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Hemostasis is a dynamic process in which the platelet and the blood vessel wall play key roles. Platelets become activated upon adhesion to von Willebrand factor (VWF) and collagen in the exposed subendothelium after injury. Platelet activation is also mediated through shear forces imposed by blood flow itself, particularly in areas where the vessel wall is diseased, and is also affected by the inflammatory state of the endothelium. The activated platelet surface provides the major physiologic site for coagulation factor activation, which results in further platelet activation and fibrin formation. Genetic and acquired influences on the platelet and vessel wall, as well as on the coagulation and fibrinolytic systems, determine whether normal hemostasis, or bleeding or clotting symptoms, will result.

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The Platelet

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Platelets are released from the megakaryocyte, likely under the influence of flow in the capillary sinuses. The normal blood platelet count is 150,000–450,000/μL. The major regulator of platelet production is the hormone thrombopoietin (TPO), which is synthesized in the liver. Synthesis is increased with inflammation and specifically by interleukin 6. TPO binds to its receptor on platelets and megakaryocytes, by which it is removed from the circulation. Thus a reduction in platelet and megakaryocyte mass increases the level of TPO, which then stimulates platelet production. Platelets circulate with an average life span of 7 to 10 days. Approximately one-third of the platelets reside in the spleen, and this number increases in proportion to splenic size, although the platelet count rarely decreases to <40,000/μL as the spleen enlarges. Platelets are physiologically very active, but are anucleate, and thus have limited capacity to synthesize new proteins.

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Normal vascular endothelium contributes to preventing thrombosis by inhibiting platelet function (Chap. 58). When vascular endothelium is injured, these inhibitory effects are overcome, and platelets adhere to the exposed intimal surface primarily through VWF, a large multimeric protein present in both plasma and in the extracellular matrix of the subendothelial vessel wall. Platelet adhesion results in the generation of intracellular signals that lead to activation of the platelet glycoprotein (Gp) IIb/IIIa (αIIbβ3) receptor and resultant platelet aggregation.

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Activated platelets undergo release of their granule contents, which include nucleotides, adhesive proteins, growth factors, and procoagulants that serve to promote platelet aggregation and blood clot formation and influence the environment of the forming clot. During platelet aggregation, additional platelets are recruited to the site of injury, leading to the formation of an occlusive platelet thrombus. The platelet plug is stabilized by the fibrin mesh that develops simultaneously as the product of the coagulation cascade.

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The Vessel Wall

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Endothelial cells line the surface of the entire circulatory tree, totaling 1−6 × 1013 cells, enough to cover a surface area equivalent to about six tennis courts. The endothelium is physiologically active, controlling vascular permeability, flow of biologically active molecules and nutrients, blood cell interactions with the vessel wall, the inflammatory response, and angiogenesis.

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The endothelium normally presents an antithrombotic surface (Chap. 58) but rapidly becomes ...

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