Intrauterine Subdural Hemorrhage Associated with Profound Deficiency of the Vitamin K Dependent Clotting Factors in an Infant Homozygous for a Common Polymorphism in the Vitamin K Epoxide Reductase Complex 1 (VKORC1) Promoter.
Authors: Schwartz Nadav , Oldenburg Johannes , Hart David , Nardi Michael , Most Ori Langer , Bonanno Clarissa , Timor-Tritsch Ilan T. , Karpatkin Margaret 
Published: April 2020

Hemorrhage in newborn infants who have not received vitamin K supplementation is a well recognized entity, but hemorrhage occurring prenatally due to deficiency of the vitamin K dependent factors is not. We report a subdural hemorrhage in a fetus at 29 weeks of gestation associated with very low levels of vitamin K dependent factors. The pregnancy was monitored by periodic ultrasound because of a previous near term stillbirth to this mother for which no etiology was identified. At 29 weeks a 4.6 × 7.7 × 8.8 cm left subdural hematoma was detected. There is no history of bleeding in this Hispanic family and no known consanguinity. His mother was not taking coumadin or any other medication, and her coagulation studies were normal. The baby was delivered by cesarean section, blood drawn for coagulation studies and 1mg Vitamin K given intramuscularly. The baby oozed from the injection and venipuncture sites. The hematocrit was 19% (mean for gestational age = 40.88) and packed red blood cells were given followed by fresh frozen plasma (10ml/kg). Platelets were 284,000/cmm. At six hours of life coagulation studies were greatly improved, the factor levels now being in the normal range for 29 weeks gestational age. Results at birth, 6 hours and 6 months are shown in the table.

At 6 hours the baby no longer oozed from venipuncture sites. He received 1mg vitamin K daily for 3 days and no further supplementation thereafter other than that contained in infant formula. The subdural hematoma was drained on day 1 of life. Growth and development at 20 months are normal. Complete sequencing of the VKORC1 gene showed a homozygous functional promoter polymorphism: VKORC1:c.[1–1639&gt;A]+[1–1639&gt;A] (VKORC1*2/*2). This A allele is associated with 25% less VKORC1 expression and protein (50% less for homozygotes) compared to the G allele. Complete sequencing of the gamma-glutamyl carboxylase gene revealed no functional abnormalities. Individuals homozygous for this VKORC1 polymorphism have a relatively low capacity to regenerate reduced vitamin K and should require more vitamin K intake than others. They are known to require less warfarin. We hypothesize that insufficient vitamin K was available in utero to this fetus to compensate for the relatively low reductase level, and he became severely factor deficient. In the extra uterine environment sufficient dietary vitamin K was available to compensate for his relatively low reductase level. It is possible that the previous unexplained stillbirth was due to hemorrhage because of a similar factor deficiency. A reason for an intrauterine paucity of vitamin K has not been determined but must be rare as 17% of Europeans and a larger number of Chinese are homozygous VKORC1*2/*2, and intrauterine hemorrhage due to this cause is not reported.

Birth 6 hours 6 months Values in parentheses are ELISA assays. Other assays are functional. nd = not done PT (sec) &gt;120 17.6 13.7 PTT (sec) 176 50.3 35.2 Fibrinogen (mg/dL) 194 196 287 % Factor II 1 39 96 % Factor V 81 nd 116 % Factor VII 3 61 99 % Factor IX 1 nd 108 % Factor X 2 (33) nd 107 % Protein C &lt;1 (18) 27 nd