ST‐Segment Elevation Myocardial Infarction (STEMI) and Pulmonary Embolism in a Hemophilia A Patient Receiving Emicizumab and recombinant Activated Factor VII

Abstract

Congenital haemophilia A is a bleeding disorder affecting roughly 1 in 5000 male children with a prevalence of around 160 000 people worldwide. 1 As a result of treatment, approximately 20%-30% of patients with haemophilia A develop allo-immune antibodies inhibiting exogenous coagulation factor VIII. For such patients before 2017, if they failed immune tolerance induction, activated prothrombin complex concentrate [aPCC; factor eight inhibitor bypassing activity (FEIBA),Takeda] for prophylaxis or on-demand and recombinant activated factor VII (rFVIIa; Novo Seven, Novo Nordisk) on-demand were the only US Food and Drug Administration (FDA) approved options. 2Emicizumab is a subcutaneously administered humanized bi-specific monoclonal antibody to factor IXa and factor X with a half-life of around 28 days. Emicizumab mimics the physiologic function of factor VIII as a cofactor in the 'intrinsic Xase complex'. FDA approved emicizumab in 2017 for patients with severe haemophilia A with circulating inhibitor and subsequently, in October 2018, for patients without inhibitor for prophylaxis, based on the pivotal series of HAVEN studies. Though in a phase 1 study of healthy volunteers, no thrombotic events occurred, in HAVEN-1 thrombotic complications were reported including thrombotic microangiopathy (TMA), cerebral venous sinus thrombosis and superficial thrombophlebitis in patients with inhibitors. 3,4 All such thrombotic complications were preceded by an average daily dose of aPCC of >100 IU/kg for more than 1 day, and no arterial thrombotic events occurred. We report the first case of STEMI in a patient treated with emicizumab.Our patient has a history of severe congenital haemophilia A with high responding inhibitor since childhood and failed immune tolerance induction. He was treated with 'on-demand' aPCC and suffered a provoked venous thromboembolism (VTE) at the age of 22 years, reportedly while receiving aPCC along with rVIIa for a joint bleed in the setting of a community-acquired pneumonia. At age 38, due to frequent joint and muscle bleeds complicated by compartment syndrome requiring fasciotomies, aPCC prophylaxis was initiated at a dose of 85 U/kg every other day with improvement in bleeding symptoms. There was no family history of VTE but given his thrombosis history we screened for thrombophilia when he established care at our institution, which showed antithrombin activity of 99% (70%-130%), protein C activity 81% (65%-145%), protein S activity 66% (66%-143%), homocysteine 10.8 µmol/L (5-15 µmol/L), no antiphospholipid antibodies or lupus anticoagulant and no factor V Leiden G1691A or prothrombin gene G20210A mutations. He is an active cigarette smoker with a 20 pack-year history. At age 40, he stopped aPCC and started emicizumab prophylaxis (3 mg/kg by subcutaneous injection once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly) with improvement in bleeding symptoms. Three months later, he was hospitalized for methicillin-sensitive Staphylococcus aureus (MSSA) septic arthritis of his left ...

Emicizumab treatment and monitoring in a paediatric cohort: real‐world data

“…Notably, both thrombosis and TMA have been reported in adolescent and adult patients who received emicizumab concomitantly with APCC 15 or rFVIIa 32 . Therefore, we currently suggest routine blood counts and renal function tests for TMA screening to be performed in patients being co‐administered with bypass agents.…”

Guidelines on the use of prophylactic factor replacement for children and adults with Haemophilia A and B

“…There is one report of non-STelevation myocardial infarction and pulmonary embolism associated with co-administration of rFVIIa. 41 No thrombotic events have been reported in association with FVIII replacement, although the numbers treated to date are low and data in young children are very limited. 42,43 Recurrence of inhibitors in people previously tolerized to FVIII…”

Emicizumab (Hemlibra®) in hemophilia A patients with inhibitors against factor VIII — guidelines of the Group for Haemostasis of the Polish Society of Haematology and Transfusion Medicine

“…A mechanism of TMA development in which enhanced thrombin generation does not seem to play the primary role has not yet been described. It is worth mentioning that one severe haemophilia A patient with inhibitor, who received recombinant activated factor VII (rFVIIa) during emicizumab prophylaxis, experienced myocardial infarction without ST-segment elevation and pulmonary embolism [25]. Up to date however, no thromboembolic complications or TMA cases have been reported for hemophilia A patients with inhibitor during concomitant administration of emicizumab and factor VIII concentrates [26,27].…”

“…HAVEN 1 trial, thromboembolic events and TMA were described only in patients who receivied emicizumab in concomitance with aPCC at a dose > 100 U/kg for > 24 h. In the HAVEN program, there were no reports on thromboembolic events or thrombotic microangiopathy in patients on emicizumab prophylaxis in concomitance with rFVIIa. Outside the clinical trials however, one case of thromboembolic complications was reported in a patient who was on emicizumab prophylaxis after rFVIIa administration) [25].…”

“…In patients with recent low inhibitor titres human factor VIII concentrate should be considered under control of clotting factor activity. Comment 1: in the HAVEN trial, no TE and TMA episodes were observed in patients with concomitant use of emicizumab and rFVIIa or emicizumab and FVIII (although, outside clinical studies, one case of thromboembolic complications was reported in a patient on emicizumab prophylaxis following rFVIIa administration) [25].…”