Chapter 15 Arterial and Venous Thrombosis and Thrombolysis © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 15. 1 Biochemistry of venous thrombosis FIGURE 15.1 Biochemistry of venous thrombosis. This figure is a juxtaposition of the proteins involved in the coagulation (green), fibrinolytic (blue), and anticoagulation (red) systems. The boxes around proteins indicate that known defects in that protein are associated with venous thrombosis. PK, prekallikrein; HK, high-molecular-weight kininogen; TF, an abbreviation for tissue factor; FVL, an abbreviation for factor V Leiden; scuPA, single chain urokinase plasminogen activator; tcuPA, two-chain urokinase plasminogen activator; tPA, tissue plasminogen activator; AT, antithrombin; APC, activated protein C; C4bBP, C4b-binding protein; PAI-1, plasminogen activator inhibitor-1. Coagulation factors XII, XI, IX, X, VII and V are represented by their roman numeral alone. The presence of an ‘a’ after the roman numeral represents an ‘activated’ protein. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 15. 2 Homocysteine metabolism FIGURE 15.2 Homocysteine metabolism. Homocysteine is metabolized by two enzymes, methionine synthase and cystathionine β-synthase. N5,N10 methylene tetrahydrofolate reductase makes an essential cofactor (MethylTHF) for methionine synthesis. B12 is a cofactor for methionine synthase and B6 is a cofactor for cystathionine β-synthase. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 15.3 The relationship of homocysteine and endothelial dysfunction. In hyperhomocysteinemic states, there is increased production of reactive oxygen species (ROS). Regardless of the etiology, increased concentrations of ROS are detrimental to the anticoagulant function of endothelium. ROS transcriptionally regulates expression and inactivates thrombomodulin, reducing protein C activation, and causing a loss of this constitutive anticoagulant protein. ROS transcriptionally regulate eNOS (NOS3) expression and uncouple endothelial NO synthetase, allowing for reduced NO production and increased ROS production. ROS also increase tissue factor and PAI-1 (not shown) mRNA and protein expression in endothelium. In addition, ROS stimulate leukocyte migration and infiltration, and smooth muscle proliferation. Together, these activities lead to vascular dysfunction and increased risk for arterial thrombosis. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease