CC BY 4.0 · TH Open 2020; 04(02): e94-e103
DOI: 10.1055/s-0040-1710032
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Synergistic Effect of Bypassing Agents and Sequence Identical Analogue of Emicizumab and Fibrin Clot Structure in the In Vitro Model of Hemophilia A

Yanan Zong
1   Department of Molecular Medicine and Surgery, Clinical Chemistry and Coagulation, Karolinska Institutet, Stockholm, Sweden
,
Aleksandra Antovic
2   Department of Medicine, Unit of Rheumatology, Karolinska Institutet and Academic Specialist Center, Center for Rheumatology, Stockholm Health Services, Stockholm, Sweden
,
Nida Mahmoud Hourani Soutari
1   Department of Molecular Medicine and Surgery, Clinical Chemistry and Coagulation, Karolinska Institutet, Stockholm, Sweden
3   Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden
,
Jovan Antovic
1   Department of Molecular Medicine and Surgery, Clinical Chemistry and Coagulation, Karolinska Institutet, Stockholm, Sweden
3   Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden
,
Iva Pruner
1   Department of Molecular Medicine and Surgery, Clinical Chemistry and Coagulation, Karolinska Institutet, Stockholm, Sweden
› Author Affiliations
Funding This study was funded by Investigator-Initiated Research grant Baxalta US Inc. (part of Takeda group of companies), Bannockburn, IL (IIR SWE-001459).
Further Information

Publication History

06 November 2019

24 March 2020

Publication Date:
21 July 2020 (online)

Abstract

Development of inhibitors to factor VIII (FVIII) occurs in approximately 30% of severe hemophilia A (HA) patients. These patients are treated with bypassing agents (activated prothrombin complex concentrate [aPCC] and recombinant activated FVII-rFVIIa). Recently, a bispecific FIX/FIXa- and FX/FXa-directed antibody (emicizumab) has been approved for the treatment of HA patients with inhibitors. However, the data from clinical studies imply that coadministration of emicizumab and bypassing agents, especially aPCC, could have a thrombotic effect.

This study was aimed to address the question of potential hypercoagulability of emicizumab and bypassing agents' coadministration, we have investigated fibrin clot formation and structure in the in vitro model of severe HA after adding sequence-identical analogue (SIA) of emicizumab and bypassing agents.

Combined overall hemostasis potential (OHP) and fibrin clot turbidity assay was performed in FVIII-deficient plasma after addition of different concentrations of SIA, rFVIIa, and aPCC. Pooled normal plasma was used as control. The fibrin clots were analyzed by scanning electron microscopy (SEM).

OHP and turbidity parameters improved with the addition of aPCC, while therapeutic concentrations of rFVIIa did not show substantial improvement. SIA alone and in combination with rFVIIa or low aPCC concentration improved OHP and turbidity parameters and stabilized fibrin network, while in combination with higher concentrations of aPCC expressed hypercoagulable pattern and generated denser clots.

Our in vitro model suggests that combination of SIA and aPCC could potentially be prothrombotic, due to hypercoagulable changes in fibrin clot turbidity and morphology. Additionally, combination of SIA and rFVIIa leads to the formation of stable clots similar to normal fibrin clots.

Supplementary Material