Annals of Hematology

, Volume 88, Issue 5, pp 485–490

6 versus 30 months anticoagulation for recurrent venous thrombosis in patients with high factor VIII

  • L. Eischer
  • V. Gartner
  • S. Schulman
  • P. A. Kyrle
  • S. Eichinger
  • for the AUREC-FVIII investigators (as listed in acknowledgements)
Original Article

Abstract

Patients with first venous thromboembolism (VTE) and high factor VIII (FVIII) are at increased risk of recurrence. It is unknown whether these patients benefit from prolonged secondary thrombophrophylaxis. In a prospective trial patients with first spontaneous VTE and FVIII levels >230 IU/dl were randomized to discontinue vitamin K Antagonist (VKA) after 6 months or to continue VKA for additional 24 months. Patients were excluded if they had a natural inhibitor deficiency, lupus anticoagulant, cancer, were pregnant, required long-term antithrombotic therapy or had acute-phase reaction. Primary study endpoints were symptomatic recurrent VTE or major bleeding within 2 years. Follow-up was continued beyond 2 years. Of 3,219 screened patients 34 met the inclusion criteria. Mean observation time was 37 months. Two of 17 patients allocated to discontinue VKA and two of 17 patients randomized to prolonged anticoagulation had recurrent VTE within 2 years. In the prolonged treatment group, one patient had recurrence during VKA therapy and one patient 4 weeks after voluntary discontinuation of VKA. One major nonfatal bleeding (severe epistaxis) after 10 months of VKA occurred in the prolonged treatment group. Five patients allocated to prolonged anticoagulation had recurrent VTE after discontinuation of VKA. The probability of recurrence at 2 years after discontinuation of VKA was 30% (95% CI 13–46%). Patients with high FVIII are at increased risk of recurrence. Our findings in a small number of patients indicate that prolonged anticoagulation seems to be effective but that the benefit is not maintained after discontinuation of anticoagulation.

Keywords

Anticoagulation High factor VIII Recurrence of venous thromboembolism Interventional trial 

References

  1. 1.
    Koster T, Blann AD, Briet E, Vandenbroucke JP, Rosendaal FR (1995) Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 345:152–155 doi:10.1016/S0140-6736(95)90166-3 PubMedCrossRefGoogle Scholar
  2. 2.
    O’Donnell J, Tuddenham EG, Manning R, Kemball-Cook G, Johnson D, Laffan M (1997) High prevalence of high factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 77:825–828PubMedGoogle Scholar
  3. 3.
    Kyrle PA, Minar E, Hirschl M, Bialonczyk C, Stain M, Schneider B, Weltermann A, Speiser W, Lechner K, Eichinger S (2000) High plasma levels of factor levels and the risk of recurrent venous thromboembolism. N Engl J Med 343:457–462 doi:10.1056/NEJM200008173430702 PubMedCrossRefGoogle Scholar
  4. 4.
    Cristina L, Benilde C, Michela C, Mirella F, Giuliana G, Gualtiero P (2004) High plasma levels of factor VIII and risk of recurrence of venous thromboembolism. Br J Haematol 124:504–510 doi:10.1046/j.1365-2141.2003.04795.x PubMedCrossRefGoogle Scholar
  5. 5.
    Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR (2005) Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA 293:2352–2361 doi:10.1001/jama.293.19.2352 PubMedCrossRefGoogle Scholar
  6. 6.
    Levine MN, Raskob G, Beyth RJ, Kearon C, Schulman S (2004) Hemorrhagic complications of anticoagulant treatment: the Seventh ACCP Conference on Antithrombotic and hrombolytic Therapy. Chest 126:287S–310SPubMedCrossRefGoogle Scholar
  7. 7.
    Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Larfars G, Nicol P, Loogna E, Svensson E, Ljungberg B, Walter H, Viering S, Nordlander S, Leijd B, Kjell-Ake J, Hjorth M, Linder O, Boberg J, Duration of Anticoagulation Trial Study Group (1995) A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 332:1661–1665 doi:10.1056/NEJM199506223322501 PubMedCrossRefGoogle Scholar
  8. 8.
    Schulman S, Granqvist S, Holmstrom M, Carlsson A, Lindmarker P, Nicol P, Eklund SG, Nordlander S, Larfars G, Leijd B, Linder O, Loogna E (1997) The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group. N Engl J Med 336:393–398 doi:10.1056/NEJM199702063360601 PubMedCrossRefGoogle Scholar
  9. 9.
    Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D’Angelo A, Pengo V, Erba N, Moia M, Ciavarella N, Devoto G, Berrettini M, Musolesi S (1996) Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 348:423–428 doi:10.1016/S0140-6736(96)01109-9 PubMedCrossRefGoogle Scholar
  10. 10.
    van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briet E (1996) Assessment of a bleeding risk index in two cohorts of patients treated with oral anticoagulants. Thromb Haemost 76:12–16PubMedGoogle Scholar
  11. 11.
    Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481 doi:10.2307/2281868 CrossRefGoogle Scholar
  12. 12.
    Moher D, Schulz KF, Altman DG (2001) The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 357:1191–1194 doi:10.1016/S0140-6736(00)04337-3 PubMedCrossRefGoogle Scholar
  13. 13.
    Agnelli G, Prandoni P, Santamaria MG, Bagatella P, Iorio A, Bazzan M, Moia M, Guazzaloca G, Bertoldi A, Tomasi C, Scannapieco G, Ageno W, Warfarin Optimal Duration Italian Trial Investigators (2001) Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators. N Engl J Med 345:165–169 doi:10.1056/NEJM200107193450302 PubMedCrossRefGoogle Scholar
  14. 14.
    Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S (2004) The risk of recurrent venous thromboembolism in men and women. N Engl J Med 350:2558–2563 doi:10.1056/NEJMoa032959 PubMedCrossRefGoogle Scholar
  15. 15.
    Eichinger S, Weltermann A, Minar E, Stain M, Schönauer V, Schneider B, Kyrle PA (2004) Symptomatic pulmonary embolism and the risk of recurrent venous thromboembolism. Arch Intern Med 164:92–96 doi:10.1001/archinte.164.1.92 PubMedCrossRefGoogle Scholar
  16. 16.
    Murin S, Romano PS, White RH (2002) Comparison of outcomes after hospitalization for deep venous thrombosis or pulmonary embolism. Thromb Haemost 88:407–414PubMedGoogle Scholar
  17. 17.
    Douketis JD, Gu CS, Schulman S, Ghirarduzzi A, Pengo V, Prandoni P (2007) The risk for fatal pulmonary embolism after discontinuing anticoagulant therapy for venous thromboembolism. Ann Intern Med 147:766–774PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • L. Eischer
    • 1
  • V. Gartner
    • 1
  • S. Schulman
    • 2
  • P. A. Kyrle
    • 1
  • S. Eichinger
    • 1
  • for the AUREC-FVIII investigators (as listed in acknowledgements)
  1. 1.Department of Internal Medicine IMedical University of ViennaViennaAustria
  2. 2.Center for HematologyKarolinska University HospitalStockholmSweden

Personalised recommendations