Multiple cellular and protein activation pathways are involved in formation, and subsequent remodeling, of a hemostatic plug at the site of a vascular injury (Fig. 2). Hemostasis protein levels vary widely in healthy populations, with typical reference ranges of 60% to 160% of the mean. Estimates of the genetic contribution to the observed variation for different proteins range from 22% to 55%, representing the largest identifiable determinant (31). ABO blood type is a major determinant of both von Willebrandfactor (vWF) (32), and factor VIII levels. However, even after adjusting for blood type, there is a genetic component to factor VIII levels that is not associated with polymorphisms within the factor VIII gene (33). It is likely that multiple genes are involved in the regulation of expression of most hemostatic proteins. Environmental factors and gene-environment interactions also contribute to hemostatic protein variability. Factor VIII and vWF levels rise during pregnancy and acute stress, and factor VII
Figure 2 Formation of a hemostatic plug. (A) Vascular injury: Endothelial disruption exposes blood to subendothelial collagen (-y^), vWF, and TF. (B) Primary hemostasis: Circulating platelets adhere to collagen and vWF via specific surface receptor complexes and undergo activation and release of prothrombotic granule contents. Conformational changes in the platelet surface integrin glycoprotein IIbIIIa permit fibrinogen (FIB) and vWF-dependent aggregation of activated platelets. (C) Secondary hemostasis: TF accelerates activation of factor VII to Vila, which converts factor X to Xa and factor IX to IXa. The phospholipid surface of activated platelets is the primary site of subsequent coagulation factor activation. Factors IXa and VIIIa activate factor X and factors Xa and Va convert Prothrombin (factor II) to thrombin (factor IIa). Sustained thrombin generation requires factor IIa activation of nonenzymatic cofactors V and VIII to accelerate activation of factors X and factor II. (D) Fibrin clot formation: Factor IIa converts fibrinogen to fibrin through distal amino terminal cleavages of alpha- and beta-chains. Fibrin molecules spontaneously polymerize and are covalently cross-linked by factor XIIIa, a thrombin-activated transglutaminase. (E) Fibrinolysis: PL binds to fibrin molecules during polymerization. tPA, released from endothelial cells, enters the fibrin clot and activates PL to P. Plasmin degrades fibrin into FDP. (F) Inhibitors: Thrombin generation and fibrinolysis are highly regulated processes. The major direct inhibitor of thrombin is AT, a member of the serine protease inhibitor (serpin) family. Factors Va and VIIIa are degraded by aPC and its cofactor, PS. When bound to TM, an endothelial surface protein, factor IIa activates PC to aPC. When not bound to fibrin, tPA and plasmin are rapidly inhibited by the serpin PAI-1 and a2AP, respectively. Abbreviations: vWF, von Willebrand factor; TF, tissue factor; PL, plasminogen; tPA, tissue plasminogen activator; P, plasmin; FDP, fibrin degradation products; AT, antithrombin; aPC, activated protein C; TM, thrombomodulin; PS, protein S; PC, protein C; PAI-1, plasminogen activator inhibitor-1; a2AP, alpha-2 antiplasmin.
levels decline with the lowering of plasma lipoproteins. Fibrinogen levels also rise in response to stress. However, a polymorphism in the fibrinogen beta-chain promoter is associated with a greater change in fibrinogen concentration after physical exertion compared with the wild type (34).
The most overt clinical expression of monogenetic mutations affecting hemostasis occurs in hemophilia, a congenital bleeding disorder due to deficiency of a single clotting factor. The most common types are hemophilia A and B, characterized by sex-linked inherited deficiencies of factor VIII and IX, respectively. Other types of hemophilia are rare and inherited in an autosomal recessive manner. More common than hemophilia A or B, but with a generally milder bleeding phenotype, is von Willebrand disease. Both quantitative and qualitative defects of vWF synthesis can cause autosomal dominant inherited bleeding disorders with incomplete penetrance. Mutations that cause qualitative vWF defects are clustered within exons that code for specific functional domains (35). However, mutations that would predict a quantitative deficiency of vWF are rarely identified at the vWF gene locus, and the range of vWF levels in obligate carriers of vWF deficiency are wide and overlap with vWF reference ranges, reflecting the combined impact of both heritable and noninheritable sources of variation on levels of hemostasis proteins (36).
Platelet activation and aggregation are complex cellular events, involving the interaction of various ligands with specific platelet surface receptors and multiple post-receptor signal transduction pathways, culminating in platelet shape change, release of granule contents, and activation of a surface heterodimer, glycoprotein IIbIIIa, which binds fibrinogen to form attachments to other activated platelets. Inherited quantitative and qualitative platelet defects are rare, produce mild to moderate bleeding symptoms, and are usually autosomal recessive heritable disorders. Drug-induced acquired platelet dysfunction is both a common complication (37) and also an effective therapeutic intervention: aspirin and clopidogrel for prevention of arterial thromboembolic complications.
Gene polymorphisms affecting platelet membrane receptors and integrins have been inconsistently associated with arterial thrombotic outcomes without convincing evidences of biological mechanisms (38).
It is now evident that most heritable risk factors for arterial and venous thromboem-bolic events are relatively weak, and it is the combination of multiple genetic risk factors plus environmental interactions that produce thrombotic phenotypes (39). Congenital, heterozygous deficiencies of antithrombin, protein C, and protein S (Fig. 2F), are identified in 1% to 5% of the patients with spontaneous venous thromboembolic events (VTE). However, two recently discovered gains of function coagulation factor polymorphisms have much higher prevalence in patients with VTEs (40). Factor V Leiden (FVL), a 1691 G to A mutation that substitutes glutamine for arginine at amino acid 506, slows the rate of factor Va cleavage by activated protein C. The allelic frequency of FVL is 2% to 15% in people of European ancestry, and it is identified in up to 40% of the patients with spontaneous VTE. The 20210 G to A mutation in the untranslated 3' region of the prothrombin gene is associated with higher prothrombin levels and an increased risk for VTE. It is present in approximately 2% of the Caucasians, and it is identified in up to 20% of the patients with VTEs.
The list of coagulation, fibrinolysis, and platelet membrane protein gene polymorphisms with putative links to arterial thrombosis continues to grow (40-42). However, due to the complexity of the atherosclerotic process and the hemostatic system, it is likely that the attributable risk will be small for such polymorphisms. Changes in clinical trial designs, including much larger sample size, will be necessary to validate the significance of current and future candidate polymorphisms.
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