Laboratory Monitoring in Emicizumab-Treated Persons with Hemophilia A

Abstract

Hemophilia A (HA) is an X-linked hereditary bleeding disorder caused by deficiency of coagulation factor (F) VIII activity. One of the greatest complications in the treatment of HA is the development of neutralizing alloantibodies, known as FVIII inhibitors. HA patients who develop FVIII inhibitors have limited treatment options available to them and experience greater disease- and treatment-related burdens than HA patients without FVIII inhibitors. Emicizumab, a recently approved bispecific monoclonal antibody, mimics the function of FVIIIa by bridging FIXa and FX to restore effective hemostasis. Although emicizumab and FVIII show some functional similarities, several key differences influence the results of standard laboratory assays when conducted in the presence of emicizumab, and can result in a misleading interpretation of coagulation assays in emicizumab-treated patients. Here, we discuss current laboratory monitoring methods, including activated partial thromboplastin time, FVIII one-stage clotting assays, FVIII chromogenic assays, and global coagulations assays; address why these conventional methods may be inappropriate for monitoring of HA patients receiving emicizumab; and suggest alternative methods applicable to monitoring HA treatment in an evolving treatment landscape.

Bridging the Missing Link with Emicizumab: A Bispecific Antibody for Treatment of Hemophilia A

“…Assessment of the hemostatic function and FVIII activity in patients under treatment with emicizumab needs special attention. 68 69 Since emicizumab causes a significant shortening of the aPTT even at very low concentrations, 52 69 use of conventional aPTT tests is futile. Diluted aPTT, however, correlates well with the plasma emicizumab concentration.…”

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

“…Currently there are very few case reports which have utilised global coagulation assays-with or without concomitant FVIII/ BPA therapy-to monitor emicizumab therapy. 10,[16][17][18][19] Given the paucity of information on emicizumab safety, and efficacy and monitoring in paediatric patients, we hereby present our prospectively-followed cohort, including infants and very young children. Special additional reference is provided regarding treatment monitoring by routine laboratory assays [activated partial thromboplastin time (aPTT) and emicizumab levels] as well as thrombin generation (TG) studies, and their clinical correlations.…”

<p>Clinical Evidence and Safety Profile of Emicizumab for the Management of Children with Hemophilia A</p>

“…Equivalent FVIII: C corresponding to therapeutic dose of emicizumab have varied widely across studies, depending on the coagulation assays that were used, whether they were global hemostatic assays or FVIII one-stage assays. 25,26 Interestingly, similar pharmacokinetic profiles and through levels of plasma emicizumab concentrations were observed in the 152 HA adult patients without FVIII-inhibitors who were enrolled in the phase 3 HAVEN 3 study (ClinicalTrials.gov number, NCT02847637), whether they were included in the QW prophylaxis regimen cohort or in the maintenance dose of 3.0 mg/kg bodyweight emicizumab every 2 weeks cohort (Q2W). Other emicizumab prophylaxis regimens were studied in the HAVEN 4 trial (ClinicalTrials.gov number, NCT03020160), in which HA adult and adolescent patients with and without FVIII-inhibitors received emicizumab subcutaneous injection every 4 weeks (Q4W).…”

“…However, FVIII:C can be accurately measured using chromogenic FVIII assay based on bovine reagent, which are unaffected by the presence of emicizumab. 26 All of these real-life situations highlight that the clinical management of HA patients receiving emicizumab may not be an easy task, despite the convenience of subcutaneous administration and infrequent dosing regimen. Therefore, we believe that the use of emicizumab prophylaxis should be overseen by experienced hemophilia comprehensive care centers.…”