Procoagulant platelets in hemostasis and thrombosis

Procoagulant platelets are characterized by sustained high cytosolic Ca2+, surface exposure of phosphatidylserine (PS) and P-selectin, and a balloon-shaped morphological transformation. These features strongly facilitate the generation of coagulation factor Xa and thrombin on the platelet membrane. Here, we provide a referenced summary of 136 mouse and human genes and proteins, implicated in the formation of procoagulant, PS-exposing platelets. A much smaller set of mouse genes and proteins is reported to be involved in thrombin-induced clot retraction. Based on this literature inventory, we generated an integrated signalling scheme of the multiple membrane receptors and channels, cytosolic, mitochondrial and plasma proteins contributing to platelet procoagulant activity and PS exposure. In the second part of this review, we describe the formation and roles of procoagulant platelets as published for mouse models of haemostasis, thrombosis and thrombo-inflammation. We also overview the evidence for procoagulant platelet formation in human arterial thrombosis, stroke, venous thromboembolism, trauma, COVID-19, and immunemediated thrombotic disorders. Finally, we define potential therapeutic targets that, once clinically validated, can serve as tailored treatment options to selectively suppress the thrombogenic activity of procoagulant platelets.