Erfelijke trombofilie en veneuze tromboembolie: klinische implicaties met betrekking tot detectie, preventie en behandeling
10 / 1999 - 10 / 2003
[Background]: Venous thromboembolism is a common disease with an annual incidence of 1 to 2 per 1000 inhabitants in Western societies. In recent years, knowledge of the pathogenesis of thrombosis has grown impressively. At present, in approximately 70% of the patients an inherited or acquired thrombophilic defect can be detected. This comprises the already known but rare antithrombin, protein C or protein S deficiency (together approximately 8%), factor V Leiden mutation (20%), prothrombin 20210A mutation (8%), mild hyperhomocysteinemia (20%), and an often familiar form of increased factor VIII levels (20%). However, the clinical implications of carrying such a defect have not or only minimally been studied. There is confusion about the need for active detection, the indication of prophylactic anticoagulant treatment, the potential contraindication of the use of oral contraceptives, the approach during pregnancy, and the optimal duration of anticoagulant treatment when venous thromboembolism occurs. Answering crucial questions about the absolute venous thromboembolic risk, either spontaneously or during high-risk situations, and the association with other clinical manifestations (such as pregnancy loss, preecclampsia, or arterial thrombosis), will profoundly affect the optimal prophylactic and therapeutic approach in carriers of the different thrombophilic defects. [Objectives]: The proposed program consists of 4 projects with their own specific objective: 1. To determine the absolute, age-specific annual incidence of spontaneous and high risk situations elicited venous thromboembolism, as well as arterial thrombotic complications, in asymptomatic carriers of the prothrombin 20210A mutation, familial mild hyperhomocysteinemia or increased factor VIII levels. 2. To determine the absolute incidence of recurrent venous thromboembolism, both spontaneous and elicited by high-risk situations, in those patients with the factor V Leiden mutation, the prothrombin 20210A mutation mild hyperhomocysteinemia or increased factor VIII levels, who already have experienced one episode of venous thromboembolism. 3. To determine the association between the above mentioned thrombophilic defects and other relevant clinical manifestations, such as idiopathic recurrent pregnancy loss and preecclampsia. 4. To validate a conservative prophylactic approach during pregnancy in asymptomatic women, and active anticoagulant prophylaxis during pregnancy in symptomatic women with one of the above mentioned thrombophilic defects. [Plan]: Projects 1 and 2 consist of both retrospective and prospective cohort studies of patients and their first degree relatives with the same defect. Project 3 is a case-control study. Project 4 is a prospective validation study of the safety and efficacy of two commonly applied, but not evidence-based, prophylactic strategies during pregnancy in women with hereditary thrombophilia. The proposed program will be performed in 4 years, with an already existing three-center infrastructure with sufficient patients and experienced clinical investigators, research physicians and trial nurses. [Relevance for cardiovascular diseases]: Venous thromboembolism is a common disease with an annual incidence of 1 to 2 per 1000 inhabitants in the Netherlands. The proposed program aims to investigate the risk of a first or recurrent venous thromboembolic episode in carriers of several new, prevalent and hereditary, thrombophilic defects. In addition, it assesses the association with other potentially thrombotic manifestations including pregnancy loss and arterial thrombosis. With this information, strategies to prevent venous thrombosis in asymptomatic (pregnant) carriers, as well as the optimal therapeutic approach when venous thromboembolism occurs, can be determined.