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Semin Vasc Med 2003; 03(1): 033-046
DOI: 10.1055/s-2003-38331
DOI: 10.1055/s-2003-38331
Congenital and Acquired Activated Protein C Resistance
Weitere Informationen
Publikationsverlauf
Publikationsdatum:
27. März 2003 (online)
ABSTRACT
Resistance to the anticoagulant action of activated protein C, APC resistance, is a highly prevalent risk factor for venous thrombosis among individuals of Caucasian origin. In most cases, APC resistance is associated with a single missense mutation in the gene for coagulation factor V (FVLeiden), which predicts the replacement of Arg506 with a Gln at one of the cleavage sites for APC in factor V. Factor V is a Janus-faced protein with dual functions, serving as an essential nonenzymatic cofactor in both pro- and anticoagulant pathways. Procoagulant factor Va, generated after proteolysis by thrombin or factor Xa, is a cofactor to factor Xa in the activation of prothrombin, whereas anticoagulant factor V, generated after proteolysis by APC, functions as a cofactor in the APC-mediated degradation of FVIIIa. The FVLeiden mutation affects the anticoagulant response to APC at two distinct levels of the coagulation pathway, as it impairs degradation of both activated factor V and activated factor VIII, the latter effect inasmuch as FVLeiden is a poor APC cofactor. Several other genetic traits, some of them quite common, are known to affect the anticoagulant response to APC, but none of them cause the same severe APC-resistance phenotype as FVLeiden and their importance as risk factors for thrombosis is unclear. A poor APC response may also result from acquired conditions, some of which are clearly involved in the pathogenesis of venous thrombosis. Venous thrombosis is a typical multifactorial disease, the pathogenesis of which involves multiple gene-gene and gene-environment interactions. In many patients with severe thrombophilia, APC resistance is found as a contributing risk factor.
KEYWORDS
Factor V - thrombophilia - APC resistance - activated protein C
REFERENCES
- 1 Stenflo J. A new vitamin K-dependent protein. >~?Purification from bovine plasma and preliminary characterization. J Biol Chem . 1976; 251 355-363
- 2 Owen W G, Esmon C T. Functional properties of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. J Biol Chem . 1981; 256 5532-5535
- 3 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
- 4 Fukudome K, Esmon C T. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. J Biol Chem . 1994; 269 26486-26491
- 5 Esmon C T. Role of coagulation inhibitors in inflammation. Thromb Haemost . 2001; 86 51-56
- 6 Healy A M, Rayburn H B, Rosenberg R D, Weiler H. Absence of the blood-clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system. Proc Natl Acad Sci U S A . 1995; 92 850-854
- 7 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
- 8 Varadi K, Rosing J, Tans G, Schwarz H P. Influence of factor V and factor Va on APC-induced cleavage of human factor VIII [letter]. Thromb Haemost . 1995; 73 730-731
- 9 Lu D S, Kalafatis M, Mann K G, Long G L. Comparison of activated protein C/protein S-mediated inactivation of human factor VIII and factor V. Blood . 1996; 87 4708-4717
- 10 Dreyfus M, Magny J F, Bridey F. et al . Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate. N Engl J Med . 1991; 325 1565-1568
- 11 Dreyfus M, Masterson M, David M. et al . Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiency. Semin Thromb Hemost . 1995; 21 371-381
- 12 Ortel T L. Clinical and laboratory manifestations of anti-factor V antibodies. J Lab Clin Med . 1999; 133 326-334
- 13 Weiss H J, Sussman I I, Hoyer L W. Stabilization of factor VIII in plasma by the von Willebrand factor. Studies on posttransfusion and dissociated factor VIII and in patients with von Willebrand's disease. J Clin Invest . 1977; 60 390-404
- 14 Yan T L, Cui J, Rehumtulla A. et al . The structure and function of murine factor V and its inactivation by protein C. Blood . 1998; 91 4593-4599
- 15 Kan W H, Majerus P W. Purification and characterization of human coagulation factor V. J Biol Chem . 1981; 256 1002-1007
- 16 Suzuki K, Dahlbäck B, Stenflo J. Thrombin-catalyzed activation of human coagulation factor V. J Biol Chem . 1982; 257 6556-6564
- 17 Tan G, Nicolaes G AF, Thomassen M L G D C. et al . Activation of human factor V by meizothrombin. J Biol Chem . 1994; 269 15969-15972
- 18 Monkovic D, Tracy P. Activation of human factor V by factor Xa and thrombin. Biochemistry . 1990; 29 1118-1128
- 19 Safa O, Morrissey J H, Esmon C T, Esmon N L. Factor VIIa/ tissue factor generates a form of factor V with unchanged specific activity, resistance to activation by thrombin, and increased sensitivity to activated protein C. Biochemistry . 1999; 38 1829-1837
- 20 Kim S W, Ortel T L, Quinn-Allen M A. et al . V modulates assembly of the prothrombinase complex. Biochemistry . 1999; 38 11448-11454
- 21 Nicolaes G A, Villoutreix B O, Dahlback 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
- 22 Hoekema L, Nicolaes G AF, Hemker H C, Tans G, Rosing J. Human factor Va1 and factor Va2: properties in the procoagulant and anticoagulant pathways. Biochemistry . 1997; 36 3331-3335
- 23 Váradi 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
- 24 Lollar P, Parker C G. Stoichiometry of the porcine factor VIII-von Willebrand factor association. J Biol Chem . 1987; 262 17572-17576
- 25 Nesheim M E, Taswell J B, Mann K G. The contribution of bovine factor V and factor Va to the activity of prothrombinase. J Biol Chem . 1979; 254 10952-10962
- 26 Rosing J, Tans G, Govers-Riemslag J WP, Zwaal R FA, Hemker H C. The role of phospholipids and factor Va in the prothrombinase complex. J Biol Chem . 1980; 255 274-283
- 27 van Dieijen G, Tans G, Rosing J, Hemker H C. The role of phospholipid and factor VIIIa in the activation of bovine factor X. J Biol Chem . 1981; 256 3433-3442
- 28 Zehnder J L, Hiraki D D, Jones C D, Gross N, Grumet F C. Familial coagulation factor V deficiency caused by a novel 4 base pair insertion in the factor V gene: factor V Stanford [erratum]. Thromb Haemost . 1999; 82 XII
- 29 Cui J, O'Shea K S, Purkayastha A, Saunders T L, Ginsburg D. Fatal haemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V. Nature . 1996; 384 66-68
- 30 Yang T L, Cui J, Taylor J M. et al . Rescue of fatal neonatal hemorrhage in factor V deficient mice by low level transgene expression. Thromb Haemost . 2000; 83 70-77
- 31 Krawczak M, Cooper D N. The human gene mutation database. Trends Genet . 1997; 13 121-122
- 32 Kane W H, Davie E W. Blood coagulation factors V and VIII: structural and functional similarities and their relationship to hemorrhagic and thrombotic disorders. Blood . 1988; 71 539-555
- 33 Kalafatis M, Rand M D, Mann K G. The mechanism of inactivation of human factor V and human factor Va by activated protein C. J Biol Chem . 1994; 269 31869-31880
- 34 Nicolaes G AF, Tans G, Thomassen M L G D C. et al . Peptide bond cleavages and loss of functional activity during inactivation of factor Va and factor VaR506Q by activated protein. J Biol Chem . 1995; 270 21158-21166
- 35 Egan J O, Kalafatis M, Mann K G. The effect of Arg(306) ] Ala and Arg(506) ] Gln substitutions in the inactivation of recombinant human factor Va by activated protein C and protein S. Protein Sci . 1997; 6 2016-2027
- 36 Eaton D L, Wood W I, Eaton D. et al . Construction and characterization of an active factor VIII variant lacking the central one-third of the molecule. Biochemistry . 1986; 25 8343-8347
- 37 Fay P J, Smudzin T M, Walker F J. 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 . 1991; 266 20139-20145
- 38 Amano K, Michnick D A, Moussalli M, Kaufman R J. Mutation at either Arg336 or Arg562 in factor VIII is insufficient for complete resistance to activated protein C (APC)-mediated inactivation: implications for the APC resistance test. Thromb Haemost . 1998; 79 557-563
- 39 Lollar P, Parker C G. pH-dependent denaturation of thrombin-activated porcine factor VIII. J Biol Chem . 1990; 265 1688-1692
- 40 Thorelli E, Kaufman R J, Dahlback 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
- 41 Koedam J A, Meijers J C, Sixma J J, Bouma B N. Inactivation of human factor VIII by activated protein C. Cofactor activity of protein S and protective effect of von Willebrand factor. J Clin Invest . 1988; 82 1236-1243
- 42 Fay P J, Coumans J V, Walker F J. von Willebrand factor mediates protection of factor VIII from activated protein C-catalyzed inactivation. J Biol Chem . 1991; 266 2172-2177
- 43 Koppelman S J, van Hoeij M, Vink T. et al . Requirements of von Willebrand factor to protect factor VIII from inactivation by activated protein C. Blood . 1996; 87 2292-2300
- 44 Walker F J. Regulation of activated protein C by protein S. The role of phospholipid in factor Va inactivation. J Biol Chem . 1981; 256 11128-11131
- 45 He X, Shen L, Villoutreix B O, Dahlback B. 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
- 46 Krishnaswamy S, Williams E B, Mann K G. The binding of activated protein C to factors V and Va. J Biol Chem . 1986; 261 9684-9693
- 47 Rosing J, Hoekema L, Nicolaes G AF. 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
- 48 Regan L M, Lamphear B J, Huggins C F, Walker F J, Fay P J. 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 . 1994; 269 9445-9452
- 49 Dahlbäck B, Carlsson M, Svensson P J. 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 U S A . 1993; 90 1004-1008
- 50 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 U S A . 1994; 91 1396-1400
- 51 Griffin J H, Evatt B, Wideman C, Fernandez J A. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood . 1993; 82 1989-1993
- 52 Koster T, Rosendaal F R, De Ronde H. et al . Venous thrombosis due to a poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet . 1993; 342 1503-1506
- 53 Svensson P J, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med . 1994; 330 517-522
- 54 Halbmayer W M, Haushofer A, Schon R, Fischer M. The prevalence of poor anticoagulant response to activated protein C (APC resistance) among patients suffering from stroke or venous thrombosis and among healthy subjects. Blood Coagul Fibrinolysis . 1994; 5 51-57
- 55 Dahlbäck B. Inherited resistance to activated protein C, a major cause of venous thrombosis, is due to a mutation in the factor V gene. Haemostasis . 1994; 24 139-151
- 56 Zöller B, Dahlbäck B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet . 1994; 343 1536-1538
- 57 Bertina R M, Koeleman B PC, Koster T. et al . Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature . 1994; 369 64-67
- 58 Zöller B, Svensson P J, He X, Dahlbäck B. Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest . 1994; 94 2521-2524
- 59 Voorberg J, Roelse J C, Koopman R. et al . Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V. Lancet . 1994; 343 1535-1536
- 60 Greengard J S, Sun X, Xu X. et al . Activated protein C resistance caused by Arg506Gln mutation in factor Va. Lancet . 1994; 343 1361-1362
- 61 Rees D C, Cox M J, Clegg J B. World distribution of factor V Leiden. Lancet . 1995; 346 1133-1134
- 62 Martinelli I. Risk factors in venous thromboembolism. Thromb Haemost . 2001; 86 395-403
- 63 Holm J, Zöller B, Berntorp E, Erhardt L, Dahlbäck B. Prevalence of factor V gene mutation amongst myocardial infarction patients and healthy controls is higher in Sweden than in other countries. J Intern Med . 1996; 239 221-226
- 64 Zivelin A, Griffin J H, Xu X. et al . A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood . 1997; 89 397-402
- 65 Ridker P M, Vaughan D E. Hemostatic factors and the risk of myocardial infarction. N Engl J Med . 1995; 333 389-390
- 66 Rosendaal F R, Siscovick D S, Schwartz S M. et al . Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood . 1997; 89 2817-2821
- 67 Cushman M, Rosendaal F R, Psaty B M. et al . Factor V Leiden is not a risk factor for arterial vascular disease in the elderly: results from the Cardiovascular Health Study. Thromb Haemost . 1998; 79 912-915
- 68 Doggen C J, Cats V M, Bertina R M, Rosendaal F R. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation . 1998; 97 1037-1041
- 69 Longstreth Jr T W, Rosendaal F R, Siscovick D S. et al . Risk of stroke in young women and two prothrombotic mutations: factor V Leiden and prothrombin gene variant (G20210A). Stroke . 1998; 29 577-580
- 70 Thorelli E, Kaufman R J, Dahlback 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
- 71 Sakata T, Kario K, Katayama Y. et al . Clinical significance of activated protein C resistance as a potential marker for hypercoagulable state. Thromb Res . 1996; 82 235-244
- 72 de Visser C M, Rosendaal F R, Bertina R M. 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
- 73 Williamson D, Brown K, Luddington R, Baglin C, Baglin T. Factor V Cambridge: a new mutation (Arg306→Thr) associated with resistance to activated protein C. Blood . 1998; 91 1140-1144
- 74 Chan W P, Lee C K, Kwong Y L, Lam C K, Liang R. A novel mutation of Arg306 of factor V gene in Hong Kong Chinese. Blood . 1998; 91 1135-1139
- 75 Norstrøm E, Thorelli E, Dahlbäck B. The APC-resistance pattern of recombinant factor V Cambridge and factor V Hong Kong (Abst). Thromb Haemost 2001;suppl July . 2001; P532
- 76 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
- 77 Bernardi F, Faioni E M, 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
- 78 Alhenc-Gelas M, Nicaud V, Gandrille S. et al . The factor V gene A4070G mutation and the risk of venous thrombosis. Thromb Haemost . 1999; 81 193-197
- 79 Faioni E M, 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
- 80 Luddington R, Jackson A, Pannerselvam S, Brown K, Baglin T. The factor V R2 allele: risk of venous thromboembolism, factor V levels and resistance to activated protein C. Thromb Haemost . 2000; 83 204-208
- 81 Siegert G, Kostka H, Gehrisch S. et al . Method-dependent influence of certain polymorphisms in the factor V B-domain on the response to activated protein C. Blood Coagul Fibrinolysis . 2000; 11 519-527
- 82 Folsom A R, Cushman M, Tsai M Y. et al . Prospective study of venous thromboembolism in relation to factor V Leiden and related factors: the Longitudinal Investigation of Thromboembolism Etiology (LITE). Thromb Haemost . 2001; 86(Suppl) 325a
- 83 Siegert G, Kostka H, Kuhlisch E. et al . Investigation of genotype-dependent differences in factor V activity as well as response to activated protein C by application of different methods. Blood Coagul Fibrinolysis . 2001; 12 683-690
- 84 Hoekema L, Castoldi E, Tans G. et al . Functional properties of factor V and factor Va encoded by the R2-gene. Thromb Haemost . 2001; 85 75-81
- 85 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
- 86 Watanabe H, Hamada H, Yamakawa-Kobayashi K, Yoshikawa H, Arinami T. 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
- 87 Le W, Yu J D, 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
- 88 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
- 89 Zehnder J L, Jain M. Recurrent thrombosis due to compound heterozygosity for factor V Leiden and factor V deficiency. Blood Coagul Fibrinolysis . 1996; 7 361-362
- 90 Simioni P, Scudeller A, Radossi P. 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 . 1996; 75 422-426
- 91 Guasch J F, Lensen R P, Bertina R M. Molecular characterization of a type I quantitative factor V deficiency in a thrombosis patient that is "pseudo homozygous" for activated protein C resistance. Thromb Haemost . 1997; 77 252-257
- 92 Castaman G, Lunghi B, Missiaglia E, Bernardi F, Rodeghiero F. 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
- 93 Delahousse B, Lochmann S, Pouplard C. et al . Pseudo-homozygous activated protein C resistance due to coinheritance of heterozygous factor V Leiden mutation and type I factor V deficiency. Variable expression when analyzed by different activated protein C resistance functional assays. Blood Coagul Fibrinolysis . 1997; 8 503-509
- 94 Lunghi B, Castoldi E, Mingozzi F, Bernardi F, Castaman G. A novel factor V null mutation detected in a thrombophilic patient with pseudo-homozygous APC resistance and in an asymptomatic unrelated subject. Blood . 1998; 92 1463-1464
- 95 Cumming A M, Tait R C, Fildes S. et al . Development of resistance to activated protein C during pregnancy. Br J Haematol . 1995; 90 725-727
- 96 Haim N, Lanir N, Hoffman R. et al . Acquired activated protein C resistance is common in cancer patients and is associated with venous thromboembolism. Am J Med . 2001; 110 91-96
- 97 Olivieri O, Friso S, Manzato F. et al . Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol . 1995; 91 465-470
- 98 Daly E, Vessey M P, Hawkins M N. et al . Risk of venous thromboembolism in users of hormone replacement therapy. Lancet . 1996; 348 977-980
- 99 Bokarewa M I, Blomback M, Egberg N, Rosen S. A new variant of interaction between phospholipid antibodies and the protein C system. Blood Coagul Fibrinolysis . 1994; 5 37-41
- 100 Zivelin A, Gitel S, Griffin J H. et al . Extensive venous and arterial thrombosis associated with an inhibitor to activated protein C. Blood . 1999; 94 895-901
- 101 Henkens C M, Bom V J, van der Meer J. Lowered APC-sensitivity ratio related to increased factor VIII-clotting activity. Thromb Haemost . 1995; 74 1198-1199
- 102 Dahlbäck B, Hillarp A, Rosen S, Zöller B. Resistance to activated protein C, the FV:Q506 allele, and venous thrombosis. Ann Hematol . 1996; 72 166-176
- 103 Rosing J, Tans G. Effects of oral contraceptives on hemostasis and thrombosis. Am J Obstet Gynecol . 1999; 180 S375-S382
- 104 Harris G M, Stendt C L, Vollenhoven B J, Gan T E, Tipping P G. Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives. Am J Hematol . 1999; 60 175-180
- 105 Luyer M D, Khosla S, Owen W G, Miller V M. Prospective randomized study of effects of unopposed estrogen replacement therapy on markers of coagulation and inflammation in postmenopausal women. J Clin Endocrinol Metab . 2001; 86 3629-3634
- 106 Dahlbäck B. Activated protein C resistance and thrombosis: molecular mechanisms of hypercoagulable state due to FVR506Q mutation. Semin Thromb Hemost . 1999; 25 273-289
- 107 Dahlbäck B. Resistance to activated protein C as risk factor for thrombosis: molecular mechanisms, laboratory investigation, and clinical management. Semin Hematol . 1997; 34 217-234
- 108 Toulon P, Adda R, Perez P. Sensitivity of the proc(r) global assay for protein C pathway abnormalities. Clinical experience in 899 unselected patients with venous thromboembolism. Thromb Res . 2001; 104 93-103
- 109 Nicolaes G AF, Thomassen M L G D C, Tans G, Rosing J, Hemker H C. Effect of activated protein C on thrombin generation and on the thrombin potential in plasma of normal and APC resistant individuals. Blood Coagul Fibrinolysis . 1997; 8 28-38
- 110 Váradi K, Moritz B, Lang H. et al . A chromogenic assay for activated protein C resistance. Br J Haematol . 1995; 90 884-891
- 111 Reitsma P H, van der Velden A P, Vogels E. et al . Use of the direct RNA amplification technique NASBA to detect factor V Leiden, a point mutation associated with APC resistance. Blood Coagul Fibrinolysis . 1996; 7 659-663
- 112 Liebman H A, Sutherland D, Bacon R, Mcgehee W. Evaluation of a tissue factor dependent factor V assay to detect factor V Leiden: demonstration of high sensitivity and specificity for a generally applicable assay for activated protein C resistance. Br J Haematol . 1996; 95 550-553
- 113 Jorquera J I, Montoro J M, Fernández M A, Aznar J A, Aznar J. Modified test for activated protein C resistance. Lancet . 1994; 344 1162-1163
- 114 Trossaërt M, Conard J, Horellou M H. et al . Modified APC resistance assay for patients on oral anticoagulants. Lancet . 1994; 344 1709
- 115 Svensson P J, Zoller B, Dahlback B. Evaluation of original and modified APC-resistance tests in unselected outpatients with clinically suspected thrombosis and in healthy controls. Thromb Haemost . 1997; 77 332-335
- 116 Hall C, Andersson N E, Andras M, Zetterberg U, Rosen S. Evaluation of a modified APTT-based method for determination of APC resistance in plasma from patients on heparin or oral anticoagulant therapy. Thromb Res . 1998; 89 203-209
- 117 Bertina R M. Laboratory diagnosis of resistance to activated protein C (APC resistance). Thromb Haemost . 1997; 78 478-482
- 118 Nicolaes G AF, Thomassen M L G D C, Vanoerle R. et al . A prothrombinase based assay for detection of resistance to activated protein C. Thromb Haemost . 1996; 76 404-410
- 119 Beauchamp N J, Daly M E, Hampton K K. et al . High prevalence of a mutation in the factor V gene within the UK population: relationship to activated protein C resistance and familial thrombosis. Br J Haematol . 1994; 88 219-222
- 120 Ridker P M, Hennekens C H, 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
- 121 Svensson P J, Zoller B, Mattiasson I, Dahlbäck B. The factor VR506Q mutation causing APC resistance is highly prevalent amongst unselected outpatients with clinically suspected deep venous thrombosis. J Intern Med . 1997; 241 379-385
- 122 Rosendaal F R, Koster T, Vandenbroucke J P, Reitsma P H. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood . 1995; 85 1504-1508
- 123 Martinelli I, Cattaneo M, Panzeri D, Mannucci P M. Low prevalence of factor V:Q506 in 41 patients with isolated pulmonary embolism. Thromb Haemost . 1997; 77 440-443
- 124 Ma A D, Abrams C S. Activated protein C resistance, factor V Leiden, and retinal vessel occlusion. Retina . 1998; 18 297-300
- 125 Seligsohn U, Zivelin A. Thrombophilia as a multigenic disorder. Thromb Haemost . 1997; 78 297-301
- 126 Rosendaal F R. Venous thrombosis: a multicausal disease. Lancet . 1999; 353 1167-1173
- 127 Bertina R M. Genetic aspects of venous thrombosis. Eur J Obstet Gynecol Reprod Biol . 2001; 95 189-192
- 128 Salomon O, Steinberg D M, 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
- 129 Rintelen C, Mannhalter C, Ireland H. et al . Oral contraceptives enhance the risk of clinical manifestation of venous thrombosis at a young age in females homozygous for factor V Leiden. Br J Haematol . 1996; 93 487-490
- 130 Tripodi A, Mannucci P M. Laboratory investigation of thrombophilia. Clin Chem . 2001; 47 1597-1606
- 131 Malm J, Laurell M, Nilsson I M, Dahlback B. Thromboembolic disease-critical evaluation of laboratory investigation. Thromb Haemost . 1992; 68 7-13
- 132 Kraaijenhagen R A, in't Anker S P, Koopman M M. et al . High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost . 2000; 83 5-9
- 133 Dykes A C, Walker I D, McMahon A D, Islam S I, Tait R C. A study of protein S antigen levels in 3788 healthy volunteers: influence of age, sex and hormone use, and estimate for prevalence of deficiency state. Br J Haematol . 2001; 113 636-641
- 134 Zoller B, Garcia de Frutos P, Hillarp A, Dahlback B. Thrombophilia as a multigenic disease. Haematologica . 1999; 84 59-70
- 135 Vandenbroucke J P, Koster T, Briët 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