Device and methods for identifying and treating aspirin non-responsive patients

• US 7,358,091 B2
• Filed: 12/14/2005
• Issued: 04/15/2008
• Est. Priority Date: 12/14/2004
• Status: Expired due to Fees

• Current Assignee: Alexion Pharmaceuticals Incorporated (Astrazeneca PLC)
• Original Assignee: Portola Pharmaceuticals, Inc. (Astrazeneca PLC)
• Inventors: Andre, Patrick, Stephens, Gillian, Phillips, David R.
• Primary Examiner(s): Weber; Jon
• Assistant Examiner(s): MARTIN, PAUL C
• Application Number:
  US11/304,054
• Publication Number:
  US 20060160165A1
• Time in Patent Office: 853 Days
• Field of Search: None
• US Class Current: 436/69
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: G01N 33/86 involving blood coagulating time or factors, or their receptors
• CPC Class Codes: G01N 33/9486 Analgesics, e.g. opiates, aspirine

Abstract

The present invention relates to methods and compositions for identifying and treating subjects in need of antithrombotic therapies but who are not responsive to aspirin.

Claims

1. A method of evaluating aspirin responsiveness in a subject, comprising:

(a) perfusing a blood sample from a subject through a channel in a perfusion device, wherein the channel has a coating which produces a blood deposit when exposed to blood and wherein the perfusion device comprises a pump which draws the blood through the channel at a selected shear rate, producing a blood deposit;

wherein the perfusion device provides real time measurements of (1) the thrombotic profile of aspirin effects in addition to P2Y₁₂ antagonism in a collagen-coated perfusion chamber assay under arterial shear rates and (2) arachidonic acid/shear-induced platelet aggregation assay in whole blood under high shear rates; and

(b) determining a status of aspirin responsiveness by measuring the level of blood deposited in the chamber and comparing the measured level of deposited blood with a control level of deposited blood, wherein said control level is selected from the group consisting of (1) a level measured using a sample of blood from said subject which has been treated with aspirin;

(2) a level measured using a sample of blood from said subject which has been contacted with a thromboxane A2 receptor antagonist; and

(3) a level previously determined to correspond to a status of aspirin responsiveness.

2. The method of claim 1, wherein whole unfractionated blood is pumped through the perfusion device.

3. The method of claim 1, wherein the blood sample is not treated with an anticoagulant.

4. The method of claim 1, wherein the blood sample is treated with an anticoagulant.

5. The method of claim 4, wherein the anticoagulant is selected from the group consisting of citrate, phenylalanine-proline-arginine-chloromethylketone and heparin.

6. The method of claim 1, wherein said selected shear rate is an arterial shear rate.

7. The method of claim 1, wherein said perfusion device further comprises a substantially flat transparent housing, wherein said channel extends through the housing with an inlet end for receiving a continuous flow of blood and an outlet end for discharging the blood.

8. The method of claim 1, wherein said coating comprises a coating selected from a group consisting of fibrillar collagen type III, fibrillar collagen type I, fibrinogen and tissue factor.

9. The method of claim 1, wherein the rate of blood deposit is sufficient to determine the extent of aspirin responsiveness within approximately 5 minutes of the start of perfusion.

10. The method of claim 1, wherein the measurement of the rate of blood deposit comprises

obtaining images of the deposited blood, and

calculating the levels of deposited blood from the images, wherein said images are obtained at least once every ten seconds during perfusion.

11. The method of claim 1, wherein said coating is human type III collagen and wherein said subject has been administered aspirin, further comprising the addition of an ADP-receptor antagonist to the sample, wherein said concentration of said antagonist in the sample is sufficient to cause a 50% inhibition of platelet aggregation relative to a sample which has been treated with aspirin but not treated with said ADP-receptor antagonist.

12. The method of claim 11, wherein said concentration of platelet ADP-receptor antagonist is approximately 10 μ

M.

13. The method of claim 1, wherein said method is insensitive to the presence of therapeutic amounts of platelet ADP-receptor antagonists in the subject'"'"'s bloodstream.

14. The method of claim 1, wherein the subject has previously been administered a compound selected from the group consisting of a GP IIb-IIIa inhibitor, dipyridamole, PLAVIX (clopidogrel bisulfate), (ticlopidine HCI), or a non-steroidal anti-inflammatory drug.