Transient Protein C Deficiency in an Infant with Factor V Leiden Heterozygous Mutation: a Rare Subgroup of Neonatal Purpura Fulminans

Case:

A Caucasian male infant, born at 39 weeks and 2 days was assessed at 7 hours of life for new onset purpuric changes in toes 1-2, and 5 of the right foot. The course of the pregnancy was complicated by a fetal cardiac mass seen on ultrasound, thus requiring a C-section. Initial course of delivery was complicated by chorioamnionitis due to maternal fever. The patient's mother was treated appropriately with antibiotics prior to delivery. After delivery, APGAR scores were 9/9/9. At day 6 of life, there was progressive discoloration of the R. foot digits 1,2,3, and 5, disproportionate to the general acrocyanosis of the rest of the body. NICU was consulted and he was promptly transferred. Initial examination showed good pulses and oxygenation of the involved limb. No other areas of disproportionate discoloration were seen.

Initial evaluation included arterial and venous duplex studies. Each exam showed no evidence of decreased blood flow. Pediatric hematology and vascular surgery were consulted. Per vascular surgery recommendations an aortic duplex was obtained, showing no evidence of thrombosis. Due to clinical picture of purpuric digits, Neonatal Purpura Fulminans was strongly suspected. Initial lab work obtained showed a WBC of 20.5, Hgb/Hct 18.2/55.4, and a platelet count of 196,000. Initial fibrinogen was undetectable. PTT and PT/INR were unable to be obtained. Protein S and Protein C Levels were drawn prior to any intervention. Initial Protein S level was 35%, and initial Protein C level was <20%. After intervention, Protein C levels were redrawn on day 4 of life, and shown to be 48%

Due to the initial lab work obtained, the patient was initially started on Fresh Frozen Plasma 20 ml/kg, and Low Molecular Weight Heparin 1.5 mg/kg q 12 hrs. Nitroglycerin paste was applied to the R. foot and toes. After Protein C levels returned undetectable, the patient was switched from FFP to protein C concentrate, (100 U/kg q12h). Warfarin was started on day 3 of life, for transition to long term anticoagulation, with a titration to goal INR of 2.5-3.0. During hospitalization, CT head w/o contrast, and a kidney ultrasound were ordered and seen to be normal. An ophthalmologic examination was also done on day 4 of life, and showed no retinal or vitreous hemorrhage. Following normal screening lab work, and proper transition to Warfarin therapy for outpatient management, patient was discharged home on day 14 of life, with close follow with hematology and genetics. Patient was discharged home on Warfarin 2 mg daily, with a goal INR >2.2.

The patient was followed by pediatric hematology after discharge. A second opinion was sought at an outside hospital, at which time patient was trialed off of Warfarin. Genetic studies showed a heterozygous mutation for Factor V Leiden R506Q polymorphism, with normal protein C levels after a trial off of Warfarin, making inherited Protein C deficiency less likely.

Discussion:

Neonatal Purpura Fulminans is a rare disorder that can be either acquired or inherited. The differential diagnosis for acquired protein C deficiency is vast, ranging from infectious causes with and without DIC, hypoxia, severe hepatic dysfunction, and severe congenital heart disease. Congenital forms of protein C deficiency are generally homozygous. However, the clinician should be aware of the possibility of Factor V Leiden heterozygous mutation causing activated protein C resistance and acquired protein C deficiency in infancy. The concern in this specific case was that the infant may have otherwise been considered to have inherited protein C deficiency until genetic testing revealed otherwise. While waiting for genetic testing results, the infant was carefully monitored on oral anticoagulation. While these measures were taken and helped to prevent thrombosis, no official guidelines are in place for surveillance, treatment, or testing frequency of Protein C levels in infancy. To date, only one other case of Neonatal Purpura Fulminans in association with Factor V R506Q mutation has been reported. In this case, the authors concluded that activated protein C resistance should be included in the evaluation of Neonatal Purpura Fulminans. We hope to build on the existing management guidelines in order to more promptly identify infants with Neonatal Purpura Fulminans and transient protein C deficiency.