ROLE OF ADP AND THROMBOXANES IN HUMAN THROMBUS FORMATION IN EX-VIVO MODELS

Adenosine diphosphate (ADP) and prostaglandin derivatives play importa nt roles in thrombogenesis. Their roles in platelet function have been extensively studied for more than three and two decades, respectively , Of further importance for thrombogenesis, and perhaps for atherogene sis as well, is that these compounds are involved in the regulation of vascular wall tone, both as constrictors and dilators, The aim of thi s brief essay is to highlight the relative importance of ADP and TxA(2 ) in collagen-induced thrombus formation at various well-defined shear conditions, To achieve this goal, we employed a human ex vivo model o f thrombus formation, because well-defined and reproducible blood shea r conditions are best created in such a device, The blood flow conditi ons varied from those encountered in healthy veins to vessels with sev ere atherosclerotic disease, These experiments were performed as parts of clinical phase I studies with novel antagonists of ADP-or TxA(2)-i nduced platelet aggregation, Probes for ADP and TxA(2) included the AD P receptor antagonist clopidogrel and the TxA(2) receptor antagonist l inotroban, respectively, Their antithrombotic activities mere compared with results obtained with the cyclo-oxygenase inhibitor aspirin, The se studies demonstrated a significant effect of both ADP and TxA(2) on collagen-induced ex vivo thrombus formation, Whereas ADP promoted pla telet thrombus formation independently of the local shear, TxA(2) prom oted platelet thrombus formation at high arterial shear only, and incr easingly by increasing shear, However, at blood flow conditions trigge ring shear-induced platelet activation and aggregation, TxA(2) formati on did not affect collagen-induced platelet thrombus formation since a spirin administration was insensitive to the thrombotic response, This contrasts with the need for ADP in shear-induced platelet aggregation , Thus, the function of ADP in human ex vivo platelet thrombus formati on appears more global than the role of TxA(2). These observations are in agreement with recent published clinical findings.