Two pediatric cases of severe hemophilia A in which emicizumab prophylaxis failed to prevent traumatic extra-articular hemorrhage

Abstract

Emicizumab reduces bleeding episodes in patients with severe hemophilia A (PwHA). Little information is available on hemostatic management of severe traumatic hemorrhages in emicizumab-treated pediatric PwHA. We assessed therapeutic efficacy and global coagulation potentials in two pediatric cases of emicizumab-treated pediatric PwHA with intracranial or retroperitoneal/iliopsoas hemorrhage. A modified clot waveform analysis (CWA) triggered by mixtures of tissue factor and ellagic acid was used to assess coagulant potentials, and maximum coagulant velocity (Ad|min1|) was calculated. One patient with intracranial hemorrhage was treated with continuous infusions of recombinant factor VIII (rFVIII) at a dose of 4-4.6 IU/kg/hr for 9 days, followed by bolus infusion at 66 IU/kg/day for 2 days and 33 IU/kg/day for an additional 2 days. The Ad|min1| was increased from 5.5 (at baseline) to 7.0-8.1 under concomitant treatment and maintained within or near normal range (IQR; 6.9-7.7). The other patient with retroperitoneal/iliopsoas hemorrhage received bolus infusions of rFVIII at 50 IU/kg/day for 20 days and every-other-day infusion of rFVIII for 8 days. The Ad|min1| was increased from 5.2 (at baseline) to 5.8-6.8 under concomitant treatment and maintained within the normal range. We successfully managed a treatment plan for severe traumatic bleeding in emicizumab-treated pediatric PwHA using modified CWA.

Keywords: Bispecific antibody; Factor VIII; Hemophilia A; Hemostatic monitoring; Severe traumatic bleeding.

Fig. 1

Time course of change in brain CT findings in Case 1. The brain CT shows an improvement in intracranial hemorrhage

Fig. 2

Clinical course of Case 1 (with intracranial hemorrhage). We measured FVIII:C using a one-stage clotting assay with two anti-Emi monoclonal antibodies. The Ad|min1| in the patient’s plasma on admission was also measured after the addition of purified FVIII inhibitor IgG to neutralize FVIII:C. The dosage of FVIII administration was 33 IU/kg on admission. Subsequently, continuous infusion of rFVIII concentrates was conducted. The patient required a 4–4.6 IU/kg/hr dose to maintain a FVIII:C of 50 IU/dL. We then measured Ad|min1| using modified CWA and FVIII:C during continuous infusion. Nine days later, the patient was administered rFVIII at 66 IU/kg for 2 days and 33 IU/kg for 2 days. Ad|min1| and FVIII:C were also measured just before FVIII administration. The gray bar represents the normal range (IQR: 6.9–7.7) of Ad|min1| in 17 healthy individuals. Symbols used: closed circles, Ad|min1| during the therapeutic period; open circles, FVIII:C during the therapeutic period; closed squares, Ad|min1| on admission; FVIII:C, FVIII activity; rFVIII, recombinant FVIII; Ad|min1|, adjusted maximum coagulation velocity; CWA, clot waveform analysis

Fig. 3

Time course of changes in abdominal CT and ultrasound findings in Case 2. Abdominal CT findings showed left retroperitoneal and iliopsoas muscle hemorrhages on days 1 and 2. Abdominal ultrasound findings showed improvement in the retroperitoneal hemorrhage

Fig. 4

Clinical course of Case 2 (with iliopsoas/retroperitoneal hemorrhage). We measured FVIII:C using a one-stage clotting assay with two anti-Emi monoclonal antibodies. Ad|min1| in his plasma on the day after admission was also measured after adding purified FVIII inhibitor IgG to neutralize FVIII:C. The patient required a 50 IU/kg/day dose to maintain a trough FVIII:C level at 24 h after FVIII administration of 20 IU/dL. From the day after admission, we measured Ad|min1| using modified CWA and FVIII:C just before FVIII administration. Twenty days later, he was given a bolus administration of rFVIII 50 IU/kg every other day for 8 days. The gray bar represents the normal range (IQR: 6.9–7.7) of Ad|min1| in 17 healthy individuals. Symbols used: closed circles, Ad|min1| during the therapeutic period; open circles, FVIII:C during the therapeutic period; closed squares, Ad|min1| on admission; FVIII:C, FVIII activity; rFVIII, recombinant FVIII; Ad|min1|, adjusted maximum coagulation velocity; CWA, clot waveform analysis