Familial Thrombophilia: A Review Analysis

Abstract

The correct approach to the management of the asymptomatic carrier with a recognized inherited thrombophilic disorder is uncertain because reliable in formation of the risk of spontaneous (unprovoked) throm bosis in these disorders is not available. To determine the best available estimate of the annual incidence of spon taneous thrombosis in asymptomatic carriers of disorders that have been linked to familial thrombophilia, we per formed a literature review. Using Medline search from 1965 to 1992, supplemented by manual searches, we re trieved all articles that presented data on antithrombin III, protein C, protein S, dysfibrinogenemia, plasmino gen, 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 mem bers 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 mem bers. The biochemical status and clinical details of all family members reported were extracted from each eligi ble article. For each abnormality the odds ratio for throm bosis 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 calcu lated. The influence of diagnostic suspicion bias in symp tomatic patients with a family history of thrombosis was reduced by recalculating the absolute incidence of throm bosis from the odds ratio after adjusting the incidence of venous thrombosis in nonaffected family members to that observed in the general population. Statistically signifi cant 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 rec ognized risk factor for thrombosis. The recalculated an nual incidence of spontaneous thrombosis was 0.6 to 1.6%/year. It is concluded that this relatively low inci dence does not warrant life-long continuous use of anti coagulant prophylaxis since the reported risk of major and fatal bleeding associated with the use of oral antico agulants is 2-3 and 0.4%/year, respectively.

Familial Association of Hypoplasminogenemia and Heterozygous Factor V Deficiency

“…The relationship between hypoplasminogenemia and thrombotic risk is a matter of debate (3)(4)(5)(6)(7). Coinheritance of hypoplasminogenemia and other thrombophilic disorders, such as protein C, protein S, and APC resistance defects, has been reported (8,(26)(27)(28)(29)(30)(31).…”

Guidelines for the Laboratory Investigation of Inherited Thrombophilias. Recommendations for the First Level Clinical Laboratories

“…Protein C deficiency, studied in unselected patients, confers a 6.5-to 10-fold increase in the relative risk of VTE (12,13,15,16) (evidence level IIa). The prevalence of the defect in healthy individuals is 0.2 to 0.3% (17,18); type I and a type II deficiency have been identified and both forms are associated in most cases with a 50% reduction in activity.…”

Epidemiology of Venous Thromboembolism

“…Age [31][32][33][34][35][36][37][38]53,69,102,260 Moderate Obesity [32][33][34][35]37,102,133,260 Minor Ethnicity 31,42,263 Minor Immobilization 34,41 Moderate Previous VTE 31,34,41,102 Severe Estrogen therapy 53,176 Minor Inherited thrombophilia 209,250,251,260 Severe Malignancy 32,34,35,37,53,[99][100][101] Moderate Heparin-inudced thrombocytopenia 234 Severe…”

“…Hence, about half of episodes of VTE in patients with hereditary thrombophilia are precipitated by acquired risk factors. 134,209,[250][251][252][253] As previously discussed, pregnancy and use of oral contraceptives are frequently precipitants of VTE in women with hereditary thrombophilias. 114,117,[120][121][122][171][172][173]196,251,[254][255][256][257][258][259] Aging also increases the risk of VTE in persons with hereditary thrombophilia, 30,198,241 with evidence that the proportional increase in risk in association with factor V Leiden is greater in the elderly.…”