Intracranial Bleeding in a Neonate

A late preterm male infant is delivered at 36 weeks’ gestation via the vaginal route. The 30-year-old gravida 3, para 3 woman has gestational diabetes mellitus and is colonized with group B Streptococcus. She receives 1 dose of betamethasone and magnesium sulfate before induction of labor for preeclampsia. The delivery is uncomplicated. Apgar scores are 6 and 7 at 1 and 5 minutes, respectively. The infant receives a 1 mg injection of vitamin K immediately after birth. There is no family history of bleeding disorders. The infant’s birthweight is 2,800 g (Fenton preterm weight: 48th percentile), and length and head circumference are proportional. He is admitted to the NICU shortly after birth with respiratory distress syndrome and requires continuous positive airway pressure at 7 cm H2O with 30% fraction of inspired oxygen and continuous cardiopulmonary monitoring. He is continued on noninvasive ventilation, gradually weaning off at 8 days after birth.While in the NICU, he has an elevated temperature (101.3°F [38.5°C]) 4 days after birth. Blood and cerebrospinal fluid (CSF) cultures are obtained. The infant’s complete blood cell count is normal. Treatment is started with ampicillin, gentamicin, and acyclovir, but he shows no clinical signs of improvement, though his vital signs are otherwise normal. He tolerates full enteral feeds of formula and human milk. To evaluate for central causes of temperature instability, head ultrasonography is performed 6 days after birth, which reveals bilateral grade III intraventricular hemorrhage (IVH) with mild ventricular dilation. Magnetic resonance imaging (MRI) of the brain reveals multiple bleeding sites, including a small infratentorial subdural and a supratentorial subarachnoid hemorrhage (Fig 1).A hematologic laboratory profile is obtained (Table). Blood and CSF cultures show no growth. He is referred to pediatric hematology-oncology for further evaluation.Infections, hemorrhagic disease of the newborn, disseminated intravascular coagulation, clotting disorders, bleeding disorders, and arteriovenous malformations or vascular tumors (including Kasabach-Merritt syndrome) are all considered in this infant with spontaneous IVH. However, many of these conditions are unlikely due to the negative blood and CSF cultures, vitamin K administration at birth, lack of family history of bleeding or clotting disorders, and normal hematologic profile.In the setting of a spontaneous bilateral grade III IVH not explained by lack of arteriovenous malformation on the MRI scan and a normal screening coagulation profile, consultation with hematology is warranted. Although rare and autosomal recessive, factor XIII (FXIII) deficiency is considered in this patient. FXIII deficiency can present with intracranial bleeding in neonates. Unlike other factor deficiencies, patients with FXIII deficiency have a normal prothrombin time (PT) and partial thromboplastin time (PTT) since FXIII is involved in fibrin clot stabilization rather than the formation of the fibrin clot itself (Fig 2). Despite the lack of family history, lack of other signs of bleeding, and the rarity of the disease, clinical suspicion is highest for FXIII deficiency given the patient’s laboratory findings and presentation.Blood samples are sent for investigation of FXIII deficiency. Initial hematology results are suggestive of congenital FXIII deficiency with a factor level of 15% (normal: 57%−192%). Patients with FXIII levels higher than 5% typically have a mild phenotype without spontaneous bleeding episodes. The severity of this patient’s symptoms is not mirrored by an equally severe factor deficiency, which is unusual. A patient with a factor level of 15% would typically experience poor wound healing and more significant bleeding with trauma or surgery, rather than an unprovoked bilateral IVH.FXIII is known as the “protein fibrin stabilizing factor,” and its role is to cross-link fibrin monomers within fibrin clots to increase structural integrity. (1)(2) FXIII also plays a role in wound healing and tissue repair. Deficiency can result from autosomal recessive–inherited mutations in either of the enzyme’s 2 subunits, FXIII-A or FXIII-B, though deficiency of FXIII-A represents 95% of cases and is generally more severe than FXIII-B deficiency. (3) The FXIII-A gene is located on chromosome 6p24-p25, and 153 mutations have been reported. (4) The FXIII-B gene is located on chromosome 1q31-32.1, and 16 mutations have been reported. (5) FXIII deficiency has an incidence of 1 in 3,000,000 to 5,000,000 in the United States and affects all sexes, races, and ethnicities equally. (2)(6)The phenotype severity of FXIII deficiency is generally inversely proportional to the factor level. Most symptomatic patients have a factor level below 30%. Umbilical cord bleeding after birth is common, occurring in ∼80% of symptomatic congenital cases. Intracranial bleeding is a relatively common presentation (∼30% of cases), especially with vaginal delivery, but this presentation usually only occurs with a factor level below 5%. (2) Unusual or unprovoked bleeding in neonates, especially intracranial and umbilical cord bleeding, warrants an evaluation for inherited disorders.Because PT and PTT are usually normal, a high clinical suspicion is necessary for further evaluation after normal coagulation studies to correctly diagnose this rare condition. The diagnosis is reached when detecting low FXIII activity using a quantitative functional FXIII activity assay.Intracranial hemorrhage is the most common cause of death in patients with untreated FXIII deficiency, but with timely diagnosis and prophylactic treatment with factor replacement, patients have normal life expectancy. (7) Generally, patients with a factor level above 5% do not experience spontaneous bleeding but can have significant bleeding during surgery or trauma. Prophylactic treatment with factor replacement is recommended for patients with mild-to-severe FXIII deficiency. Cryoprecipitate is the most widely available treatment and contains 20% to 30% of the original plasma levels of FXIII. (8) Fresh frozen plasma (FFP) is another widely available treatment but is used less often for prophylaxis. The disadvantages of cryoprecipitate and FFP are that they have an increased risk of allergic reactions and there exists a risk of bloodborne pathogen exposure, but these are often the only available treatment. (9) Virus-inactivated FXIII concentrate from pooled donor plasma contains both factor subunits and can be used universally for replacement therapy. Cortifact (CSL Behring, King of Prussia, PA) is an FDA-approved human FXIII concentrate. (10)The patient was monitored in the NICU while samples were sent for hematologic investigation. Repeat head ultrasonography revealed a maintained bilateral IVH with mildly increasing ventricular dilation. Neurosurgery was consulted, but no urgent intervention was needed. Following collaboration with national experts in FXIII deficiency, a more aggressive FXIII concentrate replacement therapy regimen was initiated due to the severe bleeding event. This consisted of intravenous 40 IU/kg every 2 weeks compared to a typical 4 to 6 weeks for deficiencies greater than 5%. Repeat FXIII measurements after replacement therapy were 96% and 141% and were associated with rapid improvement in his clinical condition.In the setting of severe bleeding not explained by basic coagulation studies, FXIII deficiency should be considered even in the absence of a family history or other bleeding symptoms.In addition to umbilical stump bleeding, a more typical presentation, infants with FXIII deficiency can present with spontaneous intraventricular bleeding in isolation.If appropriately recognized and treated, patients with FXIII deficiency can live normal lives.