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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1987 Oct;41(4):566–583.

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.

R M Pauli 1, J B Lian 1, D F Mosher 1, J W Suttie 1
PMCID: PMC1684308  PMID: 3499071

Abstract

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bechtold H., Trenk D., Jähnchen E., Meinertz T. Plasma vitamin K1-2,3-epoxide as diagnostic aid to detect surreptitious ingestion of oral anticoagulant drug. Lancet. 1983 Mar 12;1(8324):596–597. doi: 10.1016/s0140-6736(83)92852-0. [DOI] [PubMed] [Google Scholar]
  2. Becker M. H., Genieser N. B., Finegold M., Miranda D., Spackman T. Chondrodysplasis punctata: is maternal warfarin therapy a factor? Am J Dis Child. 1975 Mar;129(3):356–359. doi: 10.1001/archpedi.1975.02120400056013. [DOI] [PubMed] [Google Scholar]
  3. Blanchard R. A., Furie B. C., Jorgensen M., Kruger S. F., Furie B. Acquired vitamin K-dependent carboxylation deficiency in liver disease. N Engl J Med. 1981 Jul 30;305(5):242–248. doi: 10.1056/NEJM198107303050502. [DOI] [PubMed] [Google Scholar]
  4. Blanchard R. A., Furie B. C., Kruger S. F., Waneck G., Jorgensen M. J., Furie B. Immunoassays of human prothrombin species which correlate with functional coagulant activities. J Lab Clin Med. 1983 Feb;101(2):242–255. [PubMed] [Google Scholar]
  5. Bleyer W. A., Hakami N., Shepard T. H. The development of hemostasis in the human fetus and newborn infant. J Pediatr. 1971 Nov;79(5):838–853. doi: 10.1016/s0022-3476(71)80405-5. [DOI] [PubMed] [Google Scholar]
  6. Chong M. K., Harvey D., de Swiet M. Follow-up study of children whose mothers were treated with warfarin during pregnancy. Br J Obstet Gynaecol. 1984 Nov;91(11):1070–1073. doi: 10.1111/j.1471-0528.1984.tb15077.x. [DOI] [PubMed] [Google Scholar]
  7. Chung K. S., Bezeaud A., Goldsmith J. C., McMillan C. W., Ménaché D., Roberts H. R. Congenital deficiency of blood clotting factors II, VII, IX, and X. Blood. 1979 Apr;53(4):776–787. [PubMed] [Google Scholar]
  8. Davie E. W., Fujikawa K. Basic mechanisms in blood coagulation. Annu Rev Biochem. 1975;44:799–829. doi: 10.1146/annurev.bi.44.070175.004055. [DOI] [PubMed] [Google Scholar]
  9. Delmas P. D., Tracy R. P., Riggs B. L., Mann K. G. Identification of the noncollagenous proteins of bovine bone by two-dimensional gel electrophoresis. Calcif Tissue Int. 1984 May;36(3):308–316. doi: 10.1007/BF02405335. [DOI] [PubMed] [Google Scholar]
  10. Fasco M. J., Hildebrandt E. F., Suttie J. W. Evidence that warfarin anticoagulant action involves two distinct reductase activities. J Biol Chem. 1982 Oct 10;257(19):11210–11212. [PubMed] [Google Scholar]
  11. Gallop P. M., Lian J. B., Hauschka P. V. Carboxylated calcium-binding proteins and vitamin K. N Engl J Med. 1980 Jun 26;302(26):1460–1466. doi: 10.1056/NEJM198006263022608. [DOI] [PubMed] [Google Scholar]
  12. Ganrot P. O., Niléhn J. E. Plasma prothrombin during treatment with Dicumarol. II. Demonstration of an abnormal prothrombin fraction. Scand J Clin Lab Invest. 1968;22(1):23–28. [PubMed] [Google Scholar]
  13. Goldsmith G. H., Jr, Pence R. E., Ratnoff O. D., Adelstein D. J., Furie B. Studies on a family with combined functional deficiencies of vitamin K-dependent coagulation factors. J Clin Invest. 1982 Jun;69(6):1253–1260. doi: 10.1172/JCI110564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gundberg C. M., Hauschka P. V., Lian J. B., Gallop P. M. Osteocalcin: isolation, characterization, and detection. Methods Enzymol. 1984;107:516–544. doi: 10.1016/0076-6879(84)07036-1. [DOI] [PubMed] [Google Scholar]
  15. Gundberg C. M., Lian J. B., Gallop P. M. Measurements of gamma-carboxyglutamate and circulating osteocalcin in normal children and adults. Clin Chim Acta. 1983 Feb 28;128(1):1–8. doi: 10.1016/0009-8981(83)90049-9. [DOI] [PubMed] [Google Scholar]
  16. Gundberg C. M., Lian J. B., Gallop P. M., Steinberg J. J. Urinary gamma-carboxyglutamic acid and serum osteocalcin as bone markers: studies in osteoporosis and Paget's disease. J Clin Endocrinol Metab. 1983 Dec;57(6):1221–1225. doi: 10.1210/jcem-57-6-1221. [DOI] [PubMed] [Google Scholar]
  17. Hall J. G., Pauli R. M., Wilson K. M. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med. 1980 Jan;68(1):122–140. doi: 10.1016/0002-9343(80)90181-3. [DOI] [PubMed] [Google Scholar]
  18. Hauschka P. V., Lian J. B., Gallop P. M. Direct identification of the calcium-binding amino acid, gamma-carboxyglutamate, in mineralized tissue. Proc Natl Acad Sci U S A. 1975 Oct;72(10):3925–3929. doi: 10.1073/pnas.72.10.3925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hauschka P. V., Reid M. L. Timed appearance of a calcium-binding protein containing gamma-carboxyglutamic acid in developing chick bone. Dev Biol. 1978 Aug;65(2):426–434. doi: 10.1016/0012-1606(78)90038-6. [DOI] [PubMed] [Google Scholar]
  20. Johnson C. A., Chung K. S., McGrath K. M., Bean P. E., Roberts H. R. Characterization of a variant prothrombin in a patient congenitally deficient in factors II, VII, IX and X. Br J Haematol. 1980 Mar;44(3):461–469. doi: 10.1111/j.1365-2141.1980.tb05916.x. [DOI] [PubMed] [Google Scholar]
  21. Kort H. I., Cassel G. A. An appraisal of warfarin therapy during pregnancy. S Afr Med J. 1981 Oct 10;60(15):578–579. [PubMed] [Google Scholar]
  22. Laurell C. B. Electroimmuno assay. Scand J Clin Lab Invest Suppl. 1972;124:21–37. doi: 10.3109/00365517209102748. [DOI] [PubMed] [Google Scholar]
  23. Levy R. J., Lian J. B. gamma-Carboxyglutamate excretion and warfarin therapy. Clin Pharmacol Ther. 1979 May;25(5 Pt 1):562–570. doi: 10.1002/cpt1979255part1562. [DOI] [PubMed] [Google Scholar]
  24. Lian J. B., Roufosse A. H., Reit B., Glimcher M. J. Concentrations of osteocalcin and phosphoprotein as a function of mineral content and age in cortical bone. Calcif Tissue Int. 1982;34 (Suppl 2):S82–S87. [PubMed] [Google Scholar]
  25. McMillan C. W., Roberts H. R. Congenital combined deficiency of coagulation factors II, VII, IX and X. Report of a case. N Engl J Med. 1966 Jun 9;274(23):1313–1315. doi: 10.1056/NEJM196606092742309. [DOI] [PubMed] [Google Scholar]
  26. Melick R. A., Farrugia W., Quelch K. J. Plasma osteocalcin in man. Aust N Z J Med. 1985 Aug;15(4):410–416. doi: 10.1111/j.1445-5994.1985.tb02761.x. [DOI] [PubMed] [Google Scholar]
  27. NEWCOMB T., MATTER M., CONROY L., DEMARSH Q. B., FINCH C. A. Congenital hemorrhagic diathesis of the prothrombin complex. Am J Med. 1956 May;20(5):798–805. doi: 10.1016/0002-9343(56)90163-2. [DOI] [PubMed] [Google Scholar]
  28. Nishimoto S. K., Price P. A. Secretion of the vitamin K-dependent protein of bone by rat osteosarcoma cells. Evidence for an intracellular precursor. J Biol Chem. 1980 Jul 25;255(14):6579–6583. [PubMed] [Google Scholar]
  29. O'Neill H., Blake S., Sugrue D., Macdonald D. Problems in the management of patients with artificial valves during pregnancy. Br J Obstet Gynaecol. 1982 Nov;89(11):940–943. doi: 10.1111/j.1471-0528.1982.tb05062.x. [DOI] [PubMed] [Google Scholar]
  30. Oakley C. Pregnancy in patients with prosthetic heart valves. Br Med J (Clin Res Ed) 1983 May 28;286(6379):1680–1682. doi: 10.1136/bmj.286.6379.1680. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pauli R. M., Madden J. D., Kranzler K. J., Culpepper W., Port R. Warfarin therapy initiated during pregnancy and phenotypic chondrodysplasia punctata. J Pediatr. 1976 Mar;88(3):506–508. doi: 10.1016/s0022-3476(76)80281-8. [DOI] [PubMed] [Google Scholar]
  32. Pettifor J. M., Benson R. Congenital malformations associated with the administration of oral anticoagulants during pregnancy. J Pediatr. 1975 Mar;86(3):459–462. doi: 10.1016/s0022-3476(75)80986-3. [DOI] [PubMed] [Google Scholar]
  33. Price P. A., Nishimoto S. K. Radioimmunoassay for the vitamin K-dependent protein of bone and its discovery in plasma. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2234–2238. doi: 10.1073/pnas.77.4.2234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Price P. A., Otsuka A. A., Poser J. W., Kristaponis J., Raman N. Characterization of a gamma-carboxyglutamic acid-containing protein from bone. Proc Natl Acad Sci U S A. 1976 May;73(5):1447–1451. doi: 10.1073/pnas.73.5.1447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Price P. A., Urist M. R., Otawara Y. Matrix Gla protein, a new gamma-carboxyglutamic acid-containing protein which is associated with the organic matrix of bone. Biochem Biophys Res Commun. 1983 Dec 28;117(3):765–771. doi: 10.1016/0006-291x(83)91663-7. [DOI] [PubMed] [Google Scholar]
  36. Price P. A., Williamson M. K. Effects of warfarin on bone. Studies on the vitamin K-dependent protein of rat bone. J Biol Chem. 1981 Dec 25;256(24):12754–12759. [PubMed] [Google Scholar]
  37. Riggs B. L., Tsai K. S., Mann K. G. Effect of acute increases in bone matrix degradation on circulating levels of bone-Gla protein. J Bone Miner Res. 1986 Dec;1(6):539–542. doi: 10.1002/jbmr.5650010608. [DOI] [PubMed] [Google Scholar]
  38. Shah D. V., Swanson J. C., Suttie J. W. Abnormal prothrombin in the vitamin K-deficient rat. Thromb Res. 1984 Aug 15;35(4):451–458. doi: 10.1016/0049-3848(84)90236-6. [DOI] [PubMed] [Google Scholar]
  39. Shah D. V., Tews J. K., Harper A. E., Suttie J. W. Metabolism and transport of gamma-carboxyglutamic acid. Biochim Biophys Acta. 1978 Mar 1;539(2):209–217. doi: 10.1016/0304-4165(78)90007-7. [DOI] [PubMed] [Google Scholar]
  40. Shaul W. L., Emery H., Hall J. G. Chondrodysplasia punctata and maternal warfarin use during pregnancy. Am J Dis Child. 1975 Mar;129(3):360–362. doi: 10.1001/archpedi.1975.02120400060014. [DOI] [PubMed] [Google Scholar]
  41. Shearer M. J., Rahim S., Barkhan P., Stimmler L. Plasma vitamin K1 in mothers and their newborn babies. Lancet. 1982 Aug 28;2(8296):460–463. doi: 10.1016/s0140-6736(82)90493-7. [DOI] [PubMed] [Google Scholar]
  42. Sheffield L. J., Danks D. M., Mayne V., Hutchinson A. L. Chondrodysplasia punctata-23 cases of a mild and relatively common variety. J Pediatr. 1976 Dec;89(6):916–923. doi: 10.1016/s0022-3476(76)80596-3. [DOI] [PubMed] [Google Scholar]
  43. Soff G. A., Levin J. Familial multiple coagulation factor deficiencies. I. Review of the literature: Differentiation of single hereditary disorders associated with multiple factor deficiencies from coincidental concurrence of single factor deficiency states. Semin Thromb Hemost. 1981 Fall;7(2):112–148. doi: 10.1055/s-2007-1005073. [DOI] [PubMed] [Google Scholar]
  44. Ueno T., Suttie J. W. High-pressure liquid chromatographic-reductive electrochemical detection analysis of serum trans-phylloquinone. Anal Biochem. 1983 Aug;133(1):62–67. doi: 10.1016/0003-2697(83)90222-1. [DOI] [PubMed] [Google Scholar]

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