Normal hemostasis is best conceptualized according to its major components—vessel wall, platelet function, coagulation factor cascade, and clot inhibition/fibrinolysis. These components work together to prevent prolonged bleeding or thrombosis under normal physiologic conditions. Disruption of the vascular endothelium is a potent stimulus to clot formation. As a localized process, hemostasis by cellular and protein components acts to seal the break in vascular continuity, limit blood loss, and begin the process of wound healing. Prevention of an exuberant response that would result in pathologic thrombosis involves counterbalancing mechanisms, including anticoagulant properties of intact endothelial cells, circulating inhibitors of activated coagulation factors, and localized fibrinolytic enzymes. Most abnormalities in hemostasis involve a defect in 1 or more of the integrated steps in this coagulation process. It is important, therefore, to understand the physiology of hemostasis.
The intact endothelial cell lining of the vessel wall plays an essential role in preventing thrombus formation. First and foremost, it provides a physical barrier between circulating platelets and highly thrombogenic subendothelial connective tissue. In addition, endothelial cells are active metabolically in the regulation of blood flow, platelet aggregation, and the coagulation cascade. Endothelial cells are a primary source for production of nitric oxide and prostacyclin, both of which are important in promoting smooth muscle relaxation and vessel dilatation. Disruption of the endothelial cell surface results in unopposed smooth muscle contraction and vessel spasm. This is an effective reflex to stem blood loss and sets the stage for thrombus formation. When damaged, endothelial cells are capable of encouraging platelet adhesion, activation, and aggregation. Endothelial cells are also the primary source of von Willebrand factor (vWF) multimers, the essential cofactor for platelet adhesion to sites of vessel disruption.
Normal endothelial cells adjacent to an injury site are simultaneously crucial to limiting clot formation. Thrombin in the microenvironment causes normal endothelial cells to dramatically increase secretion of prostacyclin, which inhibits downstream platelet activation and aggregation. Thrombin also binds to endothelial cell thrombomodulin, which promotes protein C activation and subsequently downregulates further thrombin generation. Since thrombomodulin is found in greater amounts in smaller vessels, the latter function may be especially critical to the integrity of the microvasculature. Finally, endothelial cells are the primary source of tissue plasminogen activator (t-PA), the principal physiologic fibrinolytic enzyme.
Normal circulating platelets resemble an oblong disk, measuring 2–4 μm on the long axis with a volume of 5–12 fL. They are essentially fragments of megakaryocyte cytoplasm. Although lacking a nucleus, the cytoplasm contains mitochondria for aerobic metabolism, glycogen stores for anaerobic glycolysis, and specific granules whose contents are important for coagulation (Figure 28-1). Almost 20% of the platelet volume comprises these granules, whereas 25% of the protein in the platelet is actin and myosin needed for platelet contraction.
Platelet adhesion, activation, and aggregation. Platelet adhesion and ...