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• W2090510863 abstract "While the identification of heritable thrombophilic conditions in patients with venous thrombosis has important implications for their subsequent management, it also raises a considerable number of questions for the family members of these patients and the physicians who care for them. For example, should asymptomatic family members be screened for the inherited defect previously identified in the patient? Any potential benefit incurred by screening must be weighed against the costs. In addition to the monetary expenses associated with performing these tests, identification of a heritable genetic ‘defect’ in an asymptomatic person may provoke considerable anxiety, could have insurance and employment ramifications, and may lead to unnecessary therapies. When considering these issues it is important to remember that while available assays have excellent sensitivity and specificity for the identification of the genetic defects in question, the key question is whether such testing adequately predicts which asymptomatic relatives are also at risk for thrombosis and whether these events may be averted by targeted interventions (e.g. counseling against smoking, avoidance of oral contraceptives, and/or use of venous thromboembolism prophylaxis during high-risk situations). While carriage of a thrombophilic defect has clearly been shown to increase the risk of subsequent thrombosis, this risk is greatly affected by other factors (e.g. comorbidities, medications, external stressors). First-degree relatives may share some, but not all, of these additional predisposing factors, thereby altering each subject's degree of risk. As such, determination of the potential benefits of screening in this population requires carefully designed cohort studies in which asymptomatic subjects with the thrombophilic defect in question are followed for subsequent events. Such studies are infrequent given the relatively limited prevalence of the defects in question and the small number of investigators who are studying patients with hypercoaguable states. The European Prospective Cohort on Thrombophilia (EPCOT) registry takes an important first step towards answering some of these questions. This observational study has enrolled all registered male and female probands with a deficiency of protein C (PC), protein S (PS), or antithrombin (AT) or factor (F)V Leiden over a 3-year period between 1994 and 1997 with extended follow-up through 2001 [1]. Combining data from nine centers throughout Europe, the EPCOT registry is one of the largest existing prospective cohorts of individuals with heritable thrombophilias. Investigators from this longitudinal study also screen and track first-degree family members of these probands who share a similar defect. In this issue of the Journal of Thrombosis and Haemostasis, Vossen and colleagues report on 575 asymptomatic relatives of patients with venous thromboembolism who have one of these thrombophilic defects [2]. They identified a significantly increased risk of a first episode of deep vein thrombosis or pulmonary embolism in this cohort (4.5%) compared with age, gender, and region-matched controls (0.6%) over an average follow-up of nearly 6 years. The highest risk of acute thrombotic events occurred in carriers of AT deficiency or in subjects who carried two or more defects (1.7% year−1 and 1.6% year−1, respectively) and was lowest in subjects heterozygous for FV Leiden (0.1% year−1). Unfortunately, the sample size of this study was too small to allow for the systematic comparison of event rates between carriers of specific defect types. The present findings mirror those of a systematic review of four other prospective studies of asymptomatic family members of patients with venous thromboembolism who carried thrombophilic defects [3]. In reporting results based on 3641 patient-years of observation, the annual incidence of venous thromboembolism ranged from 0.6% for subjects with FV Leiden to 1.5% for individuals with deficiencies of PC, PS, or AT. Given these low event rates, the authors concluded that long-term anticoagulation as a primary preventive modality is not warranted in these asymptomatic family members given the increased risks of bleeding associated with such therapy. Most specialists in the field share this viewpoint. Unfortunately, the more difficult question of whether to screen asymptomatic family members for thrombophilic defects so that those at risk may be offered counseling and/or venous thromboembolism prophylaxis during high-risk situations has still not been definitively answered. The ability of the EPCOT registry to enlighten us regarding this issue is hindered by its non-randomized design (since decisions regarding the use of prophylaxis were left to the physician's discretion) as well as infrequency of study outcomes. The annual risk of venous thrombotic events was approximately 1.0% in 285 thrombophilic individuals who experienced additional acquired risk factors (e.g. surgery, pregnancy, prolonged immobility) during follow-up but did not receive short-term anticoagulant therapy, compared with none of the 113 individuals who received anticoagulant prophylaxis during similar high-risk situations. It is noteworthy that several prior studies have suggested beneficial effects associated with the aggressive use of venous thromboembolism prophylaxis in asymptomatic patients with thrombophilia. In two separate observational studies, each following more than 200 asymptomatic subjects with AT, PC, or PS deficiencies, use of prophylaxis during high-risk situations after identification of the defect significantly reduced the incidence of first venous thromboembolic events [4, 5]. Each of these studies was limited, however, by the non-randomized allocation to anticoagulation prophylaxis, small sample size, and inability to assess the impact of carriage of more recently identified thrombophilic conditions (e.g. FV Leiden, prothrombin G20210A mutation). Alternatively, it has been suggested that all first-degree relatives of patients with idiopathic thromboembolism are at increased risk for thrombotic events and are candidates for aggressive venous thromboembolism prophylaxis during high-risk periods, thereby negating the need for screening [6]. While attractive in its simplicity, this approach ignores the additional risk imparted by carriage of a thrombophilic defect as well as differing predispositions to thrombosis imparted by different defect types. It is therefore unclear if such an approach would be any more cost effective and it may in fact incur unnecessary risks of bleeding. Although far from definitive, the EPCOT data suggest that an intermediate approach to the management of asymptomatic family members with thrombophilic mutations might be appropriate. The vast majority of patients suffering idiopathic thrombotic events in this study were relatives of patients with AT, PC, or PS deficiency or a combination of defects. This is not surprising, as these defects, although rare, have previously been shown to predispose strongly to venous thrombosis. Targeted screening of family members of patients with one of these ‘higher risk’ mutations may be appropriate. Alternatively, only one of 173 carriers of FV Leiden suffered a venous thromboembolic event during extended follow-up. While carriage of this mutation (as well as the more recently identified prothrombin G20210A mutation) will be relatively common among patients with idiopathic venous thromboembolism, the relatively weak association with first thrombotic events in asymptomatic carriers may not warrant routine screening for these defects in their relatives. It is noteworthy that the vast majority of patients suffering thromboembolism associated with acquired risk factors in this registry had cancer or were pregnant. Event rates with shorter periods of risk (e.g. surgery, immobilization, and travel) were very low regardless of the utilization of prophylaxis. Accordingly, one could argue that screening of family members for thrombophilia should be deferred unless they are entering a prolonged period of high risk (e.g. pregnancy, cancer) in which venous thromboembolism prophylaxis might otherwise not be considered. Limiting screening to these specific subsets of relatives may decrease overall costs as well as maximize the potential benefit of targeted prophylaxis. Additional studies evaluating the costs and potential benefits of screening asymptomatic relatives for thrombophilias are needed if we are to optimize our approach to these patients. Ideally, randomized trials of screening and/or targeted prophylaxis in high-risk scenarios would be conducted—the relatively rare occurrence of specific thrombophilic conditions makes the conduct of such trials unlikely. In the interim, and as more heritable thrombophilic conditions are discovered, continued enrollment of subjects in registries such as EPCOT will be crucial if we are to understand better the actual costs and benefits of screening asymptomatic subjects. Routine screening of all potential carriers of any thrombophilic defect without well thought out plans for follow-up and subsequent management will only result in unnecessary patient anxiety, physician frustration, and excessive costs." @default.
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• W2090510863 title "Asymptomatic thrombophilia—a family affair" @default.
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