Individually Tailored By-Passing Therapy for the Management of Breakthrough Bleeds in Hemophilia Patients with Inhibitors Receiving Prophylaxis with Emicizumab

Background: Emicizumab is a recombinant, humanized, bispecific, monoclonal antibody that bridges activated factor IX and factor X to restore the function of deficient factor VIII, which is needed for effective hemostasis. Treatment of bleeding in patients with hemophilia A and inhibitors involves by-passing agents such as recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (APCC). These molecules are also used for the management of breakthrough bleeds in patients on prophylaxis with emicizumab. There may be risks in combining two procoagulant drugs. In addition, there is no validated laboratory assay to evaluate the combined effect of emicizumab with a by-passing agent. We have previously reported that thrombin generation assay (TGA) may represent a surrogate marker for monitoring by-passing therapies.

Methods: After obtaining informed consent of two patients with severe hemophilia A and high titer of inhibitors included in phase 3 HAVEN 1 trial evaluating emicizumab prophylaxis, TGA was performed to determine in vitro individual response of patients to 5 different dosages of APCC (15 -25 - 45 - 75 - 100 U/kg) and rFVIIa (45 - 90 - 150 -200 - 270 µg/kg), while on emicizumab prophylaxis. Thrombin generation was measured according to the recent recommendations published by the ISTH FVIII/FIX subcommittee.

Results: A dose dependent increase of thrombin generation was observed with both by-passing agents, rFVIIa and APCC, in platelet rich- and platelet poor-plasma. However, very low dosages of APCC i.e. 15 to 25 U/kg were sufficient to fully normalize thrombin generation in our two patients.

One patient experienced an acute spontaneous arterial bleeding while on prophylaxis regimen with emicizumab 1.5 mg/kg weekly. He had presented a dissection of an aberrant renal artery supplying the inferior pole of the left kidney responsible for a perirenal hematoma of 16x10x7 cm. The patient was suffering from arterial dysplasia, he also had high blood pressure and dyslipidemia. As the individual response of the patient to by passing agents was determined before the bleeding event, he could benefit from personally tailored by-passing therapy with APCC. He had a single "high dose" of 24 U/kg followed by 15 U/kg every 12 hours during 2 weeks and then 15 U/kg every 24 hours during one additional week, for a total treatment duration of 3 weeks. Thrombin generation capacity was 2039 nM.min with APCC 24 U/kg and 1488 nM.min with APCC 15 U/kg. Normal thrombin generation capacity is 1487±372 nM.min (mean±2SD) as determined in 100 healthy volunteers (2). The patient safely recovered with no thrombotic complication during the 3 weeks of APCC treatment. No low molecular weight heparin prophylaxis was prescribed during the treatment with APCC. HAVEN 1 study reported 9% of thrombotic complications in patients who had received multiple infusions of APCC. The coagulation capacity of patients receiving combined emicizumab and by-passing therapy may be very different. This case illustrates that global haemostasis assays may help physician to determine the individual profile of patients with by-passing agents and emicizumab and to tailor their by-passing therapy when treating breakthrough bleeding.

Conclusion: The use of an objective laboratory criterion, such as thrombin generation capacity, may be helpful to guide by-passing therapy in patients receiving emicizumab prophylaxis. In vitro spiking experiments, easy to perform, may represent valuable information for the choice of dosages that may effectively achieve haemostasis and not represent a high risk of thrombosis. Thus, individually tailored by-passing therapy may help to limit adverse events that may occur when emicizumab is used in combination with other procoagulant molecules.