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...

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Bibliographic Details
Published in:American journal of human genetics 1987-10, Vol.41 (4), p.566-583
Main Authors: PAULI, R. M, LIAN, J. B, MOSHER, D. F, SUTTIE, J. W
Format: Article
Language:English
Subjects:
1-Carboxyglutamic Acid - urine
Abnormalities, Drug-Induced
Biological and medical sciences
Calcium-Binding Proteins - blood
Child
Chromatography, High Pressure Liquid
Drug toxicity and drugs side effects treatment
Female
Fetal Diseases - chemically induced
Fingers - abnormalities
Fingers - diagnostic imaging
Humans
Male
Medical sciences
Miscellaneous (drug allergy, mutagens, teratogens...)
Nose - abnormalities
Osteocalcin
Pharmacology. Drug treatments
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
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Summary: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.
ISSN:0002-9297
1537-6605