Procoagulant platelets: novel players in thromboinflammation

Abstract

Platelets play a key role in maintaining hemostasis. However, dysregulated platelet activation can lead to pathological thrombosis or bleeding. Once a platelet gets activated, it will either become an aggregatory platelet or eventually a procoagulant platelet with both types playing distinct roles in thrombosis and hemostasis. Although aggregatory platelets have been extensively studied, procoagulant platelets have only recently come into the spotlight. Procoagulant platelets are a subpopulation of highly activated platelets that express phosphatidylserine and P-selectin on their surface, allowing for coagulation factors to bind and thrombin to be generated. In recent years, novel roles for procoagulant platelets have been identified and they have increasingly been implicated in thromboinflammatory diseases. Here, we provide an up-to-date review on the mechanisms resulting in the formation of procoagulant platelets and how they contribute to hemostasis, thrombosis, and thromboinflammation.

Keywords: calcium; mitochondria; neutrophils; platelets; thrombosis.

Graphical abstract

Figure 1.

Overview of mechanisms of procoagulant platelet formation. Platelet stimulation through agonists that induce ITAM or GPCR signaling in combination with shear or ROS can induce procoagulant platelet formation. These triggers induce a rapid rise in intracellular calcium, which enters the mitochondria. Once excessive calcium enters the mitochondria, CypD acts to form the mPTP, resulting in decrease mitochondrial membrane stability and the release of calcium back into the cytoplasm. The release of calcium through the mPTP activates TMEM16F, a phosphatidylserine (PS) scramblase, resulting in PS exposure on the platelet surface. Pathological formation of procoagulant platelets can induce thrombotic complications such as stroke and pulmonary and venous thrombosis. CypD, cyclophilin D; FcγRIIa, Fc Gamma RIIa; GPCR, G protein-coupled receptor; GPVI, glycoprotein VI; HIT, heparin-induced thrombocytopenia; ITAM, immunoreceptor tyrosine-based activation motif; mPTP, mitochondrial permeability transition pore; PAR, protease-activated receptor; ROS, reactive oxygen species; TMEM16F, transmembrane protein 16F; VITT, vaccine-induced thrombotic thrombocytopenia.