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PCI: Protein C Inhibitor?

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Chemistry and Biology of Serpins

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 425))

Abstract

Blood coagulation is a complex chain reaction of enzyme activations in which inactive zymogens are activated by proteolytic cleavage. Each newly activated enzyme in turn cleaves the next zymogen in the chain, resulting in its activation. The final enzyme in the cascade, thrombin, then cleaves soluble fibrinogen into insoluble fibrin which forms a thrombus. A single enzyme can cleave and activate multiple zymogens, thus a small initial stimulus can amplify into a massive wave of coagulation. In addition, thrombin can feedback and stimulate its own synthesis by proteolytically activating two necessary cofactors in thrombin generation, Factor Va and Factor VIIIa. Thus, the coagulation cascade proceeds by both amplification and a feedback positive mechanism, a potentially deadly combination if not closely regulated.

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References

  • Björk, I., and Lindahl, U. (1982). Mechanism of the anticoagulant action of heparin. Mol. Cell. Biochem. 48, 161–182.

    Article  PubMed  Google Scholar 

  • Bourin, M., Boffa, M., Björk, I., and Lindahl, U. (1986). Functional domains of rabbit thrombomodulin. Proc. Natl. Acad. Sci. U.S.A. 83, 5924–5928.

    Article  PubMed  CAS  Google Scholar 

  • Cooper, S. T., and Church, F. C. (1995). Reactive site mutants of recombinant protein C inhibitor. Biochim. Biophys. Acta 1246, 29–33.

    Google Scholar 

  • Cooper, S. T., Neese, L. N., Dicuccio, M., Liles, D. K., Hoffman, M., and Church, F. C. (1996). Heparin-binding serpins are not released following intravenous heparin injection. Clinical and Applied Thrombosis/Hemostasis 2, 185–191.

    Article  Google Scholar 

  • Cooper, S. T., Whinna, H. C., Jackson, T. P., Boyd, J. M., and Church, F. C. (1995). Intermolecular interactions between protein C inhibitor and coagulation proteases. Biochemistry 34, 12991–12997.

    Article  PubMed  CAS  Google Scholar 

  • Dahlback, B. (1994). Physiological anticoagulation: Resistance to activated protein C and venous thromboembolism. J. Clin. Invest. 94, 923–927.

    Article  PubMed  CAS  Google Scholar 

  • Dahlback, B., Carlsson, M., and Svensson, P. J. (1993). Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: Prediction of a cofactor to activated protein C. Proc. Natl. Acad. Sci. 90, 1004–1008.

    CAS  Google Scholar 

  • Dahlback, B., and Hildebrand, B. (1994). Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of Factor V. Proc. Natl. Acad. Sci. 91, 1396–1400.

    CAS  Google Scholar 

  • Ecke, S., Geiger, M., Resch, I., Jerabek, I., Stingl, L., Maier, M., and Binder, B. R. (1992). Inhibition of tissue kallik-rein by protein C inhibitor. Evidence for identity of protein C inhibitor with the kallikrein binding protein. J.Biol. Chem. 267, 7048–7052.

    CAS  Google Scholar 

  • Esmon, C. T. (1992). The protein C anticoagulant pathway. Arteriosclerosis and Thrombosis 12, 135–145.

    Article  PubMed  CAS  Google Scholar 

  • Esmon, C. T. (1989). The roles of protein C and thrombomodulin in the regulation of blood coagulation. J. Biol. Chem. 264, 4743–4746.

    PubMed  CAS  Google Scholar 

  • Espana, F., Berrettini, M., and Griffin, J. H. (1989). Purification and characterization of plasma protein C inhibitor. Thromb. Res. 55, 369–384.

    Article  PubMed  CAS  Google Scholar 

  • Espana, F., Estelles, A., Fernandez, P. J., Gilabert, J., Sanchez-Cuenca, J., and Griffin, J. H. (1993). Evidence for the regulation of urokinase and tissue type plasminogen activators by the serpin protein C inhibitor, in semen and blood plasma. Thromb. Hemostasis 70, 989–994.

    CAS  Google Scholar 

  • Espana, F., Fink, E., and Witzgall, K. (1995). Complexes of tissue kallikrein with protein C inhibitor in human semen and urine. Eur. J. Biochem. 234, 641.

    Article  PubMed  CAS  Google Scholar 

  • Espana, F., Gilabert, J., Estelles, A., Romeu, A., Aznar, J., and Cabo, A. (1991). Functionally active protein C inhibitor/plaminogen activator inhibitor-3 (PCI/PAI-3) is secreted in seminal vesicles, occurs at high concentrations in human seminal plama and complexes with prostate-specific antigen. Thromb. Res. 64, 309–320.

    Article  PubMed  CAS  Google Scholar 

  • Espana, F., Vicente, V., Tabernero, D., Scharrer, I., and Griffin, J. H. (1990). Determination of plasma protein C inhibitor and of two activated protein C-inhibitor complexes in normals and in patients with intravascular coagulation and thrombotic disease. Thrombosis research 59, 593–608.

    Article  PubMed  CAS  Google Scholar 

  • Geiger, M., Huber, K., Wojta, J., Stingl, L., Espana, F., Griffin, J. H., and Binder, B. R. (1989). Complex formation between urokinase and plasma protein C inhibitor in vitroand in vivo. Blood 74, 722–728.

    PubMed  CAS  Google Scholar 

  • Geiger, M., Priglinger, U., Griffin, J. H., and Binder, B. R. (1991). Urinary protein C inhibitor. Glycosaminoglycans synthesized by the epithelial kidney cell line TLC-598 enhance its interaction with urokinase. J. Biol. Chem. 266, 11851–11857.

    PubMed  CAS  Google Scholar 

  • Heeb, M. J., Espana, F., and H., G. J. (1989). Inhibition and complexation of activated protein C by two major inhibitors in plasma. Blood 73, 446–454.

    PubMed  CAS  Google Scholar 

  • Heeb, M. J., and Griffin, J. H. (1988). Physiologic inhibition of human activated protein C by al-antitrypsin. J. Biol. Chem. 263, 11613–11616.

    PubMed  CAS  Google Scholar 

  • Hofsteenge, J., Taguchi, H., and Stone, S. R. (1986). Effect of thrombomodulin on the kinetics of the interaction of thrombin with substrates and inhibitors. Biochem. J. 237, 243–251.

    PubMed  CAS  Google Scholar 

  • Hoogendoorn, H., Nesheim, M. E., and Giles, A. R. (1990). A qualitative and quantitative analysis of the activation and inactivation of protein C in vivoin a primate model. Blood 75, 2164–2171.

    PubMed  CAS  Google Scholar 

  • Hoogendoorn, H., Toh, C. H., Nesheim, M. E., and Giles, A. R. (1991). Alpha2-macroglobulin binds and inhibits activated protein C. Blood 78, 2283–2290.

    PubMed  CAS  Google Scholar 

  • Kane, W. H., and Davie, E. W. (1988). Blood coagulation factors V and VIII: Structural and functional similarities and their relationship to hemorrhagic and thrombotic disorders. Blood 71, 539–555.

    PubMed  CAS  Google Scholar 

  • Kisiel, W. (1979). Human plasma protein C: Isolation, characterization, and mechanism of activation by a-thrombin. J. Clin. Invest. 64, 761–770.

    Article  PubMed  CAS  Google Scholar 

  • Kuhn, L. A., Griffin, J. H., Fisher, C. L., Greengard, J. S., Bouma, B. N., Espana, F., and Tainer, J. A. (1990). Elucidating the structural chemistry of glycosaminoglycan recognition by protein C inhibitor. Proc. Natl. Acad. Sci. U.S.A. 87, 8506–8510.

    Article  PubMed  CAS  Google Scholar 

  • Laurell, M., Christensson, A., Abrahamsson, R-A., Stenflo, J., and Lilja, H. (1992). Protein C inhibitor in human body fluids. Seminal plasma is rich in inhibitor antigen deriving from cells throughout the male reproductive system. J. Clin. Invest. 89, 1094–101.

    Article  PubMed  CAS  Google Scholar 

  • LeBonniec, B. F., Guinto, B. F., and Esmon, C. T. (1992). Interaction of thrombin desETW with antithrombin III, the kunitz inhibitors, thrombomodulin and protein C. J. Biol. Chem. 267, 19341–19348.

    CAS  Google Scholar 

  • LeBonniec, B. F., Guinto, E. R., MacGillivray, R. T. A., Stone, S. R., and Esmon, C. T. (1993). The role of thrombin’s Tyr-Pro-Pro-Trp motif in the interaction with fibrinogen, thrombomodulin, protein C, antithrombin III and the kunitz inhibitors. J. Biol. Chem. 268, 19055–19061.

    CAS  Google Scholar 

  • Marlar, R. A., Endres-Brooks, J., and Miller, C. (1985). Serial studies of protein C and its plasma inhibitor in patients with disseminated intravascular coagulation. Blood 66, 59–63.

    PubMed  CAS  Google Scholar 

  • Marlar, R. A., and Griffin, J. H. (1980). Deficiency of protein C inhibitor in combined factor V/VIII deficiency disease. J. Clin. Invest. 66, 1186–1189.

    Article  PubMed  CAS  Google Scholar 

  • Meijers, J. C. M., Kanters, D. H. A. J., Vlooswijk, R. A. A., van Erp, H. E., Hessing, M., and Bouma, B. N. (1988). In- activation of human plasma kallikrein and factor XIa by protein C inhibitor. Biochemistry 27, 4231–4237.

    Article  PubMed  CAS  Google Scholar 

  • Minamikawa, K., Wada, H., Wakita, Y., Ohiwa, M., Tanigawa, M., Deguchi, K., Hiraoka, N., Huzioka, H., Nishioka, J., Hayashi, T., Shirakawa, S., Nakano, T., and Suziki, K. (1994). Increased activated protein C-protein C inhibitor complex levels in patients with pulmonary embolism. Thromb. Hemostasis 71, 192–194.

    CAS  Google Scholar 

  • Morito, F., Saito, H., Suzuki, K., and Hashimoto, S. (1985). Synthesis and secretion of protein C inhibitor by the human hepatoma-derived cell line, Hep G2. Biochimica et Biophysica Acta 844, 209–215.

    Article  PubMed  CAS  Google Scholar 

  • Olson, S. T., and Björk, I. (1992). Regulation of thrombin by antithrombin and heparin cofactor II. In Thrombin: Structure and Function, L. J. Berliner, ed. (New York, NY: Plenum Press ), pp. 159–217.

    Google Scholar 

  • Phillips, J. E., Cooper, S. T., Potter, E. E., and Church, F. C. (1994). Mutagenesis of recombinant protein C inhibitor reactive site residues alters target proteinase specificity. J. Biol. Chem. 269, 16696–16700.

    PubMed  CAS  Google Scholar 

  • Pratt, C. W., and Church, F. C. (1992). Heparin binding to protein C inhibitor. J. Biol. Chem. 267, 8789–8794. Pratt, C. W., Macik, B. G., and Church, F. C. (1989). Protein C inhibitor: purification and proteinase reactivity.Thromb. Res. 53, 595–602.

    Google Scholar 

  • Pratt, C. W., Whinna, H. C., and Church, F. C. (1992). A comparison of three heparin-binding serine proteinase inhibitors. J. Biol. Chem. 267, 8795–8801.

    PubMed  CAS  Google Scholar 

  • Preissner, K. T., Koyama, T., Muller, D., Tschopp, J., and Muller-Berghaus, G. (1990). Domain structure of the endothelial cell receptor thrombomodulin as deduced from modulation of its anticoagulant functions. Evidence for a glycosaminoglycan-dependent secondary binding site for thrombin. J. Biol. Chem. 265, 4915–4922.

    CAS  Google Scholar 

  • Radtke, K. P., Fernandez, J. A., Greengard, J. S., Tang, W. W., Wilson, C. B., Loskutoff, D. J., Scharrer, l., and Griffin, J. H. (1994). Protein C inhibitor is expressed in tubular cells of human kidney. J. Clin. Invest. 94, 2117–2124.

    Article  PubMed  CAS  Google Scholar 

  • Rezaie, A. R., Cooper, S. T., Church, F. C., and Esmon, C. T. (1995). Protein C inhibitor is a potent inhibitor of the thrombin-thrombomodulin complex. J. Biol. Chem. 270, 25336–25339.

    Article  PubMed  CAS  Google Scholar 

  • Rosenberg, R. D. (1977). Chemistry of the hemostatic mechanism and its relationship to the action of heparin. Fed. Proc. Fed. Am. Soc. Exp. Biol. 36, 10–18.

    CAS  Google Scholar 

  • Rosenberg, R. D., and Damus, P. S. (1973). The purification and mechanism of action of human antithrombinheparin cofactor. J. Biol. Chem. 248, 6490–6505.

    PubMed  CAS  Google Scholar 

  • Sheng, S., Pemberton, P. A., and Sager, R. (1994). Production, purification and characterization of recombinant maspin proteins. J. Biol. Chem. 269, 30988–30993.

    PubMed  CAS  Google Scholar 

  • Shirk, R. A., Elisen, M. G. L. M., Meijers, J. C. M., and Church, F. C. (1994). Role of the H helix in heparin binding to protein C inhibitor. J. Biol. Chem. 269, 28690–28695.

    PubMed  CAS  Google Scholar 

  • Shore, J. D., Olson, S. T., Craig, P. A., Choay, J., and Björk, I. (1989). Kinetics of heparin action. Ann. N. Y. Acad. Sci. 556, 75–80.

    Article  PubMed  CAS  Google Scholar 

  • Stenflo, J. (1976). A new vitamin K-dependent protein: Purification from bovine plasma and preliminary characterization. J. Biol. Chem. 251, 355.

    PubMed  CAS  Google Scholar 

  • Suzuki, K., Deyashiki, Y., Nishioka, J., Kurachi, K., Akira, M., Yamamoto, S., and Hashimoto, S. (1987). Characterization of a cDNA for human protein C inhibitor. A new member of the plasma serine protease inhibitor superfamily. J. Biol. Chem. 262, 611–616.

    PubMed  CAS  Google Scholar 

  • Suzuki, K., Deyashiki, Y., Nishioka, J., and Toma, K. (1989). Protein C inhibitor: structure and function. Thromb. Haemostas. 61, 337–342.

    CAS  Google Scholar 

  • Suzuki, K., Nishioka, J., and Hashimoto, S. (1983). Protein C inhibitor: purification from human plasma and characterization. J. Biol. Chem. 258, 163–168.

    PubMed  CAS  Google Scholar 

  • Suzuki, K., Nishioka, J., and Hashimoto, S. (1983). Regulation of activated protein C by thrombin-modified protein S. J. Biochem. 94, 699–705.

    PubMed  CAS  Google Scholar 

  • Tabernero, D., Espana, F., Vicente, V., Estelles, A., Gilabert, J., and Aznar, J. (1990). Protein C inhibitor and other components of the protein C pathway in patients with acute deep vein thrombosis during heparin treatment. Thromb. Haemost. 63, 380–382.

    CAS  Google Scholar 

  • Tanigawa, M., Wada, H., and Shiku, H. (1995). Decreased protein C inhibitor after percutaneous transluminal coronary angioplasty in patients with acute myocardial infarction. Am. J. Hematol. 49, 1.

    Google Scholar 

  • Travis, J., and Salvesen, G. S. (1983). Human plasma proteinase inhibitors. Annu. Rev. Biochem. 52, 655–709.

    Article  CAS  Google Scholar 

  • van Deerlin, V. M. D., and Tollefsen, D. M. (1991). The N-terminal acidic domain of heparin cofactor II mediates the inhibition of a-thrombin in the presence of glycosaminoglycans. J. Biol. Chem. 266, 20223–20231.

    PubMed  Google Scholar 

  • van der Meer, F. J. M., van Tilburg, N. H., van Winjgaarden, A., van der Linden, I. K., Briet, E., and Bertina, R. M. (1989). A second plasma inhibitor of activated protein C: alphal-antitrypsin. Thromb. Hemostasis 62, 756–762.

    Google Scholar 

  • Zheng, X., Geiger, M., and Binder, B. R. (1994). Inhibition of acrosin by protein C inhibitor and localization of protein C inhibitor to spermatozoa. Am. J. Physiol. 267, 1.

    Google Scholar 

  • Zheng, X. L., Ecke, S., Geiger, M., Bielek, E., Schleuning, W.-D., and Binder, B. R. (1993). Physiological inhibition of acrosin by protein C inhibitor (PCI). Throm. Haemostas. 69 (abstract# 1275), 895.

    Google Scholar 

  • Zou, Z., Anisowicz, A., Hendrix, M. J. C., Thor, A., Neveu, M., Sheng, S., Rafidi, K., Seftor, E., and Sager, R. (1994). Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells. Science 263, 526–529.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Biology and Microbiology, University of Wisconsin-La Crosse, La Crosse, Wisconsin, 54601, USA

    Scott T. Cooper

  2. Department of Pathology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7035, USA

    Frank C. Church

  3. Department of Lab Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7035, USA

    Frank C. Church

  4. Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7035, USA

    Frank C. Church

  5. Department of Center for Thrombosis, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7035, USA

    Frank C. Church

  6. Department of Hemostasis, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7035, USA

    Frank C. Church

Authors
  1. Scott T. Cooper
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  2. Frank C. Church
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Editor information

Editors and Affiliations

  1. University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

    Frank C. Church

  2. University of California, Irvine, California, USA

    Dennis D. Cunningham

  3. Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan, USA

    David Ginsburg

  4. Duke University and Durham VA Medical Centers, Durham, North Carolina, USA

    Maureane Hoffman

  5. Late of Monash University, Clayton, Victoria, Australia

    Stuart R. Stone

  6. Washington University School of Medicine, St. Louis, Missouri, USA

    Douglas M. Tollefsen

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Cooper, S.T., Church, F.C. (1997). PCI: Protein C Inhibitor?. In: Church, F.C., Cunningham, D.D., Ginsburg, D., Hoffman, M., Stone, S.R., Tollefsen, D.M. (eds) Chemistry and Biology of Serpins. Advances in Experimental Medicine and Biology, vol 425. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5391-5_5

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  • DOI: https://doi.org/10.1007/978-1-4615-5391-5_5

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