Management of acute coronary syndrome and surgical revascularization in a patient with severe Hemophilia A on emicizumab

Abstract Patients with Hemophilia A (HA) have been observed to have lower rates of cardiovascular mortality compared to the general population due to a lifelong hypocoagulable state and shorter life expectancy. However, as therapeutic options and life expectancy for these patients have improved, increased rates of cardiovascular diseases, including acute coronary syndrome (ACS), have been noted. This poses a unique challenge as the foundation of ACS management relies on antithrombotic therapies and invasive procedures which necessitate high-dose anticoagulation. Emicizumab, a bispecific antibody that mimics the function of activated Factor VIII (FVIII), further complicates matters due to its interference with common laboratory assays including partial thromboplastin time (PTT)-based assays and Activated Clotting Time (ACT), the mainstay for anticoagulation monitoring during cardiac bypass surgery. The optimal intra-operative monitoring approach for patients on emicizumab undergoing cardiac bypass surgery is unknown, and has only been described in two previous cases in the literature. We therefore describe the third case of an individual with HA on emicizumab who underwent bypass surgery, including our perioperative FVIII replacement and intra-operative monitoring approach which resulted in a positive patient outcome. A 50-year-old male with severe HA (baseline FVIII activity <1%) treated with q4 week emicizumab for 3.5 months presented to a remote community hospital with chest pain. He is known for hemophilia-associated arthropathy and well-managed HIV. Following an initial diagnosis of non-ST elevation myocardial infarction (MI), he received aspirin and therapeutic enoxaparin with FVIII replacement to mitigate bleeding risk. Shortly afterward, his clinical status deteriorated to an ST elevation MI, necessitating the addition of clopidogrel and use of emergent fibrinolytic therapy with further FVIII replacement to target a trough FVIII activity above 100% in the immediate post-lysis period. The patient was then transferred to a local centre with cardiac catheterization (CC) capability and received pre-treatment with FVIII in case coronary stenting was required. During CC, he was found to have coronary anatomy best suited for revascularization with coronary artery bypass grafting (CABG) and was transferred to a cardiac centre with highly specialized hemophilia management capabilities. In collaboration with all relevant specialists, a perioperative plan was formulated. He received bovine chromogenic guided FVIII replacement, and his perioperative period was uncomplicated. Intraoperatively, he was on bypass for 88 minutes and ACT and anti-Xa levels were monitored approximately every 15 and 30 minutes respectively. ACT remained at target between 600-800 seconds and anti-Xa levels ranged between 5-10 U/mL, correlating well with ACT values. CABG was completed in <4 hours with no bleeding or thrombotic complications. He was discharged home one week later with FVIII prophylaxis until post-operative day 14, and emicizumab. There is minimal data on managing arterial thrombosis in patients with hemophilia, and current practice revolves around factor replacement in conjunction with antithrombotic therapy to minimize bleeding risk. The use of emicizumab complicates management due to its laboratory interference including normalizing the PTT and interfering with one-stage coagulation FVIII assays, necessitating specialized lab monitoring and interpretation using non-human (bovine) reagents. Furthermore, the effect of emicizumab on ACT remains variable, with one in-vitro study describing a modest decrease on ACTs while another in vivo study reported results similar to ours, with no apparent effect on ACT. Alternatively, anti-Xa levels can be monitored when more traditional assays are rendered inaccurate, however, this can be challenging in the intraoperative setting given prolonged turnaround times compared to ACT monitoring. Therefore, a combined monitoring approach involving ACT and anti-Xa levels can be used to ensure appropriate anticoagulation in these patients. This case highlights the complex interplay between HA and ACS, balancing thrombotic and bleeding risks, as well as the nuances of lab monitoring for patients on emicizumab. Early identification of these high-risk patients and transfer to a facility with access to specialized laboratory monitoring and multidisciplinary care are required to optimize patient outcomes.

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