Coagulation factor V and thrombophilia: Background and mechanisms

Summary

Human coagulation factor V (FV) is an essential coagulation protein with functions in both the pro- and anticoagulant pathways. Failure to express and control FV functions can either lead to bleeding, or to thromboembolic disease. Both events may develop into a life-threatening condition. Since the first description of APC resistance, and in particular the description of the so-called factor V_Leiden mutation, in which a prominent activated protein C cleavage site in FV has been abolished through a mutation in the FV gene, FV has been in the center of attention of thrombosis research. In this review we describe how the functions of FV are expressed and regulated and provide an extensive description of the role that FV plays in the etiology of thromboembolic disease.

Keywords

Factor V - coagulation - thrombosis - thrombophilia - protein C pathway

• References

• 1 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-1173.
• 2 Rosendaal FR. Venous thrombosis: the role of genes, environment, and behavior. Hematology Am Soc Hematol Educ Program 2005; 1-12.
• 3 Dahlbäck B. Blood coagulation. Lancet 2000; 355: 1627-1632.
• 4 Virchow R. Phlogose und thrombose im Gefäßsystem. Gesammelte Abhandlungen zur Wissenschaftlichen Medizin Frankfurt: Staatsdruckerei; 1856
• 5 Seligsohn U, Zivelin A. Thrombophilia as a multigenic disorder. Thromb Haemost 1997; 78: 297-301.
• 6 Dahlbäck B. The protein C anticoagulant system: inherited defects as basis for venous thrombosis. Thromb Res 1995; 77: 1-43.
• 7 Williamson D, Brown K, Luddington R. et al. Factor V Cambridge: a new mutation (Arg306-->Thr) associated with resistance to activated protein C. Blood 1998; 91: 1140-1144.
• 8 Chan WP, Lee CK, Kwong YL. et al. A novel mutation of Arg306 of factor V gene in Hong Kong Chinese. Blood 1998; 91: 1135-1139.
• 9 Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh 1965; 13: 516-530.
• 10 Griffin JH, Evatt B, Zimmerman TS. et al. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-1373.
• 11 Schwarz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH. Plasma protein S deficiency in familial thrombotic disease. Blood 1984; 64: 1297-1300.
• 12 Blom AM, Villoutreix BO, Dahlbäck B. Complement inhibitor C4b-binding protein-friend or foe in the innate immune system?. Mol Immunol 2004; 40: 1333-1346.
• 13 Leger AJ, Covic L, Kuliopulos A. Protease-activated receptors in cardiovascular diseases. Circulation 2006; 114: 1070-1077.
• 14 Kempton CL, Harvey 3rd RD, Roberts HR. Novel therapeutic agents in the management of hemorrhage and thrombosis. Cardiovasc Hematol Agents Med Chem 2006; 4: 319-334.
• 15 Chackalamannil S, Xia Y, Greenlee WJ. et al. Discovery of potent orally active thrombin receptor (protease activated receptor 1) antagonists as novel antithrombotic agents. J Med Chem 2005; 48: 5884-5887.
• 16 Bernard GR, Vincent JL, Laterre PF. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709.
• 17 Sakariassen KS, Bolhuis PA, Sixma JJ. Human blood platelet adhesion to artery subendothelium is mediated by factor VIII-Von Willebrand factor bound to the subendothelium. Nature 1979; 279: 636-638.
• 18 Morrissey JH. Tissue factor: an enzyme cofactor and a true receptor. Thromb Haemost 2001; 86: 66-74.
• 19 Suzuki K, Dahlbäck B, Stenflo J. Thrombin-catalyzed activation of human coagulation factor V. J Biol Chem 1982; 257: 6556-6564.
• 20 Monkovic DD, Tracy PB. Activation of human factor V by factor Xa and thrombin. Biochemistry 1990; 29: 1118-1128.
• 21 Tans G, Nicolaes GAF, Thomassen MC. et al. Activation of human factor V by meizothrombin. J Biol Chem 1994; 269: 15969-15972.
• 22 Rick ME, Hoyer LW. Thrombin activation of factor VIII: the effect of inhibitors. Br J Haematol 1977; 36: 585-597.
• 23 Hultin MB, Jesty J. The activation and inactivation of human factor VIII by thrombin: effect of inhibitors of thrombin. Blood 1981; 57: 476-482.
• 24 Fulcher CA, Roberts JR, Zimmerman TS. Thrombin proteolysis of purified factor VIII procoagulant protein: correlation of activation with generation of a specific polypeptide. Blood 1983; 61: 807-811.
• 25 Jensen AH, Beguin S, Josso F. Factor V and VIII activation "in vivo" during bleeding. Evidence of thrombin formation at the early stage of hemostasis. Pathol Biol (Paris) 1976; 24 (Suppl): 6-10.
• 26 Gailani D, Broze Jr. GJ. Factor XI activation in a revised model of blood coagulation. Science 1991; 253: 909-912.
• 27 Baugh RJ, Broze Jr. GJ, Krishnaswamy S. Regulation of extrinsic pathway factor Xa formation by tissue factor pathway inhibitor. J Biol Chem 1998; 273: 4378-4386.
• 28 Lane DA, Caso R. Antithrombin: structure, genomic organization, function and inherited deficiency. Baillieres Clin Haematol 1989; 2: 961-998.
• 29 Mitchell L, Piovella F, Ofosu F. et al. Alpha-2-macroglobulin may provide protection from thromboembolic events in antithrombin III-deficient children. Blood 1991; 78: 2299-2304.
• 30 Schmidt B, Mitchell L, Ofosu FA. et al. Alpha- 2-macroglobulin is an important progressive inhibitor of thrombin in neonatal and infant plasma. Thromb Haemost 1989; 62: 1074-1077.
• 31 Ye S, Goldsmith EJ. Serpins and other covalent protease inhibitors. Curr Opin Struct Biol 2001; 11: 740-745.
• 32 Dahlbäck B, Villoutreix BO. Molecular recognition in the protein C anticoagulant pathway. J Thromb Haemost 2003; 1: 1525-1534.
• 33 Dahlbäck B. Progress in the understanding of the protein C anticoagulant pathway. Int J Hematol 2004; 79: 109-116.
• 34 Dahlbäck B, Villoutreix BO. Regulation of blood coagulation by the protein C anticoagulant pathway: novel insights into structure-function relationships and molecular recognition. Arterioscler Thromb Vasc Biol 2005; 25: 1311-1320.
• 35 Fuentes-Prior P, Iwanaga Y, Huber R. et al. Structural basis for the anticoagulant activity of the thrombin- thrombomodulin complex. Nature 2000; 404: 518-525.
• 36 Koeppe JR, Seitova A, Mather T. et al. Thrombomodulin tightens the thrombin active site loops to promote protein C activation. Biochemistry 2005; 44: 14784-14791.
• 37 Kalafatis M, Rand MD, Mann KG. The mechanism of inactivation of human factor V and human factor Va by activated protein C. J Biol Chem 1994; 269: 31869-31880.
• 38 He X, Shen L, Villoutreix BO. et al. Amino acid residues in thrombin-sensitive region and first epidermal growth factor domain of vitamin K-dependent protein S determining specificity of the activated protein C cofactor function. J Biol Chem 1998; 273: 27449-27458.
• 39 Nyberg P, Dahlbäck B, Garcia de Frutos P. The SHBG-like region of protein S is crucial for factor V-dependent APC-cofactor function. FEBS Lett 1998; 433: 28-32.
• 40 Evenas P, Garcia de Frutos P, Nicolaes GAF. et al. The second laminin G-type domain of protein S is indispensable for expression of full cofactor activity in activated protein C-catalysed inactivation of factor Va and factor VIIIa. Thromb Haemost 2000; 84: 271-277.
• 41 Shen L, Dahlbäck B. Factor V and protein S as synergistic cofactors to activated protein C in degradation of factor VIIIa. J Biol Chem 1994; 269: 18735-18738.
• 42 Lu D, Kalafatis M, Mann KG. et al. Comparison of activated protein C/protein S-mediated inactivation of human factor VIII and factor V. Blood 1996; 87: 4708-4717.
• 43 Nizzi Jr. FA, Kaplan HS. Protein C and S deficiency. Semin Thromb Hemost 1999; 25: 265-272.
• 44 Nicolaes GAF, Dahlbäck B. Factor V and thrombotic disease: description of a janus-faced protein. Arterioscler Thromb Vasc Biol 2002; 22: 530-538.
• 45 Vos HL. Inherited defects of coagulation factor V: the thrombotic side. J Thromb Haemost 2006; 4: 35-40.
• 46 Asselta R, Tenchini ML, Duga S. Inherited defects of coagulation factor V: the hemorrhagic side. J Thromb Haemost 2006; 4: 26-34.
• 47 Cripe LD, Moore KD, Kane WH. Structure of the gene for human coagulation factor V. Biochemistry 1992; 31: 3777-3785.
• 48 Jenny RJ, Pittman DD, Toole JJ. et al. Complete cDNA and derived amino acid sequence of human factor V. Proc Natl Acad Sci USA 1987; 84: 4846-4850.
• 49 Tracy PB, Eide LL, Bowie EJ. et al. Radioimmunoassay of factor V in human plasma and platelets. Blood 1982; 60: 59-63.
• 50 Suehiro Y, Veljkovic DK, Fuller N. et al. Endocytosis and storage of plasma factor V by human megakaryocytes. Thromb Haemost 2005; 94: 585-592.
• 51 Camire RM, Pollak ES, Kaushansky K. et al. Secretable human platelet-derived factor V originates from the plasma pool. Blood 1998; 92: 3035-3041.
• 52 Kane WH, Davie EW. Blood coagulation factors V and VIII: structural and functional similarities and their relationship to hemorrhagic and thrombotic disorders. Blood 1988; 71: 539-555.
• 53 Takahashi N, Ortel TL, Putnam FW. Single-chain structure of human ceruloplasmin: the complete amino acid sequence of the whole molecule. Proc Natl Acad Sci USA 1984; 81: 390-394.
• 54 Church WR, Jernigan RL, Toole J. et al. Coagulation factors V and VIII and ceruloplasmin constitute a family of structurally related proteins. Proc Natl Acad Sci USA 1984; 81: 6934-6937.
• 55 Poole S, Firtel RA, Lamar E. et al. Sequence and expression of the discoidin I gene family in Dictyostelium discoideum . J Mol Biol 1981; 153: 273-289.
• 56 Fernandez JA, Hackeng TM, Kojima K. et al. The carbohydrate moiety of factor V modulates inactivation by activated protein C. Blood 1997; 89: 4348-4354.
• 57 Rosing J, Bakker HM, Thomassen MC. et al. Characterization of two forms of human factor Va with different cofactor activities. J Biol Chem 1993; 268: 21130-21136.
• 58 Kim SW, Ortel TL, Quinn-Allen MA. et al. Partial glycosylation at asparagine-2181 of the second C-type domain of human factor V modulates assembly of the prothrombinase complex. Biochemistry 1999; 38: 11448-11454.
• 59 Nicolaes GAF, Villoutreix BO, Dahlbäck B. Partial glycosylation of Asn2181 in human factor V as a cause of molecular and functional heterogeneity. Modulation of glycosylation efficiency by mutagenesis of the consensus sequence for N-linked glycosylation. Biochemistry 1999; 38: 13584-13591.
• 60 Hoekema L, Nicolaes GAF, Hemker HC. et al. Human factor Va1 and factor Va2: properties in the procoagulant and anticoagulant pathways. Biochemistry 1997; 36: 3331-3335.
• 61 Varadi K, Rosing J, Tans G. et al. Factor V enhances the cofactor function of protein S in the APC-mediated inactivation of factor VIII: influence of the factor VR506Q mutation. Thromb Haemost 1996; 76: 208-214.
• 62 Pittman DD, Tomkinson KN, Michnick D. et al. Posttranslational sulfation of factor V is required for efficient thrombin cleavage and activation and for full procoagulant activity. Biochemistry 1994; 33: 6952-6959.
• 63 Esmon CT. The subunit structure of thrombin-activated factor V. Isolation of activated factor V, separation of subunits, and reconstitution of biological activity. J Biol Chem 1979; 254: 964-973.
• 64 Hibbard LS, Mann KG. The calcium-binding properties of bovine factor V. J Biol Chem 1980; 255: 638-645.
• 65 Nesheim ME, Taswell JB, Mann KG. The contribution of bovine factor V and factor Va to the activity of prothrombinase. J Biol Chem 1979; 254: 10952-10962.
• 66 Rosing J, Tans G, Govers-Riemslag JW. et al. The role of phospholipids and factor Va in the prothrombinase complex. J Biol Chem 1980; 255: 274-283.
• 67 Steen M, Dahlbäck B. Thrombin-mediated proteolysis of factor V resulting in gradual B-domain release and exposure of the factor Xa-binding site. J Biol Chem 2002; 277: 38424-38430.
• 68 Toso R, Camire RM. Removal of B-domain sequences from factor V rather than specific proteolysis underlies the mechanism by which cofactor function is realized. J Biol Chem 2004; 279: 21643-21650.
• 69 Villoutreix BO, Dahlbäck B. Structural investigation of the A domains of human blood coagulation factor V by molecular modeling. Protein Sci 1998; 7: 1317-1325.
• 70 Villoutreix BO, Bucher P, Hofmann K. et al. Molecular models for the two discoidin domains of human blood coagulation factor V. J Mol Modeling 1998; 4: 268-275.
• 71 Pellequer JL, Gale AJ, Griffin JH. et al. Homology models of the C domains of blood coagulation factors V and VIII: a proposed membrane binding mode for FV and FVIII C2 domains. Blood Cells Mol Dis 1998; 24: 448-461.
• 72 Macedo-Ribeiro S, Bode W, Huber R. et al. Crystal structures of the membrane-binding C2 domain of human coagulation factor V. Nature 1999; 402: 434-439.
• 73 Adams TE, Hockin MF, Mann KG. et al. The crystal structure of activated protein C-inactivated bovine factor Va: Implications for cofactor function. Proc Natl Acad Sci USA 2004; 101: 8918-8923.
• 74 Nicolaes GAF, Villoutreix BO, Dahlbäck B. Mutations in a potential phospholipid binding loop in the C2 domain of factor V affecting the assembly of the prothrombinase complex. Blood Coagul Fibrinolysis 2000; 11: 89-100.
• 75 Saleh M, Peng W, Quinn-Allen MA. et al. The factor V C1 domain is involved in membrane binding: identification of functionally important amino acid residues within the C1 domain of factor V using alanine scanning mutagenesis. Thromb Haemost 2004; 91: 16-27.
• 76 Autin L, Steen M, Dahlbäck B. et al. Proposed structural models of the prothrombinase (FXa-FVa) complex. Proteins 2006; 63: 440-450.
• 77 Husten EJ, Esmon CT, Johnson AE. The active site of blood coagulation factor Xa. Its distance from the phospholipid surface and its conformational sensitivity to components of the prothrombinase complex. J Biol Chem 1987; 262: 12953-12961.
• 78 Yegneswaran S, Wood GM, Esmon CT. et al. Protein S alters the active site location of activated protein C above the membrane surface. A fluorescence resonance energy transfer study of topography. J Biol Chem 1997; 272: 25013-25021.
• 79 Krishnaswamy S. Prothrombinase complex assembly. Contributions of protein-protein and proteinmembrane interactions toward complex formation. J Biol Chem 1990; 265: 3708-3718.
• 80 Pryzdial EL, Mann KG. The association of coagulation factor Xa and factor Va. J Biol Chem 1991; 266: 8969-8977.
• 81 Walker RK, Krishnaswamy S. The influence of factor Va on the active site of factor Xa. J Biol Chem 1993; 268: 13920-13929.
• 82 Betz A, Krishnaswamy S. Regions remote from the site of cleavage determine macromolecular substrate recognition by the prothrombinase complex. J Biol Chem 1998; 273: 10709-10718.
• 83 Orcutt SJ, Pietropaolo C, Krishnaswamy S. Extended interactions with prothrombinase enforce affinity and specificity for its macromolecular substrate. J Biol Chem 2002; 277: 46191-46196.
• 84 Boskovic DS, Troxler T, Krishnaswamy S. Active site-independent recognition of substrates and product by bovine prothrombinase: a fluorescence resonance energy transfer study. J Biol Chem 2004; 279: 20786-20793.
• 85 Yegneswaran S, Fernandez JA, Griffin JH. et al. Factor Va increases the affinity of factor Xa for prothrombin: a binding study using a novel photoactivable thiol-specific fluorescent probe. Chem Biol 2002; 9: 485-494.
• 86 Heeb MJ, Rehemtulla A, Moussalli M. et al. Importance of individual activated protein C cleavage site regions in coagulation factor V for factor Va inactivation and for factor Xa activation. Eur J Biochem 1999; 260: 64-75.
• 87 Gale AJ, Xu X, Pellequer JL. et al. Interdomain engineered disulfide bond permitting elucidation of mechanisms of inactivation of coagulation factor Va by activated protein C. Protein Sci 2002; 11: 2091-2101.
• 88 Nicolaes GAF, Tans G, Thomassen MC. et al. Peptide bond cleavages and loss of functional activity during inactivation of factor Va and factor VaR506Q by activated protein C. J Biol Chem 1995; 270: 21158-21166.
• 89 Mann KG, Hockin MF, Begin KJ. et al. Activated protein C cleavage of factor Va leads to dissociation of the A2 domain. J Biol Chem 1997; 272: 20678-20683.
• 90 Pellequer JL, Gale AJ, Getzoff ED. et al. Three-dimensional model of coagulation factor Va bound to activated protein C. Thromb Haemost 2000; 84: 849-857.
• 91 Nicolaes GAF, Sorensen KW, Friedrich U. et al. Altered inactivation pathway of factor Va by activated protein C in the presence of heparin. Eur J Biochem 2004; 271: 2724-2736.
• 92 Gale AJ, Tsavaler A, Griffin JH. Molecular characterization of an extended binding site for coagulation factor Va in the positive exosite of activated protein C. J Biol Chem 2002; 277: 28836-28840.
• 93 Friedrich U, Nicolaes GAF, Villoutreix BO, Dahlbäck B. Secondary substrate-binding exosite in the serine protease domain of activated protein C important for cleavage at Arg-506 but not at Arg-306 in factor Va. J Biol Chem 2001; 276: 23105-23108.
• 94 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-1008.
• 95 Dahlbäck B, Hildebrand B. Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V. Proc Natl Acad Sci USA 1994; 91: 1396-1400.
• 96 Castoldi E, Brugge JM, Nicolaes GAF. et al. Impaired APC cofactor activity of factor V plays a major role in the APC resistance associated with the factor V Leiden (R506Q) and R2 (H1299R) mutations. Blood 2004; 103: 4173-4179.
• 97 Varadi K, Rosing J, Tans G. et al. Influence of factor V and factor Va on APC-induced cleavage of human factor VIII. Thromb Haemost 1995; 73: 730-731.
• 98 Thorelli E, Kaufman RJ, Dahlbäck B. The C-terminal region of the factor V B-domain is crucial for the anticoagulant activity of factor V. J Biol Chem 1998; 273: 16140-16145.
• 99 Kalafatis M, Simioni P, Tormene D. et al. Isolation and characterization of an antifactor V antibody causing activated protein C resistance from a patient with severe thrombotic manifestations. Blood 2002; 99: 3985-3992.
• 100 Thorelli E, Kaufman RJ, Dahlbäck B. Cleavage of factor V at Arg 506 by activated protein C and the expression of anticoagulant activity of factor V. Blood 1999; 93: 2552-2558.
• 101 de Visser MC, Rosendaal FR, Bertina RM. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood 1999; 93: 1271-1276.
• 102 Bertina RM, Koeleman BP, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
• 103 Greengard JS, Sun X, Xu X. et al. Activated protein C resistance caused by Arg506Gln mutation in factor Va. Lancet 1994; 343: 1361-1362.
• 104 Voorberg J, Roelse J, Koopman R. et al. Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V. Lancet 1994; 343: 1535-1536.
• 105 Zoller B, Dahlbäck B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet 1994; 343: 1536-1538.
• 106 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-522.
• 107 Dahlbäck B. Inherited thrombophilia: resistance to activated protein C as a pathogenic factor of venous thromboembolism. Blood 1995; 85: 607-614.
• 108 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-1134.
• 109 Rees DC. The population genetics of factor V Leiden (Arg506Gln). Br J Haematol 1996; 95: 579-586.
• 110 Zivelin A, Mor-Cohen R, Kovalsky V. et al. Prothrombin 20210G>A is an ancestral prothrombotic mutation that occurred in whites approximately 24,000 years ago. Blood 2006; 107: 4666-4668.
• 111 Emmerich J, Rosendaal FR, Cattaneo M. et al. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism-- pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled- Analysis in Venous Thromboembolism. Thromb Haemost 2001; 86: 809-816.
• 112 Page C, Rubin LE, Gusberg RJ. et al. Arterial thrombosis associated with heterozygous factor V Leiden disorder, hyperhomocysteinemia, and peripheral arterial disease: importance of synergistic factors. J Vasc Surg 2005; 42: 1014-1018.
• 113 de Paula Sabino A, Ribeiro DD, Carvalho MG. et al. Factor V Leiden and increased risk for arterial thrombotic disease in young Brazilian patients. Blood Coagul Fibrinolysis 2006; 17: 271-275.
• 114 Kiechl S, Muigg A, Santer P. et al. Poor response to activated protein C as a prominent risk predictor of advanced atherosclerosis and arterial disease. Circulation 1999; 99: 614-619.
• 115 Rosendaal FR, Siscovick DS, Schwartz SM. et al. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997; 89: 2817-2821.
• 116 Ridker PM, Hennekens CH, Lindpaintner K. et al. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332: 912-917.
• 117 Juul K, Tybjaerg-Hansen A, Steffensen R. et al. Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses. Blood 2002; 100: 3-10.
• 118 Solymoss S, Tucker MM, Tracy PB. Kinetics of inactivation of membrane-bound factor Va by activated protein C. Protein S modulates factor Xa protection. J Biol Chem 1988; 263: 14884-14890.
• 119 Rosing J, Hoekema L, Nicolaes GAF. et al. Effects of protein S and factor Xa on peptide bond cleavages during inactivation of factor Va and factor VaR506Q by activated protein C. J Biol Chem 1995; 270: 27852-27858.
• 120 Norstrøm EA, Steen M, Tran S. et al. Importance of protein S and phospholipid for activated protein C-mediated cleavages in factor Va. J Biol Chem 2003; 278: 24904-24911.
• 121 Labrouche S, Javorschi S, Bernard P. et al. Molecular mechanism for APC resistance in the absence of Arg 506 mutation: factor V gene sequencing strategy. Thromb Res 1997; 87: 263-267.
• 122 Norstrøm E, Thorelli E, Dahlbäck B. Functional characterization of recombinant FV Hong Kong and FV Cambridge. Blood 2002; 100: 524-530.
• 123 van der Neut Kolfschoten M, Dirven RJ, Vos HL. et al. Factor Va is inactivated by activated protein C in the absence of cleavage sites at Arg-306, Arg-506, and Arg-679. J Biol Chem 2004; 279: 6567-6575.
• 124 Franco RF, Elion J, Tavella MH. et al. The prevalence of factor V Arg306-->Thr (factor V Cambridge) and factor V Arg306-->Gly mutations in different human populations. Thromb Haemost 1999; 81: 312-313.
• 125 Mumford AD, McVey JH, Morse CV. et al. Factor V I359T: a novel mutation associated with thrombosis and resistance to activated protein C. Br J Haematol 2003; 123: 496-501.
• 126 Steen M, Norstrøm EA, Tholander AL. et al. Functional characterization of factor V-Ile359Thr: a novel mutation associated with thrombosis. Blood 2004; 103: 3381-3387.
• 127 Hiyoshi M, Arnutti P, Prayoonwiwat W. et al. A polymorphism nt 1628G-->A (R485K) in exon 10 of the coagulation factor V gene may be a risk factor for thrombosis in the indigenous Thai population. Thromb Haemost 1998; 80: 705-706.
• 128 Le W, Yu JD, Lu L. et al. Association of the R485K polymorphism of the factor V gene with poor response to activated protein C and increased risk of coronary artery disease in the Chinese population. Clin Genet 2000; 57: 296-303.
• 129 Watanabe H, Hamada H, Yamakawa-Kobayashi K. et al. Evidence for an association of the R485K polymorphism in the coagulation factor V gene with severe preeclampsia from screening 35 polymorphisms in 27 candidate genes. Thromb Haemost 2001; 86: 1594-1595.
• 130 Lunghi B, Iacoviello L, Gemmati D. et al. Detection of new polymorphic markers in the factor V gene: association with factor V levels in plasma. Thromb Haemost 1996; 75: 45-48.
• 131 Castoldi E, Rosing J, Girelli D. et al. Mutations in the R2 FV gene affect the ratio between the two FV isoforms in plasma. Thromb Haemost 2000; 83: 362-365.
• 132 Bernardi F, Faioni EM, Castoldi E. et al. A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype. Blood 1997; 90: 1552-1557.
• 133 Yamazaki T, Nicolaes GAF, Sörensen KW. et al. Molecular basis of quantitative factor V deficiency associated with factor V R2 haplotype. Blood 2002; 100: 2515-2521.
• 134 Miteva MA, Brugge JM, Rosing J. et al. Theoretical and experimental study of the D2194G mutation in the C2 domain of coagulation factor V. Biophys J 2004; 86: 488-498.
• 135 Castaman G, Lunghi B, Missiaglia E. et al. Phenotypic homozygous activated protein C resistance associated with compound heterozygosity for Arg506Gln (factor V Leiden) and His1299Arg substitutions in factor V. Br J Haematol 1997; 99: 257-261.
• 136 Faioni EM, Franchi F, Bucciarelli P. et al. Coinheritance of the HR2 haplotype in the factor V gene confers an increased risk of venous thromboembolism to carriers of factor V R506Q (factor V Leiden). Blood 1999; 94: 3062-3066.
• 137 de Visser MC, Guasch JF, Kamphuisen PW. et al. The HR2 haplotype of factor V: effects on factor V levels, normalized activated protein C sensitivity ratios and the risk of venous thrombosis. Thromb Haemost 2000; 83: 577-582.
• 138 Castaman G, Faioni EM, Tosetto A. et al. The factor V HR2 haplotype and the risk of venous thrombosis: a meta-analysis. Haematologica 2003; 88: 1182-1189.
• 139 Martinelli I. Risk factors in venous thromboembolism. Thromb Haemost 2001; 86: 395-403.
• 140 Rosendaal FR, Koster T, Vandenbroucke JP. et al. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85: 1504-1508.
• 141 Vos HL. An online database of mutations and polymorphisms in and around the coagulation factor V gene. J Thromb Haemost 2007; 5: 185-188.
• 142 Kostka H, Siegert G, Schwarz T. et al. Frequency of polymorphisms in the B-domain of factor V gene in APC-resistant patients. Thromb Res 2000; 99: 539-547.
• 143 Leroy-Matheron C, Mallat A, Duvoux C. et al. Inhibitor against coagulation factor V after liver transplantation. Transplantation 1999; 68: 1054-1056.
• 144 Ortel TL. Clinical and laboratory manifestations of anti-factor V antibodies. J Lab Clin Med 1999; 133: 326-334.
• 145 Koyama T, Saito T, Kusano T. et al. Factor V inhibitor associated with Sjogren’s syndrome. Br J Haematol 1995; 89: 893-896.
• 146 Kamphuisen PW, Haan J, Rosekrans PC. et al. Deep-vein thrombosis and coumarin skin necrosis associated with a factor V inhibitor with lupus-like features. Am J Hematol 1998; 57: 176-178.
• 147 Ortel TL, Charles LA, Keller FG. et al. Topical thrombin and acquired coagulation factor inhibitors: clinical spectrum and laboratory diagnosis. Am J Hematol 1994; 45: 128-135.
• 148 Gibble JW, Ness PM. Fibrin glue: the perfect operative sealant?. Transfusion 1990; 30: 741-747.
• 149 Souto JC, Almasy L, Borrell M. et al. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic Analysis of Idiopathic Thrombophilia. Am J Hum Genet 2000; 67: 1452-1459.
• 150 Koeleman BP, van Rumpt D, Hamulyak K. et al. Factor V Leiden: an additional risk factor for thrombosis in protein S deficient families?. Thromb Haemost 1995; 74: 580-583.
• 151 Gandrille S, Greengard JS, Alhenc-Gelas M. et al. Incidence of activated protein C resistance caused by the ARG 506 GLN mutation in factor V in 113 unrelated symptomatic protein C-deficient patients. The French Network on the behalf of INSERM. Blood 1995; 86: 219-224.
• 152 van Boven HH, Vandenbroucke JP, Briet E. et al. Gene-gene and gene-environment interactions determine risk of thrombosis in families with inherited antithrombin deficiency. Blood 1999; 94: 2590-2594.
• 153 Salomon O, Steinberg DM, Zivelin A. et al. Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment. Arterioscler Thromb Vasc Biol 1999; 19: 511-518.
• 154 Dargaud Y, Trzeciak MC, Meunier S. et al. Two novel factor V null mutations associated with activated protein C resistance phenotype/genotype discrepancy. Br J Haematol 2003; 123: 342-345.
• 155 Vandenbroucke JP, Rosing J, Bloemenkamp KW. et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001; 344: 1527-1535.
• 156 Wu O, Robertson L, Langhorne P. et al. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thromb Haemost 2005; 94: 17-25.
• 157 Vandenbroucke JP, Koster T, Briet E. et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453-1457.
• 158 Simantov R, Lo SK, Salmon JE. et al. Factor V Leiden increases the risk of thrombosis in patients with antiphospholipid antibodies. Thromb Res 1996; 84: 361-365.
• 159 Cannegieter SC, Doggen CJ, van Houwelingen HC. et al. Travel-related venous thrombosis: results from a large population-based case control study (MEGA study). PLoS Med 2006; 3: e307.
• 160 Mather T, Oganessyan V, Hof P. et al. The 2.8 A crystal structure of Gla-domainless activated protein C. Embo J 1996; 15: 6822-6831.