Secretion (release reaction) of granule contents occurs along with changes in shape; these two events are often referred to together as platelet activation. Platelet activation is triggered by a number of factors, including he coagulation factor thrombin and ADP. Thrombin activates platelets through a special type of G-protein– coupled receptor referred to as a protease-activated receptor (PAR), which is switched on by a proteolytic cleavage carried out by thrombin. ADP is a component of dense-body granules; thus, platelet activation and ADP release begets additional rounds of platelet activation, a phenomenon referred to as recruitment. Activated platelets also produce the prostaglandin thromboxane A2 (TXA2), a potent inducer of platelet aggregation. Aspirin inhibits platelet aggregation and produces a mild bleeding defect by inhibiting cyclooxygenase, a platelet enzyme that is required for TXA2 synthesis. Although the phenomenon is less well characterized, it is also suspected that growth factors released from platelets contribute to the repair of the vessel wall following injury.
• Platelet aggregation follows their activation. The conformational change in glycoprotein IIb/IIIa that occurs with platelet activation allows binding of fibrinogen, a large bivalent plasma polypeptide that forms bridges between adjacent platelets, leading to their aggregation. Predictably, inherited deficiency of GpIIb-IIIa results in a bleeding disorder called Glanzmann thrombasthenia. The initial wave of aggregation is reversible, but concurrent activation of thrombin stabilizes the platelet plug by causing further platelet activation and aggregation, and by promoting irreversible platelet contraction. Platelet contraction is dependent on the cytoskeleton and consolidates the aggregated platelets. In parallel, thrombin also converts fibrinogen into insoluble fibrin, cementing the platelets in place and creating the definitive secondary hemostatic plug. Entrapped red cells and leukocytes are also found in hemostatic plugs, in part due to adherence of leukocytes to P-selectin expressed on activated platelets.
PLATELETADHESION,ACTIVATION,ANDAGGREGATION
EndothelialinjuryexposestheunderlyingbasementmembraneECM;plateletsadheretotheECMprimarilythroughthebindingofplateletGpIbreceptorstoVWF.
Adhesionleadstoplateletactivation,aneventassociatedwithsecretionofplateletgranulecontents,includingcalcium(acofactorforseveralcoagulationproteins)andADP(amediatoroffurtherplateletactivation);dramaticchangesinshapeandmembranecomposition;andactivationofGpIIb/IIIareceptors.
TheGpIIb/IIIareceptorsonactivatedplateletsformbridgingcrosslinkswithfibrinogen,leadingtoplateletaggregation.
Concomitantactivationofthrombinpromotesfibrindeposition,cementingtheplateletpluginplace.
The coagulation cascade is a series of amplifying enzymatic reactions that lead to the deposition of an insoluble fibrin clot. As discussed later, the dependency of clot formation on various factors differs in the laboratory test tube and in blood vessels in vivo (
Fig. 4.7 ). However, clotting in vitro and in vivo both follow the same general principles, as follows.
The cascade of reactions in the pathway can be likened to a “dance,” in which coagulation factors are passed from one partner to the next (