PB0536 - Ex vivo study of the concomitant use of plasma-derived Factor VIII/Von Willebrand Factor and emicizumab in patients with severe Hemophilia A

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

MB

Maria-Isabel Bravo, PhD

Senior Manager Discovery Research, Scientific Innovation Office
Grifols
Parets del Vallès, Catalonia, Spain

Co-Author(s)

AR

Aida Raventós

Discovery Research, Bioscience Research Group
Grifols
Parets del Vallès, Catalonia, Spain
AP

Alba Pérez

Discovery Research, Bioscience Research Group
Grifols
Parets del Vallès, Catalonia, Spain
Elena García Arias-Salgado, PhD

Senior researcher
La Paz University Hospital
Madrid, Madrid, Spain
María Teresa Alvarez-Román, MD, PhD

Head of the Thrombosis and Haemostasis Unit
La Paz University Hospital, Madrid, Spain
Madrid, Madrid, Spain
NB

Nora V V. Butta Coll

Head of Hemostasis laboratory
La Paz University Hospital
Madrid, Madrid, Spain
Víctor Jiménez Yuste, MD PhD

Head of Hematology
La Paz University Hospital
Madrid, Madrid, Spain
MC

Montserrat Costa

Discovery Research, Bioscience Research Group
Grifols
Parets del Vallès, Catalonia, Spain
TW

Todd Willis

Discovery Research, Bioscience Research Group
Grifols
Research Triangle Park, North Carolina, United States

Background: Hemophilia A (HA) patients under emicizumab prophylaxis treatment may require the concomitant use of procoagulant factors for breakthrough bleedings or immune tolerance induction. Previous studies combined emicizumab and plasma-derived Factor VIII/Von Willebrand Factor (pdFVIII/VWF) in vitro showing a non-additive effect on thrombin generation (TG).

Aims: To evaluate the procoagulant effect of ex vivo combination of samples from HA patients treated with emicizumab with a pdFVIII/VWF concentrate (Fanhdi®, Grifols).

Methods: Blood samples from 14 adult patients with severe HA without inhibitors on prophylaxis with emicizumab and 12 healthy controls (HCs) were drawn in citrate plus corn trypsin inhibitor. Samples were spiked with increasing concentrations of pdFVIII/VWF (10-400 IU/dL), rFVIIa (0.9 µg/mL) or aPCC (0.5 IU/mL) and analyzed by two global coagulation assays after activation with low tissue factor levels. Whole blood was analyzed by ROTEM coagulation assay measuring clotting time (CT) and time to maximum clot formation velocity (MAXV-t). Platelet poor plasma was analyzed by TG assay, measuring thrombin peak (TP) and endogenous thrombin potential (ETP) by calibrated automated thrombogram (Thrombinoscope™ software).

Results: Emicizumab treatment alone did not restore clotting to normal levels. The addition of pdFVIII/VWF at 50 IU/dL (≡25 IU/kg) restored these parameters within HCs normal range, similar to that observed after the addition of rFVIIa. Even higher doses of pdFVIII/VWF, up to 200IU/kg, did not result in excessive procoagulant profile. However, subtherapeutic dose of aPCC resulted in a synergistic procoagulant profile with coagulation values outside the normal range (Table 1). Moreover, coagulation parameters of both methods correlated at baseline and with increasing concentrations of pdFVIII/VWF.

Conclusion(s): The concomitant use of pdFVIII/VWF in HA patients with prophylaxis with emicizumab did not trigger a multiplying procoagulant effect. These results were aligned with previous in vitro data suggesting the low risk of overdose and thrombotic events of concomitant treatment with emicizumab and the pdFVIII/VWF concentrate.