The Antiplatelet Drug Target in Atherosclerotic Diseases
P. R. Belcher,
A. J. Drake-Holland,
M. I.M. Noble.
The aim of this review is (1) to give a rationale for anti-platelet therapy based on mechanisms of platelet rich arterial thrmbosis, (2) to point out the pitfalls involved in monitoring therapy with platelet function tests and (3) to outline the potential clinical applications of such therapy based on the various modes of action of anti-platelet drugs. The primary event in arterial thrombosis is platelet-mediated, either due to increased shear or exposed collagen, followed by fibrin-rich thrombosis. Anti-platelet therapy needs to be monitored but most platelet function tests, now in use, do not reflect in vivo function; the anticoagulant used for blood samples removes extra-cellular calcium ions, platelets are often separated before the test, or very high doses of agonist are used: all of these can give misleading results. We review means whereby platelet function can be monitored in whole blood samples anticoagulated with the pure thrombin inhibitor, hirudin. We review the available methods of modifying platelet activity and are particularly interested in agents that do not cause bleeding. Present therapy causes bleeding by interference with COX1, the P2Y12 receptor or the platelet fibrinogen receptor complex, all of which can be associated with bleeding complications. In contrast, serotonin does not influence formation of haemostatic layers although it is implicated in shear-induced aggregation and thrombus propagation by positive feedback from the large amount of intraplatelet serotonin. We suggest that further investigation of selective serotonin 5HT2 antagonism would allow effective management of intravascular thrombosis without bleeding complications. This would be safer both as prophylaxis and would also allow cardioprotection of vascular patients undergoing surgical operations.
Keywords: Thrombosis, atherothrombosis, acalcaemia, serotonin, platelets, microaggregation, macroaggregation, shear, cardioprotection
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