The Influence of Infusions of 1-Desamino-8-D-Arginine vasopressin (DDAVP) In Vivo on the Anticoaguhht Effect of Recombinant Hirudin (CGP39393) In Vitro

Summary

Hirudin is a specific, potent inhibitor of thrombin that may be a valuable antithrombotic agent. The aim of this study was to investigate the hypothesis that the haemostatic effects of DDAVP counteract the coagulation defect induced by hirudin. The effect of DDAVP was studied in vivo on the anticoagulant action of recombinant hirudin (CGP39393) in vitro. Blood samples were taken at intervals from 10 normal volunteers infused with DDAVP. Factor VIII: C rose from (mean) 0.68 IU/ml before DDAVP to 2.L9 and 2.16 IU/ml after 30 and 60 min infusion, respectively. Samples taken during DDAVP infusion showed a dose related decrease in the hirudin (0.5 and 1.0 αM) induced prolongation of the APTT that occurred at FVIII: C concentrations of up to twice normal. At higher concentrations of hirudin no effect on the APTT occurred. These results demonstrate that DDAVP infusion elevates factor VIII: C levels with an associated significant reduction in the anticoagulant effect of hirudin in vitro.

• References

• 1 Talbot MD. Biology of recombinant hirudin (CGP39393): a new prospect in the treatment of thrombosis. Semin Thromb Haemostas 1989; 15 (03) 293-301
• 2 Walenga JM, Pifarre R, Fareed J. Recombinant Hirudin as an antithrombotic agent. Drugs of the Future 1990; 15 (03) 267-280
• 3 Tate GM, Hampton KK, Davies JA. The effect of increasing concentrations of factor VIII coagulant activity on thrombin generation in vitro. Thromb Haemostas 1989; 62 (01) 77
• 4 Mertens K, Van Wijngaarden A, Bertina RM. The role of factor VIII in the activation of human blood coagulation factor X by activated factor IX. Thromb Haemostas 1985; 54 (03) 654-660
• 5 MacGregor IR, Roberts EM, Prowse CV, Broomhead AF, Ozolins M, Litka P. Fibrinolytic and haemostatic responses to desamino-D-arginine vasopressin (DDAVP) administered by intravenous and subcutaneous routes in healthy subjects. Thromb Haemostas 1988; 59 (01) 34-39
• 6 Mannucci PM. Desmopressin: A nontransfusional form of treatment for congenital and acquired bleeding disorders. Blood 1988; 72: 1449-1455
• 7 Kim HC, Salva K, Fallot PL, Karp GI, Eisele J, Matts L, Heller I, Saidi P. Patients with prolonged bleeding time of undefined etiology, and their response to desmopressin. Thromb Haemostas 1988; 59 (02) 221-224
• 8 DiMichele DM, Hathaway WmE. Use of DDAVP in inherited and acquired platelet dysfunction. Am J Haematol 1990; 33: 39-45
• 9 Hardisty RM, MacPhearson JC. A one stage FVIII AHG Assay and its use on venous and capillary plasma. Thromb Diathes Haemorrh 1962; 7: 215-219
• 10 Krstenansky JL, Owen TJ, Yates MT, Mao SJ T. Comparison of hirudin and hirudin PA C-terminal fragments and related analogs as antithrombin agents. Thromb Res 1988; 52 (02) 137-141
• 11 Braun PJ, Dennis S, Hofsteenge J, Stone SR. Use of site-directed mutagenesis to investigate the basis for the specificity of hirudin. Biochemistry 1988; 27: 6517-6522
• 12 Mao SJ T, Yates MT, Owen TJ, Krstenansky JL. Interaction of hirudin with thrombin: identification of a minimal binding domain of hirudin that inhibits clotting activity. Biochemistry 1988; 27: 8170-8173
• 13 Stone SR, Braun PJ, Hofsteenge J. Identification of regions of a thrombin involved in its interaction with hirudin. Biochemistry 1987; 26: 4617-4624
• 14 Markwardt F, Hauptmann J, Nowak G, Klessen Ch, Walsmann P. Pharmacological studies on the antithrombotic action of hirudin in experimental animals. Thromb Haemostas 1982; 47 (03) 226-229
• 15 Markwardt F, Nowak G, Stürzebecher J, Griessbach U, Walsmann P, Vogel G. Pharmacokinetics and anticoagulant effect of hirudin in man. Thromb Haemostas 1984; 52 (02) 160-163
• 16 Harvey RP, Degryse E, Stefani L, Schamber F, Cazenave J-P, Courtney M, Tolstoshev P, Lecocq J-P. Cloning and expression of a cDNA coding for the anticoagulant hirudin from the bloodsucking leech, Hirudo medicinalis. Proc Natl Acad Sci USA 1986; 83: 1084-1088
• 17 Markwardt F, Nowak G, Stürzebecher J, Vogel G. Clinico-phar-macological studies with recombinant hirudin. Thromb Res 1988; 52 (05) 393-400
• 18 Talbot MD, Ambler J, Butler KD, Findlay VS, Mitchell KA, Peters RF, Tweed MF, Wallis RB. Recombinant desulphato-hirudin (CGP39393) anticoagulant and antithrombotic properties in vivo. Thromb Haemostas 1989; 61 (01) 77-80
• 19 Kaiser B, Markwardt F. Antithrombotic and haemorrhagic effects of synthetic and naturally occurring thrombin inhibitors. Thromb Res 1986; 43 (06) 613-620
• 20 Mannucci PM. Desmopressin (DDAVP) for treatment of disorders of hemostasis. Prog Hemostas Thromb 1986; 8: 19-45
• 21 Köhler M, Hellstern P, Miyashita C, Von Blohn G, Wenzel E. Comparative study of intranasal, subcutaneous and intravenous administration of desamino-D-arginine vasopressin (DDAVP). Thromb Haemostas 1986; 55 (01) 108-111