Successful Management of Intracranial Hemorrhage with Emicizumab in a Newborn with Severe Hemophilia a: A Case Report

Introduction

Intracranial hemorrhage (ICH) is the second most common first hemorrhage in neonates with congenital Hemophilia, with an incidence of 3.4-4.0%. Nearly half (41%) of ICHs occur within the first week of life. ICH is the most feared complication of hemophilia with a high rate of morbidity and up to 20% of mortality. Timely diagnosis and prompt treatment are critical, even though the clinical signs of ICH in neonates are difficult to assess. Most studies recommend infusion of Factor VIII (FVIII) rising its plasma level to 100% as soon as possible. Unfortunately, approximately 25% to 40% of neonates develop inhibitors against FVIII after substitutive treatment; the percentage may be even higher in neonates with ICH requiring prolonged continuous treatment over days to weeks. We report a case of ICH in a newborn with severe haemophilia A (HA) treated with an initial-single dose of FVIII concentrate and then only with emicizumab.

Case report

A male neonate, born at 38+4 weeks of gestation by cesarean delivery, presented abnormal bleeding on his third day of life after heel blood sampling. Activated Partial Thromboplastin test resulted 147 seconds and FVIII was less then 1%. Family history for bleeding disorders was negative. A cerebral ultrasound scan documented a brain area suspicious for intracranial hemorrhage. Before transferring the neonate to the neonatal intensive care unit (NICU), he received an additional intravenous dose of vitamin K and 10 ml/kg fresh frozen plasma. On admission in NICU, the neonate presented alert and responsive with stable hemodynamics and vital signs. A second brain ultrasound and head MRI confirmed an intracerebral hemorrhage in the left parieto-occipital area near the splenium of the corpus callosum associated with subdural hematoma in the left temporo-occipital, occipito-mesial area, in falx cerebri and left tentorium cerebelli. Neonate received tranexamic acid infusions 40 mg/kg die and 50 IU/Kg of intravenous recombinant factor VIII concentrate (octocog alfa). Then, it was decided to start treatment with Emicizumab, a bispecific antibody mimicking FVIII, at a dose of 3 mg/kg subcutaneously once a week for 4 weeks, continuing prophylaxis at 1.5 mg/kg once a week.Serial brain ultrasound revealed progressive reduction of the ICH extension over the following weeks; one month later, brain MRI confirmed the improvement. The neonate's clinical condition remained always stable; he never showed seizures or neurological signs of impaired consciousness and his neurodevelopment is appropriate for age. MRI performed at three months of age documented complete resolution of the cerebral hemorrhage.

Discussion

Intensive FVIII replacement therapy for ICH in pups is associated with a high risk of inhibitor formation.Emicizumab, a humanised bispecific monoclonal antibody, is indicated for routine prophilaxis in patients with severe HA with and without antibodies to FVIII. Emicizumab is attractive due to its weekly or even longer dosing intervals and subcutaneous route of administration but, despite the baseline hemostasis achieved with emicizumab, acute bleeding events may still require aggressive therapy. Theoretically, it needs few days to be hemostatically effective but its in vitro coagulant potential in neonate is heterogeneous, thus we can not completely explain the therapeutic success with only one dose of FVIII.

Conclusions

The combined use of emicizumab and antifibrinolytics was successful in treating acute intracranial hemorrhage. To the best of our knowledge, this is the first pediatric case of successful management of intracranial hemorrhage with emicizumab in a newborn with severe HA.