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. 2020 Dec;40(5):606-620.
doi: 10.1055/a-1159-4273. Epub 2020 Jul 27.

Origins, Development, Current Challenges and Future Directions with Activated Prothrombin Complex Concentrate for the Treatment of Patients with Congenital Haemophilia with Inhibitors

Hans H Brackmann  1 , Wolfgang Schramm  2 , Johannes Oldenburg  1 , Viridiana Cano  3 , Peter L Turecek  4 , Claude Négrier  5
Affiliations

Origins, Development, Current Challenges and Future Directions with Activated Prothrombin Complex Concentrate for the Treatment of Patients with Congenital Haemophilia with Inhibitors

Hans H Brackmann et al. Hamostaseologie. 2020 Dec.

Abstract

Congenital haemophilia A (HA) is caused by deficiency of coagulation factor VIII (FVIII) activity, leading to spontaneous or traumatic bleeding events. While FVIII replacement therapy can treat and prevent bleeds, approximately 30% of patients with severe HA develop inhibitor antibodies that render FVIII replacement therapy ineffective. The bypassing agents (BPAs), activated prothrombin complex concentrate (aPCC) and recombinant activated FVII, first approved in 1977 and 1996, respectively, act to generate thrombin independent of pathways that involve factors IX and VIII. Both may be used in patients with congenital haemophilia and inhibitors (PwHIs) for the treatment and prevention of acute bleeds and quickly became standard of care. However, individual patients respond differently to different agents. While both agents are approved for on-demand treatment and perioperative management for patients with congenital haemophilia with inhibitors, aPCC is currently the only BPA approved worldwide for prophylaxis in PwHI. Non-factor therapies (NFTs) have a mechanism of action distinct from BPAs and have reported higher efficacy rates as prophylactic regimens. Nonetheless, treatment challenges remain with NFTs, particularly regarding the potential for synergistic action on thrombin generation with concomitant use of other haemostatic agents, such as BPAs, for the treatment of breakthrough bleeds and in perioperative management. Concomitant use of NFTs with other haemostatic agents could increase the risk of adverse events such as thromboembolic events or thrombotic microangiopathy. This review focuses on the origins, development and on-going role of aPCC in the evolving treatment landscape in the management of PwHI.

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Conflict of interest statement

Hans Hermann Brackmann has received honoraria for presentations from Takeda, Sobi and Roche. Wolfgang Schramm has participated in advisory boards for Biotest, and received honoraria for lectures from Bio&Bio AG, Biotest, Novo, Roche and Shire, a Takeda company. Johannes Oldenburg has received grant/research support from Bayer, Biotest, CSL Behring, Novo Nordisk, Octapharma, Pfizer and Shire, a Takeda company, and fees for consultancy and speakers bureaus from Bayer, Biogen, Biotest, Chugai, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, a Takeda company, and Sobi. Viridiana Cano was an employee of Shire GmbH, a Takeda company, Zürich, Switzerland during the development of this review and a stockholder in Takeda Pharmaceutical Company Limited. Peter Turecek is an employee of Baxalta Innovations GmbH, a Takeda company, Vienna, Austria and a stockholder in Takeda Pharmaceutical Company Limited. Claude Négrier has received grant/research support from CSL Behring, Octapharma, Shire, a Takeda company, and Sobi; fees for consultancy from Alnylam, Bayer, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, a Takeda company, and Sobi; and as a paid instructor for Novo Nordisk.

Figures

Fig. 1
Fig. 1
Mechanism of action for activated prothrombin complex concentrate (aPCC). APC, activated protein C; TF, tissue factor; TFPI, tissue factor pathway inhibitor.
See this image and copyright information in PMC

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