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Multiple platelet signaling and synthetic pathways are necessary for the optimal propagation and stabilization of the forming thrombus. Mutations in platelet receptors, signaling proteins, and synthetic pathways have been identified in patients with granule release and aspirin-like defects. Patients with platelet granule release and aspirin-like defects typically have mild mucocutaneous bleeding. Rare patients have been identified with an isolated defect in platelet procoagulant activity.
Defects in pathways mediating thromboxane A2 synthesis, ADP release and responsiveness, and platelet procoagulant activity have been identified in patients with congenital disorders of hemostasis ( Fig. 99.1 ). Representative disorders are described below.
Thromboxane (TxA2) is an agonist released by activated platelets, which supports both autocrine (self) and paracrine (adjacent) platelet activation. The importance of this pathway in thrombus formation is illustrated by the clinical effectiveness of aspirin. Aspirin’s antithrombotic effects are mediated through irreversible inhibition of cyclooxygenase, a key enzyme in the TxA2 synthetic pathway. Aspirin-like platelet defects are observed in patients with cyclooxygenase deficiency, and a similar phenotype is observed in patients with a deficiency of another enzyme necessary for TxA2 synthesis, thromboxane synthase. TxA2’s effectiveness depends on its ability to bind and activate the G-protein-coupled TxA2 receptor, and mutations in the TxA2 receptor have been found in kindred with a mild-platelet function disorder.
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