En to fibrin [20]. The prothrombinase reaction promotes a positive feedback loop. Increased thrombin stimulates further platelet 2-Chloro-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one activation and increased granule release. Fibrinogen and fibrin bind the integrin IIb3 and promote platelet aggregation and clot stabilization [24]. This subsequently recruits more platelets and thus propagates new sites of platelet- prothrombinase activity. The platelet-fibrin plug is stabilized by factor XIIIa which crosslinks fibrin and reinforces the clot with antifibrinolytic proteins. In particular, thrombin ctivatable fibrinolysis inhibitor (TAFIa) is incorporated into matrix. TAFIa prevents clot degradation by decreasing the number of binding sites for endogenous plasminogen and tissue plasminogen activator. Finally, the intracellular portion of platelet integrin IIb3 connects to theplatelet's intracellular actin and myosin network. Binding of fibrin to the extracellular portion of this receptor induces platelet contraction. The contractile force of the platelet, in turn, adds stress to the fibrin network, and subsequently causes clot retraction and stabilization [21,25]. In addition to supplying a phospholipid membrane structure for the coagulation complex to assemble, platelets actively secrete granules containing co-reagents necessary for clot propagation. The process of degranulation requires platelets to be activated. Secreted factors include calcium, ADP, ATP, serotonin, pyrophosphate, thromboglobulin, and activated factor Va. These small molecules and proteins are critical cofactors for fibrin formation and platelet activation. The cell-based model of hemostasis has implicated activated platelets as a crucial mediator of thrombus formation. Platelet activation, however, is a PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/9144744 highly energetic process and 1-(Cyclopropylsulfonyl)-1,4-diazepane and an emerging body of evidence has tied platelet ijms17122034 activation to mitochondria and mitochondrial regulators of apoptosis [26,27]. Despite being anucleated cells, platelets retain caspases and other key mediators of apoptosis such as Bax, Bcl -2, and Calpain [26,28]. Moreover, the shrinkage, plasma membrane vesiculation, and bleb formation of apoptotic cells is reminiscent of the conformational changes observed in "activated" platelets. Furthermore, activated platelets increase their expression of P-selectin (CD62) and exteriorize phosphatidylserine (PS) on the platelet membrane: two events that are recognized as caspase-dependent markers of cell death in other cell lines [29]. While the significance of these mitochondrial-mediated events in activated platelets remains to be determined, the appearance of apoptotic features in stored banked platelets has significant clinical implications and correlates with decreased function in transfused platelets. On the other hand, altered mitochondrial function in circulating platelets might enhance platelet function in vivo. An intriguing correlation has been established between the mitochondrial membrane potential (m) and the creation of a specialized subgroup of platelets, termed coated- platelets. Coated platelets are a select subpopulation of thrombocytes with escalated hemostatic potency that are induced in vivo by dual agonism with thrombin and collagen. Coated platelets use serotonin to retain procoagulant factors (e.g. factor V, fibrinogen, fibrin, VWF, fibronectin, 2-antiplasmin PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/22763976 and thrombospondin) and phosphatidylserine on their surface [30]. As such, coated platelets ensure that the most potent site of clot formation is localized to the desired tar.