Download PDF
Thromb Haemost 1975; 33(03): 617-631
DOI: 10.1055/s-0038-1647857
International Committee on Thrombosis and Haemostasis Task Force
Schattauer GmbH

Potentially Thrombogenic Materials in Factor IX Concentrates[*]

H. S Kingdon
1   Dental Research Center, and the Departments of Medicine, Biochemistry, and Pathology, University of North Carolina, Chapel Hill, N. C. 27514, USA
2   Academisch Ziekenhuis, Leiden, The Netherlands; Bureau of Biologics, Food and Drug Administration, Bethesda, MD 20014, USA
,
R. L Lundblad
1   Dental Research Center, and the Departments of Medicine, Biochemistry, and Pathology, University of North Carolina, Chapel Hill, N. C. 27514, USA
2   Academisch Ziekenhuis, Leiden, The Netherlands; Bureau of Biologics, Food and Drug Administration, Bethesda, MD 20014, USA
,
J. J Veltkamp
1   Dental Research Center, and the Departments of Medicine, Biochemistry, and Pathology, University of North Carolina, Chapel Hill, N. C. 27514, USA
2   Academisch Ziekenhuis, Leiden, The Netherlands; Bureau of Biologics, Food and Drug Administration, Bethesda, MD 20014, USA
,
D. L Aronson
1   Dental Research Center, and the Departments of Medicine, Biochemistry, and Pathology, University of North Carolina, Chapel Hill, N. C. 27514, USA
2   Academisch Ziekenhuis, Leiden, The Netherlands; Bureau of Biologics, Food and Drug Administration, Bethesda, MD 20014, USA
› Author Affiliations
Further Information

Publication History

Received 30 January 1975

accepted 30 January 1975

Publication Date:
24 July 2018 (online)

    Permissions and Reprints

Summary

Factor IX concentrates manufactured from human plasma and intended for therapeutic infusion in man have been suspected for some time of being potentially thrombogenic. In the current studies, assays were carried out in vitro and in vivo for potentially thrombogenic materials. It was possible to rank the various materials tested according to the amount of thrombogenic material detected. For concentrates not containing heparin, there was substantial agreement between the in vivo and in vitro assays, with a coefficient of correlation of 0.77. There was no correlation between the assays for thrombogenicity and the antithrombin III content. We conclude that many presently available concentrates of Factor IX contain substantial amounts of potentially thrombogenic enzymes, and that this fact must be considered in arriving at the decision whether or not to use them therapeutically.

* Task Force Report


 

  • References

  • 1 Aronson D. L, Dodds W. J, Mustafa A. J. A quantitative two-stage assay for Factor IX (Christmas Factor) using plasma from dogs with Christmas Disease. Thrombosis et Diathesis Haemorrhagica 1972; 37: 529
    PubMedGoogle Scholar
  • 2 Blatt P. M, Lundblad R. L, Kingdon H. S, McLean G, Roberts H. R. Thrombogenic Materials in Prothrombin Complex Concentrates. Annals of Internal Medicine 1974; 81: 766
    CrossrefPubMedGoogle Scholar
  • 3 Breen F. A, Tullis J. L. Prothrombin concentrates in treatment of Christmas Disease and allied disorders. Journal of the American Medical Associat 1969; 208: 1848
    PubMedGoogle Scholar
  • 4 Davie E. W, Ratnoff O. D. Waterfall Sequence for Intrinsic Blood Clotting. Science 1964; 145: 1310
    CrossrefPubMedGoogle Scholar
  • 5 Feissly R. La Stabilite du fibrinogene in vivo . Comptes rendus des séances de la Société de biologie et de ses filiales 1925; 92: 219
    PubMedGoogle Scholar
  • 6 Fugikawa K, Legaz M. E, Davie E. W. Bovine Factor X (Stuart Factor). Mechanism of Activation by a Protein from Russell’s Viper Venom. Biochemistry 1972; 11: 2892
    PubMedGoogle Scholar
  • 7 Fujikawa K, Legaz M. E, Kato H, Davie E. W. The Mechanism of Activation of Bovine Factor IX (Christman Factor) by Bovine Factor XIa (Activated Plasma Thromboplastin Antecedent). Biochemistry 1974; 12: 4508
    PubMedGoogle Scholar
  • 8 Heldebrant C. M, Noyes C, Kingdon H. S, Mann K. G. The Activation of Prothrombin III. The Partial Amino Acid Sequences at the Amino Terminal of Prothrombin and the Intermediates of Activation. Biochemical and Biophysical Research Communications 1973; 54: 155
    CrossrefPubMedGoogle Scholar
  • 9 Henderson E. S, Rapaport S. I. The Thrombotic Activity of Activation Product. Journal of Clinical Investigation 1962; 41: 235
    CrossrefPubMedGoogle Scholar
  • 10 Hutt E. D, Kingdon H. S. Use of Heparinase to Eliminate Heparin Inhibition in Routine Coagulation Assays. Journal of Laboratory and Clinical Medicine 1972; 79: 1027
    PubMedGoogle Scholar
  • 11 Kasper C. K. Postoperative thrombosis in Hemophilia B. New England Journal of Medicine 1973; 289: 610
    CrossrefPubMedGoogle Scholar
  • 12 Kasper C. K. Clinical Use of Factor IX Concentrates; Report on Thromboembolic Complications. Thrombosis et Diathesis Haemorrhagica 1975; 33: 642
    PubMedGoogle Scholar
  • 13 Laurell C. Quantitative Estimation of Proteins by Electrophoresis in Agarose Gel containing Antibodies. Analytical Biochemistry 1966; 15: 45
    CrossrefPubMedGoogle Scholar
  • 14 Loeliger E. A, Hensen A, Mattern M. J, Veltkamp J. J, Bruning P. F, Hemker H. C. Treatment of Hemophilia B with purified Factor IX (PPSB). Folia medica neerlandica 1967; 10: 112
    PubMedGoogle Scholar
  • 15 Macfarlane R. G. An Enzyme Cascade in the Blood Clotting Mechanism, and its Function as a Biochemical Amplifer. Nature 1964; 202: 498
    CrossrefPubMedGoogle Scholar
  • 16 Marchesi S. L, Burney R. Prothrombin Complex Concentrates and Thromboses. New England Journal of Medicine 1974; 290: 403
    CrossrefPubMedGoogle Scholar
  • 17 Pitlick F. A, Lundblad R. L, Davie E. W. The Role of Heparin in Intrinsic Blood Coagulation. Journal of Biomedical Materials Research 1969; 3: 95
    CrossrefPubMedGoogle Scholar
  • 18 Rosenberg R. D, Damus P. S. The Purification and Mechanism of Action of Human Antithrombin-Heparin Cofactor. Journal of Biological Chemistry 1973; 248: 6490
    PubMedGoogle Scholar
  • 19 Steinberg M, Dreiling B. J. Vascular Lesions in Hemophilia B. New England Journal of Medicine 1973; 289: 592
    PubMedGoogle Scholar
  • 20 Triantophyllopoulos D. C. Intravascular Coagulation following injection of prothrombin complex. American Journal of Clinical Pathology 1972; 57: 603
    CrossrefPubMedGoogle Scholar
  • 21 Wessler S. Studies in Intravascular Coagulation III. Journal of Clinical Investigation 1955; 34: 647
    CrossrefPubMedGoogle Scholar
  • 22 Wessler S, Reimer S. M. The Role of Human Coagulation Factors in Serum-induced Thrombosis. Journal of Clinical Investigation 1960; 39: 262
    CrossrefPubMedGoogle Scholar
  • 23 Wessler S, Reimer S. M, Sheps M. C. Biologic Assay of a thrombosisinducing activity in human serum. Journal of Applied Physiology 1959; 14: 943
    CrossrefPubMedGoogle Scholar
  • 24 Wessler S, Yin E. T. Experimental hypercoagulable State induced by Factor X : Comparison of the non-activated and activated forms. Journal of Laboratory and Clinical Medicine 1968; 72: 256
    PubMedGoogle Scholar