Term Infant with Bilateral Parenchymal Brain Hemorrhages.

Abstract

A small-for–gestational age term female neonate born at 38 weeks and 4 days of gestation is transferred to a level 4 NICU at 11 days of age for further evaluation and treatment of bilateral parenchymal brain hemorrhages, culture-negative meningitis, history of thrombocytopenia, coagulopathy, and transaminase elevation. The infant was born via cesarean section to a 31-year-old gravida 2, para 2-0-0-2 healthy mother due to decreased fetal movement and non-reassuring fetal heart tones. The pregnancy was complicated by gestational hypertension and suspected fetal 47,XXX chromosomes. Maternal medications during pregnancy included prenatal vitamins. Maternal prenatal infection screening results were unremarkable. Membranes ruptured at the time of delivery with thick meconium. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. The infant’s birthweight was 2,419 g.Physical examination on admission shows her weight to be 2,580 g (1.33 percentile). She is active and not ill-appearing, with a respiratory rate of 37 breaths/min, heart rate 197 beats/min, temperature 98.2°F (36.8°C), blood pressure of 98/72 mm Hg, and transcutaneous oxygen saturation of 91% in room air. The infant is noted to have a soft systolic murmur, adequate air entry bilaterally, soft non-distended abdomen with absent organomegaly, low central tone, mild extremity hypertonia, and small flat hemangioma on the right abdomen.During her initial NICU hospitalization, a chromosomal abnormality is confirmed. Magnetic resonance imaging of the brain on day 3 after birth shows extensive parenchymal hemorrhages, both ischemic and hemorrhagic in appearance. Serial head ultrasonography shows hemorrhagic progression with concurrently developing hydrocephalus. On day 9 after birth, the infant starts having intermittent episodes of fever. She develops transaminitis (with a maximum alanine aminotransferase of 754 U/L [12.6 μkat/L] and aspartate aminotransferase 444 U/L [7.4 μkat/L], transient with spontaneous improvement) with thrombocytopenia (85 × 103/μL [85 × 109/L]), hyperfibrinogenemia (nadir <69 mg/dL [0.69 g/L]), and elevated international normalized ratio (INR; 1.84). She receives antibiotic therapy for presumptive clinical bacterial meningitis. Blood and cerebrospinal fluid cultures are negative.After transfer to the level 4 NICU, an extensive evaluation for infectious diseases is performed, which includes urine and blood polymerase chain reaction (PCR) for cytomegalovirus, immunoglobulin (Ig) G and IgM testing for lymphocytic choriomeningitis virus, treponemal antibody testing, RNA testing for human immunodeficiency virus, IgA/IgM/IgG testing for Toxoplasma, serum enterovirus testing, parechovirus PCR testing, and serum parvovirus PCR testing. Complete eye examination findings are normal. Initial echocardiography shows a patent foramen ovale versus atrial septal defect. During hospitalization, she has both bleeding and thrombotic complications including a hematoma on the periumbilical abdomen after umbilical venous catheter placement, ecchymosis on her abdominal flanks after lumbar puncture positioning on day 19 after birth, a right renal vein thrombosis (RVT) on day 21, and an extensive purpura in the suprapubic region on day 27 (Fig 1).This case describes progressive coagulopathy in a term female infant with XXX karyotype, with a new skin lesion that developed on day 27 after birth; the NICU course was complicated by bleeding dyscrasia with intraparenchymal bleeding, thrombocytopenia, low fibrinogen, elevated INR, RVT, and bruising on the abdomen with minimal trauma. The differential diagnosis included infections due to group B Streptococcus, meningococcemia, angioinvasive fungi, ecthyma gangrenosum, and necrotizing fasciitis. (1) Hematologic etiologies included protein C (PC) and protein S (PS) deficiencies (collectively termed “neonatal purpura fulminans” [NPF]), antiphospholipid antibody syndrome, disseminated intravascular coagulation (DIC), cryoglobulinemia and vasculitis (antineutrophil cytoplasmic antibody associated and polyarteritis nodosa). (1)(2)The initial differential diagnosis included sepsis with DIC. Given the localization to the abdomen in an area with recent RVT, the second potential etiologic factor was extension of clotting or embolization of the clot into the vasculature supplying the skin overlying the lower abdomen with subsequent infarction. Abdominal ultrasonography showed stable nonocclusive RVT, bladder wall thickening with intraluminal clot, and scattered hepatic calcifications. Vesicles seen in the skin lesions were presumed to be due to edema. However, they were lanced and a fluid specimen obtained for viral and bacterial culture. Additional sepsis evaluation was initiated and the infant was started on broad-spectrum antibiotics with vancomycin and meropenem. After surgical consultation, the infant was transported to the operating room for emergent exploration and biopsy of skin lesion due to the concern for necrotizing fasciitis. Operative findings described underlying fascia as viable and pink. Fresh frozen biopsy sample was reviewed with the pathologist during surgery and showed thrombi through many of the vessels, but lack of a large polymorphonuclear infiltrate, purulence, or grossly seen bacteria. Wound culture was positive for Staphylococcus epidermidis (in broth only). Complete pathology report revealed thrombotic purpura with focal epidermal necrosis and thrombi being composed primarily of dense aggregates of platelets within fibrin, compatible with NPF.Consistent with the histologic findings and her clinical and laboratory findings of coagulopathy, the infant’s PC activity was significantly low (17%) on chromogenic testing. She was diagnosed with NPF, more specifically type 1 PC deficiency. Initially there was concern for balancing the risk and benefits of anticoagulation given parenchymal brain hemorrhages and the pending diagnostic testing for PC deficiency. Genetic testing via next-generation sequencing detected 2 pathologic variants (c.199G>A [p.Glu67Lys] and c.1166G>C [p.Gly389Ala]) in the PROC gene suggestive of compound heterozygous PC deficiency. Parental PC testing found that her father had a borderline low PC level of 60%, suggesting a possible heterozygous PC deficiency.NPF is a rare autosomal recessive and potentially life-threatening condition that may present in the early neonatal period, with PC deficiency being more common than PS deficiency. Mild PC deficiency affects approximately 1 in 500 individuals (3); severe PC deficiency is rare and occurs in an estimated 1 in 4 million newborns. (3) The lower limit of a normal PC level in healthy infants is 25%, (4) but PC levels do not reach normal adult ranges until after puberty. (5) PC (and PS) will also decrease in the setting of acute thrombosis, making levels challenging to interpret at times. Severe PC deficiency is typically associated with PC levels of less than 1% but NPF can be seen with levels less than 20% (4) in the setting of compound heterozygous mutations or type 2 (functional) mutations. (6) Hereditary PC deficiency is an autosomal recessive disorder, caused by a mutation in the PC (PROC) gene located in chromosome 2q14.3. PC is synthesized in the hepatocytes and circulates as a preprotein in low concentrations in the bloodstream. Once PC is activated at the surface of the endothelial cells, it acts as an anticoagulant and an indirect fibrinolytic agent, as described in Fig 2.NPF is a highly prothrombotic state, so early extensive bruising and/or thromboses should raise awareness for this condition. Initial therapy includes anticoagulation (heparin or enoxaparin), potentially fresh frozen plasma (FFP) if suspicion is high, and then once a diagnosis is made, more directed therapy can be included. Long-term treatments include lifelong PC concentrate or FFP as well as long-term anticoagulation. (4)(7)(8) Curative therapy requires liver transplantation. (6)(9)In this case, PC concentrate 25 U/kg was given daily for 4 days, then weaned to an “as needed” basis. PC concentrate replacement was transitioned to FFP infusions on day 44 after birth, as a more accessible long-term treatment option. The patient transitioned off intravenous heparin to enoxaparin sodium on day 58. Coagulation laboratory findings were very closely monitored while receiving daily FFP infusions. No exacerbations of the previous thrombotic and hemorrhagic complications developed and no further hematologic complications occurred during the NICU stay. FFP infusions were then reduced to every 2 days; however, the D-dimer notably rose before the next FFP infusion. Prothrombin fragment (10) was used as a more specific marker for a prothrombotic state, and it continued to remain elevated. The FFP dose required an increase from 10 mL/kg to 15 mL/kg on day 60. She was then safely transitioned to twice-weekly infusions without significant increases in D-dimer or prothrombin fragment. A central venous catheter was placed by pediatric surgery for ongoing infusions, and the infant was discharged from the NICU at age 2.5 months. Her PC levels stabilized near 30% by 5 months of age without further thrombotic events. FFP was discontinued and the central venous catheter was removed at 6 months of age. She continued to receive scheduled enoxaparin.PC deficiency causes a hypercoagulable state due to a predisposition to reduce thrombin generation resulting from inactivation of factors Va and VIIIa. (2).NPF is a rare, potentially life-threatening condition caused by acquired or congenital severe deficiency of PC or PS. The hallmark of NPF is dermal microvascular thrombosis. (1).DIC secondary to infection is a likely cause of acquired PC deficiency in the neonatal population. (1)(2) Once infectious causes are ruled out, a high index of suspicion is needed for a prompt diagnosis and treatment of congenital PC deficiency. (2)(11).Hereditary PC deficiency is caused by a mutation in the PROC gene. Heterozygous and acquired deficiencies are more common than homozygous deficiency. The recommended laboratory test is the PC chromogenic activity assay. (2)(12).It can be challenging to interpret PC levels in infants and genetic testing takes time. Therefore, if there is strong clinical suspicion for PC deficiency, treatment should be initiated urgently.After the neonatal period, individuals who survive may experience recurrent episodes of purpura fulminans. (12) These patients should be treated with intravenous PC concentrates. (4).