Role of ADP and thromboxanes in human thrombus formation in ex vivo models

Adenosine diphosphate (ADP) and prostaglandin derivatives play important 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 atherogenesis as well, is that these compounds are involved in the regulation of vascular wall tone, both as constrictors and dilators. The aim of this 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 of thrombus formation, because well-defined and reproducible blood shear conditions are best created in such a device. The blood flow conditions varied from those encountered in healthy veins to vessels with severe atherosclerotic disease. These experiments were performed as parts of clinical phase I studies with novel antagonists of ADP- or TxA(2)-induced platelet aggregation. Probes for ADP and TxA(2) included the ADP receptor antagonist clopidogrel and the TxA(2) receptor antagonist linotroban, respectively. Their antithrombotic activities were compared with results obtained with the cyclo-oxygenase inhibitor aspirin. These studies demonstrated a significant effect of both ADP and TxA(2) on collagen-induced ex vivo thrombus formation. Whereas ADP promoted platelet thrombus formation independently of the local shear, TxA(2) promoted platelet thrombus formation at high arterial shear only, and increasingly by increasing shear.However, at blood flow conditions triggering shear-induced platelet activation and aggregation, TxA(2) formation did not affect collagen-induced platelet thrombus formation since aspirin 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 formation appears more global than the role of TxA(2). These observations are in agreement with recent published clinical findings.