Download PDF
Thromb Haemost 1999; 81(06): 918-914
DOI: 10.1055/s-0037-1614599
Letters to the Editor
Schattauer GmbH

Activated Protein C Resistance and the FV:R506Q Mutation in a Random Population Sample

Associations with Cardiovascular Risk Factors and Coagulation Variables
Gordon D. O. Lowe
3   From the University Department of Medicine, Glasgow Royal Infirmary, Glasgow, UK
,
Ann Rumley
3   From the University Department of Medicine, Glasgow Royal Infirmary, Glasgow, UK
,
Mark Woodward
1   Department of Applied Statistics, University of Reading, and Glasgow, UK
,
Evan Reid
2   University Department of Medical Genetics, Yorkhill Hospital, Glasgow, UK
,
Joseph Rumley
3   From the University Department of Medicine, Glasgow Royal Infirmary, Glasgow, UK
› Author Affiliations
Further Information

Publication History

Received 27 April 1998

Accepted after revision 09 February 1999

Publication Date:
09 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Activated protein C (APC) resistance, defined as a low APC ratio, is associated with the factor V mutation R506Q (factor V Leiden). APC ratio may also be influenced by other clinical and coagulation variables, which we studied in 460 men and 495 women aged 25-74 years, from a random population sample (Glasgow MONICA Survey). APC ratio correlated positively with APTT; and inversely with factor VIIIc, factor IXc, antithrombin activity, prothrombin F1+2 fragment, and thrombinantithrombin complexes; but not with other coagulation variables. APC ratio decreased with age, but APTT did not. APC ratio and APTT were significantly lower in women versus men, and were significantly lower in users of oral contraceptives or hormone replacement therapy. The FV:R506Q mutation (prevalence 2.5%) was associated with lower APC ratio and protein C and S activities and with higher factor VIIIc levels; but not with increases in F1+2 fragment or thrombin-antithrombin complexes. APC ratio correlated inversely with total cholesterol and diastolic blood pressure; and in women with triglycerides, systolic blood pressure, and body mass index. Obesity was associated with a significantly lower APC ratio. In contrast, smoking markers correlated positively with APC ratio in men. These associations of APC ratio may be relevant to the increased risks of venous thrombosis with age, female sex, oestrogen use, obesity and high factor VIIIc levels. The association of APC resistance with elevated plasma levels of coagulation markers suggests that this phenotype represents an in vivo hypercoagulable state.

Current address: Dr. E. Reid, Department of Medical Genetics, Addenbrooke’s Hospital, Cambridge, UK

 

  • 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 Nat Acad Sci 1993; 90: 1004-8.
    CrossrefPubMedSearch in Google Scholar
  • 2 Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, Chandy M, Dahlbäck B, Ginter EK, Miletich JP, Rosendaal FR, Seligsohn U. Inherited thrombophilia. Thromb Haemost 1996; 76: 651-62. and 824-34.
    Thieme ConnectPubMedSearch in Google Scholar
  • 3 Bertina RM. Laboratory diagnosis of resistance to activated protein C (APC-resistance). Thromb Haemost 1997; 78: 478-82.
    Thieme ConnectPubMedSearch in Google Scholar
  • 4 Dahlbäck B. Resistance to activated protein C caused by the factor V R506Q mutation is a common risk factor for venous thrombosis. Thromb Haemost 1997; 78: 483-8.
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Axelsson F, Rosén S.. APC resistance: Product monograph. Mölndal, Sweden: Chromogenix AB; 1997
    Search in Google Scholar
  • 6 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 in activated protein C. Nature 1994; 369: 64-7.
    CrossrefPubMedSearch in Google Scholar
  • 7 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 apparently healthy men. N Engl J Med 1995; 332: 912-7.
    CrossrefPubMedSearch in Google Scholar
  • 8 Samani NJ, Lodwick D, Martin D, Kimber P. Resistance to activated protein C and risk of premature myocardial infarction (letter). Lancet 1994; 344: 1709-10.
    PubMedSearch in Google Scholar
  • 9 Kontula K, Ylikorkala A, Miettinen H, Vuorio A, Kauppinen-Mäkelin R, Hämäläinen L, Palomäki H, Kaste M. Arg506Gln factor V mutation (factor V Leiden) in patients with ischaemic cerebrovascular disease and survivors of myocardial infarction. Thromb Haemost 1995; 73: 558-60.
    Thieme ConnectPubMedSearch in Google Scholar
  • 10 Catto A, Carter A, Ireland H, Bayston TA, Philippou H, Barrett J, Lane DA, Grant PJ. Factor V Leiden gene mutation and thrombin generation in relation to the development of acute stroke. Arterioscler Thromb Vasc Biol 1995; 15: 783-5.
    CrossrefPubMedSearch in Google Scholar
  • 11 van der Bom JG, Bots ML, Haverkate F, Slagboom PE, Meijer P, de Jong TVM, 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: 265-9.
    CrossrefPubMedSearch in Google Scholar
  • 12 Rosendaal FR, Siscovick DS, Schwartz SM, Beverley RK, Psaty BM, Longstrength WT, Raghernathan TE, Koepsell TD, Reitsma PH. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997; 89: 2817-21.
    PubMedSearch in Google Scholar
  • 13 Laffan MA, Manning R. The influence of factor VIII on measurement of activated protein C resistance. Blood Coagul Fibrinolys 1996; 7: 1-6.
    PubMedSearch in Google Scholar
  • 14 O’Donnell J, Tuddenham EGD, Manning R, Kemball-Cook G, Johnson D, Laffan M. High prevalence of elevated Factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationships to the acute phase reaction. Thromb Haemost 1997; 77: 825-8.
    Thieme ConnectPubMedSearch in Google Scholar
  • 15 Lowe GDO, Rumley A, Woodward M, Morrison CE, Philippou H, Lane DA, Tunstall-Pedoe H. Epidemiology of coagulation factors, inhibitors and activation markers: The Third Glasgow MONICA Survey. I. Illustrative reference ranges by age, sex and hormone use. Br J Haematol 1997; 97: 775-84.
    CrossrefPubMedSearch in Google Scholar
  • 16 Woodward M, Lowe GDO, Rumley A, Tunstall-Pedoe H, Philippou H, Lane DA, Morrison CE. Epidemiology of coagulation factors, inhibitors and activation markers: The Third Glasgow MONICA Survey. II. Relationships to cardiovascular risk factors and prevalent cardiovascular disease. Br J Haematol 1997; 97: 785-97.
    CrossrefPubMedSearch in Google Scholar
  • 17 Lowe GDO, Rumley A, Woodward M, Reid E. Oral contraceptives and venous thromboembolism (letter). Lancet 1997; 349: 1623.
    PubMedSearch in Google Scholar
  • 18 World Health Organization Principal Investigators The World Health Organization MONICA Project (monitoring trends and determinants in cardiovascular disease): a major international collaboration. J Clin Epidemiol 1988; 41:: 105-13.
    CrossrefPubMedSearch in Google Scholar
  • 19 Beauchamp NJ, Daly ME, Cooper PC, Preston FE, Peake IR. Rapid two-stage PCR for detecting factor V G1691A mutation. Lancet 1994; 344: 694-5.
    PubMedSearch in Google Scholar
  • 20 Woodward M, Laurent K, Tunstall-Pedoe H. An analysis of risk factors for prevalent coronary heart disease by using the proportional odds model. The Statistician 1995; 44: 69-80.
    CrossrefPubMedSearch in Google Scholar
  • 21 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: 2521-4.
    CrossrefPubMedSearch in Google Scholar
  • 22 Tripodi A, Negri B, Bertina RM, Mannucci PM. Screening for the FV:Q506mutation – evaluation of thirteen plasma-based methods for their diagnostic efficacy in comparison with DNA analysis. Thromb Haemost 1997; 77: 436-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Korsan-Bengtsen K, Wilhelmsen L, Tibblin G. Blood coagulation and fibrinolysis in a random sample of 788 men 54 years old. I. Correlations between the variables of clotting and fibrinolysis. Thromb Diath Haemorr 1972; 28: 89-98.
    PubMedSearch in Google Scholar
  • 24 Korsan-Bengtsen K, Wilhelmsen L, Tibblin G. Blood coagulation and fibrinolysis in a random sample of 788 men 54 years old. II. Relations of the variables to ‘risk factors’ for myocardial infarction. Thromb Diath Haemorr 1972; 28: 99-108.
    PubMedSearch in Google Scholar
  • 25 Henkens CMA, Bom VJJ, van der Meer J. Lowered APC-sensitivity ratio related to increased factor VIII clotting activity. Thromb Haemost 1995; 74: 1198-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 26 Thomson JM, Poller L.. The activated partial thromboplastin time. In Thomson JM. ed Blood Coagulation and Haemostasis: A Practical Guide, 3rd edn. Edinburgh: Churchill Livingstone; 1985: 301-39.
    Search in Google Scholar
  • 27 Cawkwell RD. Patient’s age and the activated partial thromboplastin time test. Thromb Haemost 1978; 39: 780-1.
    Thieme ConnectPubMedSearch in Google Scholar
  • 28 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: 402-4.
    Thieme ConnectPubMedSearch in Google Scholar
  • 29 Østerud B, Robertson R, Asvarg GB, Thijssen F. Resistance to activated protein C is reduced in women using oral contraceptives. Blood Coagul Fibrinolys 1994; 5: 853-4.
    PubMedSearch in Google Scholar
  • 30 Olivieri O, Friso S, Manzato F, Guella A, Bernardi F, Lunghi B, Girelli D, Azzini M, Brocco G, Russi G, Cortocher R. Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol 1995; 91: 465-70.
    CrossrefPubMedSearch in Google Scholar
  • 31 Meade TW. Hormone replacement therapy and haemostatic function. Thromb Haemost 1997; 78: 765-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 32 Chae CU, Ridker PM, Manson JE. Postmenopausal hormone replacement therapy and cardiovascular disease. Thromb Haemost 1997; 78: 770-80.
    Thieme ConnectPubMedSearch in Google Scholar
  • 33 Nabulsi AA, Folsom AR, White A, Patsch W, Heiss G, Wu KK, Szklo M. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. N Engl J Med 1993; 328: 1069-75.
    CrossrefPubMedSearch in Google Scholar
  • 34 Balendra R.. Deep vein thrombosis of the leg: natural history and haemostatic variables. MD Thesis; University of Belfast: 1990
    Search in Google Scholar
  • 35 Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-5.
    CrossrefPubMedSearch in Google Scholar
  • 36 Ireland H, Bayston T, Thompson E, Adami A, Gonçalves C, Lane DA, Finazzi G, Barbui T. Apparent heterozygous type II protein C deficiency caused by the factor V506Arg to Gln mutation. Thromb Haemost 1995; 73: 731-2.
    Thieme ConnectPubMedSearch in Google Scholar
  • 37 Faioni EM, Franchi F, Asti D, Sacchi E, Bernardi F, Mannucci PM. Resistance to activated protein C in nine thrombophilic families: interference in a protein S functional assay. Thromb Haemost 1993; 70: 1067-71.
    Thieme ConnectPubMedSearch in Google Scholar
  • 38 Greenford JS, Eichinger S, Griffin JH, Bauer KA. Variability of thrombosis among homozygous siblings with resistance to activated protein C due to an Arg to Gln mutation in the gene for factor V. N Engl J Med 1994; 331: 1559-62.
    CrossrefPubMedSearch in Google Scholar
  • 39 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: 435-41.
    CrossrefPubMedSearch in Google Scholar
  • 40 Zöller B, Holm J, Svensson P, Dahlbäck B. Elevated levels of prothrombin activation fragment 1+2 in plasma from patients with heterozygous Arg506to Gln mutation in the factor V gene (APC-resistance) and/or inherited protein S deficiency. Thromb Haemost 1996; 75: 270-4.
    Thieme ConnectPubMedSearch in Google Scholar
  • 41 Martinelli I, Boltasso B, Duca F, Faioni E, Mannucci PM. Heightened thrombin generation in individuals with resistance to activated protein C. Thromb Haemost 1996; 75: 703-5.
    Thieme ConnectPubMedSearch in Google Scholar
  • 42 Kakkar VV, Howe CT, Nicolaides AN, Renney JTG, Clarke MB. Deep vein thrombosis of the leg – is there a ‘high risk’ group. Am J Surg 1970; 120: 527-30.
    CrossrefPubMedSearch in Google Scholar
  • 43 Nicolaides AN, Irving D.. Clinical factors and the risk of deep vein thrombosis. In Nicolaides AN. ed Thromboembolism. Aetiology, advances in prevention and management Lancaster: Medical and Technical Publishing; 1975: 193-204.
    Search in Google Scholar
  • 44 Clayton JK, Anderson JA, McNicol GP. Preoperative prediction of postoperative deep vein thrombosis. Br Med J 1976; ii: 910-2.
    PubMedSearch in Google Scholar
  • 45 Lowe GDO, Osborne DH, McArdle BM, Smith A, Carter DC, Forbes CD, McLaren D, Prentice CRM. Prediction and selective prophylaxis of venous thrombosis in elective gastrointestinal surgery. Lancet 1982; i: 409-12.
    PubMedSearch in Google Scholar
  • 46 Goldhaber SZ, Savage DD, Garrison RJ, Castelli WP, Kannel WB, McNamara PM, Gherardi G, Feinleib M. Risk factors for pulmonary embolism: the Framingham Study. Am J Med 1983; 74: 1023-8.
    CrossrefPubMedSearch in Google Scholar
  • 47 Rosendaal FR. Thrombosis in the young: epidemiology and risk factors. A focus on venous thrombosis. Thromb Haemost 1997; 78: 1-6.
    Thieme ConnectPubMedSearch in Google Scholar