Summary
The objective of this study was to determine if orally-administered PD0348292, a direct
specific factor Xa inhibitor, inhibits thrombosis following porcine carotid arterial
injury comparably to aspirin or clopidogrel alone or in combination. We further sought
to determine whether the antithrombotic efficacy in vivo could be predicted using
an ex-vivo perfusion chamber. Oral treatments included: PD0348292 (0.4, 0.9, or 4.3
mg/kg); PD0348292 (0.4 mg/kg) plus aspirin (325 mg); aspirin; clopidogrel (75 mg);
aspirin plus clopidogrel; or vehicle (n=6–10/group). Aspirin and clopidogrel were
administered 27 and four hours pre-injury and PD0348292 or vehicle was administered
four hours pre-injury. Both carotid arteries were crush-injured, and thrombus was
measured by detection of 111In-platelets over 30 minutes. Prior to injury, the antithrombotic
efficacy was assessed by ex-vivo perfusion chamber platelet deposition. PD0348292
produced dose-dependent prothrombin time (0.9- to 2.9-fold) and aPTT (1.4- to 2.5-fold)
prolongations. Bleeding times were significantly prolonged in each active drug group
compared to vehicle, but were not significantly different between drug groups. PD0348292
significantly inhibited arterial platelet deposition (x106/cm2) at 4.3(549 ± 1,066),
0.9 (399 ± 162) and 0.4 mg/kg (531 ± 470) compared to vehicle (2,242 ± 1,443). Aspirin
(992 ± 973), clopidogrel (537 ± 483), clopidogrel plus aspirin (228 ± 66) or PD0348292
plus aspirin (558 ± 317) also significantly inhibited platelet deposition, although
these values were not significantly different than with any dose of PD348292. Perfusion
chamber platelet deposition correlated significantly with in-vivo anti-thrombotic
response. In conclusion, PD0348292 inhibited arterial thrombosis comparable to aspirin
plus clopidogrel. Perfusion chamber methodology may be useful in predicting in-vivo
antithrombotic efficacy.
Keywords
Thrombosis - platelets - anticoagulants - factor Xa