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Emicizumab is a humanized monoclonal bispecific antibody that mimics the co-factorial activity of factor VIII (FVIII) by binding activated factors (F) IX and X. It can be used in patients with hemophilia A with or without inhibitors, because it is not recognized by anti-FVIII antibodies. Its use as prophylactic agent, administered subcutaneously once weekly in patients with hemophilia A and inhibitors aged > 12 years has shown a significant reduction in bleeding frequency compared with previous bypassing therapy. Nevertheless breakthrough bleeds may occur during prophylaxis with emicizumab as well as peri-operative bleeding complications, and, in those cases, standard bypassing agents (i.e. recombinant activated factor VII, rFVIIa and activated prothrombin complex concentrate (aPCC)) are still needed to control bleeding. Moreover, the lack of routine laboratory tests able to monitor in vivo the hemostatic efficacy as well as the prothrombotic potential of bypassing agents renders the clinical management most problematic. The use of the thrombin generation assay (TGA) has been proposed to individually tailor bypassing therapy and/or to monitor the efficacy of such therapy in patients undergoing surgery but with non-univocal results. Recently, Dargaud et al. proposed the use of TGA as a helpful tool to limit adverse events that may occur when emicizumab is used in association with other hemostatic drugs as in the occasion of treatment of breakthrough bleeds. In fact, in the HAVEN 1 study (NCT02622321), thrombotic microangiopathy and thrombosis were reported in 5 patients who received multiple doses of aPCC >100 IU/kg for more than 24 hours to treat breakthrough bleeds. Thus, during prophylaxis with emicizumab, it is recommended to avoid the association of multiple high doses of aPCC and to use the lowest therapeutic doses of both rFVIIa or aPCC when bypassing therapy is needed. Because the surgical setting represents a challenge in the management of patients with hemophilia and inhibitors due to the risk of peri-operative bleeding for which intensive by-passing therapy is often required, with unpredictable and sometimes suboptimal efficacy, we present here a major non-elective orthopaedic surgery performed on a patient enrolled in the HAVEN 1 study at our institution, for whom we used TGA to monitor the hemostatic efficacy of rFVIIa in combination with emicizumab. The patient was a 56-year old man with severe hemophilia A and high-responding anti-FVIII inhibitors since childhood (historical peak titer: 126 BU/mL). He was a severe bleeder who used aPCC, plasma-derived porcine FVIII and rFVIIa to treat bleeds during his life. He had previously undergone two major orthopaedic procedures in 2002 and 2012. The first was a femur fracture fixation managed with rFVIIa by continuous infusion (20 μg/kg/h) according to our local practice at that time; the patient was then switched to repeated boluses (130 μg/kg every 2h) to control severe bleeding at the surgical site. The second procedure was a total knee replacement initially managed with high-dose rFVIIa boluses (140-190 μg/kg every 2h) in order to prevent bleeding complications. However, severe blood loss (>1500 mL) and anaemia occurred, so that sequential bypassing therapy (alternate aPCC and rFVIIa every 6-8h) was given on the basis of preliminary evidence available at that time. The patient required blood transfusions in both occasions (7 and 9 units of red blood cells (RBC) respectively). On the occasion of the second procedure, TGA (see below) was used to measure coagulation activation ex vivo after the administration of bypassing agents, both pre-operatively in a non-bleeding state (testing two different doses of rFVIIa and aPCC) and then during the peri-operative period, as previously reported. In 2017, while on regular prophylaxis with emicizumab 1.5 mg/kg/week in the frame of the HAVEN 1 trial (NCT02622321), the patient required a right hip replacement due to the displacement of the screws used to fix the femoral fracture. Based on our local practice and protocol recommendations, we chose rFVIIa to manage the surgery. This decision was taken considering the strong and persistent anamnestic response previously observed in this patient, in order to save the use of FVIII for potentially lifeor limb-threatening bleeds. No thromboprophylaxis was given. Anti-FVIII inhibitors were measured pre-operatively by a chromogenic assay using bovine substrates (Chromogenix, Coamatic Factor VIII, IL) and showed 2 BU/mL. The cell blood count, D-dimer, fibrinogen, lactate dehydrogenase (LDH), haptoglobin and blood film were monitored to rule out signs of consumption, disseminated intravascular coagulation (DIC) or thrombotic microangiopathy (TMA). A thrombin generation assay (ThrombinoscopeTM, Thrombinoscope BV) was performed on platelet-rich (PRP) and platelet-poor plasma (PPP) using 1pM tissue factor and 1μM phospholipids (only in PPP) as previously described. At the time of surgery (Day 0), a pre-operative rFVIIa bolus of 98 mcg/kg was administered and repeated rFVIIa boluses of 82 mcg/kg were given every 3 hours after-

Rescue factor VIII replacement to secure hemostasis in a patient with hemophilia A and inhibitors on emicizumab prophylaxis undergoing hip replacement