ABSTRACT
OBJECTIVE: To assess the absolute risk of fetal loss associated with hereditary deficiencies of antithrombin (AT), protein C (PC) and protein S (PS), and the contribution of additional thrombophilic defects to this risk. DESIGN: A retrospective family cohort study. SETTING: A tertiary referral teaching hospital. POPULATION: Women from families with hereditary deficiencies of AT, PC and PS, and their non-deficient relatives. METHODS: We assessed the absolute risk of fetal loss, comparing deficient women with non-deficient female relatives. MAIN OUTCOME MEASURES: Early, late and total fetal loss rates; odds ratios of fetal loss. RESULTS: We evaluated 289 women, who had 860 pregnancies. The total fetal loss rates were 23% (AT deficient), 26% (PC deficient), 11% (type-I PS deficient) and 15% (type-III PS deficient), compared with 11, 18, 12 and 13% in non-deficient women, respectively. Odds ratios were 2.3 (95% CI 0.9-6.1), 2.1 (95% CI 0.9-4.7), 0.7 (95% CI 0.2-1.8) and 1.1 (95% CI 0.6-2.0), none of which reached statistical significance. Differences were mainly the result of higher late fetal loss rates in women deficient in AT (OR 11.3, 95% CI 3.0-42.0) and PC (OR 4.7, 95% CI 1.3-17.4). The concomitance of factor-V Leiden and prothrombin G20210A was observed in 19% of women, and did not increase the risk of fetal loss. CONCLUSIONS: Although absolute risks of fetal loss were high, odds ratios of total fetal loss were not statistically significant in deficient versus non-deficient women. However the higher absolute risks appeared to reflect higher late fetal loss rates as opposed to early fetal loss rates. An additional effect of concomitance of factor-V Leiden and prothrombin G20210A was not demonstrated, which may result from the exclusion of women at highest risk of venous thromboembolism, or from the small numbers sampled in the study.
Subject(s)
Abortion, Spontaneous/genetics , Factor V/genetics , Mutation , Prothrombin/genetics , Thrombophilia/genetics , Adult , Cohort Studies , Female , Genetic Testing , Hospitals, University , Humans , Nuclear Family , Odds Ratio , Point Mutation , Pregnancy , Retrospective Studies , Risk Assessment , Risk Factors , Venous Thrombosis/geneticsSubject(s)
Arterial Occlusive Diseases/diagnosis , Homocysteine/blood , Hyperhomocysteinemia/complications , Methionine , Venous Thrombosis/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Arterial Occlusive Diseases/blood , Arterial Occlusive Diseases/epidemiology , Arterial Occlusive Diseases/etiology , Cohort Studies , Fasting/blood , Female , Follow-Up Studies , Humans , Hyperhomocysteinemia/blood , Hyperhomocysteinemia/diagnosis , Hyperhomocysteinemia/epidemiology , Incidence , Male , Middle Aged , Netherlands/epidemiology , Predictive Value of Tests , Retrospective Studies , Risk Assessment , Risk Factors , Thrombosis/blood , Thrombosis/diagnosis , Thrombosis/epidemiology , Thrombosis/etiology , Time Factors , Venous Thrombosis/blood , Venous Thrombosis/epidemiology , Venous Thrombosis/etiologyABSTRACT
BACKGROUND: Absolute risks of venous thromboembolism (VTE) in protein S-, protein C-, or antithrombin-deficient subjects are mainly based on retrospective data. Screening asymptomatic relatives of these patients is disputed, though studies addressing this issue have yet to be conducted. METHODS: We prospectively followed 382 relatives of 84 probands. Participants were assessed for other thrombophilic defects and occurrence of exogenous risk factors (i.e. surgery/trauma/immobilization, malignancies, use of systemic estrogens, and pregnancy/puerperium). After screening, deficient subjects were advised to use thromboprophylaxis during exogenous risk factors; use of oral contraceptives was discouraged. RESULTS: Overall annual incidence of VTE was 1.53% (95% CI, 1.00-2.34) in deficient vs. 0.29% (0.13-0.64) in non-deficient relatives; adjusted hazard ratio, 7.0 (95% CI, 2.7-18.0). Annual incidence of unprovoked VTE was 0.95% in deficient vs. 0.05% in non-deficient subjects; age-adjusted hazard ratio, 22.3 (P = 0.003). In contrast, annual incidence of provoked VTE was 0.58% vs. 0.24%; age-adjusted hazard ratio, 2.8 (P = 0.08). Fifty-five (37%) deficient and 80 (34%) non-deficient subjects experienced 91 and 143 exogenous risk factors, respectively, during which six vs. five VTEs (6.6% vs 3.5% per risk-period) occurred, despite the higher compliance with recommended thromboprophylaxis use in deficient (51%) vs. non-deficient (22%) subjects. In deficient subjects all provoked VTEs occurred when thromboprophylaxis was not used. CONCLUSIONS: Protein S, protein C or antithrombin deficiencies confer high absolute risk of VTE. Screening and subsequent augmentation of thromboprophylaxis use may result in reduction of provoked VTE, whereas risk of unprovoked VTE could not be affected by screening.