The Chemistry and Biology of the Proteins of the Hageman Factor-Activated Pathways

  • Richard J. Ulevitch
  • Charles G. Cochrane
Part of the Comprehensive Immunology book series (COMIMUN, volume 2)


The initiation of the intrinsic clotting system, the formation of bradykinin, and one pathway of plasminogen activation all require the activation of Hageman factor (factor XII). These pathways are shown schematically in Figure 1. Activation of Hageman factor, prekallikrein plasma thromboplastin antecedent (factor XI), and the plasminogen activator are all characterized by the conversion of a zymogen to an enzymatically active protease. This singular biochemical event, activation of zymogen, can produce rapid and diverse alterations in both humoral and cellular-based mediation systems.


Plasminogen Activator Disseminate Intravascular Coagulation Ellagic Acid Disseminate Intravascular Coagulation Gouty Arthritis 
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  1. Armstrong, D., Dry, R. M. L., Keele, C. A., Markham, J. W., 1953, Observations on chemical excitants of cutaneous pain in man, J. Physiol. London 120: 326.PubMedGoogle Scholar
  2. Armstrong, D., Keele, C, A., Jepson, J. B., Stewart, J. W., 1954, Development of pain-producing substance in human plasma, Nature London 174: 791.PubMedCrossRefGoogle Scholar
  3. Armstrong, D., Jepson, J. B., Keele, C. A., Stewart, J. W., 1957, Pain-producing substance in human inflammatory exudates and plasma, J. Physiol. London 135: 350.PubMedGoogle Scholar
  4. Austen, K. F., 1974, Hageman factor-dependent coagulation, fibrinolysis and kinin generation, Transplant. Proc. 6: 39.PubMedGoogle Scholar
  5. Back, N., Munson, A. E., Guth, P. S., 1963, Anaphylactic shock in dogs, J. Amer. Med. Assoc. 183: 260.Google Scholar
  6. Bagdasarian, A., Talamo, R. C., Colman, R. W., 1973, Isolation of high molecular weight activators of human plasma prekallikrein, J. Biol. Chem. 248: 3456.PubMedGoogle Scholar
  7. Bagdasarian, A., Lahiri, B., Talamo, R. C., Wong, P., Colman, R. W., 1974, Immunochemical studies of plasma kallikrein, J. Clin. Invest. 54: 1444.PubMedCrossRefGoogle Scholar
  8. Barnhart, M. I., Sulisz, L., Bluhm, G. B., 1971, Role for fibrinogen and its derivatives in acute inflammation, in: Immunopathology of Inflammation ( B. K. Forscher and J. C. Houek, eds.), p. 59, Excerpta Medica, Amsterdam.Google Scholar
  9. Becker, E. L., Wilhelm, D. L., Miles, A. A., 1959, Enzymic nature of the serum globulin permeability factors, Nature London 183: 1264.PubMedCrossRefGoogle Scholar
  10. Beraldo, W. T., 1950, Formation of bradykinin in anaphylactic and peptone shock, Amer. J. Physiol. 163: 283.PubMedGoogle Scholar
  11. Brocklehurst, W. E., Lahiri, S. C., 1963, Formation and destruction of bradykinin during anaphy-laxis, J. Physiol. London 165: 39 P.Google Scholar
  12. Burrowes, C. E., Movat, H. Z., Soltay, M. J., 1971, The kinin system in human plasma. VI. The action of plasmin, Proc. Soc. Exp. Biol. Med. 138: 959.PubMedGoogle Scholar
  13. Cochrane, C. G., Wuepper, K., Aikin, B., Revak, S., Spiegelberg, H., 1972, The interaction of Hageman factor and immune complexes, J. Clin. Invest. 51: 2736–2745.PubMedCrossRefGoogle Scholar
  14. Cochrane, C. G., Revak, S. D., Wuepper, K. D., 1973a, Activation of Hageman factor in solid and fluid phases. A critical role of kallikrein, J. Exp. Med. 138: 1564.PubMedCrossRefGoogle Scholar
  15. Cochrane, C. G., Revak, S. D., Wuepper, K. D., Johnston, A., Morrison, D. C., Ulevitch, R., 1973b, Activation of Hageman factor and the kinin forming, intrinsic clotting, and fibrinolytic systems, in: Advances in the Biosciences ( G. Raspe, ed.), p. 237, Pergamon Press, Viowes.Google Scholar
  16. Colman, R. W., Mason, J. W., Sherry, S., 1969, The kallikreinogen-kallikrein enzyme system of human plasma. Assay of components and observations in disease states, Ann. Intern. Med. 71: 763.PubMedGoogle Scholar
  17. Colman, R. W., Bagdasarian, A., Talamo, R. C., Scott, C. F., Seavy, M., Guimaraes, J. A., Pierce, J. V., Kaplan, M., 1975, Williams trait: human kininogen deficiency with diminished levels of plasminogen proactivator, and pre-kallikrein associated with abnormalities of the Hageman factor dependent pathways, J. Clin. Invest. 56: 1650–1662.PubMedCrossRefGoogle Scholar
  18. Donaldson, V. H., Glueck, H. I., Miller, M. A., Movat, H. Z., Habal, F., 1976, Kininogen deficiency in Fitzgerald trait: role of high molecular weight kininogen in clotting and fibrinolysis, J. Cab. Clin. Mol. 87 (2): 327–337.Google Scholar
  19. Elder, J. M., Willhelm, D. L., 1958, Enzyme-like globulins from serum reproducing the vascular phonemona of inflammation V. Activable permeability factor in human serum, Br. J. Exp. Pathol. 39: 335.PubMedGoogle Scholar
  20. Erdos, E. G., Miwa, I., 1968, Effect of endotoxin shock on the plasma kallikrein-kinin system of the rabbit, Fed. Proc. Fed. Amer. Soc. Exp. Biol. 27: 92.Google Scholar
  21. Forbes, C. D., Pinsky, J., Ratnoff, O. D., 1970, Inhibition of activated Hageman factor and activated plasma thromboplastin antecedent by purified serum Cl inactivator, J. Lab. Clin. Med. 76: 809.PubMedGoogle Scholar
  22. Graham, R. C., Jr., Ebert, R. H., Ratnoff, O. D., Moses, J. H., 1965, Pathogenesis of inflammation. II. In vivo observations of the inflammatory effects of activated Hageman factor and bradykinin, J. Exp. Med. 121: 807.Google Scholar
  23. Greeff, K., Scharnagel, K., Luhr, R., Strobach, H., 1966, Die Abnahme des Kininogengehaltes des Plasmas beim toxischen anaphylaktischen und anaphylaktoiden Shock, Naunyn-Schmiedeberg’s Arch. Exp. Pathol. Pharmakol. 253: 235–245.PubMedCrossRefGoogle Scholar
  24. Griffin, J. H., Cochrane, C. G., 1976, Human factor XII, in: Methods in Enzymology, Vol. VL, Part B (L. Lorand, ed.), Academic Press, New York, in press.Google Scholar
  25. Griffin, J. H., Harper, E., Cochrane, C. G., 1975, Studies on the activation of human blood coagulation factor XII (Hageman factor) by soluble collagen, Fed. Proc. Fed. Amer. Soc. Exp. Biol. 34: 3626.Google Scholar
  26. Halonen, M., Pinckard, R. N., 1975, Intravascular effect of IgE antibody upon basophils, neutro-phils, and blood coagulation in the rabbit, J. Immunol. 115: 519.PubMedGoogle Scholar
  27. Harpel, P. C., 1972, Studies on the interaction between collagon and a plasma kallikrein-like activity, J. Clin. Invest. 51: 1813.PubMedCrossRefGoogle Scholar
  28. Honig, G. R., Lindley, A., 1971, Deficiency of Hageman factor (factor XII) in patients with the nephrotic syndrome, J. Pediatr. 78: 633.PubMedCrossRefGoogle Scholar
  29. Johnston, A. R., Cochrane, C. G., Revak, S. D., 1974, The relationship between PF/dil and activated human Hageman factor, J. Immunol. 113: 103.PubMedGoogle Scholar
  30. Jonasson, O., Becker, E. L., 1966, Release of kallikrein from guinea pig lung during anaphylaxis, J. Exp. Med. 123: 509.PubMedCrossRefGoogle Scholar
  31. Kaplan, A. P., Austen, K. F., 1971, A prealbumin activator of prekallikrein. II. Derivation of activators of prekallikrein from active Hageman factor by digestion with plasmin, J. Exp. Med. 133: 696.PubMedCrossRefGoogle Scholar
  32. Kaplan, A. P., Austen, K. F., 1972, The fibrinolytic pathway of human plasma. Isolation and characterization of the plasminogen proactivator, J. Exp. Med. 136: 1378.PubMedCrossRefGoogle Scholar
  33. Kaplan, A. P., Kay, A. B., Austen, K. F., 1972, A prealbumin activator of prekallikrein. III. Appearance of chemotactic activity for human neutrophils by the conversion of human prekallikrein to kallikrein, J. Exp. Med. 135: 81.PubMedCrossRefGoogle Scholar
  34. Kaplan, A. P., Goetzel, E. J., Austen, K. F., 1973, The fibrinolytic pathway of human plasma. II. The generation of chemotactic activity by activation of plasminogen proactivator, J. Clin. Invest. 52: 2591.PubMedCrossRefGoogle Scholar
  35. Lange, L. G., Carvalho, A., Badasarian, A., Lahini, B., Colman, R. W., 1974, Activation of Hageman factor in the nephritic syndrome, Am. J. Med. 56: 565–569.PubMedCrossRefGoogle Scholar
  36. Lepow, I. H., Ratnoff, O. D., Levy, L. R., 1958, Studies on the activation of a proesterase associated with partially purified first component of human complement, J. Exp. Med. 107: 451.PubMedCrossRefGoogle Scholar
  37. Lerner, R. G., Rappaport, S. I., Spitzer, J. M., 1968, Endotoxin-induced intravascular clotting: the need for granulocytes, Thromb. Diath. Haemorrh. 20: 430.PubMedGoogle Scholar
  38. MacKay, M. E., Miles, A. A., Schacter, C. B., Wilhelm, D. L., 1953, Susceptibility of the guinea pig to pharmacological factors from its own serum, Nature London 172: 714.PubMedCrossRefGoogle Scholar
  39. Margolis, J., 1958, Activation of a permeability factor in plasma by contact with glass, Nature London 181: 635.PubMedCrossRefGoogle Scholar
  40. Margolis, J., 1959, Hageman factor and capillary permeability, Aust. J. Exp. Biol. Med. Sci. 37: 239.PubMedCrossRefGoogle Scholar
  41. Margolius, A., Ratnoff, O. D., 1956, Observations on the hereditary nature of Hageman trait, Blood 11: 565PubMedGoogle Scholar
  42. Mason, J. W., Colman, R. W., 1969a, The role of Hageman factor in disseminated intravascular coagulation of sepsis and neoplasia, Amer. J. Clin. Path. 52: 755.Google Scholar
  43. Mason, J. W., Kleeberg, U. R., Colman, R. W., 1969b, Human plasma kallikrein and Hageman factor in endotoxin shock, Clin. Research 17: 371.Google Scholar
  44. McKay, D. G., Muller-Berghaus, G., Cruse, V., 1969, Activation of Hageman factor by ellasic acid and the generalized Schwartzman reaction, Am. J. Path. 54: 393.PubMedGoogle Scholar
  45. McKay, D. G., Latour, J. G., Lopez, A. M., 1971, Production of the generalized Schwartzman reaction by activated Hageman factor and a-adrenergic stimulation, Thromb. Diath. Haemorrhag. 26: 71.Google Scholar
  46. McMillin, C. R., Saito, H., Ratnoff, O. D., Walton, A. G., 1974, The secondary structure of human Hageman factor (factor XII) and its alternation by activating agents, J. Clin. Invest. 54: 1312.PubMedCrossRefGoogle Scholar
  47. Melmon, K. L., Webster, M. E., Goldfinger, S. E., Seegmiller, J. E., 1967, The presence of a kinin in inflammatory synovial effusion from arthritides of varying etiologies, Arthritis Rheum. 10: 13.PubMedCrossRefGoogle Scholar
  48. Meyer, A., Werle, E., 1964, in: Pathogenese, Diagnostik, Klinik und Therapie der Erkrankungen des Exokrinen Pankreas (K. Heinkel and H. Schon, eds.), p. 299, Schattauer-Verlag, Stuttgart.Google Scholar
  49. Morrison, D. C., Cochrane, C. G., 1974, Direct evidence for Hageman factor (factor XII) activation by bacterial lipopolysaccharides (endotoxins), J. Exp. Med. 140: 797.PubMedCrossRefGoogle Scholar
  50. Muller-Berghaus, G., Schneberger, R., 1971, Hageman factor activation in the generalized Shwartz- man reaction induced by endotoxin, Br. J. Haematol. 21: 513.PubMedCrossRefGoogle Scholar
  51. Nies, A. S., Forsyth, R. P., Williams, H. E., Melmon, K. L., 1968, Contributions of kinins to endotoxin shock in unanesthetized rhesus monkeys, Cir. Res. 22: 155.Google Scholar
  52. Pinckard, R. N., Tanigawa, C., Halonen, M., 1975, IgE-induced Blood coagulation alterations in the rabbit: consumption of coagulation factors XII, XI, and IX in vivo, J. Immunol. 115: 519.PubMedGoogle Scholar
  53. Ratnoff, O. D., 1966, The biology and pathology of the initial stages of Blood coagulation, in: Progress in Hematology ( E. B. Brown and C. V. Moore, eds.), Vol. 5, p. 204, Grune and Stratton, New York.Google Scholar
  54. Ratnoff, O. D., 1969, Some relationships among hemostasis, fibrinolytic phenomena, immunity and the inflammatory process, in: Advances in Immunology ( F. J. Dixon and H. Kunkel, eds.), Vol. 10, p. 146, Academic Press, New York.Google Scholar
  55. Ratnoff, O. D., Davie, E. W., 1962, The purification of activated Hageman factor (activated factor XII), Biochemistry 1: 967.PubMedCrossRefGoogle Scholar
  56. Ratnoff, O. D., Miles, A. A., 1964, The induction of permeability-increasing activity in human plasma by activated Hageman factor, Br. J. Exp. Pathol. 45: 328.PubMedGoogle Scholar
  57. Ratnoff, O. D., Naff, G. G., 1967, The conversion of C′1s to C′2 esterase by plasmin and trypsin, J. Exp. Med. 125: 337.PubMedCrossRefGoogle Scholar
  58. Revak, S. D., Cochrane, C. G., 1976, The relationship of structure and function in human Hageman factor. The association of enzymatic and binding activities with separate regions of the molecule, J. Clin. Invest. 57: 852–860.PubMedCrossRefGoogle Scholar
  59. Revak, S. D., Cochrane, C. G., Johnston, A. R., Hugli, T. E., 1974, Structural changes accompany-ing enzymatic activation of human Hageman factor, J. Clin. Invest. 54: 619.PubMedCrossRefGoogle Scholar
  60. Saito, H., Ratnoff, O. D., Donaldson, V. H., 1974, Defective activation of clotting, fibrinolytic and permeability-enhancing systems in human Fletcher trait plasma, Circ. Res. 34: 641.PubMedGoogle Scholar
  61. Saito, H., Ratnoff, O. D., Waldmann, R., Abraham, J. P., 1975, Fitzgerald trait. Deficiency in 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. 55: 1082.PubMedCrossRefGoogle Scholar
  62. Schreiber, A. A., Kaplan, A. P., Austen, K. F., 1973, Inhibition by Cl-INH of Hageman factor fragment activation of coagulation, fibrinolysis and kinin generation, J. Clin. Invest. 52: 1402.PubMedCrossRefGoogle Scholar
  63. Smink, M. M., Daniel, T. M., Ratnoff, O. D., Stavitsky, A. B., 1967, Immunologic demonstration of a deficiency of Hageman factor-like material in Hageman trait, J. Lab. Clin. Med. 69: 819.PubMedGoogle Scholar
  64. Svendsen, L., 1974, The chemistry and biology of the kallikrein-kinin system in health and disease, International Conference Report at Reston, Virginia (October 1974 ).Google Scholar
  65. Ulevitch, R. J., Letchford, D., Cochrane, C. G., 1974, A direct enzymatic assay for the esterolytic activity of activated Hageman factor, Thromb. Diath. Haemorrhag. 31: 30.Google Scholar
  66. Ulevitch, R. J., Cochrane, C. G., Morrison, D. C., Henson, P. M., 1976, A characterization of hypotensive changes associated with rapid intravascular complement activation, in preparation.Google Scholar
  67. Ward, P. A., 1967, A plasmin-split fragment of C′3 as a new chemotactic factor, J. Exp. Med. 126: 189.PubMedCrossRefGoogle Scholar
  68. Wilner, G. D., Nossel, H. L., Le Roi, E. C., 1968, Activation of Hageman factor by collagon, J. Clin. Invest. 47: 2708.Google Scholar
  69. Wuepper, K. D., 1971, Plasma prekininogenase (prekallikrein) activation: hydrolysis of native and synthetic substrates, Fed. Proc. Fed. Amer. Soc. Exp. Biol. 30: 451 (abstract 1427).Google Scholar
  70. Wuepper, K. D., 1972, Biochemistry and biology of components of the plasma kinin-forming system, in: Inflammation, Mechanisms and Control (I. H. Lepow and P. A. Ward, eds.), p. 93, Academic Press, New York.Google Scholar
  71. Wuepper, K. D., 1973, Prekallikrein deficiency in man, J. Exp. Med. 138: 1345–1355.PubMedCrossRefGoogle Scholar
  72. Wuepper, K. D., Cochrane, C. G., 1972, Plasma prekallikrein: isolation, characterization and mechanism of activation, J. Exp. Med. 135: 1.PubMedCrossRefGoogle Scholar
  73. Wuepper, K. D., Cochrane, C. G., 1975, Purification and characterization of human precursor plasma thromboplastin antecedent, in preparation.Google Scholar
  74. Wuepper, K. D., Miller, D. R., Lacombe, M. J., 1975, Flaujeac trait: deficiency of kininogen in man, Fed. Proc. Fed. Amer. Soc. Exp. Biol. 34: 3623.Google Scholar

Copyright information

© Plenum Publishing Corporation 1977

Authors and Affiliations

  • Richard J. Ulevitch
    • 1
  • Charles G. Cochrane
    • 1
  1. 1.Department of ImmunopathologyScripps Clinic and Research FoundationLa JollaUSA

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