Hereditary Deficiency of Vitamin K-dependent Coagulation Factors

Abstract

γ-Glutamyl carboxylation is a post-translational modification essential for the activity of the vitamin K dependent coagulation factors II, VII, IX, X, protein C and protein S. This carboxylation is required for normal haemostasis, because it enables calcium binding and attachment of the procoagulants and anticoagulants to phospholipids (Fig. 1A). Proteins in other tissues also undergo carboxylation including the bone Gla protein osteocalcin, matrix Gla protein and the growth arrest specific protein, gas-6. During the carboxylation reaction vitamin K hydroquinone is converted to vitamin K 2,3 epoxide which is then reduced back to vitamin K hydroquinone by the microsomal enzyme vitamin K 2,3 epoxide reductase (VKOR). Vitamin K deficiency and treatment with vitamin K antagonists are the two common acquired causes for a decrease of vitamin K dependent coagulation factors. Inherited deficiency of vitamin K dependent coagulation factors is a rare bleeding disorder reported only in a few patients (2-7). Bleeding manifestations differ among affected individuals and are usually correlated with procoagulant factor levels. Life-threatening umbilical and central nervous system bleeding may occur due to a combined effect of the inherited deficiency and lack of vitamin K in affected neonates. Hemorrhagic manifestations in childhood may include hemarthrosis and mucocutaneous bleeding and are often associated with infections and antibiotic therapy, which result in vitamin K deficiency. Skeletal abnormalities suggesting an effect on bone Gla-proteins have been reported in some probands. Autosomal recessive mode of inheritance was documented, and consanguinity was observed in several of the reported families. Human γ-glutamyl carboxylase cDNA has recently been isolated and sequenced. It contains an open reading frame of 2274 nucleotides encoding a 758-amino-acid polypeptide chain. The gene is located at 2pl.2, spans about 13 kb, and contains 15 exons. These developments hastened efforts directed for delineation of the molecular basis of inherited deficiency of vitamin K-dependent coagulation factors.