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

Am J Hum Genet. 1987 Oct;41(4):566-83.


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.

Publication types

  • Case Reports
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-Carboxyglutamic Acid / urine
  • Abnormalities, Drug-Induced*
  • Calcium-Binding Proteins / blood
  • Child
  • Chromatography, High Pressure Liquid
  • Female
  • Fetal Diseases / chemically induced
  • Fingers / abnormalities
  • Fingers / diagnostic imaging
  • Humans
  • Male
  • Nose / abnormalities
  • Osteocalcin
  • Phenotype
  • Pregnancy
  • Prothrombin / analysis
  • Radiography
  • Vitamin K / blood
  • Vitamin K / therapeutic use
  • Vitamin K 1 / analogs & derivatives
  • Vitamin K 1 / blood
  • Vitamin K Deficiency / chemically induced
  • Vitamin K Deficiency / congenital*
  • Vitamin K Deficiency / genetics
  • Warfarin / adverse effects*


  • Calcium-Binding Proteins
  • Osteocalcin
  • Vitamin K
  • vitamin K1 oxide
  • 1-Carboxyglutamic Acid
  • Warfarin
  • Vitamin K 1
  • Prothrombin