Source: https://patents.google.com/patent/US8574828
Timestamp: 2018-04-20 22:12:50
Document Index: 286205419

Matched Legal Cases: ['Application No. 200880022878', 'Application No. 10193726', 'Application No. 2006240257', 'Application No. 10193726', 'Application No. 2010', 'Application No. 2010', 'Application No. 2008', 'Application No. 2008', 'Application No. 2010', 'Application No. 10', 'Application No. 10', 'Application No. 08755007', 'Application No. 200880014577', 'Application No. 08754988']

US8574828B2 - Controlled platelet activation to monitor therapy of ADP antagonists - Google Patents
Controlled platelet activation to monitor therapy of ADP antagonists Download PDF
US8574828B2
US8574828B2 US12876730 US87673010A US8574828B2 US 8574828 B2 US8574828 B2 US 8574828B2 US 12876730 US12876730 US 12876730 US 87673010 A US87673010 A US 87673010A US 8574828 B2 US8574828 B2 US 8574828B2
US12876730
US20110065125A1 (en )
A method is provided of determining whether an individual has reduced ability to form platelet thrombi due to inhibition of platelet activation initiation, signal transduction and/or GPIIb/IIIa blockade. A blood sample is obtained from the individual being assessed. The blood sample is mixed in combination with 1) an anticoagulant; 2) sufficient buffer to maintain the pH and salt concentration of the anticoagulated blood within a range suitable for platelet aggregation; 3) a platelet GPIIb/IIIa receptor ligand immobilized on a solid surface; 4) one or more agents to enhance a signal transduction pathway and 5) a receptor activator. The combination is incubated under conditions for agglutinating particles. Platelet-mediated agglutination is assessed in the agitated mixture. The absence of agglutination indicates that the individual has a reduced ability to form platelet thrombi.
This application is a continuation of U.S. application Ser. No. 10/886,155, filed Jul. 6, 2004, now U.S. Pat. No. 7,790,362, which claims the benefit of U.S. Ser. No. 60/485,703, filed Jul. 8, 2003. Both applications are incorporated herein by reference in their entireties.
Accordingly an object of the present invention is to provide methods and kits for conducting an assay for platelet function activity on a blood sample.
FIG. 1 illustrates the mean response of one individual.
The particles may be solid (e.g., comprised of organic and inorganic polymers or latex), oil droplets (e.g., hydrocarbon, fluorocarbon, silicon fluid), or vesicles (e.g., synthetic such as phospholipids or natural such as cells and organdies). The solid particles are normally polymers, either addition or condensation polymers, which are readily dispersible in a liquid Medium. Examples of suspendable particles are polymeric materials such as latex, lipid bilayers, oil droplets, cells and hydrogels. Other particle compositions include polymers, such as nitrocellulose, cellulose acetate, poly(vinyl chloride), polyacrylamide, polyacrylate, polyethylene, polypropylene, poly(4-methylbutene), polystyrene, polymethacrylate, poly(ethylene terephthalate), nylon, poly(vinyl butyrate), polysaccharides such as dextrans and modified dextrans, etc.; either used by themselves or in conjunction with other materials. The solid particles can be comprised of polystyrene, polyacrylamide, homopolymers and copolymers of derivatives of acrylate and methacrylate, particularly esters and amides, silicones and the like.
As mentioned above, the compound is coated on the particles. Usually, the compound is covalently attached to particles. Such covalent attachment can be accomplished by well-known techniques, commonly available in the literature. See, for example, “Immobilized Enzymes,” Ichiro Chibata, Halsted Press, New York (1978) and Cuatrecasas, J. Biol. Chem., 245:3059 (1970). Briefly, as mentioned above, the surface of the particle may be polyfunctional or be capable of being polyfunctionalized. A wide variety of functional groups are available or can be incorporated. Functional groups include carboxylic acids, aldehydes, amino groups, cyano groups, ethylene groups, hydroxyl groups, mercapto groups and the like. The manner of linking a wide variety of compounds to surfaces is well known and is amply illustrated in the literature (see above). The attachment of the side member may be directly by a bond or indirectly through the intermediacy of a linking group. The length of a linking group may vary widely, depending upon the nature of the side member and of the particle.
The dyes absorb light in the range of about 750 nm-900 nm, particularly in the range of about 750-850 nm. For samples with high levels of red blood cells, the light is at about 800 nm±10 nm, which is the isobestic point for oxyhemoglobin and reduced hemoglobin. The amount of dye employed with the particles varies with the extinction coefficient of the dye in the light range of interest, the required sensitivity of the assay, the size of the particles, the mode of binding of the dye to the particles, compatibility of the dye with the particle matrix, and the like. Usually, the amount of dye incorporated is in the range of about 1 to 20 weight percent, more usually 5 to 15 weight percent. Dyes which find a particular use in the present invention are phthalocyanines. Metal free phthalocyanines absorb at approximately 700 nm (e=162,000). The metal complexes shift the absorption to either shorter or longer wavelength, most metals shift the absorption to a much shorter wavelength, but some, such as lead absorb at much longer wavelength than the metal free phthalocyanines.
The sample may be any solution, synthetic or natural, to be analyzed where the sample has been subject to an effect from a P2Y12 antagonist, particularly, a thienopyridine, potentially in combination with aspirin. The term sample includes biological tissue, including body fluids, from a host, and so forth. The sample can be examined directly or may be pretreated, usually. The present invention has particular application to samples that comprise platelets, including body fluids such as, for example, whole blood, platelet-containing blood fractions such as plasma, and the like. In one embodiment the invention has particular application to whole blood samples. The amount of the sample depends on the nature of the sample. For fluid samples such as whole anticoagulated blood, the amount of the sample is usually about 30 μl to 5000 μl, preferably, about 100 to 300 μl. The term “sample” includes unprocessed samples directly from a patient or samples that have been pretreated and prepared in any convenient liquid medium, usually an aqueous medium (e.g., sodium citrate).
After the sample has been combined with the reagents, desirably it will be heated to a temperature above room temperature, but below that which would interfere with the assay, so as to insure that the temperature can be controlled without adversely affecting the assay result. Desirably, the temperature should be at least 25°, preferably in the range of 30-40° C., more preferably about 37° C. The reaction medium is usually gently agitated upon combining of the reagents with the sample and during the period of the reaction. Agitation is sufficient to achieve and maintain homogeneity in the assay samples. The total time of the readings from the zero time (time of mixing), may range from about 10 sec. to 10 min., more usually about 30 sec. to 8 min., and preferably about 30 sec. to 3 min. The data may be analyzed by any convenient means, particularly using an algorithm that can manipulate the data in relation to calibrators and/or controls.
The level of agglutination is an indication of the platelet function activity of the sample tested. The level of agglutination may be compared against a standard of known platelet function activity. Usually, the result will be compared to a calibrator, which may be performed concomitantly or have been performed previously or, may be provided as a standard curve.
The above assays preferably may be conducted in a device, which allows the reactions in accordance with the present invention to occur and which measures the results thereof. The instrument should assess platelet function based upon the ability of activated platelets to bind fibrinogen. As activated platelets bind and agglutinate fibrinogen-coated particles, there is an increase in light transmittance. In general, an instrument to measure the result of the assay is one that can measure agglutination. Preferably, the instrument measures a change in optical signal due to agglutination. Suitable instruments include, by way of illustration and not limitation a kinetic spectrophotometer, Ultegra System® instrument (commercially available from Accumetrics, San Diego, Calif. and employed for rapid platelet function activity measurements on normal samples), or the like.
The Ultegra® System instrument is a turbidometric based optical detection system, that measures platelet induced aggregation as an increase in light transmittance. The system consists of an analyzer, disposable cartridge and controls. The cartridge contains reagents based on microparticle agglutination technology. The quality control system includes an electronic control, two levels of assayed “wet” controls (WQC), an in-cartridge humidity sensor, an in-packaging temperature indicator, and a test for concurrence of two assay channels. The analyzer controls assay sequencing, establishes the assay temperature, controls the reagent-sample mixing for the required duration, determines the degree of platelet function, displays the result and performs self-diagnostics. For use in the present methods the test cartridge of the system contains a lyophilized preparation comprising particles with covalently attached GPIIb/IIIa receptor ligand, a composition of ADP and PGE1, and buffer. The patient sample is usually citrated whole blood, which is automatically dispensed from the blood collection tube into the cartridge by the analyzer, with no blood handling required by the user. The interaction is monitored by the infrared absorbency characteristics of the particles. As the particles interact with the platelets, the agglutination of the particles is measured through the optical system of the Ultegra™ analyzer. The agglutination is detected as an increase in the transmission of infrared light through the sample. The reaction kinetics are analyzed and translated into “P2Y12 Response Units”, PRU.
In another embodiment of the present invention is a kit that includes in packaged combination a lyophilized preparation comprising particles with covalently attached fibrinogen, composition of ADP and PGE1, and buffer. The lyophilized preparation may be present in a reaction container such as a cartridge used in the instrument of analysis. For the aforementioned Ultegra® System, the lyophilized preparation may be placed in the outer wells of the four-well cartridge used in the analyzer. The kit may also include a sample collection container and/or a device for carrying out the present method. The relative amounts of reagents may be varied widely to provide for concentrations in solution of the reagents that substantially optimize the sensitivity of a determination.
The following examples are offered by way of illustration and without limitation. Parts and percentages are by weight unless otherwise indicated
Dose response testing was performed with ADP (Chronolog) and PGE1 (SIGMA) at 20 μM and 22 nM final concentrations respectively. ADP was diluted in Hepes/Saline, pH 7.4 buffer to a final concentration of 200 μM prior to use on the aggregometer. PGE1 was diluted in Hepes/Saline, pH 7.4 buffer to a final concentration of 220 nM prior to use on the aggregometer. A P2Y12 receptor blocker was diluted in DMF to final concentrations of 1 mM, 2 mM and 5 mM.
Five microliters of the diluted P2Y12 compound were spiked into 5 mL whole blood. Samples were inverted and incubated for one hour at room temperature. The whole blood baseline sample did not receive any additive. Once incubation was complete, whole blood samples were spun at 1500 rpm for 15 minutes for platelet rich plasma (PRP) and 3500 rpm for 15 minutes for platelet poor plasma (PPP). Platelet count was adjusted to approximately 250,000 μL for each sample using PPP.
1. A method for measuring inhibition of platelet aggregation by a P2Y12 antagonist, comprising the steps of: (a) providing a platelet containing blood sample from an individual treated with a P2Y12 antagonist; (b) contacting the platelet containing blood sample with particles comprising an attached GPIIb/IIIa receptor ligand, adenosine diphosphate (ADP) and prostaglandin El (PGE1) under conditions suitable for agglutination of said particles mediated by the platelet in the blood sample, and (c) assessing the agglutination to determine the level of inhibition of platelet aggregation by the P2Y12 antagonist in the individual, wherein the level of agglutination indicates whether the individual has reduced ability to form platelet aggregation in response to the P2Y12 antagonist treatment.
2. The method of claim 1, wherein the P2Y12 antagonist is a thienopyridine.
3. The method of claim 2, wherein the thienopyridine is clopidogrel.
4. The method of claim 1, wherein the platelet containing blood sample is from an individual treated with a P2Y12 antagonist and aspirin.
5. The method of claim 1, wherein the particles comprise polystyrene or latex.
6. The method of claim 1, wherein the particles comprise an infrared dye, the contact between the platelet containing blood sample and the particles forms an assay mixture, and the agglutination of the particles mediated by the platelet is assessed by irradiating the assay mixture with a light in the infrared spectrum, and assessing the transmission of infrared light from the assay mixture.
7. The method of claim 1, wherein the GPIIb/IIIa receptor ligand comprises a substance selected from the group consisting of fibrinogen, monoclonal antibody 10E5, monoclonal antibody c7E3, von Willebrand factor, fibronectin, vitronectin, a ligand that has an arginine-glycine-aspartic acid (RGD) sequence, a peptide that mimics the RGD sequence, and a peptidomimetic that mimics RGD sequence.
8. The method of claim 1, wherein the GPIIb/IIIa receptor ligand is fibrinogen.
9. The method of claim 1, which is conducted at a temperature ranging from 30° C. to 40° C., and the total time of the readings from the time of the contact among the platelet containing blood sample, the particles comprising an attached GPIIb/IIIa receptor ligand, ADP and PGE1 ranges from about 10 seconds to about 10 minutes.
10. The method of claim 1, wherein the platelet containing blood sample is a whole blood sample or a plasma sample.
11. The method of claim 10, wherein the plasma sample is a platelet rich plasma (PRP) sample.
12. The method of claim 1, wherein the particles, ADP and PGE1 are contained in an assay medium.
13. The method of claim 12, wherein the particles, ADP and PGE1 are contained in an assay medium on a disposable cartridge.
14. The method of claim 12, wherein the assay medium has an absorption peak at about 800 nm.
15. The method of claim 2, wherein the thienopyridine is ticlopidine.
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