Aspirin and thrombinogenesis

Abstract

Aspirin (ASA) not only inhibits platelet function, but increase in the rate of factor Va inactivation [12]. In patients also exerts additional anticoagulant actions. These actions are coupled with prevention of platelet activation by thromboxane (TX) A2, because only activated platelets are the source of prothrombinase and tenase complexes on their surface. Thus, ASA decreases thrombin formation in vitro and in vivo, in blood emerging from small skin incisions [1,2]. Yet, some patients experience recurrent arterial thrombotic events despite long-term preventive ASA therapy. Various reasons may lead to such episodes, one of them being so-called ASA resistance [3]. This phenomenon is still poorly defined; it could include the clinical inability of ASA to protect patients from cardiovascular events, as well as the failure of ASA to inhibit platelet function in a laboratory test system (e.g. platelet aggregation) [4], or to suppress overall TXA2 production [5]. There are at least two possible explanations for the ASA resistance phenomenon. One is hypercholesterolemia, probably by its virtue to change the physico-chemical properties of the platelet cell membrane [6]. Thus, cholesterol and atherogenic lipoproteins may increase platelet aggregability and TXA2 production [7,8], and support assembly of the prothrombinase complex and thrombin generation [9]. In patients with markedly elevated and borderline high cholesterol levels, ASA in a commonly used doses (75–300 mg/day) has negligible effect on thrombin formation, as measured by microquantitative analytical technique, at the site of microvascular injury [10,11]. On the other hand, 3 months treatment of such patients with simvastatin significantly depresses blood clotting in vivo, mainly through a reduction in thrombin generation [10,11]. Here, statin treatment seems to interfere with several interconnected steps leading to thrombin formation. They include the reduction in the rates of prothrombin activation, factor Va generation, fibrinogen cleavage, factor XIII activation, and a parallel