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Figure 6 Proposed role of cyclooxygenase (COX)-2 and COX-1 in shear stress-induced platelet aggregation. Platelet aggregability is under continuous control of COX-2–induced endothelial prostacyclin (PGI₂) that decreases calcium (Ca²⁺) by increasing the levels of cyclic adenosine monophosphate (cAMP). Shear stress starts the sequence of events by "unrolling" the plasma von Willebrand factor (vWf) and possibly by platelet deformation. Binding of the vWf A1-domain to platelet glycoprotein (GP) Ib receptors triggers intracellular Ca²⁺ mobilization with subsequent release of adenosine diphosphate (ADP) from dense granules and vWf from the alpha-granules. Adenosine diphosphate stimulates 5'-diphosphate (P2Y₁₂)-receptors on the same and other platelets to activate GP IIb/IIIa receptors that bind fibrinogen and vWf, thereby causing aggregation. Platelet COX-1–induced thromboxane (TXA₂)-formation reinforces aggregation at low or moderate shear stress but not at high shear stress (dotted lines). Shear stress-induced platelet aggregation can be prevented by blockade () of P2Y₁₂-receptors with clopidogrel.

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