PB0219 - Thrombin generation measurement in hemophilia A patients with inhibitors receiving emicizumab prophylaxis

Background: Emicizumab is a recombinant, humanized, bispecific, monoclonal antibody that bridges activated factor IX and factor X to restore the function of deficient factor VIII. Bypassing agents (BPA) are used for the management of breakthrough bleeds in patients with hemophilia A patients and inhibitors (PWHAI) on prophylaxis with emicizumab, with concerns about the risks of combining two procoagulant drugs. Thrombin generation assay (TGA) might be used to support decision-making in patients on emicizumab undergoing major surgery or experiencing breakthrough bleeds, to both predict efficacy and to potentially minimize the risk of thrombotic events.

Aims: The aim of this study was to compare different analytical conditions in order to make TGA more sensitive to the procoagulant effect of emicizumab.

Methods: TG was measured in platelet rich (PRP) and platelet poor-plasma (PPP) samples from PWIHAI receiving emicizumab. Coagulation was triggered with tissue factor (TF) 1pM or FXIa+TF; results were compared to normal values determined with the same activators. Increasing concentrations of aPCC 0-12.5-25-50 U/kg; rFVIIa 90-180-200-270µg/kg and recombinant porcine FVIII (r-pFVIII)6-12.5-25-50-100-200 IU/dL were tested.

Results: The mean endogenous thrombin potential (ETP) of PPP samples from PWIHAI receiving emicizumab, was very low 371±114nM.min when coagulation was triggered with TF1pM, while ETP was almost normalized (1014±363nM.min) in PRP [normal values 1432±229nM.min]. In PPP, we observed significantly improved ETP (1975±268nM.min), when coagulation was triggered with TF+FXIa [normal values 2110±737nM.min]. Using TF+FXIa as trigger, the addition of BPA improved TG in all plasma samples with a certain variability according to patient’s individual responses.

Conclusion(s): TG measurement in PRP or the use of TF+FXIa with PPP may be more appropriate for evaluating the procoagulant effect of emicizumab, compared to TF 1pM. Using appropriate analytical conditions, TG assay may help to monitor the efficacy of BPA and r-pFVIII in PWIHAI receiving prophylaxis with emicizumab.