Platelets are key players in cardiovascular disease, and platelet aggregation represents a central pharmacologic target, particularly in secondary prevention. However, inhibition of adenosine diphosphate and thromboxane signaling has low efficacy in preventing venous thromboembolism, necessitating the inhibition of the plasmatic coagulation cascade in this disease entity. Anticoagulation carries a significantly higher risk of bleeding complications, highlighting the need of alternative therapeutic approaches. We hypothesized that procoagulant activation (PA) of platelets promotes venous thrombus formation and that targeting PA could alleviate venous thrombosis. Here, we found elevated levels of procoagulant platelets in the circulation and in thrombi of patients with deep vein thrombosis (DVT) and pulmonary embolism, and in mice developing DVT following inferior vena cava stenosis. Furthermore, we detected PA of recruited platelets within murine venous thrombi and human pulmonary emboli. Mice with platelet-specific deficiency in central pathways of PA—cyclophilin D and transmembrane protein 16F—were more resistant toward low flow–induced venous thrombosis. Finally, we found that a clinically approved carbonic anhydrase inhibitor, methazolamide, reduced platelet procoagulant activity and alleviated murine thrombus formation without affecting trauma-associated hemostasis. These findings identify an essential role of platelet procoagulant function in venous thrombosis and delineate novel pharmacologic strategies targeting platelets in the prevention of venous thromboembolism.

中文翻译：

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促凝血小板活化促进静脉血栓形成


血小板是心血管疾病的关键参与者，血小板聚集是核心药理学靶点，尤其是在二级预防中。然而，抑制二磷酸腺苷和血栓素信号转导在预防静脉血栓栓塞方面效果不佳，因此需要抑制该疾病实体的血浆凝血级联反应。抗凝治疗发生出血并发症的风险明显更高，这凸显了替代治疗方法的必要性。我们假设血小板的促凝血激活 （PA） 促进静脉血栓形成，靶向 PA 可以缓解静脉血栓形成。在这里，我们发现深静脉血栓形成 （DVT） 和肺栓塞患者以及下腔静脉狭窄后发生 DVT 的小鼠的循环和血栓中促凝血小板水平升高。此外，我们在小鼠静脉血栓和人肺栓塞中检测到募集血小板的 PA。在 PA 的中枢途径（亲环蛋白 D 和跨膜蛋白 16F）中具有血小板特异性缺陷的小鼠对低流量诱导的静脉血栓形成更具抵抗力。最后，我们发现临床批准的碳酸酐酶抑制剂甲唑胺降低了血小板促凝活性并减轻了小鼠血栓形成，而不会影响创伤相关止血。这些发现确定了血小板促凝功能在静脉血栓形成中的重要作用，并描述了针对血小板预防静脉血栓栓塞的新药理学策略。