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DOI: 10.1055/s-0038-1645195
The Comparative Effects of Recombinant Hirudin (CGP 39393) and Standard Heparin on Thrombus Growth in Rabbits
Publication History
Received 25 August 1989
Accepted after revision 27 November 1989
Publication Date:
02 July 2018 (online)
Summary
The aim of this study was to compare the ability of standard heparin and recombinant (r-)hirudin, a specific inhibitor of thrombin, to inhibit thrombus growth in a rabbit jugular vein model. Doses of standard heparin and r-hirudin equivalent in prolonging the aPTT were first identified. The ability of these doses to inhibit 125I-fibrin accretion onto preexisting thrombi was then evaluated. 0.5 and 0.75 mg/kg of standard heparin and 0.8 and 1.25 mg/kg of r-hirudin infused over 3 h produced a mean prolongation of the aPTT of 1.5 and 2 times, respectively. In saline treated rabbits 62 ± 7 μg of 125I-fibrin were accreted on the pre-formed thrombi. The lower doses of standard heparin and r-hirudin produced a 125I-fibrin accretion of 44 ± 5 and 25 ± 4 μg, respectively (p <0.01). The two higher doses of standard heparin and r-hirudin produced a 125I-fibrin accretion of 34 ± 4 and 17 ± 3 μg, respectively (p <0.01). The increase in the dose of standard heparin up to 2.5 mg/kg produced a 125I-fibrin accretion of 26 ± 3 μg, a 58% reduction when compared with saline. The increase in the dose of r-hirudin up to 5 mg/kg produced a 125I-fibrin accretion of 12 ± 2 μg, an 81% reduction when compared with saline. No further inhibition was observed when the doses of both agents were further increased. We conclude that doses of standard heparin and r-hirudin equivalent in prolonging the aPTT have a different effect on thrombus growth inhibition, r-hirudin being twice as effective as standard heparin. Exclusive inhibition of thrombin without any other inhibiting effect on blood coagulation appears to be sufficient to inhibit thrombus growth. Our results seem to be promising in view of a clinical evaluation of r-hirudin
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References
- 1 Salzman EM, Hirsh V. Prevention of venous thromboembolism. In: Salzman EM, Hirsh V, Colman RW, Marder VJ. (eds) Hemostasis and Thrombosis: Basic Principles and Clinical Practice J P Lippincott Company; Philadelphia, PA: 1987: 1252-1265
- 2 Adar R, Salzman EM. Treatment of thrombosis of veins of the lower extremities. N Engl J Med 1975; 292: 348-350
- 3 Gallus AS, Hirsh J. Treatment of venous thromboembolic disease. Semin Thromb Haemostas 1976; 2: 291-331
- 4 Wessler S. Medical management of venous thrombosi. Annu Rev Med 1976; 27: 313-319
- 5 Chiu HM, Hirsh J, Yung WL, Regoeczi E, Gent M. Relationship between the anticoagulant and antithrombotic effects of heparin in experimental venous thrombosis. Blood 1977; 49: 171-184
- 6 Marder VJ, Soulen RL, Atichartakarn V, Budzynski AZ, Parulekar S, Kim JR, Edward N, Zahavi J, Algazy M. Quantitative venographic assessment of deep vein thrombosis in the evaluation of streptokinase and heparin therapy. J Lab Clin Med 1977; 89: 1018-1029
- 7 Hirsh J, Ofosu FA, Levine M. The development of low molecular weight heparins for clinical use. In: Verstraete M, Vermylen J, Lijnen R, Arnout J. (eds) Thrombosis and Haemostasis 1987 Leuven University Press; Leuven: 1987: 325-348
- 8 Carter CJ, Kelton JG, Hirsh J, Cerskus A, Santos AV, Gent M. The relationship between the hemorrhagic and antithrombotic properties of two molecular weight heparins in rabbits. Blood 1982; 59: 1239-1245
- 9 Buchanan MR, Boneu B, Ofosu F, Cerskus AL. The relative importance of thrombin inhibition and factor Xa inhibition to the antithrombotic effects of heparin. Blood 1985; 65: 198-201
- 10 Boneu B, Buchanan MR, Cade JF, Van RynJ, Fernandez F, Ofosu FA, Hirsh J. Effects of heparin, its low molecular weight fractions and other glycosaminoglvcans on thrombus growth in vivo. Thromb Res 1985; 40: 81-89
- 11 Van Ryn-McKenna J, Ofosu FA, Gray E, Hirsh J, Buchanan MR. Effects of dermatan sulphate and heparin on inhibition of thrombus growth in vivo. In: Ofosu FA, Danishefski I, Hirsh J. (eds) Heparin and related polisaccharides The New York Academy of Science; New York: 1989: 304-312
- 12 Fernandez F, Van Ryn J, Ofosu FA, Hirsh J, Buchanan MR. The hemorrhagic and antithrombotic effect of dermatan sulfate. Br J Haematol 1986; 64: 309-317
- 13 Markwardt F. The comeback of hirudin, an old-established anticoagulant agent. Folia Haematol 1988; 115: 10-23
- 14 Markwardt F, Hauptmann J, Novak G, Kleßen C, Walsmann P. Pharmacological studies on the antithrombotic action of hirudin in experimental animals. Thromb Haemostas 1982; 47: 226-229
- 15 Meyhack B, Heim J, Rink H, Zimmerman W, Marki W. Desulphato hirudin, a specific thrombin inhibitor: expression and secretion in yeast. Thromb Haemostas 1987; Suppl VII 33
- 16 Grossenbacher H, Auden J, Bill K, Liersch M, Marki W. Isolation and characterization of recombinant desulfato hirudin from yeast: a highly selective thrombin inhibitor. Thromb Haemostas 1987; Suppl VII 34
- 17 Talbot MD, Ambler J, Butler KD, Findlay VS, Mitchell KA, Peters RF, Tweed MF, Wallis RB. Recombinant desulphatohirudin (CGP 39393) anticoagulant and antithrombotic properties in vivo. Thromb Haemostas 1989; 61: 77-80
- 18 Giles AR. Guidelines for the use of animals in biomedical research. Thromb Haemostas 1987; 58: 1078-1084
- 19 Agnelli G, Buchanan MR, Fernandez F, Boneu B, Van Ryn J, Hirsh J, Collen D. A comparison of the thrombolytic and hemorrhagic effects of tissue-type plasminogen activator and streptokinase in rabbits. Circulation 1985; 72: 178-182
- 20 Proctor RR, Rapaport SI. The PTT with Kaolin. Am J Clin Pathol 1961; 33: 212-219
- 21 Teien AN, Lie M, Abilgaard V. Assay of heparin in plasma using a chromogenic substrate for activated factor X. Thromb Res 1976; 8: 413-416
- 22 Hogg PJ, Jackson CM. Fibrin monomers protects thrombin from inactivation by heparin-antithrombin III: implication for heparin efficacy. Proc Natl Acad Sci 1989; 86: 3619-3623