Tranexamic acid as adjunct therapy to bypassing agents in haemophiliaApatients with inhibitors

Abstract

Haemophilia patients with inhibitors require bypassing agents (BPA) like activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa) to control bleeds. Adjunct tranexamic acid (TXA) may improve haemostasis. The objective of this study was to investigate safety and haemostatic effect of TXA given in combination with BPA. Healthy volunteers (N=5) and haemophilia inhibitor patients (N=6) were enrolled in a prospective case crossover design. Controls were treated with TXA 20mgkg(-1) orally (O.R.) Patients were treated with aPCC 75IUkg(-1) intravenous (I.V.) on day 1 followed by TXA 20mgkg(-1) O.R. combined with aPCC 75IUkg(-1) I.V. on day 2. A 14-day washout occurred before crossover to rFVIIa 90μgkg(-1) I.V. ±TXA. Safety evaluation and blood sampling processes were performed at baseline, 15, 30, 60, 120, 180 and 240min post treatment. Primary outcome was maximum clot firmness (MCF) evaluated by whole blood thromboelastometry using a TF+tissue plasminogen activator-based assay. Healthy controls showed a 20-fold increase in MCF following TXA. Adjunct TXA to aPCC or rFVIIa induced a significant increase in MCF (P<0.0001) reaching levels indistinguishable from healthy controls treated with TXA (P>0.05). Infusion of aPCC or rFVIIa alone induced only 3-10 fold increase in MCF from baseline, with a decline in MCF starting after 60-120min. TXA did not increase the endogenous thrombin potential. No clinical or laboratory signs of thromboembolic events, disseminated intravascular coagulation, or hypercoagulability were observed. Combination of aPCC or rFVIIa with TXA normalizes clot stability in haemophilia patients with inhibitor as compared to healthy controls. No clinical or laboratory adverse events were observed.