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. 1977 Sep;60(3):584–594. doi: 10.1172/JCI108810

Purification of High Molecular Weight Kininogen and the Role of This Agent in Blood Coagulation

Hidehiko Saito 1
PMCID: PMC372403  PMID: 893664

Abstract

Recent studies of individuals with high molecular weight (HMW) kininogen deficiency established the importance of this plasma protein for in vitro initiation of blood coagulation. In the present study, HMW-kininogen was highly purified from human plasma by monitoring its clot-promoting activity, using Fitzgerald trait plasma as a substrate. This preparation of HMW-kininogen revealed a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (mol wt: 120,000) and released 1% of its weight as bradykinin upon incubation with plasma kallikrein. HMW-kininogen specifically repaired impaired surface-mediated plasma reactions of Fitzgerald trait plasma, but did not affect those of Hageman trait and Fletcher trait plasma. Kinin release from HMW-kininogen by trypsin, but not by plasma kallikrein, resulted in total loss of clot-promoting activity. No inhibitors of coagulation were found when all kinin activity was removed from HMW-kininogen by trypsin. The roles of HMW-kininogen, Hageman factor (HF, Factor XII), plasma prekallikrein (Fletcher factor), and plasma thromboplastin antecedent (PTA, Factor XI) in blood coagulation were studied in a purified system. HMW-kininogen was absolutely required for activation of PTA by HF and ellagic acid. The yield of activated PTA was proportional to the amount of HF, HMW-kininogen, and PTA in the mixtures, suggesting that, to activate PTA, these three proteins might form a complex in the presence of ellagic acid. No fragmentation of HF was found under these conditions. In contrast to HF, HF-fragments (mol wt: 30,000) activated PTA in the absence of HMW-kininogen and ellagic acid. Thus, it appears that in the present study PTA was activated in two distinct ways. Which pathway is the major one in whole plasma remains to be determined.

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Selected References

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

  1. Chan J. Y., Habal F. M., Burrowes C. E., Movat H. Z. Interaction between factor XII (Hageman factor), high molecular weight kininogen and prekallikrein. Thromb Res. 1976 Nov;9(5):423–433. doi: 10.1016/0049-3848(76)90198-5. [DOI] [PubMed] [Google Scholar]
  2. Colman R. W., Bagdasarian A., Talamo R. C., Scott C. F., Seavey M., Guimaraes J. A., Pierce J. V., Kaplan A. P. Williams trait. Human kininogen deficiency with diminished levels of plasminogen proactivator and prekallikrein associated with abnormalities of the Hageman factor-dependent pathways. J Clin Invest. 1975 Dec;56(6):1650–1662. doi: 10.1172/JCI108247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. DAVIS B. J. DISC ELECTROPHORESIS. II. METHOD AND APPLICATION TO HUMAN SERUM PROTEINS. Ann N Y Acad Sci. 1964 Dec 28;121:404–427. doi: 10.1111/j.1749-6632.1964.tb14213.x. [DOI] [PubMed] [Google Scholar]
  4. DINIZ C. R., CARVALHO I. F. A micromethod for determination of bradykininogen under several conditions. Ann N Y Acad Sci. 1963 Feb 4;104:77–89. doi: 10.1111/j.1749-6632.1963.tb17654.x. [DOI] [PubMed] [Google Scholar]
  5. Donaldson V. H., Glueck H. I., Miller M. A., Movat H. Z., Habal F. Kininogen deficiency in Fitzgerald trait: role of high molecular weight kininogen in clotting and fibrinolysis. J Lab Clin Med. 1976 Feb;87(2):327–337. [PubMed] [Google Scholar]
  6. Griffin J. H., Cochrane C. G. Mechanisms for the involvement of high molecular weight kininogen in surface-dependent reactions of Hageman factor. Proc Natl Acad Sci U S A. 1976 Aug;73(8):2554–2558. doi: 10.1073/pnas.73.8.2554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Habal F. M., Movat H. Z., Burrowes C. E. Isolation of two functionally different kininogens from human plasma--separation from proteinase inhibitors and interaction with plasma kallikrein. Biochem Pharmacol. 1974 Aug 15;23(16):2291–2303. doi: 10.1016/0006-2952(74)90558-9. [DOI] [PubMed] [Google Scholar]
  8. Hathaway W. E., Belhasen L. P., Hathaway H. S. Evidence for a new plasma thromboplastin factor. I. Case report, coagulation studies and physicochemical properties. Blood. 1965 Nov;26(5):521–532. [PubMed] [Google Scholar]
  9. Heck L. W., Kaplan A. P. Substrates of Hageman factor. I. Isolation and characterization of human factor XI (PTA) and inhibition of the activated enzyme by alpha 1-antitrypsin. J Exp Med. 1974 Dec 1;140(6):1615–1630. doi: 10.1084/jem.140.6.1615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kaplan A. P., Austen K. F. A pre-albumin activator of prekallikrein. J Immunol. 1970 Oct;105(4):802–811. [PubMed] [Google Scholar]
  11. Kaplan A. P., Austen K. F. A prealbumin activator of prekallikrein. II. Derivation of activators of prekallikrein from active Hageman factor by digestion with plasmin. J Exp Med. 1971 Apr 1;133(4):696–712. doi: 10.1084/jem.133.4.696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Komiya M., Kato H., Suzuki T. Bovine plasma kininogens. I. Further purification of high molecular weight kininogen and its physicochemical properties. J Biochem. 1974 Oct;76(4):811–822. [PubMed] [Google Scholar]
  13. MARGOLIS J. Activation of plasma by contact with glass: evidence for a common reaction which releases plasma kinin and initiates coagulation. J Physiol. 1958 Nov 10;144(1):1–22. doi: 10.1113/jphysiol.1958.sp006082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Matheson R. T., Miller D. R., Lacombe M. J., Han Y. N., Iwanaga S., Kato H., wuepper K. D. Flaujeac factor deficiency. Reconstitution with highly purified bovine high molecular weight-kininogen and delineation of a new permeability-enhancing peptide released by plasma kallikrein from bovine high molecular weight-kininogen. J Clin Invest. 1976 Dec;58(6):1395–1406. doi: 10.1172/JCI108595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. McMillin C. R., Saito H., Ratnoff O. D., Walton A. G. The secondary structure of human Hageman factor (factor XII) and its alteration by activating agents. J Clin Invest. 1974 Dec;54(6):1312–1322. doi: 10.1172/JCI107877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. NIEWIAROWSKI S., PROU-WARTELLE O. [Role of the contact factor (Hageman factor) in fibrinolysis]. Thromb Diath Haemorrh. 1959 Sep 1;3:593–603. [PubMed] [Google Scholar]
  17. RATNOFF O. D., DAVIE E. W., MALLETT D. L. Studies on the action of Hageman factor: evidence that activated Hageman factor in turn activates plasma thromboplastin antecedent. J Clin Invest. 1961 May;40:803–819. doi: 10.1172/JCI104314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. RATNOFF O. D., ROSENBLUM J. M. Role of Hageman factor in the initiation of clotting by glass; evidence that glass frees Hageman factor from inhibition. Am J Med. 1958 Aug;25(2):160–168. doi: 10.1016/0002-9343(58)90023-8. [DOI] [PubMed] [Google Scholar]
  19. Saito H., Ratnoff O. D., Donaldson V. H. Defective activation of clotting, fibrinolytic, and permeability-enhancing systems in human Fletcher trait plasma. Circ Res. 1974 May;34(5):641–651. doi: 10.1161/01.res.34.5.641. [DOI] [PubMed] [Google Scholar]
  20. Saito H., Ratnoff O. D. Inhibition of normal clotting and Fletcher factor activity by rabbit anti-kallikrein antiserum. Nature. 1974 Apr 12;248(449):597–598. doi: 10.1038/248597a0. [DOI] [PubMed] [Google Scholar]
  21. Saito H., Ratnoff O. D., Marshall J. S., Pensky J. Partial purification of plasma thromboplastin antecedent (factor XI) and its activation by trypsin. J Clin Invest. 1973 Apr;52(4):850–861. doi: 10.1172/JCI107249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Saito H., Ratnoff O. D., Pensky J. Radioimmunoassay of human Hageman factor (factor XII). J Lab Clin Med. 1976 Sep;88(3):506–514. [PubMed] [Google Scholar]
  23. Saito H., Ratnoff O. D., Waldmann R., Abraham J. P. Fitzgerald Trait: Deficiency of a Hitherto Unrecognized Agent, Fitzgerald Factor, Participating in Surface-Mediated Reactions of Clotting, Fibrinolysis, Generation of Kinins, and the Property of Diluted Plasma Enhancing Vascular Permeability (PF/Dil). J Clin Invest. 1975 May;55(5):1082–1089. doi: 10.1172/JCI108009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Schiffman S., Lee P. Partial purification and characterization of contact activation cofactor. J Clin Invest. 1975 Nov;56(5):1082–1092. doi: 10.1172/JCI108182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Schiffman S., Lee P. Preparation, characterization, and activation of a highly purified factor XI: evidence that a hitherto unrecognized plasma activity participates in the interaction of factors XI and XII. Br J Haematol. 1974 May;27(1):101–114. doi: 10.1111/j.1365-2141.1974.tb06778.x. [DOI] [PubMed] [Google Scholar]
  26. Schiffman S., Lee P., Waldmann R. Identity of contact activation cofactor and Fitzgerald factor. Thromb Res. 1975 May;6(5):451–454. doi: 10.1016/0049-3848(75)90161-9. [DOI] [PubMed] [Google Scholar]
  27. Soltay M. J., Movat H. Z., Ozge-Anwar A. H. The kinin system of human plasma. V. The probable derivation of prekallikrein activator from activated Hageman factor (XIIa). Proc Soc Exp Biol Med. 1971 Dec;138(3):952–958. doi: 10.3181/00379727-138-36026. [DOI] [PubMed] [Google Scholar]
  28. Weber K., Osborn M. The reliability of molecular weight determinations by dodecyl sulfate-polyacrylamide gel electrophoresis. J Biol Chem. 1969 Aug 25;244(16):4406–4412. [PubMed] [Google Scholar]
  29. Weiss A. S., Gallin J. I., Kaplan A. P. Fletcher factor deficiency. A diminished rate of Hageman factor activation caused by absence of prekallikrein with abnormalities of coagulation, fibrinolysis, chemotactic activity, and kinin generation. J Clin Invest. 1974 Feb;53(2):622–633. doi: 10.1172/JCI107597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wuepper K. D., Miller D. R., Lacombe M. J. Flaujeac trait. Deficiency of human plasma kininogen. J Clin Invest. 1975 Dec;56(6):1663–1672. doi: 10.1172/JCI108248. [DOI] [PMC free article] [PubMed] [Google Scholar]

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