Advances in bypassing agent therapy for hemophilia patients with inhibitors to close care gaps and improve outcomes

Abstract

In the past, patients with hemophilia and inhibitors have had less-than-optimal treatment and have experienced more orthopedic complications than patients without inhibitors. Bypassing agents offer the potential to close treatment gaps between inhibitor and noninhibitor patients by helping the former better attain key treatment goals, including: facilitating early initiation of treatment and hemostatic control in hemarthroses; providing effective treatment in serious hemorrhagic episodes; and performance of major surgery. Effective treatment with a bypassing agent minimizes joint and/or muscle damage and potentially can serve as an effective prophylactic agent to minimize the number of hemarthroses experienced per year, thereby mitigating the development of arthropathy. The reported efficacy of the currently available bypassing agents ranges from approximately 5080% (5064% in controlled studies) for plasma-derived activated prothrombin complex concentrate (pd-aPCC) and 8191% (in controlled studies) for recombinant activated factor VII (rFVIIa), including use in major orthopedic surgery. Both bypassing agents have undergone key improvements in their formulation and/or properties in recent years. The nanofiltered, vaporheated formulation of pd-aPCC has diminished the risk of acquiring blood-borne viral infections and the room temperature stable formulation of rFVIIa allows more convenient storage, increased ease to dissolve and inject, and smaller volumes, thereby increasing overall ease of administration. Use of recommended dosing has been demonstrated to provide effective hemostasis with a minimal number of injections for both agents. In this paper, we review the individual characteristics of pd-aPCC and rFVIIa and discuss clinical data from studies conducted in inhibitor patients that demonstrate the potential benefits of these bypassing agents in this difficult-to-treat population, and underscore the potential opportunities to close the gap in care between inhibitor and noninhibitor hemophilic patients.

The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab

“…Prophylaxis with standard bypassing agents (recombinant activated FVII [rFVIIa] and plasma‐derived activated prothrombin complex concentrate [FEIBA]) should be considered on a case‐by‐case basis according to the patient's bleeding pattern . ITI itself has been shown to reduce rates of bleeding particularly when the inhibitor titre is not very elevated.…”

“…If emicizumab is not added then recommend the same regimens as in Figure 1 Escalation 32 ITI itself has been shown to reduce rates of bleeding particularly when the inhibitor titre is not very elevated.…”

Sequential bypassing agents during major orthopedic surgery: a new approach to hemostasis

“…These distinct actions probably have a synergistic effect on hemostasis. 18 In conclusion, the outcome of our patient suggests that sequential BPA therapy is a safe and effective salvage therapy to prevent surgical bleeding in hemophilia patients with inhibitors unresponsive to single-agent BPA treatment. Whether alternating BPA agents is hemostatically more effective than single-agent BPA treatment will require a clinical trial; however, our experience suggests the use of sequential BPA therapy should be considered.…”

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

“…The haemostatic efficacy of aPCC may be enhanced by dose optimisation, with dosage and duration of treatment being dependent on the location and extent of bleeding, the patient's clinical condition and their response. 70 A clearly defined unit of potency is required for dosage calculations and clinical management. The potency designation of aPCC is expressed in arbitrary units: 1 unit of aPCC shortens the activated partial thromboplastin time (aPTT) of FVIII inhibitor-containing reference plasma by 50%.…”