High thrombin-activatable fibrinolysis inhibitor levels may protect against recurrent fetal loss.

Abstract

Thrombin-activatable fibrinolysis inhibitor (TAFI) is a procarboxypeptidase that suppresses fibrinolysis by removing C-terminal lysine residues from partially degraded fibrin [1]. These residues are involved in binding of plasminogen and tissue-type plasminogen activator, and in plasmin formation. TAFI is activated by thrombin, mainly in complex with thrombomodulin, and by plasmin. TAFI inhibits tissue plasminogen activator-induced fibrinolysis [2]. High TAFI levels might enhance the development of thrombosis, and consequently fetal loss as a result of placental thrombosis. Recently, we demonstrated that high TAFI levels are not associated with an increased risk of fetal loss [3]. On the contrary, our data suggested a decline of this risk with increasing TAFI levels. We hypothesized that high TAFI levels during normal pregnancy protect against fetal loss [4,5]. This effect might be more pronounced in pregnant women who are at increased risk of fetal loss because of thrombophilic defects. Here, we present the results of an additional analysis of data from our previously reported study, to test this hypothesis. The study population contained female subjects from four pooled retrospective family cohort studies [6–9]. These studies were designed to estimate the absolute risk of venous thromboembolism (VTE), associated with either hereditary deficiencies of antithrombin, protein C or protein S, the prothrombin 20210A mutation, elevated factor VIII:C levels, or hyperhomocysteinemia. Probands in each of these studies were consecutive patients with documented VTE or premature atherosclerosis (age, < 50 years), and one of these thrombophilic defects. Relatives, who were 15 years of age or older, were identified by pedigree analysis and were enrolled after informed consent was obtained. The studies were approved by the institutional review boards of the participating hospitals. In addition to the above-mentioned thrombophilic defects, subjects were tested for FV Leiden, and TAFI activity was measured. The assays used have been described elsewhere [3]. Detailed information on obstetric history was obtained, by using a questionnaire and reviewing medical records. Clinical data were collected prior to blood sampling. Women were evaluable if they had been pregnant before the end of the study. Women with only terminated or ectopic pregnancies were excluded from analysis. Fetal loss was defined as early fetal loss if it had occurred