Procoagulant function of platelets. (A) Plasma membrane phospholipids are asymmetrically distributed in resting platelets, with PS confined to the inner leaflet. After platelet activation by potent agonists, high levels of sustained intracellular calcium triggers scramblase activity. Scramblase activation results in the loss of phospholipid asymmetry and PS exposure on the outer leaflet of the platelet membrane, providing the requisite surface for rapid thrombin generation. (B) PS exposure can be induced through two distinct cell-death pathways; apoptosis and necrosis. Apoptosis results in assembly of the Bak/Bax mitochondrial membrane pore, causing release of cytochrome C (CytC), caspase activation, and substrate proteolysis. Necrotic cell death can be initiated by elevated cytosolic Ca²⁺, causing a loss in mitochondrial membrane potential and subsequent formation of a mitochondrial permeability transition pore (mPTP). mPTP formation results in bioenergetic failure through ATP depletion with consequent reactive oxygen species (ROS) generation, leading to loss of membrane integrity. (C) Platelets can also contribute to thrombin generation via activation of FXII through the release of polyphosphate from dense granules. (D) Whether there are additional cell death pathways regulating PS exposure and the procoagulant function of platelets remains unclear. PC indicates phosphatidylcholine.