Many of the common problems in clinical practice today relate to thrombosis. The underlying final pathophysiological process in myocardial infarction and stroke is thrombus formation (thrombogenesis). Common cardiovascular disorders such as atrial fibrillation and heart failure are also associated with thrombogenesis. Thrombosis is also a clinical problem in various cancers and after surgery, especially orthopaedic.
Routes to inhibiting platelet function
Over 150 years ago Virchow recognised three prerequisites for thrombogenesis: abnormal blood flow, vessel wall abnormalities, and blood constituent abnormalities. This concept has been extended by modern knowledge of the endothelial function, flow characteristics, and blood constituents including haemorheological factors, clotting factors, and platelet physiology. As thrombus consists of platelets and fibrin (and often bystanding erythrocytes) optimum antithrombotic prophylactic therapy can and should be directed towards both.
### Aspirin and agents acting on the cyclo-oxygenase pathway
Aspirin irreversibly inhibits cyclo-oxygenase by acetylation of amino acids that are next to the active site. In platelets, this is the rate limiting step in synthesis of thromboxane A2, and inhibition occurs in the megakaryocyte so that all budding platelets are dysfunctional. Because platelets are unable to regenerate fresh cyclo-oxygenase in response, the effect of aspirin remains as long as the lifespan of the platelet (generally about 10 days). A severe weakness of aspirin is that its specificity for cyclo-oxygenase means it has little effect on other pathways of platelet activation. Thus aspirin fails to prevent aggregation induced by thrombin and only partially inhibits that induced by ADP and high dose collagen. Antithrombotic doses used in clinical trials have varied widely from less than 50 mg to over 1200 mg/day, with no evidence of any difference in clinical efficacy. Absorption is over 80% with extensive presystemic metabolism to salicylic acid. Only the parent acetylsalicylic acid has any significant effect on platelet function.
Key components of Virchow's triad (VWF=von Willebrand factor)
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Contraindications …