OC 24.1 - Synergy of red blood cells and tranexamic acid in the inhibition of fibrinolysis

Background: Postpartum haemorrhage (PPH) is the leading cause of maternal death world-wide. Maternal anaemia strongly increases the risk of PPH. The Woman trial showed that the antifibrinolytic tranexamic acid (TXA) reduces PPH deaths. The Woman-2 trial is now assessing whether TXA can prevent PPH in anaemic women. Low RBC-counts promote fibrinolysis by altering fibrin structure and plasminogen activation. We explore the effect of low RBC counts on the potency of TXA.

Aims: To examine if the RBC content of fibrin clots affects the anti-fibrinolytic potency of TXA.

Methods: We used ball sedimentation assay (BS) and elastic motion thromboelastography (ClotPro) to monitor the lysis of fibrin containing plasminogen and tissue-type plasminogen activator (tPA) at various RBC-counts and TXA concentrations. We examined the anti-fibrinolytic potency of TXA with parallel line bioassay analysis of lysis times and with dose-response curves of lysis inhibition, over a range of tPA and TXA concentrations.

Results: Compared to RBC-free fibrin, the anti-fibrinolytic potency of 4–64 µM TXA was increased in the presence of RBC at 10–40%(V/V). This effect was consistent at all TXA concentrations and RBC counts in both BS and ClotPro assays. The maximal increase in TXA potency was 2.7-fold at 64 µM TXA and 20% (V/V) RBC (Fig.1A). The prolongation of lysis time in response to varying TXA concentration indicated that RBC increased the number of target sites available for TXA binding (Ltmax in Fig.1B) without any significant change in the TXA concentration needed to achieve a half-maximal effect (Ks in Fig.2B). These extra TXA binding sites are probably presented by the higher fraction of plasmin residing in unbound form in a fibrin meshwork of thinner fibers which is formed in the presence of RBCs.

Conclusion(s): RBCs increase the anti-fibrinolytic potency of TXA. Higher doses of TXA may be required to inhibit fibrinolysis in severely anaemic women.