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Safer Surgery Using Zymogen Protein C Concentrate

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Oxygen Transport to Tissue XXXI

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 662))

Abstract

This is the first case (November 12, 2007) of peri-operative use of zymogen protein C (ZPC) for a heterozygote Protein C deficient (50%) patient with heterozygosity for the prothrombin gene mutation. The surgery involved total left hip replacement. The patient was 74 years of age and at very high-risk for Deep Vein Thrombosis (DVT) thus possible lung emboli. He was a survivor of Venous thrombo-embolism (VTE) in 1999.

For this case the need for increased heparin to prevent a reoccurrence of thrombosis led to a further concern of internal bleeding and possible infection. As proposed by the authors in previous publications the use of a ZPC concentrate would decrease the chance of a thrombosis, with minimum or no internal bleeding. ZPC is activated at the endothelium cell surface and on the surface of the platelets where and when it is needed, therefore providing a safer procedure.

This protocol was implemented by administering ZPC concentrate 1 day prior to surgery and continuing for 10 days after. Slightly higher than normal blood loss occurred, however, a safe procedure was achieved without dangerous side effects while several additional benefits were experienced (level of PC activity as high as 235% above normal were measured during the procedure.). It is felt that positive effects were the result of increased blood flow and oxygen transport to the tissues by reducing blood sludging in the microcirculation. Further studies on Protein C dose levels will be necessary to provide economical, safe and efficacious use of Protein C products.

It is suggested that ZPC should be considered for patients with high probability of VTE which could cause thrombotic occlusion of the pulmonary and peripheral vasculature. These phenomena can result in hypoxia and hypo perfusion causing organ failure and death.

Our research includes a focused effort to optimize upstream and downstream bio-processing to produce both zymogen and activated Protein C at a lower cost and to examine the medical indications that could benefit from a more available and affordable Protein C product.

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References

  1. Andersson, L., 1991, Recognition of phosphate groups by immobilized aluminum (III) ions. J. Chromatogr. 539:327–334.

    Article  CAS  Google Scholar 

  2. Andersson, L., Porath, J., 1986, Isolation of phosphoproteins by immobilized metal (Fe+++) affinity chromatography. Anal. Biochem. 154:250–254.

    Article  PubMed  CAS  Google Scholar 

  3. Bertina, R.M., 1988, Protein C and Related Proteins. Churchill Livingstone, New York.

    Google Scholar 

  4. Bicher, H. I., Bruley, D. F., Knisely, M. H., 1973, Anti-adhesive drugs and tissue oxygenation. Adv. Exp. Med. Biol. Plenum Press, 37B:657–667.

    CAS  Google Scholar 

  5. Bruley, D.F, 1998, Protein C-The Ultimate Anticoagulant/Antithrombotic?, in: C.A.Thibeault and L.M. Savage (eds.). Anticoagulant, Antithrombotic, and Thrombolytic Thearapeutics II. Springer, Southborough, MA (IBC Library Series).

    Google Scholar 

  6. Bruley, D. F., 2009, Zymogen protein C concentrate for safer heterozygote surgery, “I am a Guinea Pig!”. Adv. Exp. Med. Biol., Oxygen Transport To Tissue XXX, Springer, Vol.645,:115–121.

    Article  CAS  Google Scholar 

  7. Bruley, D.F., Drohan, W.N., 1990, Advances in Applied Biotechnology Series, Protein C and related anticoagulants, 11, Gulf Publications, Houston, TX.

    Google Scholar 

  8. Clouse, L.H., Comp, P.C., 1986, The regulation of hemostasis: the Protein C system. N. Engl. J. Med. 314:1298–1304.

    Article  PubMed  CAS  Google Scholar 

  9. Colucci, M., 1984, Influence of protein C activation on blood coagulation and fibrinolysis in squirrel monkeys. J. Clin. Invest. 74:200–204.

    Article  PubMed  CAS  Google Scholar 

  10. Comp, P., Esmon, C., 1981, Generation of fibrinolytic activity by infusion of activated protein C into dogs. J. Clin. Invest. 68:1221–1228.

    Article  PubMed  CAS  Google Scholar 

  11. Dreyfus, M., Magny, J.F. Bridey, F. et al., 1991, Treatment of homologous protein C deficiency and neonatal purpurafulminans with a purified protein C concentrate. N. Engl. J. Med. 325:1565–1568.

    Article  PubMed  CAS  Google Scholar 

  12. Esmon, C. T., 1989, The roles of protein C and thrombomodulin in the regulation of blood coagulation. J. Biol. Chem. 264:4743.

    PubMed  CAS  Google Scholar 

  13. Fernlund, P., Stenflo, J., 1982, Amino acid sequence of the light chain of bovine protein C. J. Biol. Chem. 257:12170–12179.

    CAS  Google Scholar 

  14. Gruber, A., Griffin, J.H., Harker, L.A., Hanson, S.R., 1989, Inhibition of platelet-dependent thrombosis formation by human activated protein C in a primate model. Blood. 73:639–642.

    PubMed  CAS  Google Scholar 

  15. Kisiel, W., 1979, Human plasma protein C: Isolation, characterization and mechanism of activation by a thrombin. J. Clin. Invest. 4:761.

    Article  Google Scholar 

  16. Kisiel, W., Carnfield, W. M., Ericsson, L.H., Davie, E. W., 1977, Anticoagulant properties of bovine plasma protein C following activation by thrombin. Biochemistry. 1:5824.

    Article  Google Scholar 

  17. Laemmli, U.K., 1970, Cleavage of the structural proteins during the assembly of the head of bacteriophage T4. Nature. 227:680–685.

    Article  PubMed  CAS  Google Scholar 

  18. Lee, J., Thiessen, E. E., and Bruley, D. F., “Anticoagulant/anti-inflammatory/antithrombotic Protein C Production-Metal Ion/Protein Intefacial Interaction in Immobilized Metal Affinity Chromatography,” Proceeding of the annual ISOTT Conference.

    Google Scholar 

  19. Life Magazine, May 31, 1948.

    Google Scholar 

  20. Manco-Johnson, M., Nuss, R., 1992, Protein C concentrate prevents peripartum thrombosis. Am. J. Hematol. 40:69–70.

    Article  PubMed  CAS  Google Scholar 

  21. Marlar, R. A., Montgomery, R. R., Broakman, A. W., 1989, Diagnosis and treatment of homozygous protein C deficiency. Report of the working party on homozygous protein C deficiency of the subcommittee on protein C and protein S, International Committee on Thrombosis and Haemostasis. J. Paediatrics. 114:528–534.

    Article  CAS  Google Scholar 

  22. Odegaard, O. R., Try, K., Anderson, T. R., 1987, Protein C: an automated activity assay. Haemostasis. 17:109–113.

    PubMed  CAS  Google Scholar 

  23. Okajima, K., Koga, S., Kaji, M., et al., 1990, Effect of protein C and activated protein C on coagulation and fibrinolysis on normal human subjects. Thromb. Haemostas. 3:48–53.

    Google Scholar 

  24. Porath, J., 1992, Immobilized metal ion affinity chromatography. Prot. Express. Purif. 3:263–281.

    Article  CAS  Google Scholar 

  25. Porath, J., Carlsson, J., Olsson, I., Belfrage, G., 1975, Metal chelate affinity chromatography, a new approach to protein fractionation. Nature. 258:598–599.

    Article  PubMed  CAS  Google Scholar 

  26. Ramadan, N., Porath, J., 1985, Fe3+-hydroxamate as immobilized metal affinity-adsorbent for protein chromatography. J. Chromatogr. 321:93–104.

    Article  PubMed  CAS  Google Scholar 

  27. Sulkowski, E., 1988, Immobilized metal ion affinity of proteins on IDA-Fe3+, Makromol. Chem. Macromol. Symp. 17:335–348.

    Article  CAS  Google Scholar 

  28. Tadepalli, S. S., Bruley, D. F., Kang, K. A., Drohan, W. N., 1997, Immobilized metal affinity chromatography process identification and scale-up for protein C production. In: Harrison, D. K., Delpy, D. T. (eds.), ISOTT XIX. Advances in Experimental Medicine and Biology, Vol. 428. Plenum Press, New York, 31–43.

    Google Scholar 

  29. Thiessen, E. E., and D. F. Bruley, 2003 “Theoretical Studies of IMAC Interfacial Phenomena for the Production of Protein C,” Oxygen Transport to Tissue XXV in Adv. Exp. Med. Biol. 540:183.

    CAS  Google Scholar 

  30. Velander, W. H., Johnson, J. L., Page, R. L., et. al., 1992, High-level expression of a heterologous protein in the milk of transgenic swine using the cDNA encoding human protein. C. Proc. Natil. Acad. Sci. 89:12003–12007.

    Article  CAS  Google Scholar 

  31. Vukovich, T., Auberger, K., Weil, J., Engelmann, H., Knobl, P., Hadorn, H. B., 1988, Replacement therapy for a homozygous protein C deficiency-state using a concentrate of human protein C and S. Br. J. Haematol. 70:435–440.

    Article  CAS  Google Scholar 

  32. Winslow, R., 1995, Increased use of blood-thinning drugs could prevent 40,000 strokes a year, Wall St. J. September, 8.

    Google Scholar 

  33. Winzerling, J. J., Patrick, B., Porath, J., 1992, How to use immobilized metal ion affinity chromatography, Methods: Compan. Methods Enzymol. 4:4–13.

    Article  CAS  Google Scholar 

  34. Wong, J. W., Albright, R. L., Wang, N. H., 1991, Immobilized metal ion affinity chromatography (IMAC) chemistry and bioseparations applications. Sep. Purif. Methods. 20:49–106.

    Article  CAS  Google Scholar 

  35. Wu, H., Bruley, D. F., 1999, Homologous blood protein separation using immobilized metal affinity chromatography – protein C Separation from prothrombin with application to the separation of factor IX and prothrombin. Biotechnol. Prog. 15:928–931.

    Article  PubMed  CAS  Google Scholar 

  36. Wu, H., Bruley, D. F., 2002, Chelator, metal ion and buffer studies for protein C separation. Comp. Biochem. Physiol., A. 132:213–220.

    Article  Google Scholar 

  37. Wu, H., Bruley, D. F., Kang, K. A., 1998, Protein C separation from human blood plasma Cohn fraction IV-1 using immobilized metal affinity chromatography. in: Hudetz, A. G., Bruley, D. F. (eds.), ISOTT XX. Advances in Experimental Medicine and Biology, Vol. 454. Plenum Press, New York, 697–704.

    Google Scholar 

  38. Wu, H., Bruley, D. F., Kang, K. A., Drohan, W. N., 1997, Protein C separation from human plasmas Cohn fraction IV-1 using immobilized metal affinity chromatography, Topical Conference on Separation Science and Technologies – Proceedings of the 1997 Annual AIChE Meeting, 1443–1448.

    Google Scholar 

  39. Yu She,M.Ac.,Lic.Ac.,Dipl.Ac., yshe@umbc.edu, 2007,EllicottCity,MD,USA

    Google Scholar 

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Acknowledgments

We want to thank Suzanne Bruley and Eileen Thiessen for the typing and proofing of this manuscript.

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Authors and Affiliations

  1. Synthesizer, Inc., 2773 Westminster Road, Ellicott City, MD, 21043, USA

    Duane F. Bruley

  2. Department of Orthopaedic Surgery, Johns Hopkins University, 4940 Eastern Ave., Baltimore, MD, 21224, USA

    Simon C. Mears

  3. Division of Hematology, Department of Medicine, Johns Hopkins, 720 Rutland Avenue/ Ross 1025, Baltimore, MD, 21205-2196, USA

    Michael B. Streiff

Authors
  1. Duane F. Bruley
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  2. Simon C. Mears
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  3. Michael B. Streiff
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Corresponding author

Correspondence to Duane F. Bruley .

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Editors and Affiliations

  1. School of Medicine, Yamagata University, Yamagata, 990-9585, Japan

    Eiji Takahashi

  2. Westminster Rd 2773, Ellicott City, 21043, U.S.A.

    Duane F. Bruley

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Bruley, D.F., Mears, S.C., Streiff, M.B. (2010). Safer Surgery Using Zymogen Protein C Concentrate. In: Takahashi, E., Bruley, D. (eds) Oxygen Transport to Tissue XXXI. Advances in Experimental Medicine and Biology, vol 662. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-1241-1_63

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