Skip to main content
SpringerLink
Log in

Activated Protein C Resistance, Factor V Leiden, and Venous Thromboembolism

  • Conference paper
Pulmonary Embolism

  • 116 Accesses

Summary

Factor V Leiden mutation is the most common inherited defect of coagulation currently known, with a prevalence between 3% and 6% in Caucasian populations. The result of a single adenine-for-guanine point mutation in the gene coding for coagulation factor V, factor V Leiden leads to a hypercoagulable state in part by rendering a key binding site on coagulation factor Va partially resistant to the anticoagulant effects of activated protein C. Clinically, this state is referred to as activated protein C resistance. Individuals affected by factor V Leiden appear to be at significantly increased risks of first and recurrent venous thrombosis, particularly those events not associated with cancer, surgery, or trauma. Moreover, risks of venous thrombosis among carriers of factor V Leiden dramatically increase in the presence of other acquired coagulation defects including hyperhomocysteinemia and oral contraceptive use. Screening programs for factor V Leiden must carefully consider the prevalence of mutation in a given population, the absolute as well as relative risks imparted by the mutation, and the benefit-to-risk ratio associated with any therapeutic intervention based upon a positive test finding. Ongoing clinical studies such as the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial will help to determine whether individuals who carry factor V Leiden and have had a first venous thrombosis should be considered for chronic, low-dose anticoagulation therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 54.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

  1. Schafer AI (1997) The primary and secondary hypercoagulable states. In: Schafer AI (ed) Molecular mechanisms of hypercoagulable states. Landes Bioscience, 1997

    Google Scholar 

  2. Dahlbäck B, Carlsson M, Svensson PJ (1993) 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: 1004 - 1008

    Article  PubMed  Google Scholar 

  3. Svensson PJ, Dahlbäck B (1994) Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 330: 517 - 522

    Article  PubMed  CAS  Google Scholar 

  4. Koster T, Rosendaal FR, de Ronde H, Briet E, Vandenbroucke JP, Bertina RM (1993) Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 342: 1503-1506

    Google Scholar 

  5. Bertina RM, Koeleman B, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH (1994) Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 369: 64 - 67

    Article  PubMed  CAS  Google Scholar 

  6. Zoller B, Dahlbäck B (1994) Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet 343: 1536 - 1538

    Article  PubMed  CAS  Google Scholar 

  7. Voorberg J, Roelse J, Koopman R, Buller H, Berends F, ten Cate JW, Mertens K, van Mourik JA (1994) Association of idiopathic venous thromboembolism with single point mutation at Arg506 of factor V. Lancet 343: 1535 - 1536

    Article  PubMed  CAS  Google Scholar 

  8. Ridker PM, Miletich JP, Hennekens CH, Buring JE (1997) Ethnic distribution of factor V Leiden among 4047 American men and women: implications for venous thromboembolism screening. JAMA 277: 1305 - 1307

    CAS  Google Scholar 

  9. Rees DC, Cox M, Clegg JB (1995) World distribution of factor V Leiden. Lancet 346: 1133 - 1134

    Article  PubMed  CAS  Google Scholar 

  10. Chan LC, Bourke C, Lam CK, Liu HW, Brookes S, Jenkins V, Pasi J (1996) Lack of activated protein C resistance in healthy Hong Kong chinese blood donors—correlation with absence of Arg 506 Gln mutation of factor V gene. Thromb Haemost 75: 522 - 523

    PubMed  CAS  Google Scholar 

  11. Fujimura H, Kambayashi J, Monden M, Kato H, Miyata T (1995) Coagulation factor V Leiden mutation may have a racial background. Thromb Haemost 74: 1381

    PubMed  CAS  Google Scholar 

  12. Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP (1995) 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 332: 912 - 917

    Article  PubMed  CAS  Google Scholar 

  13. Ridker PM, Miletich JP, Stampfer MJ, Goldhaber SZ, Lindpaintner K, Hennekens CH (1995) Factor V Leiden and recurrent idiopathic venous thromboembolism. Circulation 92: 2800 - 2802

    Google Scholar 

  14. Simioni P, Prandoni P, Lensing AWA, Scudeller A, Sardella C, Prins MH, Villalta S, Dazzi F, Girolami A (1997) The risk of recurrent venous thromboembolism in patients with an Arg506-GIn mutation in the gene for factor V (factor V Leiden). N Engl J Med 336: 399 - 403

    Article  PubMed  CAS  Google Scholar 

  15. Price DT, Ridker PM (1997) Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med 127: 895 - 903

    PubMed  CAS  Google Scholar 

  16. Ridker PM for the PREVENT Investigators (1998) Long-term, low-dose warfarin among venous thrombosis patients with and without factor V Leiden mutation: rationale and design for the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial. Vasc Med (1998) 3: 67 - 73

    Google Scholar 

  17. Sun X, Evatt B, Griffin JH (1994) Blood coagulation factor Va abnormality associated with resistance to activated protein C in venous thrombophilia. Blood 83: 3120 - 3125

    PubMed  CAS  Google Scholar 

  18. De Ronde H, Bertina RM (1994) Laboratory diagnosis of APC resistance: a critical evaluation of the test and the development of diagnostic criteria. Thromb Haemost 72: 880 - 886

    PubMed  Google Scholar 

  19. Tosetto A, Rodeghiero F (1995) Diagnosis of APC resistance in patients on oral anticoagulants. Thromb Haemost 73: 732 - 733

    PubMed  CAS  Google Scholar 

  20. Cadroy Y, Sie P, Alhenc-Gelas M, Aiach M (1995) Evaluation of APC resistance in the plasma of patients with Q506 mutation of factor V (factor V Leiden) and treated with oral anticoagulants. Thromb Haemost 73: 734 - 735

    PubMed  CAS  Google Scholar 

  21. Gilmore G, Thom J, Baker RI (1996) Diagnosis of APC resistance in patients on standard or low molecular weight heparin. Thromb Haemost 75: 267 - 269

    Google Scholar 

  22. Le DT, Griffin JH, Greengard JS, Mujumdar V, Rapaport SI (1995) Use of a generally applicable tissue factor-dependent factor V assay to detect activated protein C-resistant factor Va in patients receiving warfarin and in patients with lupus anticoagulant. Blood 85: 1704 - 1711

    PubMed  CAS  Google Scholar 

  23. Nathwani AC, Tuddenham EGD (1992) Epidemiology of coagulation disorders. Bailliere's Clin Haemotol 5: 383 - 439

    Article  CAS  Google Scholar 

  24. Zoller B, Svensson PJ, He X, Dahlbäck B (1994) 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 94: 2521 - 2524

    Article  PubMed  CAS  Google Scholar 

  25. Griffin JH, Evatt B, Wildeman C, Fernandez JA (1993) Anticoagulant protein C pathway defective in the majority of thrombophilic patients. Blood 82: 1989 - 1993

    PubMed  CAS  Google Scholar 

  26. Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH (1995) High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 85: 1504 - 1508

    PubMed  CAS  Google Scholar 

  27. Ridker PM, Glynn RJ, Miletich JP, Goldhaber SZ, Stampfer MJ, Hennekens CH (1997) Age-specific incidence rates of venous thromboembolism among carriers of factor V Leiden. Ann Intern Med 126: 528 - 531

    PubMed  CAS  Google Scholar 

  28. Ridker PM, Hennekens CH, Selhub J, Miletich JP, Malinow MR, Stampfer MJ (1997) Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risks of future venous thromboembolism. Circulation 95: 1777 - 1782

    Article  PubMed  CAS  Google Scholar 

  29. Vandenbroucke JP, Koster T, Briet E, Reitsma PH, Bertina RM, Rosendaal FR (1994) Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 344: 1453 - 1457

    Article  PubMed  CAS  Google Scholar 

  30. Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Buller HR, Vandenbroucke JP (1995) Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet 346: 1593 - 1596

    Article  PubMed  CAS  Google Scholar 

  31. Rintelen C, Mannhalter C, Ireland H, Lane DA, Knobl P, Lechner K, Pabinger I (1996) 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 93: 487490

    Google Scholar 

  32. Vandenbroucke JP, van der Meer FJM, Helmerhorst FM, Rosendaal FR (1996) Factor V Leiden: should we screen oral contraceptive users and pregnant women? BMJ 313: 1127 - 1130

    CAS  Google Scholar 

  33. Holm J, Zoller B, Svensson P, Berntorp E, Erhardt L, Dahlbäck B (1994) Myocardial infarction associated with homozygous resistance to activated protein C. Lancet 344: 952 - 953

    Article  PubMed  CAS  Google Scholar 

  34. Emmerich J, Poirier O, Evans A, Marques-Vidal, Arveiler D, Luc G, Aiach M, Cambien F (1995) Myocardial infarction, arg 506 to gln factor V mutation, and activated protein C resistance. Lancet 345: 321

    Article  PubMed  CAS  Google Scholar 

  35. Prohaska W, Mannebach H, Schmidt M, Gleichmann U, Kleesiek K (1995) Evidence against heterozygous coagulation factor V 1691 G — A mutation with resistance to activated protein C being a risk factor for coronary artery disease and myocardial infarction. J Mol Med 73: 521 - 524

    Google Scholar 

  36. Demarmels, Biasiutti F, Merlo C, Furan M, Sulzer I Binder BR, Lammle B (1995) No association of APC resistance with myocardial infarction. Blood Coagula Fibrinolysis 6: 456 - 459

    Article  Google Scholar 

  37. Halbmayer WM, Haushofer A, Schon R, Fischer M (1994) 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 Coagula Fibrinolysis 5: 51-57

    Google Scholar 

  38. Simioni P, de Ronde H, Prandoni P, Saladini M, Bertina RM, Girolami A (1995) Ischemic stroke in young patients with activated protein C resistance: a report of 3 cases belonging to three different kindreds. Stroke 26: 885 - 890

    Article  PubMed  CAS  Google Scholar 

  39. Albucher JF, Guiraud-Chaumeil B, Choller F, Cadroy Y, Sie P (1996) Frequency of resistance to activated protein C due to factor V mutation in young mutation with ischemic stroke. Stroke 27: 766 - 767

    PubMed  CAS  Google Scholar 

  40. Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM, Longstreth WT, Raghunathan TE, Koepsell TD, Reitsma PH (1997) Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 89: 2817 - 2821

    PubMed  CAS  Google Scholar 

  41. Ridker PM (1997) Fibrinolytic and inflammatory markers for arterial occlusion: the evolving epidemiology of thrombosis and hemostasis. Thromb Haemost 78: 53 - 59

    PubMed  CAS  Google Scholar 

  42. Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH (1993) Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 341: 1165 - 1168

    Article  PubMed  CAS  Google Scholar 

  43. Ridker PM, Hennekens CH, Stampfer MJ, Manson JE, Vaughan DE (1994) Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 343: 940 - 943

    Article  PubMed  CAS  Google Scholar 

  44. Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Shen C, Newcomer LM, Goldhaber SZ, Hennekens CH (1992) Baseline fibrinolytic state and the risk of future venous thrombosis. A prospective study of endogenous tissue-type plasminogen activator and plasminogen activator inhibitor. Circulation 85: 1822-1827

    Google Scholar 

  45. Wilhelmsen L, Svärdsudd K, Korsan-Bengtsen K, Larsson B, Welin L,Tibblin G (1984) Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 311: 501 - 505

    CAS  Google Scholar 

  46. Ridker PM, Cushman M, Stampfer MJ, Tracey RP, Hennekens CH (1997) Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. New Engl J Med 336: 973 - 979

    Article  PubMed  CAS  Google Scholar 

  47. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH (1998) Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation 97: 425 - 428

    Article  PubMed  CAS  Google Scholar 

  48. Hirsh J (1995) The optimal duration of anticoagulation therapy for venous thromboembosis. N Engl J Med 332: 1710 - 1711

    Article  PubMed  CAS  Google Scholar 

  49. Myers TM, Hull RD, Weg JG (1995) Antithrombotic therapy for venous thromboembolic disease. Chest 108: 4: 335S - 351S

    Article  Google Scholar 

  50. Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Larfars G, Nicol P, Loogna E, Svensson E, Ljungberg B, Walter H et al (1995) A comparison of six weeks with six months of oral anticoagulation therapy after a first episode of venous thromboembolism. N Engl J Med 332: 1661 - 1665

    Article  PubMed  CAS  Google Scholar 

  51. Prandoni P, Lensing AWA, Buller HR et al (1992) Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 327: 1128 - 1133

    Article  PubMed  CAS  Google Scholar 

  52. Prandoni P, Lensing A, Cogo A et al (1996) The long term clinical course of acute deep venous thrombosis. Ann Intern Med 125: 1 - 7

    PubMed  CAS  Google Scholar 

  53. Schulman S, Granqvist S, Holmstrom M et al (1997) The duration of oral anticoagulant therapy after a second epidose of venous thromboembolism. N Engl J Med 336: 393 - 398

    Article  PubMed  CAS  Google Scholar 

  54. Fihn SD, Callahan CM, Martin DC et al for the National Consortium of Anticoagulation Clinics (1996) The risk for and severity of bleeding complications in elderly patients treated with warfarin. Ann Intern Med 124: 970 - 979

    Google Scholar 

  55. Goodman SG, Langer A, Durica S et al (1994) Safety and anticoagulation effect of a low-dose combination of warfarin and aspirin in clinically stable coronary artery disease. Am J Cardiol 74: 657 - 661

    Article  PubMed  CAS  Google Scholar 

  56. Coumadin Aspirin Reinfarction Study (CARS) Investigators (1997) Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Lancet 350: 389 - 396

    Google Scholar 

  57. Meade TW, Roderick PJ, Brennan PJ, Wilkes HC, Kelleher CC (1992) Extra-cranial bleeding and other symptoms due to low dose aspirin and low intensity oral anticoagulation. Thromb Haemost 68: 1 - 6

    PubMed  CAS  Google Scholar 

  58. Medical Research Council's General Practice Research Framework (1998) Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men with increased risk. Lancet 351: 233 - 241

    Article  Google Scholar 

  59. Poller L, MacCallum PK, Thomson JM, Kerns W (1990) Reduction of factor VII coagulant activity (VIIC), a risk factor for ischemic heart disease, by fixed dose warfarin: a double blind crossover study. Br Heart J 63: 231 - 233

    Article  PubMed  CAS  Google Scholar 

  60. Millenson MM, Bauer KA, Kistler JP et al (1992) Monitoring "mini-intensity" anticoagulation with warfarin: comparison of the prothrombin time using a sensitive thromboplastin with prothrombin fragment F 1 + 2 levels. Blood 79: 2034 - 2038

    PubMed  CAS  Google Scholar 

  61. Bern MM, Likich JJ, Wallach SR et al (1990) Very low doses of warfarin can prevent thrombosis in central vein catheters. Ann Intern Med 112: 423 - 428

    PubMed  CAS  Google Scholar 

  62. Bern MM, Bothe A, Bistrian B et al (1986) Prophylaxis against central vein thrombosis with low-dose warfarin. Surgery 99: 216 - 220

    PubMed  CAS  Google Scholar 

  63. Millenson MM, Bauer KA (1996) Pathogenesis of venous thrombolembolism. In: Hull R, Pineo GF (eds) Disorders of thrombosis. WB Saunders, Philadelphia, pp 175 - 190

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, USA

    Paul M. Ridker

  2. Section of Cardiology, Boston University Medical Center, Boston, MA, 02115, USA

    Daniel T. Price

Authors
  1. Paul M. Ridker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel T. Price
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. The First Department of Internal Medicine, Mie University School of Medicine, 174-2 Edobashi, 514-8507, Tsu, Mie, Japan

    Takeshi Nakano M.D. (Professor) (Professor)

  2. Cardiovascular Division, Department of Medicine, Brigham and Woman’s Hospital Harvard Medical School, 75 Francis Street, 02115, Boston, MA, USA

    Samuel Z. Goldhaber M.D. (Associate Professor) (Associate Professor)

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer Japan

About this paper

Cite this paper

Ridker, P.M., Price, D.T. (1999). Activated Protein C Resistance, Factor V Leiden, and Venous Thromboembolism. In: Nakano, T., Goldhaber, S.Z. (eds) Pulmonary Embolism. Springer, Tokyo. https://doi.org/10.1007/978-4-431-66893-0_3

Download citation

  • DOI: https://doi.org/10.1007/978-4-431-66893-0_3

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-66895-4

  • Online ISBN: 978-4-431-66893-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation