PERINATAL DEVELOPMENT OF VITAMIN K-DEPENDENT HEMOSTASIS

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Although all neonates are severely Vitamin K deficient at birth by comparison with adults, some will have abnormalities of vitamin K-dependent hemostasis. Our previous work demonstrated the presence of significant concentrations of undercarboxylated and thus, dysfunctional protein C and prothrombin in 3-15% of otherwise healthy term and pre-term neonates at birth. The clinical significance of these findings, especially in pre-term infants, remains to be determined; however, investigation of the mechanisms underlying the production of undercarboxylated vitamin K dependent proteins will improve our understanding of neonatal hemostasis and create a foundation for improved treatment (e.g., possible antenatal maternal vitamin K supplementation). We hypothesize that the neonatal production of abnormal undercarboxylated vitamin K-dependent coagulation proteins is related to the functional activity of the hepatic vitamin K cycle and gamma-glutamyl carboxylase, as well as deficiency of vitamin K1. This proposed investigation is the first attempt to study the relationship between vitamin K metabolism and the production of undercarboxylated proteins. The presence of undercarboxylated vitamin K-dependent proteins (for this project: Protein C, Prothrombin, and Bone Gla Protein) will be determined in 200 paired healthy term neonatal blood samples obtained at birth and at 3 days of life following a 1 mg prophylactic dose of vitamin K1. Vitamin K1, vitamin K1 epoxide and total vitamin K-dependent protein levels will also be measured in these paired samples. Relationships between: 1) the distribution of vitamin K metabolites and the presence of undercarboxylated protein, and 2) the increasing amounts of total vitamin K-dependent protein produced (as a measure of substrate presented to the carboxylase) and the production of abnormal undercarboxylated protein, will be evaluated in the paired samples. Underlying mechanism(s) for the production of undercarboxylated proteins in the neonate can be evaluated by these types of analyses. This study will improve our understanding of the development of vitamin K-dependent hemostasis during a crucial period of rapid change in human development, and provide insight into both normal and impaired response to hemostatic challenges in the perinatal period. The results obtained from this investigation will be important in laying the foundation for improved therapeutic strategies in the future.