Thromb Haemost 1996; 75(01): 004-010
DOI: 10.1055/s-0038-1650212
Original Article
Schattauer GmbH Stuttgart

The 1691 G → A Mutation in the Factor V Gene: Relationship to Activated Protein C (APC) Resistance and Thrombosis in 65 Patients

Catherine Leroy-Matheron
1   The Unitè d’Hèmostase et de Thrombose et, Centre Hospitalier et Universitaire Henri Mondor, Crèteil, France
,
Martine Levent
1   The Unitè d’Hèmostase et de Thrombose et, Centre Hospitalier et Universitaire Henri Mondor, Crèteil, France
,
Jean-Michel Pignon
2   The Unitè de Biologie Molèculaire, Service Central d’ Hèmatologie Biologique, Centre Hospitalier et Universitaire Henri Mondor, Crèteil, France
,
Caio Mendonça
1   The Unitè d’Hèmostase et de Thrombose et, Centre Hospitalier et Universitaire Henri Mondor, Crèteil, France
,
Michèle Gouault-Heilmann
1   The Unitè d’Hèmostase et de Thrombose et, Centre Hospitalier et Universitaire Henri Mondor, Crèteil, France
› Institutsangaben
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Publikationsverlauf

Received 25. Juli 1995

Accepted after revision 29. September 1995

Publikationsdatum:
10. Juli 2018 (online)

Summary

Four hundred fifty subjects were screened for the 1691 G → A mutation in the factor V gene. Two hundred ninety-seven patients were referred to us for unexplained thrombosis, 133 were family members of these patients and 20 were normal subjects. We studied the relationships between the mutation, resistance to APC and thrombosis. Among the 450 subjects tested, 65 belonging to 42 families were found to have the 1691 G → A mutation in one (n = 61) or both alleles (n = 4). The prevalence of the mutation in the thrombotic patients was 13%. Resistance to APC was tested for in 247 subjects not on anticoagulant treatment (4 homozygous and 44 heterozygous for the mutation, and 199 individuals without the mutation). Incomplete cosegregation of heterozygosity for the 1691 G → A mutation with APC resistance (APC-SR <2.4 or n-APC-SR <0.75) was observed, showing that the functional assay alone is insufficient for a firm diagnosis. In patients carrying the mutation, elevated levels of prothrombin fragment 1+2 and D-dimers pointed to increased thrombin generation in vivo. Clinical manifestations in the heterozygous subjects were very similar to those reported in heterozygous PC or PS deficiencies, but the first thrombotic event occurred later than in PC- or PS-deficient patients. Homozygosity for the factor V gene mutation appears to be a far more benign thrombotic disorder than homozygous PC and PS deficiencies.

 
  • References

  • 1 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 1993; 90: 1004-1008
  • 2 Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. The Lancet 1993; 342: 1503-1506
  • 3 Aillaud MF, Succo E, Alhenc-Gelas M, Gandrille S, Brunet D, Pouymayou K, Alessi MC, Aiach M, Juhan-Vague I. Résistance à la protéine C activée (RPCA): étude prospective sur 6 mois. Proc Congr Angio Gèneve 1994 113. (abstract)
  • 4 Trossaërt M, Conard J, Horellou MH, Elalamy I, Samama MM. Prévalence de la résistance à la protéine C activée chez 175 patients ay ant des antécédents thromboemboliques veineux. Proc Congr Angio Genève 1994 114. (abstract)
  • 5 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-522
  • 6 Griffin JH, Evatt B, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood 1993; 82: 1989-1993
  • 7 Beauchamp NJ, Daly ME, Hampton KK, Cooper PC, Preston FE, 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. BrJ Haematol 1994; 88: 219-222
  • 8 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 1994; 91: 1396-1400
  • 9 Sun X, Evatt B, Griffin JH. Blood coagulation factor Va abnormality associated with resistance to activated protein C in venous thrombophilia. Blood 1994; 83: 3120-3125
  • 10 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der VeldenPA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67
  • 11 Gandrille S, Alhenc-Gelas M, Aiach M. A rapid screening method for the factor V Arg 506 Gin mutation. Blood Coagulation and Fibrinolysis 1995; 6: 245-247
  • 12 Amiral J, Grosley B, Boyer-Neumann C, Marfaing-Koka A, Peynaud-Debayle E, Wolf M, Meyer D. New direct assay of free protein S antigen using two distinct monoclonal antibodies specific for the free form. Blood Coagulation and Fibrinolysis 1994; 5: 179-186
  • 13 Wolf M, Boyer-Neumann C, Martinolli JL, Leroy-Matheron C, Amiral J, Meyer D, Larrieu MJ. A new functional assay for human protein S activity using activated factor Va as substrate. Thromb Haemost 1989; 62: 1144-1145
  • 14 Nicham F, Guichaoua JF, Contant G, Martinoli JL. Dosage rapide de l’activité de la protéine C. Ann Biol Clin 1986; 46: 805-809
  • 15 Martinoli JL, Stocker K. Fast functional protein C assay using Protac, a novel protein C activator. Thromb Res 1986; 43: 253-264
  • 16 Ødegard OR, Lie M, Abilgaard U. Heparin cofactor activity measured with an amidolytic method. Thromb Res 1975; 6: 287-294
  • 17 Pelzer H, Schwarz A, Stiiber W. Determination of human prothrombin activation fragment 1+2 in plasma with an antibody against a synthetic peptide. Thromb Haemost 1991; 65: 153-159
  • 18 Pelzer H, Schwarz A, Heimburger N. Determination of human thrombin-antithrombin III complex in plasma with an enzyme-linked immunosorbent assay. Thromb Haemost 1988; 59: 101-106
  • 19 Alhenc-Gelas M, Gandrille S, Aubry ML, Emmerich J, Fiessinger JN, Aiach M. Unexplained thrombosis and factor V Leiden mutation. Lancet 1994; 344: 555-556
  • 20 Stirling D, White A, Clarkson J, Stewart A, Ludlam CA. A comparison between functional and genetic testing for activated protein C resistance (APCR). Blood Coagulation and Fibrinolysis 1995; 6: 154 (abstract)
  • 21 Vooerberg J, Roelse J, Koopman R, Biiller H, Berends F, Ten CateJW, Mertens K, van Mourik JA. Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V. Lancet 1994; 343: 1535-1536
  • 22 Borg JY, Beufé S, Vasse M, Monconduit M, Frebourg T. Relations risque thrombotique – phénotype – génotype dans une grande famille avec facteur V Leiden. Proc Congr Angio Genève 1994 106. (abstract)
  • 23 Zöller B, Svensson PJ, He X, Dahlback B. Identification of the same factor V mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest 1994; 94: 2521-2524
  • 24 Greengard JS, Eichinger S, Griffin JH, Bauer KA. Brief report: variability of thrombosis.among homozygous siblings with resistance to activated protein C due to an Arg → Gin mutation in the gene for factor V. N Engl J Med 1994; 331: 1559-1562
  • 25 Scarano L, Simioni P, Gavasso S, Sardella C, Rossi L, Scudeller A, Giro-lami A. FI+2 and TAT levels in patients with inherited APC-resistance. Thromb Haemost 1995; 73: 1366 (abstract)
  • 26 Kalafatis M, Bertina RM, Rand MD, Mann KG. Characterization of factor V from APC-resistant patients homozygous for the Arg 506 → Gin mutation. Thromb Haemost 1995; 73: 1362 (abstract)
  • 27 Engesser L, Broekmans AW, Briet E, Brommer EJP, Bertina RM. Hereditary protein S deficiency: clinical manifestations. Ann Int Med 1987; 106: 677-682
  • 28 Gouault-Heilmann M, Leroy-Matheron C, Levent M. Inherited protein S deficiency: clinical manifestations and laboratory findings in 63 patients. Thromb Res 1994; 76: 269-279
  • 29 Broekmans AW, Conard J. Hereditary protein C deficiency. In: Protein C and Related Proteins Bertina RM. eds Churchill; Livingstone: 1988: 160-181
  • 30 Van der BomJG, Kluft C, Bots ML, Haverkate F, Slagboom E, Meijer P, Grobbee DE. Factor V mutation, APC resistance and myocardial infarction in the Rotterdam study. Thromb Haemost 1995; 73: 1373 (abstract)
  • 31 Emmerich J, Poirier O, Evans A, Marques-Vidal P, Arveiler D, Luc G, Aiach M, Cambien F. Myocardial infarction is not associated with the Arg 506 to Gin factor V mutation causing resistance to activated protein C. Thromb Haemost 1995; 73: 1373 (abstract)
  • 32 Seligsohn U, Berger A, Abend M. Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn. N Engl J Med 1984; 310: 559-562
  • 33 Mahasandana C, Suvatte V, Chuansumrit A, Marlar RA, Manco-Johnson MJ, Jacobson LJ, Hathaway WE. Homozygous protein S deficiency in an infant with purpura fulminans. J Pediat 1990; 117: 750-753
  • 34 Heeb MJ, Mesters RM, Tans G, Rosing J, Griffin JH. Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C. J Biol Chem 1993; 268: 2872-2877