Prothrombin gene G2 0210A mutation
Prevalence. Like the factor V Leiden mutation, the prothrombin gene G20210A mutation is more common among Caucasians than among those of African or Asian descent.31 Prothrombin mutation is estimated to cause a 2.5-fold relative risk of first DVT.32
Testing considerations. If cost or availability of the polymerase chain reaction assay are issues, a reasonable course of action would be to reserve the assay for patients with factor V Leiden mutation. Data suggest that patients with both factor V and prothrombin gene G20210A mutations are at significantly higher risk for recurrent VTE; consider prolonged anticoagulation.33
Hyperhomocysteinemia
Evidence accumulating over the past decade has shown an increased risk of VTE with elevated homocysteine levels. A case-control study by den Heijer et al34 in 1996 demonstrated a relative risk for first thrombosis of 2.5 in those with a homocysteine level above the 95th percentile of the control group’s levels (which in that study corresponded to a homocysteine level of 18.5 micromoles per liter or above). This predisposition to thrombosis has also been demonstrated in subsequent meta-analyses.35,36
When homocysteine levels are elevated in the presence of factor V Leiden or the prothrombin gene G20210A mutation, risk of thrombosis appears to increase beyond that associated with any one defect alone, perhaps as high as 50-fold risk.37-39
Management Implications of Test Results
If testing for activated protein C resistance is possible and the result is positive, confirmatory testing for factor V Leiden is indicated. If the patient is homozygous for factor V Leiden (rare), or is heterozygous for factor V Leiden and has the prothrombin gene G20210A defect, consider a prolonged course of anticoagulation, perhaps even for the rest of the patient’s life.
We base these suggestions on the high rate of VTE detected among individuals who are homozygous for factor V Leiden30 and on a recent study that showed the relative risk of recurrent thrombosis to be 2.6 for those with factor V Leiden and prothrombin gene G20210A mutations, versus for those heterozygous for factor V Leiden alone.33 This recent study also showed that the relative risk of recurrent thrombosis was not increased in those heterozygous for the Factor V Leiden mutation alone compared to those without this mutation.33
If either the factor V Leiden or the prothrombin gene G20210A mutation is present, consider prolonging the planned course of anticoagulation (although the data to support this decision are less compelling). Data are limited and conflicting regarding the appropriate length and intensity of anticoagulation therapy for patients with inherited prothrombotic defects.33,40-42 When prolonging anticoagulation for these patients, try to balance the risk of a recurrent thrombotic event with the risk of a bleeding complication from chronic anticoagulation.
Prolonged anticoagulation may also be indicated if the homocysteine level is elevated and either the factor V Leiden or the prothrombin gene G20210A mutation is present. In addition, therapy with folate, pyridoxine, and vitamin B12 should be initiated in cases of elevated homocyteine levels. We recommend the use of these vitamins based on a meta-analysis which demonstrated that folate supplementation at a dose of 0.5 mg to 5 mg/day lowered homocysteine levels by approximately 25% and vitamin B12 supplementation at a dose of 0.5 mg/day led to a further reduction of approximately 7%. In this same meta-analysis, pyridoxine at a mean dose of 16.5 mg daily did not demonstrate further lowering of the homocysteine level; however, as it is safe, inexpensive and well-tolerated, we still recommend its use.43
Finally, while less common than the hypercoagulable states discussed above, the antiphospholipid antibody syndrome should be targeted as part of first-tier testing because of its clear impact on management. If the antiphospholipid antibody testing (such as the lupus anticoagulant or anticardiolipin antibody) results are positive, lifelong anticoagulation44 and perhaps a higher target international normalized ratio are considerations.
Second-tier testing: Pursuing less common defects
If the preceding evaluation is unrevealing for a patient with high-risk characteristics, consider pursuing “second-tier” testing. Such testing may include functional and immunologic assays for protein C, protein S, and anti-thrombin III deficiencies, all of which are heterozygous abnormalities caused by multiple mutations and, thus, not detectable with genetic assays.
Patients will likely be taking anticoagulation medication when these tests are administered; thus, test results must be interpreted with caution. Testing for these deficiencies is most reliable if conducted at least 2 weeks after anticoagulation has been discontinued. Again, the incidence of protein C, protein S, and antithrombin III deficiencies is low, and the yield of testing therefore is also likely to be low.