Hemophilia A is an X-linked coagulation disorder due to reduced levels of factor 8 with an incidence of 1 in 5000 male childbirth [1].Hemophilia A is confirmed by demonstrating low circulating levels of factor 8 (severe< 1%, moderate 1–5%, mild 5–50% of normal) or by genetic analysis. Severe Hemophilia A may present in the neonatal period.
In this report, we describe the occurrence of Multisystem Inflammatory Syndrome- Neonate (MIS-N) in a 2-day-old baby diagnosed with Hemophilia A. Transplacental transfer of antibodies occurs following maternal COVID-19 disease. This may lead to a hyperinflammatory state in the newborn called Multisystem Inflammatory Syndrome-Neonate (MIS-N). There have been very few cases of MIS-N reported so far [2]. The concomitant occurrence of MIS-N with other disorders, such as Hemophilia A, will pose diagnostic and therapeutic challenges in the pandemic era. This case report highlights the need to have a high index of suspicion to make a timely diagnosis.
Case presentation
A 2-day-old male baby, born to a primigravida mother at 39 weeks of gestation by a forceps delivery, with a birth weight of 2.8 kg, presented to the Emergency Department (ED) with swelling on the left thigh, poor feeding, and lethargy. There was no family history of bleeding disorder. The baby was noted to have apnea in ED requiring intubation. After admission to the NICU, the baby was ventilated and stabilized. Examination showed bulging anterior fontanelle, anisocoria, and a 3 × 1 cm bluish swelling on the left thigh at the site of vitamin K injection. He had multiple episodes of seizures in the form of tonic posturing of all 4 limbs. Investigations showed anemia (Hemoglobin- 12.8 g/dL), normal leukocyte and platelet counts (Total count- 15,500 cells/μl, platelet-1.6 lac/μl). C-reactive protein (CRP) was 13 mg/L (normal < 10 mg/L). The coagulation profile showed normal prothrombin time (PT) and an isolated activated partial thromboplastin time (APTT) prolongation (PT-20.1 s control-13.3 s, international normalized ratio (INR) -1.60, APTT>120S). A Neurosonogram on day 2 of life, showed a subdural hemorrhage (SDH) of 8 mm in the left frontotemporal region. Packed red cells and fresh frozen plasma were transfused after drawing samples for clotting factors. Factor 8 activity was < 1% and a diagnosis of hemophilia A was made. He was started on Factor 8 at 125 IU twice a day (targeting 100% factor levels), anticonvulsants, and antibiotics (Cefotaxime and Gentamicin). Computerized tomography (CT) scan on day 3 showed an SDH of 10 mm thickness in the left frontotemporoparietal region.
On day 4 of life, the baby was hemodynamically stable and euglycemic but required continued mechanical ventilation and an increased oxygen requirement. There was also a rising trend in CRP (101 mg/L on day 4) despite changing the antibiotics to Meropenem and Amikacin (Fig. 1). There was conjugated hyperbilirubinemia -total bilirubin of 18.9 mg/dL and direct bilirubin of 2.58 mg/dL.
Considering an antenatal history of maternal SARS-CoV-2 at 32 weeks of gestation, the baby was evaluated for MIS-N. Anti SARS-CoV-2 IgG antibody test was positive (IgG − 4.36- reactive) in the baby. Maternal and neonatal reverse transcription-polymerase chain reaction (RT-PCR) for SARS-CoV-2 were negative. Further investigations revealed elevated inflammatory markers: Lactate dehydrogenase (LDH) -1071 U/L, ferritin-448 ng/ml, and D-dimer-973 ng/ml. Hence the baby was given intravenous immunoglobulin (IVIG - 1 g/kg for 2 days) and methylprednisolone (1 mg/kg every 12 h for 6 days and tapered over 4 days).
The baby improved and the ventilatory requirements were reduced. On day 6, the baby was extubated to room air. The CRP and other inflammatory markers also showed a decreasing trend. An echocardiogram (ECHO) showed prominent left coronaries with aneurysmal dilatation and normal ventricular function (ejection fraction − 77%). Factor 8 was continued targeting 100% levels. Factor 8 inhibitor assay was negative. The intracranial bleed was managed conservatively by the neurosurgery team.
Serial monitoring of laboratory parameters showed an increase in CRP and other inflammatory markers on day 14 (Fig. 1), but the baby continued to improve clinically. However, on day 16 of life, the baby developed seizures and an MRI showed increased bilateral SDH (maximum diameter - 2.3 cm and 0.5 cm on left and right respectively) with a midline-shift to right. There were features suggestive of total brain injury and communicating hydrocephalus. Due to the progression of the intracranial bleed, the baby underwent left parietal craniostomy with subdural hematoma evacuation on day 17 of life. Post-surgery, the seizures were controlled with phenytoin and levetiracetam. The baby was started on breastfeeds. There were no focal neurological deficits. Gene analysis showed a hemizygous intron 22 inversion in the F8 gene on chromosome X (NM_000132.3) confirming Hemophilia A. The baby is now 2-months old and thriving on breast milk alone. He is on factor 8 replacement, is seizure-free on levetiracetam, and is currently under neurodevelopmental follow-up.
