Degranulation also results in release of serotonin and adenosine diphosphate (ADP) from dense granules. Serotonin causes vasoconstriction. ADP binds to GPCR on the surface of platelets, activating additional platelets. [Note: Some antiplatelet drugs, such as clopidogrel, are ADP-receptor antagonists.] Platelet-derived growth factor (involved in wound healing), VWF, FV, FXIII, and FI are among other proteins released from α granules. [Note: Platelet-activating factor (PAF), an ether phospholipid (see p. 202) synthesized by a variety of cell types including endothelial cells and platelets, binds PAF receptors (GPCR) on the surface of platelets and activates them.] 2. Morphologic change: The change in shape of activated platelets from discoidal to spherical with pseudopod-like processes that facilitate platelet–platelet and platelet–surface interactions (Fig. 35.23) is initiated by the release of Ca2+ from dense granules. Ca2+ bound to calmodulin (see p. 133) mediates the activation of myosin light chain kinase that phosphorylates the myosin light chain, resulting in a major reorganization of the platelet cytoskeleton.
C. Aggregation
Activation causes dramatic changes in platelets that lead to their aggregation. Structural changes in a surface receptor (GPIIb/IIIa) expose binding sites for fibrinogen. Bound FI molecules link activated platelets to one another (Fig. 35.24), with a single FI able to bind two platelets. FI is converted to FIa by FIIa and then covalently cross-linked by FXIIIa coming from both the blood and the platelets. [Note: The exposure of PS on the surface of activated platelets allows formation of the Xase complex (VIIIa, IXa, X, and Ca2+) with subsequent formation of FXa and generation of FIIa.] Fibrin formation (secondary hemostasis) strengthens the platelet plug. [Note: Rare defects in the platelet receptor for FI result in Glanzmann thrombasthenia (decreased platelet function), whereas autoantibodies to this receptor are a cause of immune thrombocytopenia (decreased platelet number).]
Unnecessary activation of platelets is prevented because 1) an intact vascular wall is separated from the blood by a monolayer of endothelial cells, preventing the contact of platelets with collagen; 2) endothelial cells synthesize prostaglandin I2 (PGI2, or prostacyclin) and nitric oxide, each of which causes vasodilation; and 3) endothelial cells have a cell surface ADPase that converts ADP to adenosine monophosphate.
V. CHAPTER SUMMARY
Blood clotting (coagulation) is designed to rapidly stop bleeding from a damaged blood vessel in order to maintain a constant blood volume (hemostasis). Coagulation is accomplished through formation of a clot (thrombus) consisting of a plug of platelets and a meshwork of the protein fibrin (Fig. 35.25).