Clinical Evidence for Rebound Hypercoagulability After Discontinuing Oral Anticoagulants for Venous Thromboembolism

David Keith Cundiff, MD


Medscape J Med. 2008;10(11):258 

In This Article


Rebound hypercoagulability (elevated levels of fibrinogen, fibrinopeptide A, thrombin, thrombin-antithrombin III complexes, coagulation factors VII and IX levels, and activated thromboplastin) occurs in vitro in the first few weeks after discontinuation of vitamin K antagonists (VKAs), and by 2 months these tests are no longer abnormal.[1,2,3,4] Relative to abruptly withdrawing warfarin, rebound thrombin generation is not reduced by an additional month of a low, fixed dose of warfarin.[3] Tapering VKAs has been reported to ameliorate rebound hypercoagulability[1] and as nonbeneficial.[4]

Several studies have reported increased rates of thrombotic complications within 2 months of discontinuing warfarin.[2,5,6,7]

Randomized controlled trials (RCTs) of anticoagulation with oral anticoagulants (OACs), such as VKAs and ximelagatran, for venous thromboembolism (VTE) generally have compared venous and arterial thrombosis rates for patients only while on study. If rebound hypercoagulability due to OACs causes thrombosis in the weeks following discontinuation of anticoagulation, then this should be considered in the interpretation of studies of anticoagulation.

This article analyzes RCTs of VTE treatment with OACs in which VTE recurrence rates per month within 2 months of discontinuation of OACs can be compared with subsequent VTE recurrence rates. Several questions are addressed:

  • What is the rate of VTE recurrence (1) while patients are taking OACs, (2) in the 2-month period following discontinuation of OACs, and (3) from > 2 months until the end of the trial?

  • How do short- and long-duration OAC arms of the RCTs compare with VTE recurrences over the entire duration of the trials?

  • How do short- and long-duration OAC arms of the RCTs compare with total adverse events (VTE recurrences plus major bleeding) over the entire duration of the trials?

  • What is the estimated rate of VTE recurrences possibly attributable to rebound hypercoagulability?

  • Are rates of VTE recurrences possibly related to hypercoagulability (the first 2 months after stopping treatment) similar to when OAC treatment is given for ≤ 3 months compared with ≥ 6 months?


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