Recombinant factor VIIa reverses the inhibitory effect of aspirin or aspirin plus clopidogrel on in vitro thrombin generation

Background: Antiplatelet drugs constitute the therapy of choice for acute coronary syndromes, but bleeding can be a side-effect requiring treatment. Restoration of normal platelet activity is also mandatory before urgent surgery. This study investigated: (a) whether a regimen of aspirin or clopidogrel plus aspirin significantly inhibited platelet thrombin generation (TG); and (b) the reversal of this inhibition by recombinant activated factor VII (rFVIIa). Methods and results: TG was evaluated by the lag time, time to peak, peak of TG, and area under the curve after 35 min of assay (AUC(0 -> 35 min)). These measures were examined by the calibrated automated thrombography method in 22 healthy volunteers, 22 volunteers after a 100 mg day(-1) aspirin intake (200 mg first day) for 5-7 days, and 22 healthy volunteers after aspirin 100 mg day(-1) (200 mg first day) plus clopidogrel 75 mg day(-1) (300 mg first day) for 4-7 days. The TG parameters were measured under basal conditions and after platelet stimulation by sodium arachidonate (AA), adenosine 5'-diphosphate (ADP), collagen and rFVIIa in normal non-aspirinated as well as in vivo aspirinated platelet-rich plasma (PRP) or aspirin plus clopidogrel PRP. Lag time was shorter (P < 0.05), and peak of TG and AUC(0 -> 35 min) were significantly greater (P < 0.01 for both), in PRP activated with ADP, collagen, AA or FVIIa than in non-activated PRP from normal subjects. Both non-activated PRP and activated PRP prepared from platelets obtained from volunteers after aspirin intake showed significant prolongation of the time parameters but there was less effect on peak of TG and AUC(0 -> 35 min). For most parameters, aspirin plus clopidogrel administration showed to be more effective compared with the effect obtained by aspirin alone. When rFVIIa was added to ASA-PRP or ASA + Clop PRP, lag time (P < 0.001 for all) and time to peak (P < 0.001-0.017) were significantly shortened, indicating that rFVIIa reverses the inhibitory effect of these anti-aggregating agents. Conclusion: Platelets activated by AA, ADP, collagen or FVIIa triggered TG. This effect was inhibited by aspirin plus clopidogrel, suggesting an additional benefit of this drug combination for preventing thrombosis. rFVIIa reverses the inhibitory effect of aspirin or aspirin plus clopidogrel, and could be useful for bleeding complications or when acute surgery is needed during treatment with these antiplatelet drugs.