Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of the warfarin embryopathy: clues to the mechanism of teratogenicity of coumarin derivatives.
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.
D015055:1-Carboxyglutamic Acid / Q000652:urine; D000014:Abnormalities, Drug-Induced; D002135:Calcium-Binding Proteins / Q000097:blood; D002648:Child; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced; D005385:Fingers / Q000002:abnormalities / Q000000981:diagnostic imaging; D006801:Humans; D008297:Male; D009666:Nose / Q000002:abnormalities; D015675:Osteocalcin; D010641:Phenotype; D011247:Pregnancy; D011516:Prothrombin / Q000032:analysis; D011859:Radiography; D014812:Vitamin K / Q000097:blood / Q000627:therapeutic use; D010837:Vitamin K 1 / Q000031:analogs & derivatives / Q000097:blood; D014813:Vitamin K Deficiency / Q000139:chemically induced / Q000151:congenital* / Q000235:genetics; D014859:Warfarin / Q000009:adverse effects*
D002135:Calcium-Binding Proteins; D015675:Osteocalcin; D014812:Vitamin K; C016186:vitamin K1 oxide; D015055:1-Carboxyglutamic Acid; D014859:Warfarin; D010837:Vitamin K 1; D011516:Prothrombin