vitamin-k-1 and Abnormalities--Drug-Induced

We have evaluated a boy who had excessive bleeding and bruising from birth and showed markedly prolonged prothrombin times, partially correctable by oral vitamin K administration. Additional laboratory studies demonstrated decreased activities of plasma factors II, VII, IX, and X; near normal levels of immunologically detected and calcium binding-independent prothrombin; undercarboxylation of prothrombin; excess circulating vitamin K epoxide; decreased excretion of carboxylated glutamic acid residues; and abnormal circulating osteocalcin. These results all are consistent with effects resulting from decreased posttranslational carboxylation secondary to an inborn deficiency of vitamin K epoxide reductase. This individual also had nasal hypoplasia, distal digital hypoplasia, and epiphyseal stippling on infant radiographs, all of which are virtually identical to features seen secondary to first-trimester exposure to coumarin derivatives. Therefore, by inference, the warfarin embryopathy is probably secondary to warfarin's primary pharmacologic effect (interference with vitamin K-dependent posttranslational carboxylation of glutamyl residues of various proteins) and may result from undercarboxylation of osteocalcin or other vitamin K-dependent bone proteins.

Topics: 1-Carboxyglutamic Acid; Abnormalities, Drug-Induced; Calcium-Binding Proteins; Child; Chromatography, High Pressure Liquid; Female; Fetal Diseases; Fingers; Humans; Male; Nose; Osteocalcin; Phenotype; Pregnancy; Prothrombin; Radiography; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin

The vitamin K-dependent hemostatic factors are present in reduced quantities at birth and may decrease further in the first few days of life. Administration of vitamin K1 on day 1 prevents hemorrhagic disease of the newborn. Maternal ingestion of anticonvulsants puts the newborn at greater risk from hemorrhage, possibly as a result of induction of fetal microsomal enzymes with a resultant increased oxidative degradation of vitamin K which gives rise to a vitamin K deficiency and other concomitant clinical results, for example skeletal defects. Evidence for this sequence of events is presented and the widespread effect of vitamin K deficiency on the fetus is discussed.

Topics: Abnormalities, Drug-Induced; Animals; Blood Coagulation Factors; Bone and Bones; Chick Embryo; Female; Hemostasis; Humans; Maternal-Fetal Exchange; Microsomes, Liver; Oxidation-Reduction; Phenytoin; Pregnancy; Vitamin K 1; Vitamin K Deficiency; Vitamin K Deficiency Bleeding; Warfarin

Topics: Abnormalities, Drug-Induced; Animals; Bone and Bones; Cleft Lip; Cleft Palate; Dose-Response Relationship, Drug; Embryo Implantation; Embryo, Mammalian; Female; Fetal Death; Hemorrhage; Mice; Mice, Inbred Strains; Placenta Diseases; Pregnancy; Prothrombin Time; Sodium Chloride; Time Factors; Vitamin K; Vitamin K 1; Warfarin