Review of the Data
Does presence of thrombophilia alter the intensity of anticoagulation for VTE?
If thrombophilia increases the risk of VTE recurrence while on anticoagulation, then a more intense level of anticoagulation might prevent future VTE. There are no studies investigating higher intensity of anticoagulation, but if standard anticoagulation were insufficient for patients with identifiable thrombophilia, one might expect to observe increased recurrence rates among patients with thrombophilia treated with standard warfarin therapy.
In a substudy of the Extended Low-Intensity Anticoagulation for Unprovoked Venous ThromboEmbolism (ELATE) trial, the risk of recurrence of VTE among treated subjects was very low overall, and the presence of thrombophilic abnormalities was not associated with significantly higher risk.5 Observational studies have found VTE recurrence rates are low in patients treated with warfarin, with or without thrombophilia.6-8
The impact of the initial level of anticoagulation on recurrence after the completion of the treatment period has been evaluated. Although one study suggested that patients with substandard levels of anticoagulation were at an increased risk of subsequent VTE, this was not confirmed in the Leiden Thrombophilia Study (LETS). 9,10
In sum, the majority of data do not suggest a significantly increased risk of recurrent VTE in patients with thrombophilia treated with standard anticoagulation. Therefore, treatment with warfarin to a goal INR of 2 to 3 is sufficient.
Does presence of thrombophilia alter duration of VTE treatment?
A major decision clinicians face when caring for VTE patients is the duration of anticoagulation treatment. The current ACCP recommendation for treatment of a provoked VTE is three months, with treatment for an unprovoked VTE three months or lifelong.11 If the presence of thrombophilia increases the risk of recurrence after cessation of anticoagulation treatment, longer duration of treatment might be indicated. One of the goals of thrombophilia testing should be to identify those patients.
Overall, the recurrence rate after first VTE is high, with a cumulative incidence of 25% at five years, 30% at eight years, and 56% at 20 years.12,13
Deficiency of natural inhibitors of coagulation.
Deficiency of a natural inhibitor of coagulation has been associated with a risk of recurrence of VTE of as much as 10% per year, according to some studies.6,14 However, the estimates are based on studies that include individuals from thrombosis-prone families, and selection bias might have contributed to the high recurrence rates.1 In the unselected population represented in the LETS study, only a modest elevation was seen in the estimated risk of recurrence for patients with inhibitor deficiencies.15
Testing for deficiency of inhibitors offers little prognostic information beyond that obtained when determining whether a VTE event is provoked or unprovoked. In studies that have separately examined subjects with provoked vs. unprovoked VTE, deficiency of an inhibitor is not associated with increased risk of recurrence.15,16
Abnormal function or level of anticoagulation factors.
Factor V Leiden (FVL) is the most common cause of inherited thrombophilia and is associated with as much as a sixfold increase in VTE risk, while the prothrombin gene mutation is associated with a twofold increase.17,18
In contrast, the evidence associating these mutations with recurrent VTE risk is not as consistent. Although a study conducted at a referral center in Italy found an increased risk of recurrence with either Factor V Leiden or prothrombin gene mutation, a large meta-analysis of 23 studies found increased risk only with Factor V Leiden.19,20 Another meta-analysis demonstrated only a modest increased risk of recurrence in subjects with Factor V Leiden or prothrombin gene mutation, and a prospective study from Austria found no increased risk of recurrence with Factor V Leiden two years after discontinuation of anticoagulation.18,21 Additionally, when using patients with unprovoked VTE as reference, there was no increased risk of recurrence among patients homozygous for Factor V Leiden or the prothrombin gene mutation.22