Factor v Leiden and activated protein C resistance

Advances in Clinical Chemistry

Volumn 49, Issue 1, 2009, Pages 121-157

  Segers, Olivier ^a   Castoldi, Elisabetta ^a  

^a MAASTRICHT UNIVERSITY   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

BLOOD CLOTTING FACTOR 5; BLOOD CLOTTING FACTOR 5 LEIDEN;

ACTIVATED PROTEIN C RESISTANCE; GENETICS; HUMAN; MUTATION; PATHOPHYSIOLOGY; PHYSIOLOGY; REVIEW;

ACTIVATED PROTEIN C RESISTANCE; FACTOR V; HUMANS; MUTATION;

EID: 73349141742     PISSN: 00652423     EISSN: None     Source Type: Book Series    
DOI: 10.1016/S0065-2423(09)49006-1     Document Type: Article

References (235)

1. F.R. Rosendaal, Venous thrombosis: a multicausal disease, Lancet 353 (9159) (1999) 1167-1173.
2. B. Dahlbäck, Advances in understanding pathogenic mechanisms of thrombophilic disorders, Blood 112 (1) (2008) 19-27.
3. B. Dahlbäck, B.O. Villoutreix, The anticoagulant protein C pathway, FEBS Lett. 579 (15) (2005) 3310-3316.
4. J.H. Griffin, B. Evatt, T.S. Zimmerman, A.J. Kleiss, C. Wideman, Deficiency of protein C in congenital thrombotic disease, J. Clin. Invest. 68 (5) (1981) 1370-1373.
5. P.C. Comp, C.T. Esmon, Recurrent venous thromboembolism in patients with a partial deficiency of protein S, N. Engl. J. Med. 311 (24) (1984) 1525-1528.
6. H.P. Schwarz, M. Fischer, P. Hopmeier, M.A. Batard, J.H. Griffin, Plasma protein S deficiency in familial thrombotic disease, Blood 64 (6) (1984) 1297-1300.
7. B. Dahlbäck, M. Carlsson, P.J. Svensson, 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 90 (3) (1993) 1004-1008.
8. R.M. Bertina, B.P. Koeleman, T. Koster, F.R. Rosendaal, R.J. Dirven, H. de Ronde, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C, Nature 369 (6475) (1994) 64-67.
9. J. Stenflo, A new vitamin K-dependent protein. Purification from bovine plasma and preliminary characterization, J. Biol. Chem. 251 (2) (1976) 355-363.
10. J.P. Miletich, G.J. Broze, Jr., Beta protein C is not glycosylated at asparagine 329. The rate of translation may influence the frequency of usage at asparagine-X-cysteine sites, J. Biol. Chem. 265 (19) (1990) 11397-11404.
11. W. Kisiel, Human plasma protein C: isolation, characterization, and mechanism of activation by alpha-thrombin, J. Clin. Invest. 64 (3) (1979) 761-769.
12. L.O. Mosnier, B.V. Zlokovic, J.H. Griffin, The cytoprotective protein C pathway, Blood 109 (8) (2007) 3161-3172.
13. C.J. Jackson, M. Xue, Activated protein C-an anticoagulant that does more than stop clots, Int. J. Biochem. Cell Biol. 40 (12) (2008) 2692-2697.
14. P. Patracchini, V. Aiello, P. Palazzi, E. Calzolari, F. Bernardi, Sublocalization of the human protein C gene on chromosome 2q13-q14, Hum. Genet. 81 (2) (1989) 191-192.
15. D.C. Foster, S. Yoshitake, E.W. Davie, The nucleotide sequence of the gene for human protein C, Proc. Natl. Acad. Sci. USA 82 (14) (1985) 4673-4677.
16. J. Stenflo, Y. Stenberg, A. Muranyi, Calcium-binding EGF-like modules in coagulation proteinases: function of the calcium ion in module interactions, Biochim. Biophys. Acta 1477 (1-2) (2000) 51-63.
17. R.G. Di Scipio, M.A. Hermodson, S.G. Yates, E.W. Davie, A comparison of human prothrombin, factor IX (Christmas factor), factor X (Stuart factor), and protein S, Biochemistry 16 (4) (1977) 698-706.
18. B. Dahlbäck, J. Stenflo, High molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein, Proc. Natl. Acad. Sci. USA 78 (4) (1981) 2512-2516.
19. F.J. Walker, Regulation of activated protein C by a new protein. A possible function for bovine protein S, J. Biol. Chem. 255 (12) (1980) 5521-5524.
20. T.M. Hackeng, K.M. Sere, G. Tans, J. Rosing, Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor, Proc. Natl. Acad. Sci. USA 103 (9) (2006) 3106-3111.
21. M. Ndonwi, G. Broze, Jr., Protein S enhances the tissue factor pathway inhibitor inhibition of factor Xa but not its inhibition of factor VIIa-tissue factor, J. Thromb. Haemost. 6 (6) (2008) 1044-1046.
22. H.K. Ploos van Amstel, P.H. Reitsma, C.P. van der Logt, R.M. Bertina, Intron-exon organization of the active human protein S gene PS alpha and its pseudogene PS beta: duplication and silencing during primate evolution, Biochemistry 29 (34) (1990) 7853-7861.
23. B. Dahlbäck, A. Lundwall, J. Stenflo, Primary structure of bovine vitamin K-dependent protein S, Proc. Natl. Acad. Sci. USA 83 (12) (1986) 4199-4203.
24. S.M. Rezende, R.E. Simmonds, D.A. Lane, Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex, Blood 103 (4) (2004) 1192-1201.
25. C.T. Esmon, W.G. Owen, Identification of an endothelial cell cofactor for thrombincatalyzed activation of protein C, Proc. Natl. Acad. Sci. USA 78 (4) (1981) 2249-2252.
26. N.L. Esmon, W.G. Owen, C.T. Esmon, Isolation of a membrane-bound cofactor for thrombin-catalyzed activation of protein C, J. Biol. Chem. 257 (2) (1982) 859-864.
27. D.J. Stearns-Kurosawa, S. Kurosawa, J.S. Mollica, G.L. Ferrell, C.T. Esmon, The endothelial cell protein C receptor augments protein C activation by the thrombin- thrombomodulin complex, Proc. Natl. Acad. Sci. USA 93 (19) (1996) 10212-10216.
28. K. Fukudome, X. Ye, N. Tsuneyoshi, O. Tokunaga, K. Sugawara, H. Mizokami, et al. Activation mechanism of anticoagulant protein C in large blood vessels involving the endothelial cell protein C receptor, J. Exp. Med. 187 (7) (1998) 1029-1035.
29. M.F. Scully, C.H. Toh, H. Hoogendoorn, R.P. Manuel, M.E. Nesheim, S. Solymoss, et al. Activation of protein C and its distribution between its inhibitors, protein C inhibitor, alpha 1-antitrypsin and alpha 2-macroglobulin, in patients with disseminated intravascular coagulation, Thromb. Haemost. 69 (5) (1993) 448-453.
30. H. Ishii, H.H. Salem, C.E. Bell, E.A. Laposata, P.W. Majerus, Thrombomodulin, an endothelial anticoagulant protein, is absent from the human brain, Blood 67 (2) (1986) 362-365.
31. J. Ye, L.W. Liu, C.T. Esmon, A.E. Johnson, The fifth and sixth growth factor-like domains of thrombomodulin bind to the anion-binding exosite of thrombin and alter its specificity, J. Biol. Chem. 267 (16) (1992) 11023-11028.
32. C.T. Esmon, N.L. Esmon, K.W. Harris, Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation, J. Biol. Chem. 257 (14) (1982) 7944-7947.
33. N.L. Esmon, R.C. Carroll, C.T. Esmon, Thrombomodulin blocks the ability of thrombin to activate platelets, J. Biol. Chem. 258 (20) (1983) 12238-12242.
34. J. Polgar, I. Lerant, L. Muszbek, R. Machovich, Thrombomodulin inhibits the activation of factor XIII by thrombin, Thromb. Res. 43 (5) (1986) 685-690.
35. 2+ binding to a high affinity site that does not contain gamma-carboxyglutamic acid, J. Biol. Chem. 258 (9) (1983) 5554-5560.
36. A.R. Rezaie, S.T. Cooper, F.C. Church, C.T. Esmon, Protein C inhibitor is a potent inhibitor of the thrombin-thrombomodulin complex, J. Biol. Chem. 270 (43) (1995) 25336-25339.
37. K. Fukudome, C.T. Esmon, Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor, J. Biol. Chem. 269 (42) (1994) 26486-26491.
38. Z. Laszik, A. Mitro, F.B. Taylor, Jr., G. Ferrell, C.T. Esmon, Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway, Circulation 96 (10) (1997) 3633-3640.
39. N.L. Esmon, L.E. DeBault, C.T. Esmon, Proteolytic formation and properties of gammacarboxyglutamic acid-domainless protein C, J. Biol. Chem. 258 (9) (1983) 5548-5553.
40. L.M. Regan, J.S. Mollica, A.R. Rezaie, C.T. Esmon, The interaction between the endothelial cell protein C receptor and protein C is dictated by the gamma-carboxyglutamic acid domain of protein C, J. Biol. Chem. 272 (42) (1997) 26279-26284.
41. A. Slungaard, J.A. Fernandez, J.H. Griffin, N.S. Key, J.R. Long, D.J. Piegors, et al. Platelet factor 4 enhances generation of activated protein C in vitro and in vivo, Blood 102 (1) (2003) 146-151.
42. N. Diez, R. Montes, A. Alonso, P. Medina, S. Navarro, F. Espana, et al. Association of increased fibrinogen concentration with impaired activation of anticoagulant protein C, J. Thromb. Haemost. 4 (2) (2006) 398-402.
43. W.H. Kane, E.W. Davie, Blood coagulation factors V and VIII: structural and functional similarities and their relationship to hemorrhagic and thrombotic disorders, Blood 71 (3) (1988) 539-555.
44. K. Segers, B. Dahlbäck, G.A. Nicolaes, Coagulation factor V and thrombophilia: background and mechanisms, Thromb. Haemost. 98 (3) (2007) 530-542.
45. P.J. Fay, Factor VIII structure and function, Int. J. Hematol. 83 (2) (2006) 103-108.
46. F.J. Walker, Regulation of activated protein C by protein S. The role of phospholipid in factor Va inactivation, J. Biol. Chem. 256 (21) (1981) 11128-11131.
47. H.M. Bakker, G. Tans, T. Janssen-Claessen, M.C. Thomassen, H.C. Hemker, J.H. Griffin, et al., The effect of phospholipids, calcium ions and protein S on rate constants of human factor Va inactivation by activated human protein C, Eur. J. Biochem. 208 (1) (1992) 171-178.
48. M.D. Smirnov, C.T. Esmon, Phosphatidylethanolamine incorporation into vesicles selectively enhances factor Va inactivation by activated protein C, J. Biol. Chem. 269 (2) (1994) 816-819.
49. E.A. Norstrøm, M. Steen, S. Tran, B. Dahlbäck, Importance of protein S and phospholipid for activated protein C-mediated cleavages in factor Va, J. Biol. Chem. 278 (27) (2003) 24904-24911.
50. J.A. Oliver, D.M. Monroe, F.C. Church, H.R. Roberts, M. Hoffman, Activated protein C cleaves factor Va more efficiently on endothelium than on platelet surfaces, Blood 100 (2) (2002) 539-546.
51. M. Kalafatis, M.D. Rand, K.G. Mann, The mechanism of inactivation of human factor V and human factor Va by activated protein C, J. Biol. Chem. 269 (50) (1994) 31869-31880.
52. G.A. Nicolaes, G. Tans, M.C. Thomassen, H.C. Hemker, I. Pabinger, K. Váradi, 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. 270 (36) (1995) 21158-21166.
53. E.R. Guinto, C.T. Esmon, Loss of prothrombin and of factor Xa-factor Va interactions upon inactivation of factor Va by activated protein C, J. Biol. Chem. 259 (22) (1984) 13986-13992.
54. A.J. Gale, X. Xu, J.L. Pellequer, E.D. Getzoff, J.H. Griffin, Interdomain engineered disulfide bond permitting elucidation of mechanisms of inactivation of coagulation factor Va by activated protein C, Protein Sci. 11 (9) (2002) 2091-2101.
55. J. Rosing, L. Hoekema, G.A. Nicolaes, M.C. Thomassen, H.C. Hemker, K. Váradi, 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. 270 (46) (1995) 27852-27858.
56. B. Dahlbäck, Inhibition of protein Ca cofactor function of human and bovine protein S by C4b-binding protein, J. Biol. Chem. 261 (26) (1986) 12022-12027.
57. R.H. van de Poel, J.C. Meijers, J. Rosing, G. Tans, B.N. Bouma, C4b-binding protein protects coagulation factor Va from inactivation by activated protein C, Biochemistry 39 (47) (2000) 14543-14548.
58. L.F. Maurissen, M.C. Thomassen, G.A. Nicolaes, B. Dahlbäck, G. Tans, J. Rosing, et al. Re-evaluation of the role of the protein S-C4b binding protein complex in activated protein C-catalyzed factor Va-inactivation, Blood 111 (6) (2008) 3034-3041.
59. S. Yegneswaran, G.M. Wood, C.T. Esmon, A.E. Johnson, 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. 272 (40) (1997) 25013-25021.
60. S. Yegneswaran, M.D. Smirnov, O. Safa, N.L. Esmon, C.T. Esmon, A.E. Johnson, Relocating the active site of activated protein C eliminates the need for its protein S cofactor. A fluorescence resonance energy transfer study, J. Biol. Chem. 274 (9) (1999) 5462-5468.
61. M.E. Nesheim, W.M. Canfield, W. Kisiel, K.G. Mann, Studies of the capacity of factor Xa to protect factor Va from inactivation by activated protein C, J. Biol. Chem. 257 (3) (1982) 1443-1447.
62. K. Suzuki, J. Stenflo, B. Dahlbäck, B. Teodorsson, Inactivation of human coagulation factor V by activated protein C, J. Biol. Chem. 258 (3) (1983) 1914-1920.
63. E.A. Norstrøm, S. Tran, M. Steen, B. Dahlbäck, Effects of factor Xa and protein S on the individual activated protein C-mediated cleavages of coagulation factor Va, J. Biol. Chem. 281 (42) (2006) 31486-31494.
64. E. Castoldi, B. Lunghi, F. Mingozzi, P. Ioannou, G. Marchetti, F. Bernardi, New coagulation factor V gene polymorphisms define a single and infrequent haplotype underlying the factor V Leiden mutation in Mediterranean populations and Indians, Thromb. Haemost. 78 (3) (1997) 1037-1041.
65. C.A. Mitchell, S.M. Jane, H.H. Salem, Inhibition of the anticoagulant activity of protein S by prothrombin, J. Clin. Invest. 82 (6) (1988) 2142-2147.
66. M.D. Smirnov, O. Safa, N.L. Esmon, C.T. Esmon, Inhibition of activated protein C anticoagulant activity by prothrombin, Blood 94 (11) (1999) 3839-3846.
67. S. Tran, E. Norstrøm, B. Dahlbäck, Effects of prothrombin on the individual activated protein C-mediated cleavages of coagulation factor Va, J. Biol. Chem. 283 (11) (2008) 6648-6655.
68. S. Yegneswaran, P.M. Nguyen, A.J. Gale, J.H. Griffin, Prothrombin amino terminal region helps protect coagulation factor Va from proteolytic inactivation by activated protein C, Thromb. Haemost. 101 (1) (2009) 55-61.
69. S. Solymoss, M.M. Tucker, P.B. Tracy, Kinetics of inactivation of membrane-bound factor Va by activated protein C. Protein S modulates factor Xa protection, J. Biol. Chem. 263 (29) (1988) 14884-14890.
70. R.J. Preston, S. Tran, J.A. Johnson, F.N. Ainle, S. Harmon, B. White, et al. Platelet factor 4 impairs the anticoagulant activity of activated protein C, J. Biol. Chem. 284 (9) (2009) 5869-5875.
71. P.J. Fay, Factor VIII structure and function, Thromb. Haemost. 70 (1) (1993) 63-67.
72. L.M. Regan, B.J. Lamphear, C.F. Huggins, F.J. Walker, P.J. Fay, Factor IXa protects factor VIIIa from activated protein C. Factor IXa inhibits activated protein C-catalyzed cleavage of factor VIIIa at Arg562, J. Biol. Chem. 269 (13) (1994) 9445-9452.
73. P.J. Fay, T.L. Beattie, L.M. Regan, L.M. O'Brien, R.J. Kaufman, Model for the factor VIIIa-dependent decay of the intrinsic factor Xase. Role of subunit dissociation and factor IXa-catalyzed proteolysis, J. Biol. Chem. 271 (11) (1996) 6027-6032.
74. P.J. Fay, T.M. Smudzin, F.J. Walker, Activated protein C-catalyzed inactivation of human factor VIII and factor VIIIa. Identification of cleavage sites and correlation of proteolysis with cofactor activity, J. Biol. Chem. 266 (30) (1991) 20139-20145.
75. P.J. Fay, F.J. Walker, Inactivation of human factor VIII by activated protein C: evidence that the factor VIII light chain contains the activated protein C binding site, Biochim. Biophys. Acta 994 (2) (1989) 142-148.
76. J.A. Koedam, J.C. Meijers, J.J. Sixma, B.N. Bouma, Inactivation of human factor VIII by activated protein C. Cofactor activity of protein S and protective effect of von Willebrand factor, J. Clin. Invest. 82 (4) (1988) 1236-1243.
77. B. Dahlbäck, B. Hildebrand, 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 91 (4) (1994) 1396-1400.
78. L. Shen, B. Dahlbäck, Factor V and protein S as synergistic cofactors to activated protein C in degradation of factor VIIIa, J. Biol. Chem. 269 (29) (1994) 18735-18738.
79. D. Lu, M. Kalafatis, K.G. Mann, G.L. Long, Comparison of activated protein C/protein S-mediated inactivation of human factor VIII and factor V, Blood 87 (11) (1996) 4708-4717.
80. K. Váradi, J. Rosing, G. Tans, I. Pabinger, B. Keil, H.P. Schwarz, 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. 76 (2) (1996) 208-214.
81. E. Thorelli, R.J. Kaufman, B. Dahlbäck, The C-terminal region of the factor V B-domain is crucial for the anticoagulant activity of factor V, J. Biol. Chem. 273 (26) (1998) 16140-16145.
82. E. Thorelli, R.J. Kaufman, B. Dahlbäck, Cleavage of factor V at Arg 506 by activated protein C and the expression of anticoagulant activity of factor V, Blood 93 (8) (1999) 2552-2558.
83. L. Shen, X. He, B. Dahlbäck, Synergistic cofactor function of factor V and protein S to activated protein C in the inactivation of the factor VIIIa-factor IXa complex-species specific interactions of components of the protein C anticoagulant system, Thromb. Haemost. 78 (3) (1997) 1030-1036.
84. A.J. Gale, T.J. Cramer, D. Rozenshteyn, J.R. Cruz, Detailed mechanisms of the inactivation of factor VIIIa by activated protein C in the presence of its cofactors, protein S and factor V, J. Biol. Chem. 283 (24) (2008) 16355-16362.
85. R.H. van de Poel, J.C. Meijers, B.N. Bouma, C4b-binding protein inhibits the factor V-dependent but not the factor V-independent cofactor activity of protein S in the activated protein C-mediated inactivation of factor VIIIa, Thromb. Haemost. 85 (5) (2001) 761-765.
86. K. Nogami, H. Wakabayashi, P.J. Fay, Mechanisms of factor Xa-catalyzed cleavage of the factor VIIIa A1 subunit resulting in cofactor inactivation, J. Biol. Chem. 278 (19) (2003) 16502-16509.
87. K. Nogami, H. Wakabayashi, K. Schmidt, P.J. Fay, Altered interactions between the A1 and A2 subunits of factor VIIIa following cleavage of A1 subunit by factor Xa, J. Biol. Chem. 278 (3) (2003) 1634-1641.
88. P.J. Fay, T. Beattie, C.F. Huggins, L.M. Regan, Factor VIIIa A2 subunit residues 558-565 represent a factor IXa interactive site, J. Biol. Chem. 269 (32) (1994) 20522-20527.
89. L.M. O'Brien, M. Mastri, P.J. Fay, Regulation of factor VIIIa by human activated protein C and protein S: inactivation of cofactor in the intrinsic factor Xase, Blood 95 (5) (2000) 1714-1720.
90. F. Varfaj, J. Neuberg, P.V. Jenkins, H. Wakabayashi, P.J. Fay, Role of P1 residues Arg336 and Arg562 in the activated-Protein-C-catalysed inactivation of Factor VIIIa, Biochem. J. 396 (2) (2006) 355-362.
91. X. Sun, B. Evatt, J.H. Griffin, Blood coagulation factor Va abnormality associated with resistance to activated protein C in venous thrombophilia, Blood 83 (11) (1994) 3120-3125.
92. B. Zöller, B. Dahlbäck, Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis, Lancet 343 (8912) (1994) 1536-1538.
93. J. Voorberg, J. Roelse, R. Koopman, H. Buller, F. Berends, J.W. ten Cate, et al. Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V, Lancet 343 (8912) (1994) 1535-1536.
94. J.S. Greengard, X. Sun, X. Xu, J.A. Fernandez, J.H. Griffin, B. Evatt, Activated protein C resistance caused by Arg506Gln mutation in factor Va, Lancet 343 (8909) (1994) 1361-1362.
95. M.J. Heeb, Y. Kojima, J.S. Greengard, J.H. Griffin, Activated protein C resistance: molecular mechanisms based on studies using purified Gln506-factor V, Blood 85 (12) (1995) 3405-3411.
96. C. Aparicio, B. Dahlbäck, Molecular mechanisms of activated protein C resistance. Properties of factor V isolated from an individual with homozygosity for the Arg506 to Gln mutation in the factor V gene, Biochem. J. 313 (Pt. 2) (1996) 467-472.
97. M.J. Heeb, A. Rehemtulla, M. Moussalli, Y. Kojima, R.J. Kaufman, 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. 260 (1) (1999) 64-75.
98. M. van der Neut Kolfschoten, R.J. Dirven, G. Tans, J. Rosing, H.L. Vos, R.M. Bertina, The activated protein C (APC)-resistant phenotype of APC cleavage site mutants of recombinant factor V in a reconstituted plasma model, Blood Coagul. Fibrinolysis 13 (3) (2002) 207-215.
99. B. Dahlbäck, The discovery of activated protein C resistance, J. Thromb. Haemost. 1 (1) (2003) 3-9.
100. T. Koster, F.R. Rosendaal, H. de Ronde, E. Briet, J.P. Vandenbroucke, R.M. Bertina, Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study, Lancet 342 (8886-8887) (1993) 1503-1506.
101. J.H. Griffin, B. Evatt, C. Wideman, J.A. Fernandez, Anticoagulant protein C pathway defective in majority of thrombophilic patients, Blood 82 (7) (1993) 1989-1993.
102. P.J. Svensson, B. Dahlbäck, Resistance to activated protein C as a basis for venous thrombosis, N. Engl. J. Med. 330 (8) (1994) 517-522.
103. M.C. de Visser, F.R. Rosendaal, R.M. Bertina, A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis, Blood 93 (4) (1999) 1271-1276.
104. F. Rodeghiero, A. Tosetto, Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism, Ann. Intern. Med. 130 (8) (1999) 643-650.
105. D.C. Rees, M. Cox, J.B. Clegg, World distribution of factor V Leiden, Lancet 346 (8983) (1995) 1133-1134.
106. D.C. Rees, The population genetics of factor V Leiden (Arg506Gln), Br. J. Haematol. 95 (4) (1996) 579-586.
107. F.H. Herrmann, M. Koesling, W. Schroder, R. Altman, R. Jimenez Bonilla, S. Lopaciuk, et al. Prevalence of factor V Leiden mutation in various populations, Genet. Epidemiol. 14 (4) (1997) 403-411.
108. H. Cai, B. Hua, L. Fan, Q. Wang, S. Wang, Y. Zhao, A novel mutation (G2172C) of factor V gene in a chinese family with activated protein C resistance associated with venous thromboembolism, J. Thromb. Haemost. 7 (Suppl. 2) (2009) 1044 (Abstract).
109. G. Lucotte, G. Mercier, Population genetics of factor V Leiden in Europe, Blood Cells Mol. Dis. 27 (2) (2001) 362-367.
110. M.J. Cox, D.C. Rees, J.J. Martinson, J.B. Clegg, Evidence for a single origin of factor V Leiden, Br. J. Haematol. 92 (4) (1996) 1022-1025.
111. B. Zöller, L. Norlund, H. Leksell, J.E. Nilsson, H. von Schenck, U. Rosen, et al. High prevalence of the FVR506Q mutation causing APC resistance in a region of southern Sweden with a high incidence of venous thrombosis, Thromb. Res. 83 (6) (1996) 475-477.
112. A. Zivelin, J.H. Griffin, X. Xu, I. Pabinger, M. Samama, J. Conard, et al. A single genetic origin for a common Caucasian risk factor for venous thrombosis, Blood 89 (2) (1997) 397-402.
113. P.G. Lindqvist, P.J. Svensson, B. Dahlbäck, K. Marsal, Factor V Q506 mutation (activated protein C resistance) associated with reduced intrapartum blood loss-a possible evolutionary selection mechanism, Thromb. Haemost. 79 (1) (1998) 69-73.
114. P.G. Lindqvist, B. Zöller, B. Dahlbäck, Improved hemoglobin status and reduced menstrual blood loss among female carriers of factor V Leiden-an evolutionary advantage? Thromb. Haemost. 86 (4) (2001) 1122-1123.
115. F.M. van Dunne, A.J. de Craen, B.T. Heijmans, F.M. Helmerhorst, R.G. Westendorp, Gender-specific association of the factor V Leiden mutation with fertility and fecundity in a historic cohort. The Leiden 85-Plus Study, Hum. Reprod. 21 (4) (2006) 967-971.
116. W. Gopel, M. Ludwig, A.K. Junge, T. Kohlmann, K. Diedrich, J. Moller, Selection pressure for the factor-V-Leiden mutation and embryo implantation, Lancet 358 (9289) (2001) 1238-1239.
117. F.M. van Dunne, C.J. Doggen, M. Heemskerk, F.R. Rosendaal, F.M. Helmerhorst, Factor V Leiden mutation in relation to fecundity and miscarriage in women with venous thrombosis, Hum. Reprod. 20 (3) (2005) 802-806.
118. B.A. Kerlin, S.B. Yan, B.H. Isermann, J.T. Brandt, R. Sood, B.R. Basson, et al. Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia, Blood 102 (9) (2003) 3085-3092.
119. D. Mari, P.M. Mannucci, F. Duca, S. Bertolini, C. Franceschi, Mutant factor V (Arg506Gln) in healthy centenarians, Lancet 347 (9007) (1996) 1044.
120. D.C. Rees, Y.T. Liu, M.J. Cox, P. Elliott, J.S. Wainscoat, Factor V Leiden and thermolabile methylenetetrahydrofolate reductase in extreme old age, Thromb. Haemost. 78 (5) (1997) 1357-1359.
121. M. Kalafatis, R.M. Bertina, M.D. Rand, K.G. Mann, Characterization of the molecular defect in factor VR506Q, J. Biol. Chem. 270 (8) (1995) 4053-4057.
122. J.O. Egan, M. Kalafatis, K.G. Mann, The effect of Arg306->Ala and Arg506->Gln substitutions in the inactivation of recombinant human factor Va by activated protein C and protein S, Protein Sci. 6 (9) (1997) 2016-2027.
123. E. Castoldi, J.M. Brugge, G.A. Nicolaes, D. Girelli, G. Tans, J. Rosing, 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 103 (11) (2004) 4173-4179.
124. E. Castoldi, J. Rosing, Factor V Leiden: a disorder of factor V anticoagulant function, Curr. Opin. Hematol. 11 (3) (2004) 176-181.
125. P. Simioni, A. Scudeller, P. Radossi, S. Gavasso, B. Girolami, D. Tormene, et al. "Pseudo homozygous" activated protein C resistance due to double heterozygous factor V defects (factor V Leiden mutation and type I quantitative factor V defect) associated with thrombosis: report of two cases belonging to two unrelated kindreds, Thromb. Haemost. 75 (3) (1996) 422-426.
126. P. Simioni, E. Castoldi, B. Lunghi, D. Tormene, J. Rosing, F. Bernardi, An underestimated combination of opposites resulting in enhanced thrombotic tendency, Blood 106 (7) (2005) 2363-2365.
127. L. Bajzar, M. Kalafatis, P. Simioni, P.B. Tracy, An antifibrinolytic mechanism describing the prothrombotic effect associated with factor VLeiden, J. Biol. Chem. 271 (38) (1996) 22949-22952.
128. A.C. Parker, L.V. Mundada, A.H. Schmaier, W.P. Fay, Factor VLeiden inhibits fibrinolysis in vivo, Circulation 110 (23) (2004) 3594-3598.
129. F.R. Rosendaal, T. Koster, J.P. Vandenbroucke, P.H. Reitsma, High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance), Blood 85 (6) (1995) 1504-1508.
130. H. Bounameaux, Factor V Leiden paradox: risk of deep-vein thrombosis but not of pulmonary embolism, Lancet 356 (9225) (2000) 182-183.
131. K.J. van Stralen, C.J. Doggen, I.D. Bezemer, E.R. Pomp, T. Lisman, F.R. Rosendaal, Mechanisms of the factor V Leiden paradox, Arterioscler. Thromb. Vasc. Biol. 28 (10) (2008) 1872-1877.
132. W.K. Ho, G.J. Hankey, D.J. Quinlan, J.W. Eikelboom, Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review, Arch. Intern. Med. 166 (7) (2006) 729-736.
133. A. Marchiori, L. Mosena, M.H. Prins, P. Prandoni, The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies, Haematologica 92 (8) (2007) 1107-1114.
134. R.P. Lensen, R.M. Bertina, H. de Ronde, J.P. Vandenbroucke, F.R. Rosendaal, Venous thrombotic risk in family members of unselected individuals with factor V Leiden, Thromb. Haemost. 83 (6) (2000) 817-821.
135. F.R. Rosendaal, Risk factors for venous thrombotic disease, Thromb. Haemost. 82 (2) (1999) 610-619.
136. J.A. Heit, J.L. Sobell, H. Li, S.S. Sommer, The incidence of venous thromboembolism among Factor V Leiden carriers: a community-based cohort study, J. Thromb. Haemost. 3 (2) (2005) 305-311.
137. R.F. Franco, P.H. Reitsma, Genetic risk factors of venous thrombosis, Hum. Genet. 109 (4) (2001) 369-384.
138. J.P. Vandenbroucke, T. Koster, E. Briet, P.H. Reitsma, R.M. Bertina, F.R. Rosendaal, Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation, Lancet 344 (8935) (1994) 1453-1457.
139. J. Rosing, G. Tans, G.A. Nicolaes, M.C. Thomassen, R. van Oerle, P.M. van der Ploeg, et al. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives, Br. J. Haematol. 97 (1) (1997) 233-238.
140. R.J. Kim, R.C. Becker, Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies, Am. Heart J. 146 (6) (2003) 948-957.
141. Z. Ye, E.H. Liu, J.P. Higgins, B.D. Keavney, G.D. Lowe, R. Collins, et al. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66, 155 cases and 91, 307 controls, Lancet 367 (9511) (2006) 651-658.
142. J. Cui, D.T. Eitzman, R.J. Westrick, P.D. Christie, Z.J. Xu, A.Y. Yang, et al. Spontaneous thrombosis in mice carrying the factor V Leiden mutation, Blood 96 (13) (2000) 4222-4226.
143. D.T. Eitzman, R.J. Westrick, X. Bi, S.L. Manning, J.E. Wilkinson, G.J. Broze, et al. Lethal perinatal thrombosis in mice resulting from the interaction of tissue factor pathway inhibitor deficiency and factor V Leiden, Circulation 105 (18) (2002) 2139-2142.
144. D.T. Eitzman, R.J. Westrick, Y. Shen, P.F. Bodary, S. Gu, S.L. Manning, et al. Homozygosity for factor V Leiden leads to enhanced thrombosis and atherosclerosis in mice, Circulation 111 (14) (2005) 1822-1825.
145. C.M. Henkens, V.J. Bom, J. van der Meer, Lowered APC-sensitivity ratio related to increased factor VIII-clotting activity, Thromb. Haemost. 74 (4) (1995) 1198-1199.
146. M.A. Laffan, R. Manning, The influence of factor VIII on measurement of activated protein C resistance, Blood Coagul. Fibrinolysis 7 (8) (1996) 761-765.
147. J. Matsuda, K. Gohchi, M. Tsukamoto, M. Gotoh, N. Saitoh, K. Kawasugi, Resistance to activated protein C in systemic lupus erythematosus patients with antiphospholipid antibodies, Eur J Haematol 53 (3) (1994) 188-189.
148. S. Ehrenforth, K.P. Radtke, I. Scharrer, Acquired activated protein C-resistance in patients with lupus anticoagulants, Thromb. Haemost. 74 (2) (1995) 797-798.
149. O. Olivieri, S. Friso, F. Manzato, A. Guella, F. Bernardi, B. Lunghi, et al. Resistance to activated protein C in healthy women taking oral contraceptives, Br. J. Haematol. 91 (2) (1995) 465-470.
150. J.I. Jorquera, J.M. Montoro, M.A. Fernandez, J.A. Aznar, J. Aznar, Modified test for activated protein C resistance, Lancet 344 (8930) (1994) 1162-1163.
151. M. Trossaert, J. Conard, M.H. Horellou, M.M. Samama, H. Ireland, T.A. Bayston, et al. Modified APC resistance assay for patients on oral anticoagulants, Lancet 344 (8938) (1994) 1709.
152. H. de Ronde, R.M. Bertina, Careful selection of sample dilution and factor-V-deficient plasma makes the modified activated protein C resistance test highly specific for the factor V Leiden mutation, Blood Coagul. Fibrinolysis 10 (1) (1999) 7-17.
153. F. Bernardi, E.M. Faioni, E. Castoldi, B. Lunghi, G. Castaman, E. Sacchi, et al. A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype, Blood 90 (4) (1997) 1552-1557.
154. L. Hoekema, E. Castoldi, G. Tans, D. Girelli, D. Gemmati, F. Bernardi, et al., Functional properties of factor V and factor Va encoded by the R2-gene, Thromb. Haemost. 85 (1) (2001) 75-81.
155. J.M. Brugge, P. Simioni, F. Bernardi, D. Tormene, B. Lunghi, G. Tans, et al. Expression of the normal factor V allele modulates the APC resistance phenotype in heterozygous carriers of the factor V Leiden mutation, J. Thromb. Haemost. 3 (12) (2005) 2695-2702.
156. G.A. Nicolaes, M.C. Thomassen, G. Tans, J. Rosing, H.C. Hemker, Effect of activated protein C on thrombin generation and on the thrombin potential in plasma of normal and APC-resistant individuals, Blood Coagul. Fibrinolysis 8 (1) (1997) 28-38.
157. G.A. Nicolaes, M.C. Thomassen, R. van Oerle, K. Hamulyák, H.C. Hemker, G. Tans, et al. A prothrombinase-based assay for detection of resistance to activated protein C, Thromb. Haemost. 76 (3) (1996) 404-410.
158. K. Váradi, J. Rosing, G. Tans, H.P. Schwarz, Influence of factor V and factor Va on APCinduced cleavage of human factor VIII, Thromb. Haemost. 73 (4) (1995) 730-731.
159. M.C. de Visser, A. van Hylckama Vlieg, G. Tans, J. Rosing, A.E. Dahm, P.M. Sandset, et al. Determinants of the APTT- and ETP-based APC sensitivity tests, J. Thromb. Haemost. 3 (7) (2005) 1488-1494.
160. D. Williamson, K. Brown, R. Luddington, C. Baglin, T. Baglin, Factor V Cambridge: a new mutation (Arg306->Thr) associated with resistance to activated protein C, Blood 91 (4) (1998) 1140-1144.
161. A.J. ten Cate, Y.T. van de Hoek, P.H. Reitsma, H. ten Cate, P. Smits, Mutation screening for thrombophilia: two cases with factor V Cambridge without activated protein C resistance, Thromb. Haemost. 87 (5) (2002) 919-920.
162. A. Santamaria, J.M. Soria, I. Tirado, J. Mateo, I. Coll, J.C. Souto, et al. Double heterozygosity for Factor V Leiden and Factor V Cambridge mutations associated with low levels of activated protein C resistance in a Spanish thrombophilic family, Thromb. Haemost. 93 (6) (2005) 1193-1195.
163. V. Le Cam-Duchez, M.H. Chretien, P. Saugier-Veber, J.Y. Borg, Factor V Cambridge mutation and activated proteinCresistance assays, Thromb.Haemost. 95 (3) (2006) 581-583.
164. W.P. Chan, C.K. Lee, Y.L. Kwong, C.K. Lam, R. Liang, A novel mutation of Arg306 of factor V gene in Hong Kong Chinese, Blood 91 (4) (1998) 1135-1139.
165. R. Liang, C.K. Lee, M.S. Wat, Y.L. Kwong, C.K. Lam, H.W. Liu, Clinical significance of Arg306 mutations of factor V gene, Blood 92 (7) (1998) 2599-2600.
166. E. Norstrøm, E. Thorelli, B. Dahlbäck, Functional characterization of recombinant FV Hong Kong and FV Cambridge, Blood 100 (2) (2002) 524-530.
167. M. van der Neut Kolfschoten, R.J. Dirven, H.L. Vos, G. Tans, J. Rosing, R.M. Bertina, 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. 279 (8) (2004) 6567-6575.
168. A.D. Mumford, J.H. McVey, C.V. Morse, K. Gomez, M. Steen, E.A. Norstrøm, et al. Factor V I359T: a novel mutation associated with thrombosis and resistance to activated protein C, Br. J. Haematol. 123 (3) (2003) 496-501.
169. M. Steen, E.A. Norstrøm, A.L. Tholander, P.H. Bolton-Maggs, A.Mumford, J.H.McVey, et al. Functional characterization of factor V-Ile359Thr: a novel mutation associated with thrombosis, Blood 103 (9) (2004) 3381-3387.
170. B. Lunghi, L. Iacoviello, D. Gemmati, M.G. Dilasio, E. Castoldi, M. Pinotti, et al. Detection of new polymorphic markers in the factor V gene: association with factor V levels in plasma, Thromb. Haemost. 75 (1) (1996) 45-48.
171. T. Yamazaki, G.A. Nicolaes, K.W. Sorensen, B. Dahlbäck, Molecular basis of quantitative factor V deficiency associated with factor V R2 haplotype, Blood 100 (7) (2002) 2515-2521.
172. M. van der Neut Kolfschoten, R.J. Dirven, H.L. Vos, R.M. Bertina, The R2-haplotype associated Asp2194Gly mutation in the light chain of human factor V results in lower expression levels of FV, but has no influence on the glycosylation of Asn2181, Thromb. Haemost. 89 (3) (2003) 429-437.
173. J.W. Govers-Riemslag, E. Castoldi, G.A. Nicolaes, G. Tans, J. Rosing, Reduced factor V concentration and altered FV1/FV2 ratio do not fully explain R2-associated APCresistance, Thromb. Haemost. 88 (3) (2002) 444-449.
174. E. Castoldi, J. Rosing, D. Girelli, L. Hoekema, B. Lunghi, F. Mingozzi, et al., Mutations in the R2 FV gene affect the ratio between the two FV isoforms in plasma, Thromb. Haemost. 83 (3) (2000) 362-365.
175. N. Martinelli, D. Girelli, P. Ferraresi, O. Olivieri, B. Lunghi, F. Manzato, et al., Increased factor VIII coagulant activity levels in male carriers of the factor V R2 polymorphism, Blood Coagul. Fibrinolysis 18 (2) (2007) 125-129.
176. G. Castaman, E.M. Faioni, A. Tosetto, F. Bernardi, The factor V HR2 haplotype and the risk of venous thrombosis: a meta-analysis, Haematologica 88 (10) (2003) 1182-1189.
177. A. Tosetto, M. Simioni, D. Madeo, F. Rodeghiero, Intraindividual consistency of the activated protein C resistance phenotype, Br. J. Haematol. 126 (3) (2004) 405-409.
178. K.H. Orstavik, P. Magnus, H. Reisner, K. Berg, J.B. Graham, W. Nance, Factor VIII and factor IX in a twin population. Evidence for a major effect of ABO locus on factor VIII level, Am. J. Hum. Genet. 37 (1) (1985) 89-101.
179. J.M. Soria, L. Almasy, J.C. Souto, A. Buil, E. Martinez-Sanchez, J. Mateo, et al. A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility, Blood 101 (1) (2003) 163-167.
180. M. Berger, M. Mattheisen, B. Kulle, H. Schmidt, J. Oldenburg, H. Bickeboller, et al. High factor VIII levels in venous thromboembolism show linkage to imprinted loci on chromosomes 5 and 11, Blood 105 (2) (2005) 638-644.
181. M. Berger, H. Moscatelli, B. Kulle, B. Luxembourg, K. Blouin, M. Spannagl, et al. Association of ADAMDEC1 haplotype with high factor VIII levels in venous thromboembolism, Thromb. Haemost. 99 (5) (2008) 905-908.
182. J.C. Roelse, M.M. Koopman, H.R. Buller, J.W. ten Cate, B. Montaruli, J.A. van Mourik, et al. Absence of mutations at the activated protein C cleavage sites of factor VIII in 125 patients with venous thrombosis, Br. J. Haematol. 92 (3) (1996) 740-743.
183. M.I. Bokarewa, G. Falk, K. Bremme, M. Blomback, B. Wiman, Search for mutations in the genes for coagulation factors V and VIII with a possible predisposition to activated protein C resistance, Eur. J. Clin. Invest. 27 (4) (1997) 340-345.
184. W.C. Hooper, A. Dilley, H. Austin, N.K. Wenger, J. Benson, B.L. Evatt, et al. Absence of mutations at APC cleavage sites Arg306 in factor V and Arg336, Arg562 in factor VIII in African-Americans, Thromb. Haemost. 79 (1) (1998) 236.
185. J. Brummer, J. Groth, R. Flayeh, C. Wagener, R. Jung, Absence of mutations at the APC interacting sites of factor VIII in Caucasians, Thromb. Haemost. 87 (1) (2002) 170.
186. A. Tripodi, V. Chantarangkul, P.M. Mannucci, Hyperprothrombinemia may result in scquired activated protein C reistance, Blood 96 (9) (2000) 3295-3296.
187. G. Castaman, A. Tosetto, M. Simioni, M. Ruggeri, D. Madeo, F. Rodeghiero, Phenotypic APC resistance in carriers of the A20210 prothrombin mutation is associated with an increased risk of venous thrombosis, Thromb. Haemost. 86 (3) (2001) 804-808.
188. J.M. Brugge, G. Tans, J. Rosing, E. Castoldi, Protein S levels modulate the activated protein C resistance phenotype induced by elevated prothrombin levels, Thromb. Haemost. 95 (2) (2006) 236-242.
189. E. Castoldi, P. Simioni, D. Tormene, M.C. Thomassen, L. Spiezia, S. Gavasso, et al. Differential effects of high prothrombin levels on thrombin generation depending on the cause of the hyperprothrombinemia, J. Thromb. Haemost. 5 (5) (2007) 971-979.
190. S.R. Poort, F.R. Rosendaal, P.H. Reitsma, R.M. Bertina, A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis, Blood 88 (10) (1996) 3698-3703.
191. E. Castoldi, T.M. Hackeng, Regulation of coagulation by protein S, Curr. Opin. Hematol. 15 (5) (2008) 529-536.
192. A. Dahm, A. Van Hylckama Vlieg, B. Bendz, F. Rosendaal, R.M. Bertina, P.M. Sandset, Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis, Blood 101 (11) (2003) 4387-4392.
193. S.N. Tchaikovski, B. van Vlijmen, M. Thomassen, E. Castoldi, L.L. Peeters, G. Tans, et al. Changes in the coagulation system in humans and mice during pregnancy, J. Thromb. Haemost. 7 (2009) Abstracts from XXII ISTH Congress.
194. J. Rosing, Mechanisms ofOCrelated thrombosis, Thromb. Res. 115 (Suppl. 1) (2005) 81-83.
195. B. Brenner, Haemostatic changes in pregnancy, Thromb. Res. 114 (5-6) (2004) 409-414.
196. A.M. Cumming, R.C. Tait, S. Fildes, A. Yoong, S. Keeney, C.R. Hay, Development of resistance to activated protein C during pregnancy, Br. J. Haematol. 90 (3) (1995) 725-727.
197. G. Sarig, Y. Michaeli, N. Lanir, B. Brenner, N. Haim, Mechanisms for acquired activated protein C resistance in cancer patients, J. Thromb. Haemost. 3 (3) (2005) 589-590.
198. H.A. van Vliet, R.M. Bertina, A.E. Dahm, F.R. Rosendaal, J. Rosing, P.M. Sandset, et al. Different effects of oral contraceptives containing different progestogens on protein S and tissue factor pathway inhibitor, J. Thromb. Haemost. 6 (2) (2008) 346-351.
199. H.F. Negaard, P.O. Iversen, B. Ostenstad, M.C. Mowinckel, P.M. Sandset, Increased acquired activated protein C resistance in unselected patients with hematological malignancies, J. Thromb. Haemost. 6 (9) (2008) 1482-1487.
200. M. Marchetti, E. Castoldi, H.M. Spronk, R. van Oerle, D. Balducci, T. Barbui, et al. Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia vera, Blood 112 (10) (2008) 4061-4068.
201. C. Taralunga, R. Gueguen, S. Visvikis, V. Regnault, C. Sass, G. Siest, et al., Phenotypic sensitivity to activated protein C in healthy families: importance of genetic components and environmental factors, Br. J. Haematol. 126 (3) (2004) 392-397.
202. T. Arsov, D. Miladinova, M. Spiroski, Factor V Leiden is associated with higher risk of deep venous thrombosis of large blood vessels, Croat. Med. J. 47 (3) (2006) 433-439.
203. T. Mueller, R. Marschon, B. Dieplinger, D. Haidinger, A. Gegenhuber, W. Poelz, et al. Factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations are not associated with chronic limb ischemia: the Linz Peripheral Arterial Disease (LIPAD) study, J. Vasc. Surg. 41 (5) (2005) 808-815.
204. A. Gurgey, R. Rustemov, H. Parlak, G. Balta, Prevalence of factor V Leiden and methylenetetrahydrofolate reductase C677T mutations in Azerbaijan, Thromb. Haemost. 80 (3) (1998) 520-521.
205. N.V. Lipay, V.V. Dmitriev, M.B. Borisenok, Thrombotic complications during cancer treatment in children, Exp. Oncol. 29 (3) (2007) 231-235.
206. B. Boyanovsky, M. Russeva, V. Ganev, M. Penev, M. Baleva, Prevalence of factor V Leiden and prothrombin 20210 A variant in Bulgarian patients with pulmonary thromboembolism and deep venous thrombosis, Blood Coagul. Fibrinolysis 12 (8) (2001) 639-642.
207. V. Cikes, I. Abaza, V. Krzelj, I.M. Terzic, R. Tafra, A. Trlaja, et al. Prevalence of factor V Leiden and G6PD 1311 silent mutations in Dalmatian population, Arch. Med. Res. 35 (6) (2004) 546-548.
208. S.L. Xenophontos, M. Hadjivassiliou, N. Ayrton, A. Karagrigoriou, M. Pantzaris, A.N. Nicolaides, et al. Spectrum and prevalence of prothrombotic single nucleotide polymorphism profiles in the Greek Cypriot population, Int. Angiol. 21 (4) (2002) 322-329.
209. T.L. Benfield, M. Dahl, B.G. Nordestgaard, A. Tybjaerg-Hansen, Influence of the factor V Leiden mutation on infectious disease susceptibility and outcome: a population-based study, J. Infect. Dis. 192 (10) (2005) 1851-1857.
210. K. Kontula, A. Ylikorkala, H. Miettinen, A. Vuorio, R. Kauppinen-Makelin, L. Hamalainen, et al. Arg506Gln factor V mutation (factor V Leiden) in patients with ischaemic cerebrovascular disease and survivors of myocardial infarction, Thromb. Haemost. 73 (4) (1995) 558-560.
211. F. Bauduer, A. Zivelin, L. Ducout, E. Shpringer, U. Seligsohn, The prevalence of factor V G1691A but not of prothrombin G20210A and methylenetetrahydrofolate reductase C677T is remarkably low in French Basques, J. Thromb. Haemost. 2 (2) (2004) 361-362.
212. E. Cochery-Nouvellon, F. Vitry, P. Cornillet-Lefebvre, N. Hezard, L. Gillot, P. Nguyen, Interleukin-10 promoter polymorphism and venous thrombosis: a case-control study, Thromb. Haemost. 96 (1) (2006) 24-28.
213. E. Oger, K. Lacut, G. Le Gal, F. Couturaud, J.H. Abalain, B. Mercier, et al. Interrelation of hyperhomocysteinemia and inherited risk factors for venous thromboembolism. Results from the E.D.I.TH. study: a hospital-based case-control study, Thromb. Res. 120 (2) (2007) 207-214.
214. M. Aleksic, P. Jahn, J. Heckenkamp, K. Wielckens, J. Brunkwall, Comparison of the prevalence of APC-resistance in vascular patients and in a normal population cohort in Western Germany, Eur. J. Vasc. Endovasc. Surg. 30 (2) (2005) 160-163.
215. B. Hoppe, F. Tolou, T. Dorner, H. Kiesewetter, A. Salama, Gene polymorphisms implicated in influencing susceptibility to venous and arterial thromboembolism: frequency distribution in a healthy German population, Thromb. Haemost. 96 (4) (2006) 465-470.
216. A. Gialeraki, M. Politou, L. Rallidis, E. Merkouri, C. Markatos, D. Kremastinos, et al. Prevalence of prothrombotic polymorphisms in Greece, Genet. Test 12 (4) (2008) 541-547.
217. J.W. Blom, C.J. Doggen, S. Osanto, F.R. Rosendaal, Malignancies, prothrombotic mutations, and the risk of venous thrombosis, JAMA 293 (6) (2005) 715-722.
218. G. Mozsik, G. Rumi, A. Domotor, M. Figler, B. Gasztonyi, E. Papp, et al. Involvement of serum retinoids and Leiden mutation in patients with esophageal, gastric, liver, pancreatic, and colorectal cancers in Hungary, World J Gastroenterol. 11 (48) (2005) 7646-7650.
219. I. Olafsson, S. Hjaltadottir, P.T. Onundarson, R. Porarinsdottir, V. Haraldsdottir, Prevalence of factor V(Q506) and prothrombin 20210 A mutations in an apparently healthy Icelandic population and patients suffering from venous thrombosis, Thromb. Haemost. 79 (3) (1998) 685-686.
220. A.D. Pherwani, P.C. Winter, P.T. McNamee, C.C. Patterson, C.M. Hill, J.K. Connolly, et al. Is screening for factor V Leiden and prothrombin G20210A mutations in renal transplantation worthwhile? Results of a large single-center U.K. study, Transplantation 76 (3) (2003) 603-605.
221. C.H. Martini, C.J. Doggen, C. Cavallini, F.R. Rosendaal, P.M. Mannucci, No effect of polymorphisms in prothrombotic genes on the risk of myocardial infarction in young adults without cardiovascular risk factors, J. Thromb. Haemost. 3 (1) (2005) 177-179.
222. G. Sottilotta, C. Mammi, G. Furlo, V. Oriana, C. Latella, V. Trapani Lombardo, High Incidence of Factor V Leiden and Prothrombin G20210A in Healthy Southern Italians, Clin. Appl. Thromb. Hemost. 15 (3) (2009) 356-359.
223. E. Berge, K.B. Haug, E.C. Sandset, K.K. Haugbro, M. Turkovic, P.M. Sandset, The factor V Leiden, prothrombin gene 20210GA, methylenetetrahydrofolate reductase 677CT and platelet glycoprotein IIIa 1565TC mutations in patients with acute ischemic stroke and atrial fibrillation, Stroke 38 (3) (2007) 1069-1071.
224. E. Nizankowska-Mogilnicka, L. Adamek, P. Grzanka, T.B. Domagala, M. Sanak, M. Krzanowski, et al. Genetic polymorphisms associated with acute pulmonary embolism and deep venous thrombosis, Eur. Respir. J. 21 (1) (2003) 25-30.
225. S. Barreirinho, A. Ferro, M. Santos, E. Costa, J. Pinto-Basto, A. Sousa, et al. Inherited and acquired risk factors and their combined effects in pediatric stroke, Pediatr. Neurol. 28 (2) (2003) 134-138.
226. V. Djordjevic, L.J. Rakicevic, D. Mikovic, M. Kovac, P. Miljic, D. Radojkovic, et al. Prevalence of factor V leiden, factor V cambridge, factor II G20210A and methylenetetrahydrofolate reductase C677T mutations in healthy and thrombophilic Serbian populations, Acta Haematol. 112 (4) (2004) 227-229.
227. J. Hudecek, M. Dobrotova, J. Hybenova, J. Ivankova, V. Melus, R. Pullmann, et al. Factor V Leiden and the Slovak population, Vnitr. Lek. 49 (11) (2003) 845-850.
228. J.M. Garcia-Gala, V. Alvarez, C.R. Pinto, I. Soto, M.F. Urgelles, M.J. Menendez, et al. Factor V Leiden (R506Q) and risk of venous thromboembolism: a case-control study based on the Spanish population, Clin. Genet. 52 (4) (1997) 206-210.
229. F. Frances, O. Portoles, F. Gabriel, D. Corella, J.V. Sorli, A. Sabater, et al. Factor V Leiden (G1691A) and prothrombin-G20210A alleles among patients with deep venous thrombosis and in the general population from Spain, Rev. Med. Chil. 134 (1) (2006) 13-20.
230. J. Holm, B. Zöller, E. Berntorp, L. Erhardt, B. Dahlbäck, Prevalence of factor V gene mutation amongst myocardial infarction patients and healthy controls is higher in Sweden than in other countries, J. Intern. Med. 239 (3) (1996) 221-226.
231. J. Holm, B. Zöller, P.J. Svensson, E. Berntorp, L. Erhardt, B. Dahlbäck, Myocardial infarction associated with homozygous resistance to activated protein C, Lancet 344 (8927) (1994) 952-953.
232. N. Akar, E. Akar, G. Dalgin, A. Sozuoz, K. Omurlu, S. Cin, Frequency of Factor V (1691 G -> A) mutation in Turkish population, Thromb. Haemost. 78 (6) (1997) 1527-1528.
233. S. Kabukcu, N. Keskin, A. Keskin, E. Atalay, The frequency of factor V Leiden and concomitance of factor V Leiden with prothrombin G20210A mutation and methylene tetrahydrofolate reductase C677T gene mutation in healthy population of Denizli, Aegean region of Turkey, Clin. Appl. Thromb. Hemost. 13 (2) (2007) 166-171.
234. N.J. Beauchamp, M.E. Daly, K.K. Hampton, P.C. Cooper, F.E. Preston, I.R. Peake, High prevalence of a mutation in the factor V gene within the U.K. population: relationship to activated protein C resistance and familial thrombosis, Br. J. Haematol. 88 (1) (1994) 219-222.
235. J.H. Griffin, J.A. Fernández, A.J. Gale, L.O. Mosnier, J. Thromb. Haemost. 5 (Suppl. 1) (2007) 73-80.