Download PDF
Semin Thromb Hemost 2002; 28(S1): 079-086
DOI: 10.1055/s-2002-30200
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Purity, Activity, and Virus Safety of a Pasteurized Antithrombin Concentrate

Albrecht Gröner, Thomas Nowak, Jürgen Römisch
  • Research Laboratories Aventis Behring GmbH, Marburg, Germany
Further Information

Publication History

Publication Date:
17 May 2002 (online)

    Permissions and Reprints

Products derived from human plasma are employed for a wide variety of indications, including immunoglobulins for passive immunization,[1] clotting factors for the treatment of patients with hemophilia and related diseases,[2] [3] [4] [5] albumin for volume restoration,[6] and fibrin sealants for vascular and other surgical applications.[7] The purity and safety of these and other products derived from human plasma are sources of continuing concern.[8] [9]

Antithrombin (AT) is a plasmatic protease inhibitor that controls many clotting factors[10] [11] and that also has anti-inflammatory actions that are independent of its effects on coagulation.[12] [13] [14] [15] [16] AT has been used effectively for the treatment of hereditary and acquired AT deficiencies.[17]

This article summarizes the manufacturing process for Kybernin P, a pasteurized AT concentrate, and presents new data related to its purity, activity, and virus safety.

REFERENCES

  • 1 Lee M L, Gale R P, Yap P L. Use of intravenous immunoglobulin to prevent or treat infections in persons with immune deficiency.  Annu Rev Med . 1997;  48 93-102
    CrossrefPubMedGoogle Scholar
  • 2 Mannucci P M. Clinical evaluation of viral safety of coagulation factor VIII and IX concentrates.  Vox Sang . 1993;  64 197-203
    PubMedGoogle Scholar
  • 3 Hedner U, Bjoern S, Bernvil S S, Tegborn L, Stigendahl L. Clinical experience with human plasma-derived factor VIIa in patients with hemophilia A and high titer inhibitors.  Haemostasis . 1989;  19 335-342
    PubMedGoogle Scholar
  • 4 Federici A B, Mannucci P M. Optimizing therapy with factor VIII/von Willebrand factor concentrates in von Willebrand disease.  Haemophilia . 1998;  4(Suppl 3) 7-10
    CrossrefPubMedGoogle Scholar
  • 5 Seremetis S V, Aledort L M. Congenital bleeding disorders: rational treatment options.  Drugs . 1993;  45 541-547
    PubMedGoogle Scholar
  • 6 Gerard J L, Bricard H. Indications and role of albumin for vascular loading in the operating room.  Ann Fr Anesth Reanim . 1996;  15 481-490
    CrossrefPubMedGoogle Scholar
  • 7 Jackson M R, Gillespie D L, Longenecker E G. Hemostatic efficacy of fibrin sealant (human) on expanded polytetrafluorethylene carotid patch angioplasty: a randomized clinical trial.  J Vasc Surg . 1999;  30 461-467
    PubMedGoogle Scholar
  • 8 Ingerslev J. Safety of plasma derivatives.  Haemostasis . 1994;  24 311-323
    PubMedGoogle Scholar
  • 9 Hilfenhaus J. Virus safe plasma proteins: elimination of the viruses of risk by manufacturing procedure.  Transfus Sci . 1990;  11 35S-41S
    CrossrefPubMedGoogle Scholar
  • 10 Schuster H-P. AT III in septicemia with DIC.  Intensive Care Med . 1993;  19 S16-S18
    CrossrefPubMedGoogle Scholar
  • 11 Mammen E F. Antithrombin: its physiological importance and role in DIC.  Semin Thromb Hemost . 1998;  24 19-25
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Okajima K, Uchiba M. The anti-inflammatory properties of antithrombin III: new therapeutic implications.  Semin Thromb Hemost . 1998;  24 27-32
    PubMedGoogle Scholar
  • 13 Dunzendorfer S, Kaneider N, Rabensteiner A. Cell-surface heparan sulfate proteoglycan-mediated regulation of human neutrophil migration by the serpin antithrombin III.  Blood . 2001;  97 1079-1085
    CrossrefPubMedGoogle Scholar
  • 14 Ostrovsky L, Woodman R C, Payne D, Teoh D, Kubes P. Antithrombin III prevents and rapidly reverses leukocyte recruitment in ischemia/reperfusion.  Circulation . 1997;  96 2302-2310
    PubMedGoogle Scholar
  • 15 Shanley T P, Vasi N, Stark J, Morris C. Anti-thrombin III deficiency primes the endothelial inflammatory response via upregulation of adhesion molecules.  Crit Care Med (Abst) . 1999;  1(Suppl) 271
    PubMedGoogle Scholar
  • 16 Souter P J, Thomas S, Hubbard A R. Antithrombin inhibits lipopolysaccharide-induced tissue factor and interleukin-6 production by mononuclear cells, human umbilical vein cells, and whole blood.  Crit Care Med . 2001;  29 134-139
    PubMedGoogle Scholar
  • 17 Menache D. Antithrombin III concentrates.  Hematol Oncol Clin N Am . 1992;  6 1115-1120
    PubMedGoogle Scholar
  • 18 Cohn E J, Gurd F RN, Surgenor D M. A system for the separation of the components of human blood: quantitative procedures for the separation of the protein components of human plasma.  J Am Chem Soc . 1950;  72 465-474
    CrossrefPubMedGoogle Scholar
  • 19 Committee for Proprietary Medicinal Products. Note for Guidance on Virus Validation Studies: The Design, Contribution and Interpretation of Studies Validating the Inactivation and Removal of Viruses. London: European Agency for the Evaluation of Medicine Products. 1996. Pub. no. CPMP/ BWP/268/95
  • 20 Committee for Proprietary Medicinal Products. Note for Guidance on Plasma-Derived Medicinal Products. London: European Agency for the Evaluation of Medicine Products Pub. no. CPMP/BWP/269/95 1996
    Google Scholar
  • 21 Hilfenhaus J, Bernhardt D, Brazel D. La produzione di antithrombina III umana altamente purificata e virus safe. In: Mannucci PM, Mardelli F, Vicari G, eds. Anticoagulanti Natureli e Patologica Tromboembolica Heidelberg: Springer-Verlag 1993: 27-38
    Google Scholar
  • 22 Römisch J, List W, Bernhardt D. Nanofiltration bei der Herstellung des PPSB-Konzentrates Beriplex P/N.  Hämostaseologie . 1995;  15 171-178
    PubMedGoogle Scholar
  • 23 Ishizawa M, Kobayashi Y, Miyamura T, Matsuura S. Simple procedure of DNA isolation from human serum.  Nucleic Acids Res . 1991;  19 5792
    PubMedGoogle Scholar
  • 24 Biescas H, Gensana M, Fernandez J. Characterization and viral safety validation study of a pasteurized therapeutic concentrate of antithrombin III obtained through affinity chromatography.  Haematologica . 1998;  83 305-311
    PubMedGoogle Scholar
  • 25 Nunez H, Drohan W N. Purification of antithrombin III (human).  Semin Hematol . 1991;  28 24-30
    PubMedGoogle Scholar
  • 26 Ronneberger H. Assay of possible formation of antigenic components in heat-treated plasma protein preparations.  Arch Toxicol Suppl . 1986;  9 447-450
    PubMedGoogle Scholar
  • 27 O'Reilly M S, Pirie-Shepherd S, Lane W S, Folkman J. Antiangiogenic activity of the cleaved conformation of the serpin antithrombin.  Science . 1999;  285 1926-1928
    CrossrefPubMedGoogle Scholar
  • 28 Gray E, Walker A D, Heath A B. A collaborative study to establish the 2nd International Standard for Antithrombin Concentrate.  Thromb Haemost . 1999;  1 46-50
    PubMedGoogle Scholar
  • 29 Murphy P, Nowak T, Lemon S M, Hilfenhaus J. Inactivation of hepatitis A virus by heat treatment in aqueous solution.  J Med Virol . 1993;  41 61-64
    PubMedGoogle Scholar
  • 30 Nowak T, Klockman U, Hilfenhaus J. Inactivation of viruses related to hepatitis C virus by pasteurization in human plasma derivatives.  Biologicals . 1992;  20 83-85
    PubMedGoogle Scholar
  • 31 Clemens R, Weidmann E, Merkle W. Virus safety of a pasteurized antithrombin III concentrate: preclinical and clinical data.  Arzneimmittelforschung . 1987;  37 759-762
    PubMedGoogle Scholar
  • 32 Roggendorf M, Delvos U, Novakova-Banet A. Virus safety of pasteurized antithrombin III concentrate.  Thromb Haemost (Letter) . 1991;  65 212
    PubMedGoogle Scholar
  • 33 Aventis Behring. Data on file. 
    Google Scholar
      >