Abstract
Trombin-activatable fibrinolysis inhibitor (TAFI) is a procarboxypeptidase which suppresses fibrinolysis by removing carboxy-terminal lysine residues from partially degraded fibrin. A recent study in pregnant mice suggested that fibrin degradation products induced by the subsequent generation of thrombin and fibrin, cause apoptosis of throphoblasts and consequently fetal loss. This effect was reversed by anticoagulant and antifibrinolytic drugs, and by depletion of fibrinogen. We hypothesized that increased levels of TAFI during normal pregnancy in humans may similarly protect against fetal loss. This effect might be more pronounced in women with increased thrombin generation due to thrombophilic defects. To test this hypothesis, we analysed data from four pooled family cohort studies, which originally were designed to estimate the absolute risk of venous thromboembolism, associated with either hereditary deficiencies of antithrombin, protein C or protein S, factor V Leiden, the prothrombin 20210A mutation, elevated plasma levels of factor VIII:C, or hyperhomocysteinemia. The present study addressed fetal loss in female probands and relatives. In addition to above mentioned thrombophilic defects, TAFI activity was measured. Fetal loss rates were compared in women with high TAFI levels (³ 126 U/dl) and women with normal TAFI levels.
Of 1557 women, 175 were excluded because they were younger than 15 years of age, had deceased or did not consent. Another 444 women were not evaluable because they had never been pregnant or had had only terminated pregnancies, and 95 women because of missing TAFI measurements. The remaining 843 women (including probands) were analysed, of whom 95 women had high TAFI levels and 748 women had normal TAFI levels. Age at time of first pregnancy was comparable in both groups, as was the distribution of thrombophilic defects. Results are summarized in the table.
18 women (18.9 %) with high TAFI levels experienced any, i.e. early or late fetal loss, compared to 205 women (27.5 %) with normal TAFI levels (p= 0.074). Overall 17 women (17.9 %) with high TAFI levels experienced one or recurrent early fetal loss compared to 180 women (24.2 %) with normal TAFI levels (p= 0.173). 1 woman (1.1 %) with high TAFI level had experienced recurrent early fetal loss, compared to 53 women (7.1 %) with normal TAFI levels (p=0.023). The number of fetal losses per woman ranged from 2 to 8 in women with normal TAFI levels (median was 2 fetal losses), while it was 2 in the woman with high TAFI level. In conclusion, women with high TAFI levels had less recurrent fetal loss in comparison with women with normal TAFI levels. Our results support the assumption that high TAFI levels protects against recurrent fetal loss.
Normal TAFI levels High TAFI levels p-value Age at 1st pregnancy, median (range), yr 24.8 (11-42) 24.1 (17-40 ) TAFI levels, U/dL, mean (SD) 99.7 (13.6) 137.1 (10.6) Women, n (n=748) (n=95) Total fetal loss, n (%) 206 (27.5) 18 (18.9) 0.074 early 180 (24.2) 17 (17.9) 0.173 late 29 (3.9) 2 (2.1) 0.383 Total recurrent fetal loss, n (%) 56 (7.5) 2 (2.1) 0.050 early 53 (7.1) 1 (1.1) 0.023 late 2 (0.3) 0 (0) 0.613
High thrombin-activatable fibrinolysis inhibitor levels may protect against recurrent fetal loss