Consensus recommendations on appropriate coagulation tests during emicizumab administration in Saudi Arabia.

Am J Blood Res 2022;12(3):82-87 www.AJBlood.us /ISSN:2160-1992/AJBR0142124 Review Article Consensus recommendations on appropriate coagulation tests during emicizumab administration in Saudi Arabia Tarek Owaidah1, Abdulakareem Almomen2, Ahmed Tarawah3, Ashraf Warsi4, Fawaz Alkasim5, Hazzaa Alzahrani6, Mahassen Saleh7, Ohoud Kashari8, Wasil Jastaniah9,10 Hematology and Transfusion Medicine, Department of Pathology and Laboratory Medicine (MBC 10), King Faisal Specialist Hospital and Research Center Alfaisal University, Riyadh, Saudi Arabia; 2Medicine-Hematology, King Saud University Medical City and Blood and Cancer Center, Riyadh, Saudi Arabia; 3Paediatric Haematology, Madina Maternity and Children Hospital, Medina, Saudi Arabia; 4Adult Haematology, College of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia; Princess Norah Oncology Centre, King Abdelaziz Medical City, Ministry of National Guard Health Affairs-WR, Jeddah, Saudi Arabia; 5Paediatric Haematology, Maternity and Children Hospital, Riyadh, Saudi Arabia; 6Adult Haematology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; 7Paediatric Haematology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; 8Paediatric Haematology, East Jeddah General Hospital, Jeddah, Saudi Arabia; 9Pediatrics and Pediatric Hematology/Oncology/BMT, College of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia; 10Princess Norah Oncology Center, King Abdulaziz Medical City, Ministry of National Guard Health Affairs WR, Jeddah, Saudi Arabia 1 Received January 31, 2022; Accepted May 5, 2022; Epub June 20, 2022; Published June 30, 2022 Abstract: Introduction: Emicizumab is a bispecific monoclonal antibody with the ability to bridge FIXa and FX, mimic FVIII, and restore normal hemostasis in patients with hemophilia A. Moreover, substantial evidence has shown that emicizumab-treated patients do not require monitoring, except before surgery or invasive procedures. However, introducing this novel drug to the market poses some challenges to physicians and clinical laboratories due to its interaction with conventional coagulation tests. Methods: Given the challenges and laboratory interactions posed by this novel drug, there is an unmet clinical need to develop clear recommendations for emicizumab laboratory monitoring to highlight which laboratory tests should be used, which tests should be avoided, and when these tests should be performed. These expert recommendations are essential to prevent inappropriate testing or misleading interpretations and reduce the extra costs of unnecessary monitoring. Results: A consensus meeting was conducted in December 2019, including top experts on hemophilia from Saudi Arabia, to discuss this issue. Conclusion: The experts agreed that, aPTT (activated Partial Thromboplastin Time)-based tests are not suitable for laboratory monitoring patients treated with emicizumab. Only FVIII chromogenic assays based on bovine FIX and FX proteins can be used to measure FVIII levels. They reviewed and recommended the type and time of testing for anti-factor VIII antibodies. Drug levels should be measured using the recommended test only when the anti-drug antibody (ADA) is clinically suspected and after excluding other causes (such as patient non-compliance). Keywords: Consensus, coagulation test, emicizumab, haemophilia, Kingdom of Saudi Arabia Introduction The deficiency of coagulation factor VIII (FVIII) causes hemophilia A (HA). Patients with HA require lifelong treatment with FVIII replacement therapy starting at an early age [1, 2]. However, approximately 20-30% of the patients with severe HA develop antibodies (inhibitors) that neutralize FVIII and compromise treatment outcomes [3]. In Saudi Arabia, approximately 29% of patients with HA develop FVIII inhibitors, and those with FVIII inhibitors tend to have a severe form of the disease [4]. Emicizumab is a bispecific monoclonal antibody, functionally similar to FVIII, enabling it to bridge activated FIX and FX together to restore hemostasis. Routine prophylaxis is recommended to prevent or reduce bleeding episodes in adult and pediatric patients, including new- KSA consensus on emicizumab testing borns, with HA (congenital factor VIII deficiency), with or without factor VIII inhibitors. In 2019, the Saudi Food and Drug Authority (SFDA) approved emicizumab at a loading dose of 3 mg/kg body weight through subcutaneous injection once every week for the first four weeks, followed by a maintenance dose of 1.5 mg/kg once every week, 3 mg/kg once every two weeks, or 6 mg/kg once every four weeks [5-7]. Current coagulation assays Current laboratory coagulation tests evaluate the coagulation potential of the patients. Activated partial thromboplastin time (aPTT) is a global coagulation assay used to assess the coagulation potential in individuals with coagulation disorders. Current laboratory tests for FVIII activity include (1) the one-stage FVIII clotting assay, (2) the two-stage FVIII clotting assay, and (3) the chromogenic substrate assay. The one-stage FVIII clotting assay is the most widely used coagulation assay to measure plasma FVIII activity. The assay evaluates the ability of the patient’s plasma to shorten the aPTT after mixing it with FVIII-deficient plasma [8-11]. The two-stage FVIII clotting assay, developed as an alternative to the one-stage FVIII clotting assay, is based on the same idea of considering FVIII concentration as the rate-limiting step of the reaction [12]. The FVIII chromogenic substrate assay measures the FVIII-dependent activation of FX using purified human or bovine coagulation factors [13]. This test consists of two steps. In the first step, patient plasma is added to a reaction mixture containing FIXa, FX, calcium ions, phospholipids, and trace amounts of thrombin. Thrombin triggers the activation of FVIII and the subsequent FIXamediated activation of FX. FXa production is proportional to the concentration of FVIII in the plasma samples. In the second step, the amount of FXa produced is quantified using a chromogenic peptide substrate that binds selectively to FXa [14]. Assays to detect FVIII inhibitors in patients with HA were used to monitor hemostasis. The test is based on comparing the residual FVIII activity in a mixture of patient plasma samples and normal pooled plasma with the residual FVIII activity in a mixture of diluent and normal pooled plasma. This comparison allows the 83 quantification of the reduction in FVIII activity due to FVIII inhibitors. The standardized assay to measure FVIII inhibitors is the Bethesda assay, later modified as the Nijmegen-Bethesda assay [15]. In the presence of emicizumab, the clot-based Bethesda assay is not specific, hence, a modified chromogenic Bethesda assay was developed. This assay uses the same methodology as the one-stage-based assay, with the difference in the detection step; the bovine chromogenic substrate that offers a more sp (...truncated)