Familial thrombophilia: A review analysis

The correct approach to the management of the asymptomatic carrier with a recognized inherited thrombophilic disorder is uncertain because reliable information of the risk of spontaneous (unprovoked) thrombosis in these disorders is not available. To determine the best available estimate of the annual incidence of spontaneous thrombosis in asymptomatic carriers of disorders that have been linked to familial thrombophilia, we performed a literature review. Using Medline search from 1965 to 1992, supplemented by manual searches, we retrieved all articles that presented data on antithrombin III, protein C, protein S, dysfibrinogenemia, plasminogen, histidine-rich glycoprotein, heparin cofactor II, and fibrinolysis in relation to thrombosis. Publications were included in the analysis if they (1) reported one or more probands with thrombotic disease and a heterozygous biochemical abnormality of the hemostatic system, (2) assessed the presence of this abnormality in family members independent of the presence or absence of a history of thrombotic disease, and (3) assessed the presence of a history of thrombotic disease in all available family members. The biochemical status and clinical details of all family members reported were extracted from each eligible article. For each abnormality the odds ratio for thrombosis was compared in family members with and without the biochemical abnormality. If applicable, thrombosis-free survival and age-specific incidences of thrombosis were calculated. The thrombotic episodes were classified as spontaneous or secondary to a recognized risk factor, and the proportion of spontaneous episodes was calculated. The influence of diagnostic suspicion bias in symptomatic patients with a family history of thrombosis was reduced by recalculating the absolute incidence of thrombosis from the odds ratio after adjusting the incidence of venous thrombosis in nonaffected family members to that observed in the general population. Statistically significant associations between the presence of a biochemical abnormality and a history of venous thrombosis were found for antithrombin III deficiency types 1 and 2a and 2b, protein C deficiency type 1, and protein S deficiency type I. Dysfibronogenemia was statistically significantly associated with venous as well as arterial thrombosis. Thirty-five to 67% of the events were classified as being provoked, as they occurred following exposure to a recognized risk factor for thrombosis. The recalculated annual incidence of spontaneous thrombosis was 0.6 to 1.6%/year. It is concluded that this relatively low incidence does not warrant life-long continuous use of anticoagulant prophylaxis since the reported risk of major and fatal bleeding associated with the use of oral anticoagulants is 2-3 and 0.4%/year, respectively.