Thrombin Generation in a Hemophilic Newborn

Abstract

In hemophilia, excessive bleeding during delivery and in the neonatal period is a rare event.A French study of 754 hemophilic neonates corroborate their postulation – only 8 % of the newborns showed clinically overt bleeding, in 71.5 % of the patients the diagnosis was made after the neonatal-period. These findings are surprising since the trauma of a normal vaginal delivery may result in bleeding such as echymosis or hematomas even in healthy neonates and should be enough to trigger major bleeding in neonates suffering from hemophilia [1, 2]. The reasons for the low incidence of bleeding in patients with hemophilia in the neonatal period probably are the peculiarities of the neonatal hemostatic system. Healthy term neonates have low values of many clotting factors but also of inhibitors, especially low antithrombin (AT), tissue factor pathway inhibitor (TFPI), and protein C. Despite low procoagulant factors they have an excellent hemostasis [3, 4]. In previous work we have focused on this discrepancy between clinically excellent hemostasis and prolonged conventional clotting tests and have shown that these physiological low levels of the natural inhibitors AT and TFPI in neonatal plasma compensate for low concentrations of clotting factors by allowing sufficient thrombin generation despite low prothrombin levels [3–5]. Conventional in vitro clotting assays such as activated partial thrombin time (aPTT) and prothrombin time (PT) give a very simplified picture of the relative importance of various components of the clotting system. In recent years, studies have shown that plasma activation via the extrinsic pathway by addition of low amounts of lipidated tissue factor (TF) as activator is probably more compatible with the physiological milieu [6] and suitable for a sensitive detection of the effects of different levels of proand anticoagulants, including different levels of factor VIII from 50 to 150 %, on thrombin generation (TG) [7]. The aim of this study was to measure the TG after activation with small amounts of TF in FVIII-deficient neonatal plasma to investigate whether physiologic low levels of TFPI and AT in neonatal plasma may explain the low bleeding incidence in neonates with hemophilia. In lack of enough hemophilic neonatal plasma, normal neonatal plasma was pooled and FVIII depleted. Then the effect of raising TFPI and AT to adult plasma levels was investigated. TG of one hemophilic newborn was also measured.