Characterization of AIM2 DNA-Binding Properties and Filament Formation

High levels of thrombin-activatable fibrinolysis inhibitor (TAFI) are a supposed risk factor for thrombosis. However, results from previous studies are conflicting.We assessed the absolute risk of venous and arterial thromboembolism in subjects with high TAFI levels (> 126 U/dl) versus subjects with normal levels, and the contribution of other concomitant thrombophilic defects. Relatives from four identical cohort studies in families with either deficiencies of antithrombin, protein C or protein S, prothrombin 202 1 OA, high factorVIII levels, or hyperhomocysteinemia were pooled. Probands were excluded. Of 1,940 relatives, 187 had high TAR levels. Annual incidences of venous thromboembolism were 0.23% in relatives with highTAFI levels versus 0.26% in relatives with normal TAFI levels (adjusted relative risk [RR] 0.8; 95% confidence interval [0], 0.5-1.3). For arterial thrombosis these were 0.3 1 % versus 0.23% (adjusted RR 1.4; 95% Cl, 0.9-2.2). High levels of factor VIII, IX and XI were observed more frequently in relatives with high TAR levels. Only high factor VIII levels were associated with an increased risk of venous and arterial thrombosis, independently of TAR levels. None of these concomitant defects showed interaction with high TAR levels. High TAR levels were not associated with an increased risk of venous and arterial thromboembolism in thrombophilic families

Pregnancy-related thrombosis and fetal loss in women with thrombophilia

This thesis addresses the absolute risk of pregnancy related venous thromboembolism and fetal loss in women with thrombophilic defects, either single or multiple. The presented studies were performed to assess: 1 The absolute risk of venous thromboembolism during pregnancy and puerperium in women with hereditary deficiencies of antithrombin, protein C or protein S, and the contribution of other concomitant thrombophilic defects to this risk. 2 The absolute risk of fetal loss in women with hereditary deficiencies of either antithrombin, protein C or protein S, and the contribution of other concomitant thrombophilic defects to this risk. 3 The effects of thromboprophylaxis during pregnancy on fetal loss rates in women with hereditary deficiencies of either antithrombin, protein C or protein S. 4 The risk of a second fetal loss in carriers and non-carriers of either factor V Leiden or prothrombin G20210A after a first unexplained fetal loss. 5 The absolute risk of venous and arterial thromboembolism associated with high TAFI levels, and the contribution of other concomitant thrombophilic defects to this risk. 6 The absolute risk of fetal loss in women with high TAFI levels.

High risk of pregnancy-related venous thromboembolism in women with multiple thrombophilic defects

Pregnancy is associated with an increased risk of venous thromboembolism, which probably varies according to the presence of single or multiple thrombophilic defects. This retrospective family cohort study assessed the risk of venous thromboembolism during pregnancy and puerperium, and the contribution of concomitant thrombophilic defects in families with hereditary antithrombin, protein C or protein S deficiencies. Probands were excluded. Of 222 female relatives, 101 were deficient and 121 non-deficient. Annual incidences of venous thromboembolism were 1.76% in deficient women versus 0.19% in non-deficient women [adjusted relative risk (RR) 11.9; 95% confidence interval (CI), 3.9-36.2]. Other single and multiple thrombophilic defects increased the risk in deficient women from 1.55% to 2.14% and 2.92%, and in non-deficient women from 0.16% to 0.09% and 0.54% respectively. Deficient women were at lower risk (1.37%; 0.80-2.19) than deficient women that had never been pregnant (2.96%; 1.53-5.18); RR 0.5 (0.2-0.99). This difference was due to the predominance of events related to oral contraceptives in deficient women that had never been pregnant (75%), while 71% of events in deficient women that had had at least one pregnancy were pregnancy-related. In conclusion, women with hereditary deficiencies of antithrombin, protein C or protein S are at high risk of pregnancy-related venous thromboembolism. This risk is increased by multiple additional thrombophilic defects

Reduction of high fetal loss rate by anticoagulant treatment during pregnancy in antithrombin, protein C or protein S deficient women

Hereditary thrombophilia is associated with an increased risk of fetal loss. Assuming that fetal loss is due to placental thrombosis, anticoagulant treatment might improve pregnancy outcome. In an observational family cohort study, we prospectively assessed the effects of anticoagulant drugs on fetal loss rates in women with hereditary deficiencies of antithrombin, protein C or protein S. The cohort contained 376 women (50 probands and 326 deficient or non-deficient relatives). Probands were consecutive deficient patients with venous tromboembolism. Thromboprophylaxis during pregnancy was recommended in deficient women, irrespective of prior venous thromboembolism, and in non-deficient women with prior venous thromboembolism. Outcome of first pregnancy was analysed in 55 eligible women. Of 37 deficient women, 26 (70%) received thromboprophylaxis during pregnancy, compared with three of 18 (17%) non-deficient women. Fetal loss rates were 0% in deficient women with thromboprophylaxis versus 45% in deficient women without (P = 0.001) and 7% in non-deficient women without thromboprophylaxis (P = 0.37). The adjusted relative risk of fetal loss in women who received thromboprophylaxis versus women who did not was 0.07 (95% confidence interval 0.001-0.7; P = 0.02). Our data suggest that anticoagulant treatment during pregnancy reduces the high fetal loss rate in women with hereditary deficiencies of antithrombin, protein C or protein S

Aspirin plus Heparin or Aspirin Alone in Women with Recurrent Miscarriage

BACKGROUND: Aspirin and low-molecular-weight heparin are prescribed for women with unexplained recurrent miscarriage, with the goal of improving the rate of live births, but limited data from randomized, controlled trials are available to support the use of these drugs. METHODS: In this randomized trial, we enrolled 364 women between the ages of 18 and 42 years who had a history of unexplained recurrent miscarriage and were attempting to conceive or were less than 6 weeks pregnant. We then randomly assigned them to receive daily 80 mg of aspirin plus open-label subcut aneous nadroparin (at a dose of 2850 IU, starting as soon as a viable pregnancy was demonstrated), 80 mg of aspirin alone, or placebo. The primary outcome measure was the live-birth rate. Secondary outcomes included rates of miscarriage, obstetrical complications, and maternal and fetal adverse events. RESULTS: Live-birth rates did not differ significantly among the three study groups. The proportions of women who gave birth to a live infant were 54.5% in t he group receiving aspirin plus nadroparin (combination-therapy group), 50.8% in the aspirin-only group, and 57.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, −2.6 percentage points; 95% confidence interval [CI], −15.0 to 9.9; aspirin only vs. placebo, −6.2 percentage points; 95% CI, −18.8 to 6.4). Among 299 women who became pregnant, the live-birth rates were 69.1% in the combination-therapy group, 61.6% in the aspirin-only group, and 67.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, 2.1 percentage points; 95% CI, −10.8 to 15.0; aspirin alone vs. placebo −5.4 percentage points; 95% CI, −18.6 to 7.8). An increased tendency to bruise and swelling or itching at the injection site occurred significantly more frequently in the combination-therapy group than in the other two study groups. CONCLUSIONS: Neither aspirin combined with nadroparin nor aspirin alone improved the live-birth rate, as compared with placebo, among women with unexplained recurrent miscarriage. (Current Controlled Trials number, ISRCTN58496168.)Stef P. Kaandorp, Mariëtte Goddijn, Joris A.M. van der Post, Barbara A. Hutten, Harold R. Verhoeve, Karly Hamulyák, Ben Willem Mol, Nienke Folkeringa, Marleen Nahuis, Dimitri N.M. Papatsonis, Harry R. Büller, Fulco van der Veen and Saskia Middeldor