Thromb Haemost 1980; 44(02): 081-086
DOI: 10.1055/s-0038-1650089
Original Article
Schattauer GmbH Stuttgart

A Comparison of the in Vitro and in Vivo Thrombogenic Activity of Factor IX Concentrates Using Stasis (Wessler) and Non-Stasis Rabbit Models

C V Prowse
The Edinburgh and South-East Scotland Regional Blood Transfusion Centre, Royal Infirmary, Edinburgh, U.K.
,
A E Williams
*   Teaching and Research Centre, University of Edinburgh, Western General Hospital, Edinburgh, U.K.
› Author Affiliations
Further Information

Publication History

Received 28 April 1980

Accepted 25 August 1980

Publication Date:
13 July 2018 (online)

Summary

The thrombogenic effects of selected factor IX concentrates were evaluated in two rabbit models; the Wessler stasis model and a novel non-stasis model. Concentrates active in either the NAPTT or TGt50 in vitro tests of potential thrombogenicity, or both, caused thrombus formation in the Wessler technique and activation of the coagulation system in the non-stasis model. A concentrate with low activity in both in vitro tests did not have thrombogenic effects in vivo, at the chosen dose. Results in the non-stasis model suggested that the thrombogenic effects of factor IX concentrates may occur by at least two mechanisms. A concentrate prepared from platelet-rich plasma and a pyrogenic concentrate were also tested and found to have no thrombogenic effect in vivo.

These studies justify the use of the NAPTT and TGt50 in vitro tests for the screening of factor IX concentrates prior to clinical use.

 
  • References

  • 1 Menaché D, Fauvert R, Soulier JP. Utilisation en hépatologie d'une fractione contenant la prothrombine, le complexe proconvertine – Stuart et le facteur hémophilique B. Pathol Biol (Paris) 1959; 7: 2515-2523
  • 2 Tullis JL, Breen F. Christmas factor concentrates: the clinical use of several preparations. Bibl Haematol 1970; 34: 40-51
  • 3 Kasper CK. Thromboembolic complications (following the use of factor IX concentrates). Thromb Diath Haemorrh 1975; 33: 640-644
  • 4 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
  • 5 Hedner U, Nilsson IM, Bergentz SE. Various prothrombin complex concentrates and their effect on coagulation and fibrinolysis in vivo. Thromb Haemostas 1976; 35: 386-395
  • 6 Hedner U, Nilsson IM, Bergentz SE. Studies on the thrombogenic activities in two prothrombin complex concentrates. Thromb Haemostas 1979; 42: 1022-1032
  • 7 Preston FE, Winfield DA, Malia RG, Blackburn EK. Serial coagulation changes in the coagulation system following clotting factor concentrate infusion. Thromb Diath Haemorrh 1975; 34: 475-482
  • 8 Preston FE, Malia RG, Lilleyman JS, Blackburn EK. Heparinised clotting factor concentrates in patients with Christmas disease and liver disease. Thromb Haemostas 1977; 38: 504-509
  • 9 Kingdon HS, Lundblad RL, Veltkamp JJ, Aronson DL. Potentially thrombogenic materials in factor IX concentrates. Thromb Diath Haemorrh 1975; 33: 617-631
  • 10 Sas G, Owens RE, Smith JK, Middleton S, Cash JD. In vitro spontaneous thrombin generation in human factor IX concentrates. Br J Haematol 1975; 31: 25-35
  • 11 Cash JD, Owens R, Dalton RG, Prescott RJ. Thrombogenicity of factor IX concentrates: in vitro and in vivo (rabbit) studies. Vox Sang 1978; 35: 105-110
  • 12 Wessler S, Reimer SM, Sheps MC. Biologic assay of a thrombosis-inducing activity in human serum. J Appl Physiol 1959; 14: 943-946
  • 13 Pepper DS, Banheygi D, Howie A, Cash JD. In vitro thrombogenicity tests of factor IX concentrates. Br J Haematol 1977; 36: 573-583
  • 14 Prowse CV, Pepper DS, Cash JD, Patterson M. Thrombogenicity screening of factor IX concentrates. Thromb Haemostas 1977; 38: 728-729
  • 15 Prowse CV, Chirnside A, Elton R. In vitro thrombogenicity tests of factor IX concentrates. I: A survey of available assays. Thromb Haemostas 1979; 42: 1355-1367
  • 16 Foster PR, Patterson MR, Johnson AJ, Middleton SM. Thrombogenicity of factor IX concentrates and polyethylene glycol processing. Thromb Res 1980; 17: 273-279
  • 17 Pepper DS, Prowse CV. Chromatography of human prothrombin complex on dextran sulphate agarose. Thromb Res 1977; 11: 687-692
  • 18 Levin J, Bang F. Clottable protein in Limulus blood: its localisation and kinetics of its coagulation by endotoxin. Fed Proc 1966; 25: 497
  • 19 Ellis BC, Stransky A. A quick and accurate method for the determination of fibrinogen in plasma. J Lab Clin Med 1961; 58: 477-488
  • 20 Hardisty RM, Ingram GI C. Bleeding Disorders: Investigation and management. Blackwell Scientific Publications Ltd., Oxford: 1965
  • 21 Kierulf P, Godal H. Fibrinemia in medical patients screened by the ethanol gelation test. Acta Med Scand 1971; 190: 185-190
  • 22 Smith JK, Snape TJ, Bidwell E, Edwards R, Gunson HH. Preparation of factor IX concentrate from platelet-rich plasma. Thromb Haemostas 1977; 37: 363-366
  • 23 Prowse CV, Boffa MC, Guthrie C, Pepper DS. In vitro thrombogenicity tests of factor IX concentrates. II: Effects of phospholipids and heparin. Thromb Haemostas 1979; 42: 1368-1377
  • 24 Wessler S, Yin ET. Experimental hypercoagulable state induced by factor X. Comparison of the non-activated and activated forms. J Lab Clin Med 1968; 72: 256-260
  • 25 Triantaphyllopoulous DC. Intravascular coagulation following injection of prothrombin complex. Am J Clin Pathol 1972; 57: 603-610
  • 26 Vermylen J, Schetz J, Semeraro N, Mertens F, Verstraete M. Evidence that activated prothrombin concentrates enhance platelet coagulant activity. Br J Haematol 1978; 38: 235-242
  • 27 Penner J, Leach K, Rohwedder J. Thrombogenic characteristics of activated and standard concentrates of prothrombin complex. Thromb Haemostas 1977; 38: 316a
  • 28 Giles AR, Mann KG, Nesheim ME, Tracy PB, Blajchman MA. A correlation between the coagulant active phospholipid content of prothrombin complex concentrates and in vivo thrombogenicity. Blood 1979; 54: 279 a