acquires a coagulation waveform from the optical information acquired by the acquisition unit  401 . The calculation unit  403  calculates parameters related to differentiation of the coagulation waveform according to the expression stored in the storage unit  402 . The calculation unit  403  may further calculate the coagulation time, the coagulation waveform, the waveform of rate and the like from the optical information acquired by the acquisition unit  401 . Then, the calculation unit  403  calculates, based on the calculation results and the like, the value of Expression 1 according to Expression 1 above stored in the storage unit  402 . 
     In step S 103 , the determination unit  404  determines whether or not the value of Expression 1 calculated by the calculation unit  403  exceeds the reference value stored in the storage unit  402 . When the value of Expression 1 exceeds the reference value, the processing proceeds to step S 104 . In step S 104 , the determination unit  404  transmits to the output unit  405  a determination result that there is not a high possibility of the antibody against a coagulation factor having appeared in the blood specimen. On the other hand, when the value of Expression 1 is equal to or less than the reference value, the processing proceeds to step S 105 . In step S 105 , the determination unit  404  transmits to the output unit  405  a determination result that there is a high possibility of the antibody against a coagulation factor having appeared in the blood specimen. 
     In step S 106 , the output unit  405  outputs the determination result, the output unit  405  displays the determination result on the display unit  41 , or the output unit  405  makes a printer to print the determination result. Alternatively, the determination result may be output by voice. Thus, the determination result can be provided to the user as reference information on the blood specimen. 
     As an example of a screen displaying the analysis result, a screen for displaying the result of analyzing the process of coagulation of a blood specimen using an APTT measuring reagent and a calcium solution will be described with reference to  FIG. 13 . A screen D 1  includes an area D 11  for displaying a specimen number, an area D 12  for displaying a measurement item name, a button D 13  for displaying a detailed screen, an area D 14  for displaying measurement data and time, an area D 15  for displaying measurement results, an area D 16  for displaying analysis information, and an area D 17  for displaying a coagulation waveform and its primary differential curve. 
     In the area D 15 , measurement items and measurement values are displayed. In the area D 15 , “APTT sec” is the activated partial thromboplastin time. In the area D 15 , the values of the parameters related to differentiation of the coagulation waveform such as the value of Expression 1 and |min1| may be displayed. 
     In the area D 16 , analysis items and reference information are displayed. In the area D 16 , “Index” is the value of the parameter related to differentiation of the coagulation waveform used for the determination. “Reference Value (Reference)” is a reference value corresponding to the parameter value used for the determination. “Determination (Reference)” is a determination result by the blood specimen analyzer. In  FIG. 13 , it is shown that there is a high possibility of the antibody against a coagulation factor having appeared in the blood specimen. It is desirable that the diagnosis as to whether or not the antibody against a coagulation factor has appeared in a patient is performed with consideration of not only this judgment result but also information such as other inspection results. Accordingly, “(Reference)” is displayed to indicate that the determination result by the blood specimen analyzer according to the present embodiment and the reference value are reference information. In  FIG. 13 , the determination result is displayed by the letters “Possibility of Appearance of Antibody”, but the determination result may be displayed with a symbol such as a flag or a graphic indicator. Alternatively, the determination result may be output by voice. 
     Hereinafter, the present invention will be described with reference to examples, but is not limited to these examples. 
     EXAMPLES 
     Example 
     Discrimination by Average Change Rate of Coagulation Rate 
     (1) Reagent 
     As commercially available APTT measuring reagents, Thrombocheck APTT-SLA (Sysmex Corporation) and Actin FS (Siemens Healthcare Diagnostics Inc.) were used. As a coagulation initiation reagent containing calcium ions, a 20 mM calcium chloride solution (Sysmex Corporation) was used. 
     (2) Blood specimen • Severe hemophilia A plasma specimen 10 specimens (Severe Haemophilia A; factor VIII activity &lt;1.0 IU/d1): 
     VS-HA specimen 5 specimens (factor VIII activity &lt;0.2 IU/dl) 
     MS-HA specimen 5 specimens (factor VIII activity 0.2 IU/dl to 1.0 IU/dl) • Hemophilia A specimen in which the antibody has appeared 10 specimens: 
     HA-inh 10 specimens (factor VIII activity &lt;0.2 IU/dl) 
     (3) Preparation and measurement of measurement sample 
     For preparing and measuring a measurement sample, a fully automated blood coagulation measurement device CS-2000i (Sysmex Corporation) was used. A blood coagulation analyzing reagent (50 μL) was added to a plasma specimen (50 μL), and the mixture was incubated at 37° C. for 3 minutes. Then, a measurement sample was prepared by adding a 20 mM calcium chloride solution (50 μL). The transmittance of the measurement sample was continuously measured for 420 seconds from the addition of the calcium chloride solution. The following plasma specimens were used. 
     (4) Analysis Results 
     A change with time in transmittance was plotted to obtain a coagulation waveform. The coagulation waveform data was primarily differentiated to obtain waveform data of rate. In addition, time to |min1|, |min1| and time to |min2| were calculated as the coagulation time and the parameters related to differentiation of the coagulation waveform. These parameters were applied to the following Expression 1 to calculate the average change rate of the coagulation rate. The results are shown in  FIG. 14 . 
       [Mathematical Expression 2] 
       (½×|min1|)/(time to |min1|−time to |min2|)  Expression 1
 
     As is apparent from  FIG. 14 , the specimen (HA-inh) in which the antibody has appeared and the severe hemophilia A specimens (VS-HA, MS-HA) could be distinguished with very high accuracy (p&lt;0.01) by comparing each average change rate of the coagulation rate calculated with the Expression 1 above. As shown in a comparative example described later, these specimens are distinguished with p&lt;0.05 with known parameters. The above results are superior in that it is possible to distinguish specimens (HA-inh) in which the antibody has appeared and the severe hemophilia A specimens (VS-HA, MS-HA) with higher accuracy than known parameters. According to the discrimination by the parameters calculated by Expression 1 above, the probabilities of false positives and false negatives can be suppressed. As a result, VS-HA with a factor VIII activity of less than 0.2 IU/dl and hemophilia in which the antibody has appeared can be discriminated with higher accuracy than before, and thus it is possible to select a treatment policy suitable for each patient. 
     Comparative Example 
     Discrimination by Maximum Coagulation Rate |min1| 
     With respect to the specimen (HA-inh) in which the antibody has appeared and the severe hemophilia A specimens (VS-HA, MS-HA), the parameters related to differentiation acquired in the coagulation waveform analysis in the above example |min2| (maximum coagulation rate) were compared. The results are shown in  FIG. 15 . 
     As is apparent from  FIG. 15 , the specimen (HA-inh) in which the antibody has appeared and the severe hemophilia A specimens (VS-HA, MS-HA) could be distinguished (p&lt;0.05) by comparing each of the maximum coagulation rates. However, the specimens could not be distinguished with p of less than 0.01. That is, the discrimination based on the maximum coagulation rate is not so highly accurate as the discrimination results based on the parameter calculated by Expression 1. In the discrimination based on the maximum coagulation rate, the probabilities of false positives and false negatives cannot be suppressed as the discrimination is made by the parameter calculated with Expression 1.