PB0690 - Factor X consumption could cause attenuation of emicizumab effect; A case report of severe hemophilia A with inhibitor treated by emicizumab and factor VIII-bypassing agents

Background: In patients with hemophilia A and inhibitor (PwHA-I), emicizumab prevents bleeding events dramatically. However, in situations requiring intensive treatment with factor(F) VIII-bypassing agents (BPA) and emicizumab, behavior of factor FX and its effect has been poorly studied.

Aims: To evaluate whether coagulation potential could be affected by FX in PwHA-I treated with emicizumab and BPA.

Methods: A 59-year-old man with HA-I receiving emicizumab prophylaxis was admitted to our hospital because of acute gangrenous cholecystitis (day 0). He received percutaneous transhepatic gallbladder drainage (day 3) and laparoscopic cholecystectomy (day 7) under repeated administration of recombinant activated FVII (rFVIIa) every three hours. On day 10, rotational thromboelastometry (ROTEM) revealed poor effect of rFVIIa. Little deterioration was seen by adding anti-emicizumab antibody in vitro to his whole blood, suggesting the reduced activity of emicizumab. Considering consumption of FX, plasma-derived FVIIa/FX agent (pdFVIIa/X; Byclot®, available only in Japan) was administered, resulting in considerable recovery of ROTEM parameters. He was discharged on day 19 uneventfully. The FX antigen (FX:Ag) and thrombin generation assay (TGA) were measured retrospectively.

Results: The FX:Ag was 107.5% at his baseline. Administration of pdFVIIa/FX restored FX:Ag (pre/post 47.2%/125.5%) and peak thrombin (pre/post 181 nM/336 nM). In vitro addition of anti-emicizumab antibody depressed peak thrombin to 20 nM in pre-sample and to 87 nM in post-sample. The difference of the depressed peak thrombin value by the addition of anti-emicizumab antibody, considered as a surrogate marker of emicizumab activity, was greater in post-sample (Δ249 nM) than in pre-sample (Δ161 nM). Another parameter, time-to-peak in TGA also showed the similar pattern (see Table). No anti-drug antibody was detected in his plasma and plasma concentration of emicizumab was 19.5 μg/ml.

Conclusion(s): In intensive treatment with rFVIIa under emicizumab prophylaxis in PwHA-I, attenuation of emicizumab effect might occur due to FX consumption.