Species Regulate Agonist - Initiated Platelet Phosphatidylserine Exposure

Platelet phosphatidylserine (PS) exposure amplifies thrombin generation by facilitating assembly of the tenase and prothrombinase complexes. In this process, PS, which had been limited to the platelet membrane inner leaflet, is rapidly equilibrated between the inner and outer leaflets of the platelet membrane. This results in the exposure of PS to the plasma milieu. The importance of PS exposure in normal hemostasis is illustrated by the congenital disorder Scott syndrome, a bleeding diathesis characterized by delayed hemostasis and impaired wound healing. In Scott syndrome, absence of the protein TMEM16F results in a defect in agonist-initiated scramblase activity and platelet PS exposure. Distinct mechanisms regulate agonist-initiated PS exposure in platelets relative to other platelet responses, such as platelet aggregation and granule release. Even when strongly stimulated, only a subpopulation of platelets demonstrates high-level PS exposure. And, relative to these other platelet responses, PS exposure is delayed. In fact, several minutes pass before high levels of PS can be detected on the activated platelet surface. In addition to this high-level PS exposure, low-level PS exposure is broadly present on stimulated platelets when PS exposure is analyzed using lactadherin. The relative physiological importance of lowand high-level PS exposure is uncertain. Relatively little is known about the intracellular mechanisms that specifically regulate high-level agonist-initiated platelet PS exposure. The importance of extracellular calcium and elevated cytoplasmic calcium (Ca cyt ) levels in the regulation of high-level PS exposure and scramblase activity is well appreciated, and both store-operated calcium-entry (SOCE) and noncapacitative calcium-entry mechanisms have been implicated in the regulation of agonist-initiated PS exposure. Potential determinants of prolonged Ca cyt elevation have been identified, including tyrosine kinases, which potentiate, and isoforms of protein kinase C, which inhibit, calcium signal generation and procoagulant activity. Increased potassium efflux through Ca-activated K+ channels may also facilitate PS exposure. Mitochondrial events have been implicated as important determinants of platelet PS exposure. The mitochondrial permeability transition pore (mPTP) is a nonselective multiprotein pore that spans the inner mitochondrial membrane, the formation of which causes a rapid loss of mitochondrial