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. 1969 Dec;48(12):2251–2259. doi: 10.1172/JCI106191

Congenital dysprothrombinemia: an inherited structural disorder of human prothrombin

Sandor S Shapiro 1, Jose Martinez 1, Ruth R Holburn 1
PMCID: PMC297482  PMID: 5355338

Abstract

A large family has been studied, 11 of whose members have half-normal plasma concentrations of biological prothrombin activity. The pattern of inheritance is autosomal. By use of a specific immunoassay, affected family members have been shown to possess normal quantities of immunoreactive prothrombin, whose immunologic properties seem identical with those of the normal zymogen. Prothrombin isolation from the plasma of one such individual gave normal yields of protein but half-normal amounts of prothrombin activity. Activation of this material in the “intrinsic” and “extrinsic” systems, in concentrated sodium citrate, or by trypsin, gives rise to half, or less, of the thrombin clotting and esterase activities expected from a comparable normal prothrombin preparation. During the clotting of blood from an affected individual, all material with the mobility of prothrombin disappears. Immunoelectrophoresis of the serum reveals a normal nonthrombin “pro piece,” and an additional activation product with an electrophoretic mobility intermediate between that of prothrombin and of “pro piece.” These results suggest that affected individuals are heterozygotes in whom half the prothrombin molecules synthesized are structurally abnormal, since they undergo some alterations during activation, but are incapable of releasing the active enzyme, thrombin.

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Selected References

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

  1. Arnon R., Shapira E. Antibodies to papain. A selective fractionation according to inhibitory capacity. Biochemistry. 1967 Dec;6(12):3942–3950. doi: 10.1021/bi00864a041. [DOI] [PubMed] [Google Scholar]
  2. Aronson D. L., Ménaché D. Chromatographic analysis of the activation of human prothrombin with human thrombokinase. Biochemistry. 1966 Aug;5(8):2635–2640. doi: 10.1021/bi00872a022. [DOI] [PubMed] [Google Scholar]
  3. BARNHART M. I., ANDERSON G. F., BAKER W. J. Immunochemical studies on proteins important in blood coagulation. Thromb Diath Haemorrh. 1962 Oct 1;8:21–36. [PubMed] [Google Scholar]
  4. BORCHGREVINK C. F., EGEBERG O., POOL J. G., SKULASON T., STORMORKEN H., WAALER B. A study of a case of congenital hypoprothrombinaemia. Br J Haematol. 1959 Jul;5:294–301. doi: 10.1111/j.1365-2141.1959.tb04037.x. [DOI] [PubMed] [Google Scholar]
  5. Beighton P. X-linked recessive inheritance in the Ehlers-Danlos syndrome. Br Med J. 1968 Aug 17;3(5615):409–411. doi: 10.1136/bmj.3.5615.409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Blombäck M., Blombäck B., Mammen E. F., Prasad A. S. Fibrinogen Detroit--a molecular defect in the N-terminal disulphide knot of human fibrinogen? Nature. 1968 Apr 13;218(5137):134–137. doi: 10.1038/218134a0. [DOI] [PubMed] [Google Scholar]
  7. Childs B., Der Kaloustian V. M. Genetic heterogeneity. N Engl J Med. 1968 Nov 28;279(22):1205–contd. doi: 10.1056/NEJM196811282792206. [DOI] [PubMed] [Google Scholar]
  8. DAY H. J., ZARAFONETIS C. J. Coagulation studies in four patients with Ehlers-Danlos syndrome. Am J Med Sci. 1961 Nov;242:565–573. [PubMed] [Google Scholar]
  9. DEBASTOS O., RENO R. S., CORREA O. T. A STUDY OF THREE CASES OF FAMILIAL CONGENITAL HYPOPROTHROMBINAEMIA (FACTOR II DEFICIENCY). Thromb Diath Haemorrh. 1964 Jul 31;11:497–505. [PubMed] [Google Scholar]
  10. Denson K. W., Biggs R., Mannucci P. M. An investigation of three patients with Christmas disease due to an abnormal type of factor IX. J Clin Pathol. 1968 Mar;21(2):160–165. doi: 10.1136/jcp.21.2.160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. EHRENPREIS S., SCHERAGA H. A. Observations on the analysis for thrombin and the inactivation of fibrin monomer. J Biol Chem. 1957 Aug;227(2):1043–1061. [PubMed] [Google Scholar]
  12. ELLIS B. C., STRANSKY A. A quick and accurate method for the determination of fibronogen in plasma. J Lab Clin Med. 1961 Sep;58:477–488. [PubMed] [Google Scholar]
  13. Egeberg O. Inherited fibrinogen abnormality causing thrombophilia. Thromb Diath Haemorrh. 1967 Feb 28;17(1-2):176–187. [PubMed] [Google Scholar]
  14. FANTL P., MARR A. G., SAWERS R. J. Investigation of a haemorrhagic disease due to beta-prothromboplastin deficiency complicated by a specific inhibitor of thromboplastin formation. Australas Ann Med. 1956 Aug;5(3):163–176. doi: 10.1111/imj.1956.5.3.163. [DOI] [PubMed] [Google Scholar]
  15. Feinstein D., Chong M. N., Kasper C. K., Rapaport S. I. Hemophilia A: polymorphism detectable by a factor 8 antibody. Science. 1969 Mar 7;163(3871):1071–1072. doi: 10.1126/science.163.3871.1071. [DOI] [PubMed] [Google Scholar]
  16. Forman W. B., Ratnoff O. D., Boyer M. H. An inherited qualitative abnormality in plasma fibrinogen: fibrinogen Cleveland. J Lab Clin Med. 1968 Sep;72(3):455–472. [PubMed] [Google Scholar]
  17. GOUDEMAND M., FOUCAUT M., HUTIN A., PARQUET-GERNEZ A. LES ANTICOAGULANTS CIRCULANTS ANTI-FACTEUR VIII AU COURS DE L'H'EMOPHILIE A (NATURE ET M'ECANISME D'ACTION.) Nouv Rev Fr Hematol. 1963 Nov-Dec;3:703–722. [PubMed] [Google Scholar]
  18. Ganrot P. O., Niléhn J. E. Immunochemical determination of human prothrombin. Scand J Clin Lab Invest. 1968;21(3):238–244. doi: 10.3109/00365516809076990. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. HASSELBACK R., MARION R. B., THOMAS J. W. Congenital hypofibrinogenemia in five members of a family. Can Med Assoc J. 1963 Jan 5;88:19–22. [PMC free article] [PubMed] [Google Scholar]
  21. Harris H. Enzyme and protein polymorphism in human populations. Br Med Bull. 1969 Jan;25(1):5–13. doi: 10.1093/oxfordjournals.bmb.a070670. [DOI] [PubMed] [Google Scholar]
  22. Hoyer L. W., Breckenridge R. T. Immunologic studies of antihemophilic factor (AHF, factor VIII): cross-reacting material in a genetic variant of hemophilia A. Blood. 1968 Dec;32(6):962–971. [PubMed] [Google Scholar]
  23. JOSSO F., PROU-WARTELLE O., SOULIER J. P. [Study of a case of congenital hypoprothrombinemia]. Nouv Rev Fr Hematol. 1962 Sep-Oct;2:647–672. [PubMed] [Google Scholar]
  24. Josso F., Lavergne J. M., Weilland C., Soulier J. P. Etude immunologique de la prothrombine et de la thrombine humaines. Thromb Diath Haemorrh. 1967 Dec 31;18(3-4):311–324. [PubMed] [Google Scholar]
  25. Kerr C. B. Genetics of human blood coagulation. J Med Genet. 1965 Dec;2(4):254–303. doi: 10.1136/jmg.2.4.254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. LANCHANTIN G. F., FRIEDMANN J. A., DEGROOT J., MEHL J. W. Preparation of human plasma prothrombin and some of its sedimentation properties. J Biol Chem. 1963 Jan;238:238–243. [PubMed] [Google Scholar]
  27. Lanchantin G. F., Hart D. W., Friedmann J. A., Saavedra N. V., Mehl J. W. Amino acid composition of human plasma prothrombin. J Biol Chem. 1968 Oct 25;243(20):5479–5485. [PubMed] [Google Scholar]
  28. Laurell C. B. Quantitative estimation of proteins by electrophoresis in agarose gel containing antibodies. Anal Biochem. 1966 Apr;15(1):45–52. doi: 10.1016/0003-2697(66)90246-6. [DOI] [PubMed] [Google Scholar]
  29. MILLER K. D. Chromatographic isolation of plasma prothrombin and t trans-alpha-glucosylase. J Biol Chem. 1958 Apr;231(2):987–995. [PubMed] [Google Scholar]
  30. Mammen E. F., Prasad A. S., Barnhart M. I., Au C. C. Congenital dysfibrinogenemia: fibrinogen Detroit. J Clin Invest. 1969 Feb;48(2):235–249. doi: 10.1172/JCI105980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. POOL J. G., DESAI R., KROPATKIN M. Severe congenital hypoprothrombinemia in a Negro boy. Thromb Diath Haemorrh. 1962 Nov 15;8:235–240. [PubMed] [Google Scholar]
  32. QUICK A. J., HUSSEY C. V. Hereditary hypoprothrombinaemias. Lancet. 1962 Jan 27;1(7222):173–177. doi: 10.1016/s0140-6736(62)91073-5. [DOI] [PubMed] [Google Scholar]
  33. QUICK A. J., PISCIOTTA A. V., HUSSEY C. V. Congenital hypoprothrombinemic states. AMA Arch Intern Med. 1955 Jan;95(1):2–14. doi: 10.1001/archinte.1955.00250070018002. [DOI] [PubMed] [Google Scholar]
  34. Roberts H. R., Grizzle J. E., McLester W. D., Penick G. D. Genetic variants of hemophilia B: detection by means of a specific PTC inhibitor. J Clin Invest. 1968 Feb;47(2):360–365. doi: 10.1172/JCI105732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. SCHEIDEGGER J. J. Une micro-méthode de l'immuno-electrophorèse. Int Arch Allergy Appl Immunol. 1955;7(2):103–110. [PubMed] [Google Scholar]
  36. SCHULTZE H. E., SCHWICK G. Uber den Mechanismus der Thrombinbildung im isolierten System. Hoppe Seylers Z Physiol Chem. 1951;289(1):26–43. [PubMed] [Google Scholar]
  37. SEEGERS W. H., McCLAUGHRY R. I., FAHEY J. L. Some properties of purified prothrombin and its activation with sodium citrate. Blood. 1950 May;5(5):421–433. [PubMed] [Google Scholar]
  38. Shapiro S. S. Human prothrombin activation. Science. 1968 Oct 4;162(3849):127–129. doi: 10.1126/science.162.3849.127. [DOI] [PubMed] [Google Scholar]
  39. Shapiro S. S., Martinez J. Human prothrombin metabolism in normal man and in hypocoagulable subjects. J Clin Invest. 1969 Jul;48(7):1292–1298. doi: 10.1172/JCI106095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Shapiro S. S. The immunologic character of acquired inhibitors of antihemophilic globulin (factor 8) and the kinetics of their interaction with factor 8. J Clin Invest. 1967 Feb;46(2):147–156. doi: 10.1172/JCI105517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Von Felten A., Duckert F., Frick P. G. Familial disturbance of fibrin monomer aggregation. Br J Haematol. 1966 Nov;12(6):667–677. doi: 10.1111/j.1365-2141.1966.tb00152.x. [DOI] [PubMed] [Google Scholar]
  42. WOLF P. A modification for routine laboratory use of Stefanini's method of estimating factor V activity in human oxalated plasma. J Clin Pathol. 1953 Feb;6(1):34–38. doi: 10.1136/jcp.6.1.34. [DOI] [PMC free article] [PubMed] [Google Scholar]

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