Cell death pathways in platelet biology. Many of the features of apoptotic and necrotic cell death (see bottom table) are common to platelets. (I) Platelet aging: Recent studies have demonstrated an important role for Bak/Bax-mediated apoptosis in control of platelet lifespan. In this model, anucleate circulating platelets possess finite amounts of Bcl_XL, Bak, and Bax. With no significant means for further protein translation, the cellular levels of Bcl_XL decline over time, at a rate faster then their proapoptotic counterparts. After 7 to 10 days, this results in the release of Bak/Bax, the formation of Bak/Bax pores in the outer membrane of the mitochondria, and eventual MOMP. This triggers the typical intrinsic apoptotic cascade including cytochrome c (Cyt C) release, caspase activation and substrate proteolysis, resulting in proteolytic destruction of the cell, membrane blebbing/vesiculation and phosphatidylserine (PS) exposure (II) In contrast, potent activation of platelets by thrombin and collagen leads to the formation of a platelet phenotype consistent with necrosis. Potent activation leads to sustained elevated cytosolic calcium, mitochondrial calcium overload, and formation of the mitochondrial permeability transition pore (MPTP). This facilitates the mitochondrial permeability transition (mitochondrial membrane depolarization, Δψ_m), ATP depletion and excess production of reactive oxygen species (ROS), facilitated by the mitochondrial inner membrane protein cyclophilin D (CypD). Additional consequences of mitochondrial injury include sustained elevated calcium, calpain activation, PS exposure and loss of plasma membrane integrity. Functionally, platelets undergoing necrosis possess both procoagulant and proinflammatory characteristics.