The history of FEIBA: a lifetime of success in the treatment of haemophilia complicated by an inhibitor

Abstract

The development of alloantibodies that inhibit the function of factor VIII (FVIII) or factor IX (FIX) is the most serious complication associated with the treatment of haemophilia. Bleeding events in patients with high-titre inhibitors generally cannot be managed with factor replacement therapy and require alternative strategies for haemostatic support. For over 30 years, the activated prothrombin complex concentrate (aPCC) FEIBA has been used to bypass the need for FVIII and FIX and control bleeding in inhibitor patients. Several large clinical studies have shown that FEIBA provides effective haemostasis in at least 80% of acute bleeding episodes and is well tolerated. Current limitations of bypassing therapy include a lack of laboratory assays to monitor treatment and an unpredictable haemostatic effect.

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

“…Plasma-derived aPCC (infused as single doses ranging between 50 and 100 U/kg every 612 hours not to exceed 200 U/kg/day) is an aPCC-containing vitamin-K-dependent coagulation protein. Prothrombin (factor II) and FXa are purported to be the primary active components (the prothrombinase complex), with other components, including other vitamin-K-dependent proteins, contributing to the overall hemostatic effect [Negrier et al 2006b]. The precise mechanism(s) by which pd-aPCC facilitates hemostasis has not yet been determined but appears to principally involve conversion of prothrombin in the prothrombinase complex (FIIFXa) into thrombin downstream from the point of inhibitor blockade in the coagulation pathway.…”

“…Further, pd-aPCC and rFVIIa have been shown to be effective in patients with inhibitors undergoing minor and major surgical and invasive diagnostic and therapeutic procedures, including orthopedic surgery [Balkan et al 2010;Hedner and Ingerslev, 1998;Shapiro et al 1998;Ingerslev et al 1996]. Both products have been used in the home-treatment setting with success [Gomperts, 2006;Negrier et al 2006b;Key et al 1998]. While long-term prophylaxis with both bypassing agents has been shown to reduce joint hemorrhages, there have been mixed results in the prevention of progressive orthopedic damage [Valentino, 2010;Konkle et al 2007;Morfini et al 2007a;Hilgartner et al 2003;Kreuz et al 2000].…”

How we treat a hemophilia A patient with a factor VIII inhibitor

“…42 To better tailor treatment in individual patients some have looked to thromboelastography and endogenous thrombin potential. Unfortunately, clinical studies linking these tests with clinical outcomes are lacking 7,43 ; therefore, treatment with rfVIIa and FEIBA VH must be adjusted according to clinical outcomes rather than laboratory testing results.…”

“…Low-titer inhibitors comprise 25% to 50% of observed inhibitors and approximately 10% of these are considered transient, disappearing over weeks to months despite continued treatment with fVIII. [7][8][9][10] …”

Global clotting assays - monitoring the effect of by-passing agents in haemophilia patients with inhibitors

“…These findings could suggest that a dosage for APCC of 75 IU/ kg would be preferable (50IU/kg -too low and 100IU/kg -too high) and that a prolongation of the intervals between administrations of rFVIIa would be safe, hypothesis which should be proved further on a larger number of explorations. (17) What concerns the correlation between haemostatic impact and clinical outcome it seems to be a reality in our small cohort of patients. Nevertheless, it is not to be overlooked that in two patients, despite the persistent good TGA values, they continued to bleed and the addition of the second BPA was mandatory, assuring the stop of the hemorrhage.…”