Thrombophilia and Recurrent DVT

Abstract & Commentary

By Andrew S. Artz, MD, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationships relevant to this field of study.

Synopsis: The risk of recurrent venous thromboembolism (VTE) during extended anticoagulant therapy for thrombophilia remains poorly defined. Investigators analyzed 661 patients with idiopathic VTE who had been randomized to extended prophylaxis after three months of initial anticoagulation using either low intensity (INR 1.5-1.9) or standard intensity (INR 2.0-3.0) anticoagulation. Thrombophilic defects were identified in 42% of patients. The rate of recurrent VTE of only 0.9% per patient year was not influenced by thrombophilic abnormalities. Antiphospholipid antibodies trended toward increased recurrence (HR, 2.9; 95% CI: 0.9- 10.5). The presence of thrombophilic defects did not increase the risk of recurrent VTE during extended anticoagulation relative to patients with idiopathic VTE without thrombophilic defects.

Source: Kearon C, et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood. 2008;112:4432-4436.

An acquired, or hereditary, thrombophilic abnormality will be identified in around 30%-60% of unprovoked (aka, idiopathic) venous thromboembolism (VTE). A variety of thrombophilic defects have been described, such as factor V Leiden, the prothrombin gene mutation, anticardiolipin antibodies, elevated factor VIII and homocysteine, as well as deficiencies of antithrombin, protein C, and protein S. Although VTE recurrence is considerable after stopping anticoagulation, thrombophilic defects do not appear to increase the risk of VTE recurrence relative to patients without such a thrombophilia.1 Limited data have been published on whether thrombophilia influences the risk of recurrent VTE while on anticoagulation therapy.

Kearon et al evaluated extended duration anticoagulation following three months of anticoagulation for unprovoked VTE, comparing low-intensity warfarin (INR 1.5-1.9) to standard-intensity (INR 2.0-3.0) in the ELATE trial.2 The data demonstrated that low-intensity extended prophylaxis was less effective in preventing recurrent VTE relative to standard-intensity treatment. The author examined this dataset for the impact of thrombophilic defects on VTE recurrence risk while on anticoagulation. Thrombophilic risk factors assessed included factor V Leiden, prothrombin gene variant 20210 G>A, anti-thrombin deficiency, lupus anticoagulant, anticardiolipin antibody, elevated homocysteine, elevated factor VIII above the 90th percentile, or elevated factor XI above the 90th percentile. In the ELATE trial, 739 patients were enrolled. Only 661 were included in the present retrospective analysis. Some patients had known anticardiolipin antibodies before screening and were excluded (2.1% of total), and some refused to participate. Thrombophilic defects included factor V Leiden in 26.5%, the prothrombin gene mutation in 9.3%, an antiphospholipid antibody in 8.2%, and antithrombin deficiency in 3.6%. Ten percent of patients had elevated factor VIII, factor XI, and homocysteine. Proteins C and S were not assessed, as patients were on warfarin. In summary, 42% had no abnormality, 41% had one abnormality, 14% had two abnormalities, and 2% had three abnormalities. The mean follow-up was 2.3 years, with a mean rate of 0.9% per year risk of recurrent DVT on warfarin. The recurrence risk was considerably higher at 1.5% in the low-intensity arm relative to 0.4% in the standard intensity arm.

Comparing patients with one of the seven identified thrombophilic defects to those without showed no increased risk of recurrence (HR, 0.7; 95% CI, 0.3-2.0). Individual defects did not confer an increased risk, although among 54 patients with anti-phospholipid antibody, three events occurred that translated into a 2.3% annual recurrence risk (HR of 2.9, 95% CI: 0.8 to 10.5).

Commentary

The duration of anticoagulation is one of the major management challenges of venous thromboembolism (VTE). In unprovoked VTE, the authors previously confirmed that extended prophylaxis, after three months of anticoagulation using low-intensity anticoagulation (INR 1.5-1.9), increases the risk of VTE recurrence relative to standard-intensity anticoagulation (INR 2.0-3.0). For unprovoked VTE, a search for thrombophilic defects will uncover an acquired or inherited defect in a considerable portion. VTE recurrence risk, after discontinuation of anticoagulation, appears similar to those with an identified thrombophilic defect compared to those without.

In this report, Kearon et al, using the ELATE clinical trial database, found that among patients with thrombophilic defects of factor V Leiden, prothrombin gene mutation, elevated homocysteine, factor VIII and XI, or antithrombin deficiency, VTE recurrence appeared similarly low relative to those without such an identified defect. Further, harboring two or more defects did not increase VTE risk. Although the numbers were quite small (ie, three events), patients with antiphospholipid antibody showed a non-significant trend toward increased recurrence on extended prophylaxis. Of note, patients with known antibodies prior to screening for the study were excluded.

This analysis has important limitations. First, not all thrombophilic defects were assayed, such as deficiencies of proteins C and S. Second, some of the defects are relatively mild thrombophilic risk factors, such as factors XIII and XI. Most importantly, the number of recurrent VTE events was relatively small. While the relative risks appeared similar in patients receiving standard- and low-intensity anticoagulation, most events occurred in the low-intensity prophylaxis cohort. As Kearon et al point out, the recurrence risk was only 0.4% per patient year using standard-intensity anticoagulation. Thus, we must be cautious about inferences regarding recurrence risk, as standard-intensity prophylaxis is the norm in clinical practice. Similarly, there are inadequate numbers of patients having two defects for factor V Leiden (homozygosity) to draw conclusions.

These results must also be interpreted in the context of the study. Thrombophilic defects did not increase recurrence risk compared to patients with unprovoked DVT. One can assume most patients with unprovoked VTE have a thrombophilic defect, whether identified or occult.

The findings of this study provide confidence of a low DVT recurrence risk using extended standard-intensity warfarin prophylaxis, even among subjects with a thrombophilic defect. The results are consistent with prior data showing a low recurrence rate using anticoagulation for secondary prophylaxis among patients harboring a factor V Leiden mutation3 or uncommon thrombophilic defects.4 The presence of an antiphospholipid antibody could heighten recurrence risk of VTE, but the data are inadequate to recommend a different prophylactic strategy (eg, INR of 2.5-3.5).

References

1. Baglin T, et al. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet. 2003; 362:523-526.

2. Kearon C, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003;349:631-639.

3. Kearon C, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med. 1999;340:901-917.

4. Baglin C, et al. Risk of recurrent venous thromboembolism in patients with the factor V Leiden (FVR506Q) mutation: effect of warfarin and prediction by precipitating factors. East Anglian Thrombophilia Study Group. Br J Haematol. 1998;100:764-768.