Thromb Haemost 1997; 78(01): 483-488
DOI: 10.1055/s-0038-1657574
New aspects of APC resistance
Schattauer GmbH Stuttgart

Resistance to Activated Protein C Caused by the Factor V R506Q Mutation ls a Common Risk Factor for Venous Thrombosis

Björn Dahlbäck
Department of Clinical Chemistry, University of Lund, Malmö, Sweden
› Author Affiliations
Further Information

Publication History

Publication Date:
12 July 2018 (online)

 
  • References

  • 1 Dahlbäck B, Stenflo J. The protein C anticoagulant system. In: The protein C anticoagulant system. Stamatoyannopoulos G, Nienhuis AW, Majerus PW, Varmus H. (eds) 02. nded. Saunders, Philadelphia: 1994. pp 599-628
  • 2 Esmon CT, Schwarz HP. An update on clinical and basic aspects of the protein C anticoagulant pathway. Trends Cardiovasc Med 1995; 05: 141-8
  • 3 Dahlbäck B. The protein C anticoagulant system: inherited defects as basis for venous thrombosis. Thromb Res 1995; 77: 1-43
  • 4 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
  • 5 Arnljots B, Dahlbäck B. Protein S as an in vivo cofactor to activated protein C in prevention of microarterial thrombosis in rabbits. J Clin Invest 1995; 95: 1987-1993
  • 6 Dahlbäck B. Inherited thrombophilia: resistance to activated protein C as a pathogenic factor of venous thromboembolism. Blood 1995; 85: 607-614
  • 7 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
  • 8 Dahlbäck B. Thrombophilia. The discovery of activated protein C resistance. In: Thrombophilia. The Discovery of Activated Protein C Resistance. Friedmann T, Gianelli FG. (eds), 33. ed. Academic Press; New York: 1995. pp. 135-175
  • 9 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
  • 10 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
  • 11 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67
  • 12 Sun X, Evatt BL, Griffin JH. Blood coagulation factor Va abnormality associated with resistance to activated protein C in venous thrombophilia. Blood 1994; 83: 3120-3125
  • 13 Vooiberg J, Roelse J, Koopman R, Büller H, Berends F, ten CateJW, Mertens K, van Mourik JA. Association of idiopathic thromboembolism with single point mutation at Arg506 of factor V. Lancet 1994; 343: 1535-1536
  • 14 Greengard JS, Sun X, Xu X, Fernandez JA, Griffin JH, Evatt BL. Activated protein C resistance caused by Arg506Gln mutation in factor Va. Lancet 1994; 343: 1362-1363
  • 15 Zöller B, Svensson PJ, 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
  • 16 Cox M, Rees DC, Martinsson JJ, Clegg JB. Evidence for a single origin of factor V Leiden. Br J Haematol 1996; 92: 1022-1025
  • 17 Hillarp A, Zöller B, Dahlbäck B. The FVR506Q mutation causing APC-resistance has a single origin. Thromb Res. in press
  • 18 Zevelin A, Griffin JH, Xu X, Pabinger I, Samama M, Conard J, Brenner B, Eldor A, Seligsohn U. A single genetic origin for the common Caucasian factor V mutation predisposing to thrombosis. Blood 1996; 89: 397-402
  • 19 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-1134
  • 20 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-521
  • 21 Griffin JH, Evatt BL, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in a majority of thrombophilic patients. Blood 1993; 82: 1989-1993
  • 22 Koster T, Rosendaal FR, de Ronde F, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor response to activated protein C: Leiden thrombophilia study. Lancet 1993; 342: 1503-1506
  • 23 Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C Resistance). Blood 1995; 85: 1504-1508
  • 24 Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apperendy healthy men. N Engl J Med 1995; 332: 912-917
  • 25 Beauchamp NJ, Daly ME, Hampton KK, Cooper PC, Preston E, Peake IR. 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
  • 26 Kalafatis M, Bertina RM, Rand MD, Mann KG. Characterization of the molecular defect in factor VR506Q. J Biol Chem 1995; 270: 4053-4057
  • 27 Nicolaes GAF, Tans G, Thomassen MCLGD, Hemker HC, Pabinger I, Varadi K, Schwarz HP, Rosing J. 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
  • 28 Rosing J, Hoekema L, Nicolaes GAF, Thomassen MCLGD, Hemker HC, Varadi K, Schwarz HP, Tans G. 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
  • 29 Heeb MJ, Kojima Y, Greengard JS, Griffin JH. Activated protein C resistance: Molecular mechanisms based on studies using purified Gln506-factor V. Blood 1995; 85: 3405-3411
  • 30 Aparicio C, Dahlbäck B. 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 1996; 313: 467-472
  • 31 Zöller B, Holm J, Svensson PJ, Dahlbäck B. Elevated levels of prothrombin activation fragment 1+2 in plasma from patients with inherited APC-resistance and/or protein S deficiency. Thromb Haemost 1996; 75: 270-274
  • 32 Simioni P, Scarano L, Gavasso S, Sardella C, Girolami B, Scudeller A, Girolami A. Prothrombin fragment 1+2 and thrombin-antithrombin complex levels in patients with inherited APC-resistance due to factor V Leiden mutation. Br J Haematol 1996; 92: 435-441
  • 33 Jorquera JI, Montoro JM, Fernandez MA, Aznar JA, Aznar J. Modified test for activated protein C resistance. Lancet 1994; 344: 1162-1163
  • 34 Trossaërt M, Conard J, Horellou MH, Samama MM, Ireland H, Bayston TA, Lane DA. Modified APC resistance assay for patients on oral anticoagulants. Lancet 1994; 344: 1709
  • 35 Svensson PJ, Zöller B, Dahläck B. Evaluation of original and modified APC-resistance tests in unselected outpatients with clinically suspected thrombosis and in healthy controls. Thromb Haemost. in press
  • 36 Lane D, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, Chandy M, Dahlbäck B, Ginter EK, Miletich JP, Rosendaal F, Seligsohn U. Inherited thrombophilia: part 1. Thromb Haemost 1996; 76: 651-662
  • 37 Lane D, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, Chandy M, Dahlbäck B, Ginter EK, Miletich JP, Rosendaal F, Seligsohn U. Inherited thrombophilia: part 2. Thromb Haemost 1996; 76: 824-834
  • 38 Sakata T, Kario K, Katayama Y, Matsuyama T, Kato H, Miyata T. Clinical significance of activated protein C resistance as a potential marker for hypercoagulable state. Thromb Res 1996; 82: 235-244
  • 39 Fisher M, Fernández JA, Amerisco SF, Xie D, Gruber A, Paganini-Hill A, Griffin JH. Activated protein C resistance in ischemic stroke not due to factor V arginine506→glutamine mutation. Stroke 1996; 27: 1163-1166
  • 40 van der Bom JG, Bots ML, Haverkate F, Slagboom PE, Meijer P, de Jong PT, Hofman A, Grobbee DE, Kluft C. Reduced response to activated protein C is associated with increased risk for cerebrovascular disease. Ann Intern Med 1996; 125: 265-269
  • 41 Brey RL, Coull BM. Cerebral venous thrombosis. Role of activated protein C resistance and factor V gene mutation. Stroke 1996; 27: 1719-1720
  • 42 Matsuda J, Gohchi K, Tsakamoto M, Gotoh M, Saitoh N, Kawasugi K. Resistance to activated protein C in systemic lupus erythematosus patients with antiphospholipid antibodies. Eur J Haematol 1994; 53: 188-189
  • 43 Ehrenforth S, Radtke KP, Scharrer I. Acquired activated protein C-resistance in patients with lupus anticoagulants. Thromb Haemost 1995; 74: 797-798
  • 44 Halbmayer WM, Haushofer A, Schön R, Fischer M. Influence of lupus anticoagulant on a commercial available kit for APC- resistance. Thromb Haemost 1994; 72: 643-651
  • 45 Geschwandtner ME, Lechner K, Pabinger I. Erroneously low APC ratio in patients with lupus anticoagulant. Ann Hematol 1995; 70: 169-170
  • 46 Matsuda J, Gotoh M, Gohchi K, Kawasugi K, Tsukamoto M, Saitoh N. Resistance to activated protein C activity of an anti- beta(2)-glycoprotein i antibody in the presence of beta(2)- glycoprotein I. Br J Haematol 1995; 90: 204-206
  • 47 Pötzsch B, Kawamura H, Preissner KT, Schmidt M, Seelig C, Miiller-Berghaus G. Acquired protein C dysfunction but not decreased activity of thrombomodulin is a possible marker of thrombophilia in patients with lupus anticoagulant. J Lab Clin Med 1995; 125: 56-65
  • 48 Cumming AM, Tait RC, Fildes S, Yoong A, Keeney S, Hay CRM. Development of resistance to activated protein C during pregnancy. Br J Haematol 1995; 90: 725-727
  • 49 Cumming AM, Tait RC, Fildes S, Hay CRM. Diagnosis of APC-resistance during pregnancy. Br J Haematol 1996; 92: 1026-1029
  • 50 Mathonnet F, de Mazancourt P, Bastenaire B, Morot M, Benattar N, Beufe S, Borg JY, Giudicelli Y. Activated protein C sensitivity ratio in pregnant women at delivery. Br J Haematol 1996; 92: 244-246
  • 51 Henkens CM, Bom VJJ, van der Meer J. Lowered APC- sensitivity ratio related to increased factor VIII-clotting activity. Thromb Haemost 1995; 74: 1198-1199
  • 52 Henkens CMA, Bom VJJ, Seinen AJ, van der Meer J. Sensitivity to activated protein C; influence of oral contraceptives and sex. Thromb Haemost 1995; 73: 402-404
  • 53 Toulon P, Gris JC, LeQuerrec A, Mamet L. Acquired activated protein C (APC) resistance in women taking oral contraceptives. Blood 1994; 84 (Suppl. 01) 260
  • 54 Østerud B, Robertsen R, Åsvang GB, Thijssen F. Resistance to activated protein C is reduced in women using oral contraceptives. Blood Coagul Fibrinolysis 1994; 5: 853-854
  • 55 Olivieri O, Friso S, Manzato F, Guella A, Bemardi F, Lunghi B, Girelli D, Azzini M, Brocco G, Russi C, Corrocher R. Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol 1995; 91: 465-470
  • 56 Koeleman BPC, Reitsma PH, Allaart RC, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood 1994; 84: 1031-1035
  • 57 Zöller B, Berntsdotter A, Garcia de Frutos P, Dahlbäck B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995; 85: 3518-3523
  • 58 Gandrille S, Greengard JS, Alhenc Gelas M, Juhan-Vague I, Abgrall JF, Jude B, Griffin JH, Aiach M. Incidence of activated protein C resistance caused by the ARG 506 GLN mutation in factor V in 113 unrelated symptomatic protein C-deficient patients. Blood 1995; 86: 219-224
  • 59 Hallam PJ, Millar DS, Krawczak M, Kakkar VV, Cooper DN. Population differences in the frequency of the factor V leiden variant among people with clinically symptomatic protein c deficiency. J Med Genet 1995; 32: 543-545
  • 60 Rosendaal FR. Oral contrceptives and screening for factor V Leiden. Thromb Haemost 1996; 75: 524-525
  • 61 Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453-4157
  • 62 Hellgren M, Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thromboembolism associated with pregnancy and oral contraceptives. Am J Obstet Gynecol 1995; 173: 210-213
  • 63 Bokarewa MI, Bremme K, Blombäck M. Arg506-Gln mutation in factor V and risk of thrombosis during pregnancy. Br J Haematol 1996; 92: 473-478
  • 64 Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Büller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet 1995; 346: 1593-1596
  • 65 Rintelen C, Mannhalter C, Ireland H, Lane DA, Knobl P, Lechner K, Pabinger I. 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
  • 66 Bauer KA. Management of patients with hereditary defects predisposing to thrombosis including pregnant women. Thromb Haemost 1995; 74: 94-100
  • 67 Rintelen C, Pabinger I, Knöbl P, Lechner K, Mannhalter C. Probability of recurrence of thrombosis in patients with and without factor V Leiden. Thromb Haemost 1996; 75: 229-232
  • 68 Ridker PM, Miletich JP, Stampfer MJ, Goldhaber SZ, Lindpaintner K, Hennekens CH. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. Circulation 1995; 92: 2800-2802
  • 69 Szucs T, Osterkom D, Schramm W. Public health economic evaluation of screening for APC resistance (Leiden mutation) in new oral contraceptive users. Med Klin 1996; 91: 317-319