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

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.

Thrombin generation assays are versatile tools in blood coagulation analysis: A review of technical features, and applications from research to laboratory routine

“…The accumulated knowledge about the mode of action of bypassing agents substantially enabled by TGA methods prompted the use of TGA as tool to monitor their pharmacokinetics and pharmacodynamics. This made possible to use biomarkers of coagulation measured by TGA for treatment monitoring of these bypassing agents which otherwise cannot be measured in the absence of suitable tests to directly determine the active ingredients 23,25,56 …”

“…This made possible to use biomarkers of coagulation measured by TGA for treatment monitoring of these bypassing agents which otherwise cannot be measured in the absence of suitable tests to directly determine the active ingredients. 23 , 25 , 56 …”

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“…In their contribution, Hans Brackmann and other renowned experts in the field provide a comprehensive review on the management of patients with hemophilia A and inhibitors, thereby focusing on the use of activated prothrombin complex concentrate. 14…”

Real-world data in patients with congenital hemophilia and inhibitors: final data from the FEIBA Global Outcome (FEIBA GO) study

“…1 aPCC has been commercially available since 1977 and, during the past 40 years, randomized clinical trials and observational studies have demonstrated the efficacy of aPCC as on-demand therapy for the control of bleeding events, as prophylaxis, and for the perioperative management of patients with hemophilia A or B and inhibitors. [16][17][18][19][20][21] The safety of aPCC administered either as prophylaxis or on-demand therapy was also evaluated in a post-authorization safety surveillance (PASS) study in patients with hemophilia and inhibitors, as well as in a meta-analysis of 39 studies with safety data relating to the use of aPCC. 22,23 The FEIBA Global Outcome (FEIBA GO; EUPAS6691) study was designed to describe the long-term, real-world effectiveness, safety, and quality-of-life outcomes for patients with congenital hemophilia A or B and high-responding inhibitors receiving aPCC (FEIBA) treatment in routine clinical practice.…”