Download PDF
Thromb Haemost 1991; 65(05): 497-503
DOI: 10.1055/s-0038-1648179
Original Article
Schattauer GmbH Stuttgart

Studies on the Contact System of Coagulation during Therapy with High Doses of Recombinant IL-2: Implications for Septic Shock

C Erik Hack
The Central Laboratory of the Netherlands Red Cross Blood Transfusion Service and Laboratory for Experimental and Clinical Immunology, University of Amsterdam
,
John Wagstaff
1   The Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands
,
Robert J M Strack Van Schijndel
2   Medical Intensive Care Unit, Free University Hospital, Amsterdam, The Netherlands
,
Anke J M Eerenberg
The Central Laboratory of the Netherlands Red Cross Blood Transfusion Service and Laboratory for Experimental and Clinical Immunology, University of Amsterdam
,
Herbert M Pinedo
1   The Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands
,
Lambertus G Thijs
2   Medical Intensive Care Unit, Free University Hospital, Amsterdam, The Netherlands
,
Jan H Nuijens
The Central Laboratory of the Netherlands Red Cross Blood Transfusion Service and Laboratory for Experimental and Clinical Immunology, University of Amsterdam
› Author Affiliations
Further Information

Publication History

Received 17 September 1990

Accepted after revision 09 January 1991

Publication Date:
24 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

Patients treated with high doses of interleukin-2 (IL-2) because of cancer, develop hemodynamic and vasopermeability changes, that resemble those observed in sepsis. These patients thus provide a unique opportunity to study the early events in the development of septic shock. We analysed the changes that occurred in the contact system of coagulation in plasma from 4 patients, who together received seven 12-day cycles of high doses of IL-2. Levels of factor XII and prekallikrein during the cycles progressively fell to 50 and 30% of their initial levels, respectively, whereas significant increases in plasma factor XIIa-and kallikrein-C1-inhibitor complexes were not observed (in 3 out of 211 samples slightly increased levels of both complexes were found). The reductions in factor XII and prekallikrein were only in part due to protein leakage, since levels were still significantly lower, i. e., 80 and 50%, respectively, when corrected for albumin decreases. Levels of high molecular weight kininogen (HMWK) also decreased during IL-2 therapy, however, this decrease paralleled that of albumin. SDS-PAGE analysis of plasma HMWK did not reveal increased cleavage of this protein. The reduction of factor XII and prekallikrein, corrected for protein leakage, significantly correlated with albumin levels and inversely with daily cumulative weight gain in the patients.

Thus, we demonstrate that factor XII and prekallikrein decrease during IL-2 therapy. As these decreases, already observed after 1 day treatment, were disproportional to that of albumin, a negative acute phase reactant, and correlated with signs of the vascular leak syndrome, we favor the explanation that they reflected activation rather than a decreased synthesis of the contact system proteins. Further studies are needed to substantiate this hypothesis.

 

  • References

  • 1 Cochrane CG, Griffin JH. The biochemistry and pathophysiology of the contact system of plasma. Adv Immunol 1982; 33: 241-304
    PubMedSearch in Google Scholar
  • 2 Colman RW. Surface-mediated defense mechanisms. The plasma contact activation system. J Clin Invest 1984; 73: 1249-1253
    CrossrefPubMedSearch in Google Scholar
  • 3 Griffin JH, Cochrane CG. Human factor XII (Hageman factor). Methods Enzymol 1976; 45: 56-65
    PubMedSearch in Google Scholar
  • 4 Kaplan AP, Silverberg M. The coagulation-kinin pathway of human plasma. Blood 1987; 70: 1-15
    PubMedSearch in Google Scholar
  • 5 Griffin JH. The role of surface in surface-dependent activation of Hageman factor (Factor XII). Proc Natl Acad Sci USA 1978; 75: 1998-2002
    CrossrefPubMedSearch in Google Scholar
  • 6 De Agostini A, Lijnen HR, Pixley RA, Colman RW, Schapira M. Inactivation of factor XII active fragment in normal plasma. Predominant role of C1-Inhibitor. J Clin Invest 1984; 73: 1542-1549
    CrossrefPubMedSearch in Google Scholar
  • 7 Pixley RA, Schapira M, Colman RW. The regulation of human factor XIIa by plasma proteinase inhibitors. J Biol Chem 1985; 260: 1723-1729
    PubMedSearch in Google Scholar
  • 8 Schapira M, Scott CF, Colman RW. Contribution of plasma protease inhibitors to the inactivation of kallikrein in plasma. J Clin Invest 1982; 69: 462-468
    CrossrefPubMedSearch in Google Scholar
  • 9 Harpel PC, Lewin MF, Kaplan AP. Distribution of plasma kallikrein between C1-Inhibitor and α2-macroglobulin in plasma utilizing a new assay for α2-macroglobulin-kallikrein complexes. J Biol Chem 1985; 260: 4257-4263
    PubMedSearch in Google Scholar
  • 10 Van den Graaf F, Koedam JA, Griffin JH, Bouma BN. Interaction of human plasma kallikrein and its light chain with C1-inhibitor. Biochemistry 1983; 22: 4860-4866
    CrossrefPubMedSearch in Google Scholar
  • 11 Van der Graaf F, Koedam JA, Bouma BN. Interaction of kallikrein in human plasma. J Clin Invest 1983; 71: 149-158
    CrossrefPubMedSearch in Google Scholar
  • 12 Kozin F, Cochrane CG. The contact activation system of plasma: Biochemistry and pathophysiology. In: Inflammation: Basic Principles and Clincal Correlates Gallin JI, Goldstein IM, Snyderman R. (eds) Raven Press Ltd; New York: 1988. pp 101-120
  • 13 Yamamoto T, Cochrane CG. Guinea pig Hageman factor as a vascular permeability enhancement factor. Am J Pathol 1981; 105: 164-175
    PubMedSearch in Google Scholar
  • 14 Regoli D, Barable J. Pharmacology of bradykinin and related kinins. J Pharmacol Rev 1980; 32: 1-45
    PubMedSearch in Google Scholar
  • 15 Schapira M, Despland E, Scott CF, Boxer LA, Colman RW. Purified human plasma kallikrein aggregates human blood neutrophils. J Clin Invest 1982; 69: 1199-1201
    CrossrefPubMedSearch in Google Scholar
  • 16 Wachtfogel YT, Kuchich U, James H, Scott CF, Shapira M, Zimmerman M, Cohen AB, Colman RW. Human plasma kallikrein releases neutrophil elastase during blood coagulation. J Clin Invest 1983; 72: 1672-1677
    CrossrefPubMedSearch in Google Scholar
  • 17 Colman RW, Edelman R, Scott CF, Gilman RM. Plasma kallikrein activation and inhibition during typhoid fever. J Clin Invest 1978; 61: 287-296
    CrossrefPubMedSearch in Google Scholar
  • 18 Mason JM, Kleeberg V, Dolan P, Colman RW. Plasma kallikrein and Hageman factor in gram-negative bacteremia. Ann Intern Med 1970; 73: 545-551
    CrossrefPubMedSearch in Google Scholar
  • 19 Kalter ES, Daha MR, Ten Cate JW, Verhoef J, Bouma BN. Activation and inhibition of Hageman factor-dependent pathways and the complement system in uncomplicated bacteremia or bacterial shock. J Infect Dis 1985; 151: 1019-1027
    CrossrefPubMedSearch in Google Scholar
  • 20 Robinson JA, Kloduycky ML, Lock HH, Racic MR, Gunner RM. Endotoxin, prekallikrein, complement and systemic vascular resistance sequential measurements in man. Am J Med 1975; 59: 61-67
    CrossrefPubMedSearch in Google Scholar
  • 21 Colman RW. The role of plasma proteases in septic shock. N Engl J Med 1989; 320: 1207-1209
    CrossrefPubMedSearch in Google Scholar
  • 22 Nuijens JH, Huijbrechts CCM, Eerenberg AJM, Abbink JJ, Strack van Schijndel RJM, Felt-Bersma RJF, Thijs LG, Hack CE. Qualification of plasma factor XIIa-C1-Inhibitor and kallikrein-C1-Inhibitor complexes in sepsis. Blood 1988; 72: 1841-1848
    PubMedSearch in Google Scholar
  • 23 Hack CE, Nuijens JH, Strack van Schijndel RJM, Abbink JJ, Eerenberg AJM, Thijs LG. A model for the interplay of inflammatory mediators is sepsis: A study in 48 patients. Intensive Care Med 1990; 16 [Suppl]: S 187-191
    CrossrefPubMedSearch in Google Scholar
  • 24 Gaynor ER, Vitek L, Sticklin L, Creekmore SP, Ferraro ME, Thomas JX, Fisher SG, Fisher RI. The hemodynamic effects of treatment with Interleukin-2 and lymphokine activated killer cells. Ann Intern Med 1988; 109: 953-958
    CrossrefPubMedSearch in Google Scholar
  • 25 Ognibene FP, Rosenberg SA, Lotze M, Skibber J, Parker MM, Shelhamer JH, Parillo JE. Interleukin-2 administration causes reversible hemodynamic changes and left ventricular dysfunction similar to those seen in septic shock. Chest 1988; 94: 750-754
    CrossrefPubMedSearch in Google Scholar
  • 26 Thijs LG, Hack CE, Strack van Schijndel RJM, Nuijens JH, Wolbink GJ, Eerenberg-Belmer AJM, van der Vail H, Wagstaff J. Activation of the complement system during immunotherapy with recombinant Interleukin-2: Relation to the development of side effects. J Immunol 1990; 144: 2419-2424
    PubMedSearch in Google Scholar
  • 27 Nuijens JH, Huijbregts CCM, Cohen M, Navis GO, de Vries A, Eerenberg AJM, Bakker JC, Hack CE. Detection of activation of the contact system of coagulation in vitro and in vivo: Quantification of activated Hageman factor-C1-inhibitor and kallikrein-C1-inhibitor complexes by specific radioimmunoassays. Thromb Haemostas 1987; 58: 778-785
    PubMedSearch in Google Scholar
  • 28 Kerberiou DM, Bouma BN, Griffin JH. Immunochemical studies of high molecular weight kininogen and of its complexes with prekalli-krein or kallikrein. J Biol Chem 1980; 255: 3952-3958
    PubMedSearch in Google Scholar
  • 29 Berrettini M, Laemmle B, White T, Heeb MJ, Schwarz HP, Zuraw B, Curd J, Griffin JH. Detection of in vitro and in vivo cleavage of high molecular weight kininogen in human plasma by immunoblotting with monoclonal antibodies. Blood 1986; 68: 455-462
    PubMedSearch in Google Scholar
  • 30 Hoekzema R, Hannema AJ, Swaak AJG, Paardekooper J, Hack CE. Low molecular weight Clq in systemic lupus erythematosus. J Immunol 1985; 135: 265-271
    PubMedSearch in Google Scholar
  • 31 Rosenberg SA, Lotze MT, Mule JJ. New approaches to immunotherapy of cancer using interleukin-2. Ann Intern Med 1988; 108: 853-864
    CrossrefPubMedSearch in Google Scholar
  • 32 Reddigari S, Kaplan AP. Cleavage of human high molecular weight kininogen by purified kallikreins and upon contact activation of plasma. Blood 1988; 71: 1334-1340
    PubMedSearch in Google Scholar
  • 33 Shifman MA, Pizzo SV. The in vivo metabolism of antithrombin III and antithrombin III complexes. J Biol Chem 1982; 257: 3243-3250
    PubMedSearch in Google Scholar
  • 34 Fuchs HE, Shifman MA, Pizzo SV. In vivo catabolism of α1-proteinase inhibitor-trypsin, antithrombin III-thrombin and α2-mac-roglobulin-methylamine. Biochim Biophys Acta 1982; 716: 151-159
    CrossrefPubMedSearch in Google Scholar
  • 35 Chibber G, Cohen A, Lane S, Färber A, Meloni FJ, Schmaier AH. Immunoblotting of plasma in a pregnant patient with hereditary angiooedema. J Lab Clin Med 1990; 115: 112-121
    PubMedSearch in Google Scholar
  • 36 Schmaier AH, Färber A, Schein R, Sprung C. Structural changes of plasma high molecular weight kininogen after in vitro activation and in sepsis. J Lab Clin Med 1988; 112: 182-192
    PubMedSearch in Google Scholar
  • 37 Cole T, Inglis AS, Roxburgh CM, Howlett GJ, Schreiber G. Major acute phase ai-protein of the rat is homologous to bovine kininogen and contains the sequence for bradykinin: its synthesis is regulated at the mRNA level. FEBS Lett 1985; 182: 57-61
    CrossrefPubMedSearch in Google Scholar
  • 38 Knowles BB, Howe CC, Aden DP. Human hepatocellular carcinoma cell lines secrete the major plasma proteins and hepatitis b surface antigen. Science 1980; 209: 497-499
    CrossrefPubMedSearch in Google Scholar
  • 39 Perlmutter DH, Dinarello CA, Punsal PI, Colten HR. Cachectin/ Tumor necrosis factor regulates hepatic acute-phase gene expression. J Clin Invest 1986; 78: 1349-1354
    CrossrefPubMedSearch in Google Scholar
  • 40 Rosenstein M, Ettinghausen SE, Rosenberg SA. Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin-2. J Immunol 1986; 137: 1735-1742
    PubMedSearch in Google Scholar
  • 41 Damle NK, Doyle LV, Bender JR, Bradley EC. Interleukin-2 activated human lymphocytes exhibit enhanced adhesion to normal vascular endothelial cells and cause their lysis. J Immunol 1987; 138: 1779-1785
    PubMedSearch in Google Scholar
  • 42 Aronson FR, Libby P, Brandon ER, Janicka MW, Mier JW. ID2 rapidly induces natural killer cells adhesion to human endothelial cells. A potential mechanism for endothelial injury. J Immunol 1988; 141: 158-163
    PubMedSearch in Google Scholar
  • 43 Damle NK, Doyle LV. IL-2-activated human killer lymphocytes but not their secreted products mediate increase in albumin flux across cultured endothelial monolayers. Implications for vascular leakage syndrome. J Immunol 1989; 142: 2660-2669
    PubMedSearch in Google Scholar
  • 44 Hugh TE. Structure and function of the anaphylatoxins. Springer Semin Immunopathol 1984; 7: 193-219
    CrossrefPubMedSearch in Google Scholar
  • 45 Vogt W. Anaphylatoxins: possible roles in disease. Complement 1986; 3: 177-188
    CrossrefPubMedSearch in Google Scholar
  • 46 Thijs LG, Hack CE, Strack van Schijndel RJM, Nuijens JH, Wolbink GJ, Eerenberg-Belmer AJM, van der Vail H, Wagstaff J. Complement activation and high-dose of interleukin-2. Lancet 1989; 2: 395
    PubMedSearch in Google Scholar
  • 47 Smedly LA, Tonnesen MG, Sandhaus RA, Haslett C, Guthrie LA, Johnston RB, Henson PM, Worthen GS. Neutrophil mediated injury to endothelial cells. Enhancement by endotoxin and essential role for neutrophil elastase. J Clin Invest 1985; 77: 1233-1243
    PubMedSearch in Google Scholar
  • 48 Martin W. Neutrophils kill pulmonary endothelial cells by a hydrogen peroxide dependent pathway. Am Rev Respir Dis 1984; 130: 209-213
    CrossrefPubMedSearch in Google Scholar
  • 49 Mason DT, Melmon KL. Effects of bradykinin on fore-arm venous tone and vascular resistance in man. Circ Res 1965; 17: 106-113
    CrossrefPubMedSearch in Google Scholar
  • 50 Colman RW, Flores DN, de la Cadena RA, Scott CF, Lousens L, Barr PJ, Hoffman IB, Kneppers F, Fisher D, Idell S, Pisarello J. Recombinant di-antitrypsin attenuates experimental gram-negative septicemia. Am J Pathol 1988; 130: 418-426
    PubMedSearch in Google Scholar
  • 51 Beutler B, Cerami A. Cachectin: more than a tumor necrosis factor. N Engl J Med 1987; 316: 379-385
    CrossrefPubMedSearch in Google Scholar
  • 52 Beutler B, Milsark IW, Cerami A. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effects of endotoxin. Science 1985; 229: 869-871
    CrossrefPubMedSearch in Google Scholar
  • 53 Fraker DL, Langstein HN, Norton JA. Passive immunization against tumor necrosis factor partially abrogates interleukin 2 toxicity. J Exp Med 1989; 170: 1015-1020
    CrossrefPubMedSearch in Google Scholar
  • 54 Egbring R, Schmidt W, Fuchs G, Havermann K. Demonstration of granulocytic proteases in plasma of patients with acute leukemia and septicemia with coagulation defects. Blood 1977; 49: 219-231
    PubMedSearch in Google Scholar
  • 55 Hack CE, Nuijens JH, Felt-Bersma RJF, Schreuder WO, Eerenberg-Belmer AJM, Paardekooper J, Bronsveld W, Thijs LG. Elevated plasma levels of the anaphylatoxins C3a and C4a are associated with a fatal outcome in sepsis. Am J Med 1989; 86: 20-26
    CrossrefPubMedSearch in Google Scholar