Download PDF
Thromb Haemost 1992; 68(05): 511-515
DOI: 10.1055/s-0038-1646309
Original Article
Schattauer GmbH Stuttgart

A Novel Rat Model of Thrombogenicity: Its Use in Evaluation of Prothrombin Complex Concentrates and High Purity Factor IX Concentrates

L F McLaughlin
The National Science Laboratory, Scottish National Blood Transfusion Service, Edinburgh, UK
,
O Drummond
The National Science Laboratory, Scottish National Blood Transfusion Service, Edinburgh, UK
,
I R MacGregor
The National Science Laboratory, Scottish National Blood Transfusion Service, Edinburgh, UK
› Author Affiliations
Further Information

Publication History

Received 14 March 1992

Accepted after revision 22 June 1992

Publication Date:
04 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

A non-stasis rodent model of thrombogenicity has been used for dose-ranging studies with a conventional prothrombin complex concentrate (PCC) and to evaluate high purity factor IX concentrates from different manufacturers. Fibrin monomer (soluble fibrin) and fibrinopeptide A (FPA) were monitored before and after infusion of test solution. FPA was found to be the more sensitive and reproducible indicator of thrombogenicity and exhibited a dose-related elevation after infusion of the PCC at doses of between 100–300 IU/kg. In contrast the amounts of FPA generated after 300 IU/kg of the high purity factor IX products were similar to control infusions of albumin.

 

  • REFERENCES

  • 1 Kasper CK. Thromboembolic complications. Thromb Diath Haemorrh 1975; 33: 640-644
    PubMedGoogle Scholar
  • 2 Cederbaum AI, Blatt PM, Roberts HR. Intravascular coagulation with the use of human prothrombin complex concentrates. Ann Intern Med 1976; 84: 633-687
    CrossrefPubMedGoogle Scholar
  • 3 Marassi A, Manzullo V, di Carlo V, Manucci PM. Thromboembolism following prothrombin complex concentrates and major surgery in liver disease. Thromb Haemostas 1978; 39: 787-788
    PubMedGoogle Scholar
  • 4 Campbell EW, Neff S, Bowdler AJ. Therapy with factor IX concentrate resulting in DIC and thromboembolic phenomena. Transfusion 1978; 18: 94-97
    CrossrefPubMedGoogle Scholar
  • 5 Menache D. Prothrombin complex concentrates: Clinical use. Ann NY Acad Sci 1981; 370: 747-756
    CrossrefPubMedGoogle Scholar
  • 6 Giles AR, Nesheim ME, Hoogendoorn H, Tracy PB, Mann KG. The coagulant-active phospholipid is a major determinant of in vivo thrombogenicity of prothrombin complex (factor IX) concentrates in rabbits. Blood 1982; 59: 401-407
    PubMedGoogle Scholar
  • 7 Magner A, Aronson DL. Toxicity of factor IX concentrates in mice. Dev Biol Stand 1979; 44: 185-188
    PubMedGoogle Scholar
  • 8 Cash JD, Dalton RG, Middleton S, Smith JK. Studies on the thrombogenicity of Scottish factor IX concentrates in dogs. Thromb Diath Haemorrh 1975; 33: 632-639
    PubMedGoogle Scholar
  • 9 Hedner U, Nilsson IM, Bergentz S-E. Various prothrombin complex concentrates and their effect on coagulation and fibrinolysis in vivo. Thromb Haemostas 1976; 35: 386-395
    PubMedGoogle Scholar
  • 10 Hedner U, Nilsson IM, Bergentz S-E. Studies on the thrombogenic activities in two prothrombin complex concentrates. Thromb Haemostas 1979; 42: 1022-1032
    PubMedGoogle Scholar
  • 11 Littlewood JD, Dawes J, Smith JK, Feldman PA, Haddon ME, McQuillan TA, Foster PR, Ferguson J, Prowse CV. Studies on the effect of heart treatment on the thrombogenicity of factor IX concentrates in dogs. Br J Haematol 1987; 65: 463-468
    CrossrefPubMedGoogle Scholar
  • 12 MacGregor IR, Ferguson JF, Dawes J, McLaughlin L, Prowse CV. Thrombogenicity of a factor IX concentrate quantitated in a canine model. Blood Coagulation and Fibrinolysis 1990; 1: 23-30
    CrossrefPubMedGoogle Scholar
  • 13 MacGregor IR, Ferguson JM, McLaughlin LF, Burnouf T, Prowse CV. Comparison of high purity factor IX concentrates and a pro thrombin complex concentrate in a canine model of thrombogenicity. Thromb Haemostas 1991; 66: 609-613
    PubMedGoogle Scholar
  • 14 Wiman B, Ranby M. Determination of soluble fibrin in plasma by a rapid and quantitative spectrophotometric assay. Thromb Haemostas 1986; 55: 189-193
    PubMedGoogle Scholar
  • 15 Drummond O, McLaughlin LF, MacGregor IR. Development of a radioimmunoassay for rat fibrinopeptide A. Br J Haematol 1991; 77 (Suppl1) 59
    PubMedGoogle Scholar
  • 16 Middleton SM, Bennet IH, Smith JK. A therapeutic concentrate of coagulation factors II, IX and X from citrated factor VIII depleted plasma. Vox Sang 1973; 24: 441-456
    PubMedGoogle Scholar
  • 17 Burnouf T, Michalski C, Goudemand M, Huart JJ. Properties of a highly purified human plasma factor IX: a therapeutic concentrate prepared by conventional chromatography. Vox Sang 1989; 57: 225-232
    PubMedGoogle Scholar
  • 18 Menache D, Behre HE, Orthner CL, Nunez H, Anderson HD, Triantophyllopoulos DC, Kasow DP. Coagulation factor IX concentrate: method of preparation and assessment of potential in vivo thrombogenicity in animal models. Blood 1984; 64: 1220-1227
    PubMedGoogle Scholar
  • 19 Mannucci PM, Bauer KA, Gringeri A, Barzegar S, Bottasso B, Simoni L, Rosenberg RD. Thrombin generation is not increased in the blood of hemophilia B patients after the infusion of purified factor IX concentrate. Blood 1990; 76: 2540-2545
    PubMedGoogle Scholar
  • 20 Kim HC, McMillan CW, White GC, Bergman GE, Saidi P. Clinical experience of a new monoclonal antibody purified factor IX: half-life, recovery and safety in patients with haemophilia B. Semin Haematol 1990; 27 (Suppl2): 30-35
    PubMedGoogle Scholar
  • 21 Giles AR. Guidelines for the Use of Animals in Biomedical Research. Thromb Haemostas 1987; 58: 1078-1084
    PubMedGoogle Scholar
  • 22 MacGregor I, McLaughlin L. Measurement of soluble fibrin in a variety of animal species. Thromb Res 1989; 55: 651-656
    CrossrefPubMedGoogle Scholar
  • 23 Kingdon HS, Lundbald RL, Veltkamp JJ, Aronson DL. Potentially thrombogenic materials in factor IX concentrates. Thromb Diath Haemorrh 1975; 33: 617-631
    PubMedGoogle Scholar
  • 24 Giles AR, Johnson M, Hoogendorf M, Blajchman M, Hirsh J. The thrombogenicity of prothrombin complex concentrates: 1. The relationship between in vitro characteristics and in vivo thrombogenicity in rabbits. Thromb Res 1980; 17: 353-366
    CrossrefPubMedGoogle Scholar
  • 25 Harrison J, Abilgaard C, Lazerson J, Culbertson R, Anderson G. Assessment of thrombogenicity of prothrombin complex concentrates in a porcine model. Thromb Res 1985; 38: 173-188
    CrossrefPubMedGoogle Scholar
  • 26 Prowse CV, Williams AE. A comparison of the in vitro and in vivo thrombogenic activity of factor IX concentrates using stasis (Wessler) and non-stasis rabbit models. Thromb Haemostas 1980; 44: 81-86
    PubMedGoogle Scholar
  • 27 Mannucci PM, Bauer KA, Gringeri A, Barzegar S, Santagostino E, Tradati FC, Rosenberg RD. No activation of the common pathway of the coagulation cascade after a highly purified factor IX concentrate. Br J Haematol 1991; 79: 606-611
    CrossrefPubMedGoogle Scholar
  • 28 Wessler S, Reimer SM, Sheps MC. Biological assay of a thrombosis-inducing activity in human serum. J Appl Physiol 1959; 14: 943-946
    CrossrefPubMedGoogle Scholar