Effect of Heparin on the Activation of Factor XII and the Contact System in Plasma

Summary

We examined in purified systems and in human plasma whether heparin serves as a contact system activating compound. Purified human factor XII zymogen was not activated by heparin through an autoactivation mechanism, but was activated in the presence of purified prekallikrein. Zn²⁺ (12 εM) did not support autoactivation by heparin. The activation of factor XII and the contact system by heparin in plasma anticoagulated with citrate or with hirudin (not chelating ions) was examined by the cleavage of ¹²⁵I-labeled factor XII and high molecular weight kininogen (HK). Heparin at 1.6 and 16 USP U/ml was not able to produce activation, in contrast to dextran sulfate (20 εg/ml) which supported activation of both factor XII and HK. This study indicates that heparinized plasma does not support activation of the contact system mediated through activation of factor XII. It is not expected that heparin anticoagulant therapy will contribute to activation of the contact system.

• References

• 1 Colman RW. Surface-mediated defense reactions. The plasma contact activation system. Perspectives. J Clin Invest 1984; 73: 1249-53
• 2 Pierce JV, Webster ME. Purification and some properties of the two different kallidinogens. In: Hypotensive Peptides.. Erdos EG, Back N, Sicuteri F. (eds) Springer, New York: 1966. p 130
• 3 Scott CF, Silver LD, Schapira M, Colman RW. Cleavage of human high molecular weight kininogen markedly enhances its coagulant activity: Evidence that this molecule exists as a procofactor. J Clin Invest 1984; 73: 954-62
• 4 Brash JL, Scott CF, Hove P, Wojcienchowski P, Colman RW. Mechanism of transient absorption of fibrinogen from plasma to solid surfaces: Role of the contact and fibrinolytic systems. Blood 1988; 71: 932-9
• 5 Shore JD, Day DE, Bock PE, Olson ST. Acceleration of surface-dependent autocatalytic activation of blood coagulation factor XII by divalent metal ions. Biochemistry 1987; 26: 2250-8
• 6 Shimada T, Kato H, Iwanaga S. Accelerating effect of zinc ions on the surface-mediated activation of factor XII and prekallikrein. J Biochem 1987; 102: 913-21
• 7 Pixley RA, Schapira M, Colman RW. The regulation of human factor XIIa by plasma proteinase inhibitors. J Biol Chem 1985; 260: 1723-9
• 8 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: 1542-9
• 9 Pixley RA, Schmaier A, Colman RW. Effect of negatively charged activating compounds on inactivation of factor XIIa by C1 inhibitor. Arch Biochem Biophys 1987; 256: 490-8
• 10 Pixley RA, Schmaier A, Colman RW. The effect of factor XII activating compounds on factor XIIa and XIIf inhibition by C1 inhibitor. Fed Proc 1986; 45: 1638
• 11 Colman RW, Scott CF, Pixley RA, De La Cadena RA. Effect of heparin on the inhibition of the contact system enzymes. Ann N Y Acad Sci 1989; 556: 95-103
• 12 Ofosu FA, Danishefsky I, Hirsh J. Heparin and Related Polysaccharides. Structure and Activities. Ann N Y Acad Sci 1989 Vol. 556
• 13 Pixley RA, Schapira M, Colman RW. Effect of heparin on the inactivation rate of human activated factor XII by antithrombin III. Blood 1985; 66: 198-203
• 14 Hojima Y, Cochrane CG, Wiggins RC, Austen KF, Stevens RL. In vitro activation of the contact (Hageman Factor) system of plasma by heparin and chondroitin sulfate E. Blood 1984; 63: 1453-9
• 15 Silverberg M, Diehl SV. The autoactivation of factor XII (Hageman Factor) induced by low-Mr heparin and dextran sulfate. Biochem J 1987; 248: 715-20
• 16 Griep MA, Fujikawa K, Nelsestuen GL. Possible basis for the apparent surface selectivity of the contact activation of human blood coagulation factor XII. Biochemistry 1986; 25: 6688-94
• 17 Pixley RA, Stumpo LG, Birkmeyer K, Silver L, Colman RW. A monoclonal antibody recognizing an icosapeptide sequence in the heavy chain of human factor XII inhibits surface-catalyzed activation. J Biol Chem 1987; 262: 10140-5
• 18 Scott CF, Liu CY, Colman RW. Human plasma prekallikrein: A rapid high-yield method for purification. Eur J Biochem 1979; 100: 77-83
• 19 Kerbiriou DM, Griffin JH. Human high molecular weight kininogen. Studies of structure-functional relationships and of proteolysis of the molecule occurring during contact activation of plasma. J Biol Chem 1979; 254: 12020-7
• 20 Proctor RR, Rapaport SI. The partial thromboplastin time with kaolin. The simple screening test for the first stage plasma clotting factor deficiencies. Am J Clin Pathol 1961; 36: 212-19
• 21 Fraker PJ, Speck Jr SJ. Protein and cell membrane iodinations with a sparingly soluble chloroamide. 1,3,4,6-tetrachloro-3a,6a-diphenylglycoluril. Biochem Biophys Res Commun 1978; 80: 849-57
• 22 Tuszynski GP, Knight L, Piperno JR, Walsh PN. Labeling of platelet surface proteins with ¹²⁵I by the iodogen method. Anal Biochem 1983; 106: 118-22
• 23 Kaufman N, Page JD, Pixley RA, Schein R, Schmaier AH, Colman RW. α₂-Macroglobulin-kallikrein complexes detect contact system activation in hereditary angioedema and human sepsis. Blood 1991; 77: 2660-7
• 24 Veloso D, Silver LD, Hahn S, Colman RW. A monoclonal anti-human plasma prekallikrein antibody that inhibits activation of prekallikrein by factor XIIa on a surface. Blood 1987; 70: 1053-62
• 25 Thompson RE, Mandle Jr R, Kaplan AP. Characterization of high molecular weight kininogen. Procoagulant activity associated with the light chain of kinin-free high molecular weight kininogen. J Exp Med 1978; 147: 488-99
• 26 Mori K, Nagasawa S. Studies on human high molecular weight kininogen II. Structural change of HMW kininogen by the action of human plasma kallikrein. J Biochem 1981; 89: 1465-73
• 27 Griffin JH. Role of surface in surface-dependent activation of Hageman factor (blood coagulation factor XII). Proc Natl Acad Sci (USA) 1978; 75: 1998-2002
• 28 Rosenberg RD, Damus PS. The purification and mechanism of action of human antithrombin-heparin cofactor. J Biol Chem 1973; 248: 6490-505
• 29 Stein PL, Van Zonneveld A-J, Pannekoek H, Strickland S. Structural domains of human tissue-type plasminogen activator that confer stimulation by heparin. J Biol Chem 1989; 264: 15441-4
• 30 Lijnen HR, Hoylaerts M, Collen D. Heparin binding properties of human histidine-rich glycoprotein. Mechanism and role in the neutralization of heparin in plasma. J Biol Chem 1983; 258: 3803-8
• 31 Bjork I, Olson ST, Sheffer RG, Shore JD. Binding of heparin to human high molecular weight kininogen. Biochemistry 1989; 28: 1213-21
• 32 Moskowitz RW, Schwartz HJ, Michel B, Ratnoff OD. Generation of kinin-like agents by chondroitin sulfate, heparin, chitin sulfate, and human articular cartilage: Possible pathophysiologic implications. J Lab Clin Med 1970; 76: 790-8
• 33 Harpel PC, Lewin HJ, Kaplan AP. Distribution of plasma kallikrein between C1-inactivator and α₂-macroglobulin, in plasma utilizing in a new assay for α₂-macroglobin complexes. J Biol Chem 1985; 260: 4257-63
• 34 Tans G, Rosing J, Berrettini M, Lammle B, Griffin JH. Autoactivation of human plasma prekallikrein. J Biol Chem 1987; 262: 11308-14
• 35 Heimark RL, Davie EW. Bovine and human plasma prekallikrein. Meth Enzymol 1981; 80: 157-71