A recombinant hirudin (IK-HIR02) in healthy volunteers. II. Effects on platelet adhesion and platelet-induced thrombin generation time.
The pharmacodynamic effects of different intravenous and subcutaneous doses of a new recombinant hirudin (IK-HIR02) on platelet adhesion, platelet-induced thrombin formation and on platelet count have been studied in 18 healthy volunteers in a bicenter study. Single intravenous bolus injections of 0.1, 0.2 and 0.3 mg/kg IK-HIR02 in 6 volunteers caused a significant dose-dependent prolongation of platelet-induced thrombin generation time (PITT) and a significant inhibition of platelet adhesion to glass. Single subcutaneous doses of 0.1, 0.25 and 0.5 mg/kg IK-HIR02 slightly prolonged PITT and inhibited platelet adhesion to glass for up to 8 h. Repeat subcutaneous injections of 0.3 mg/kg IK-HIR02 b.i.d. in 6 healthy volunteers led to a prolongation of PITT and also to a reduction of platelet adhesion. In platelet-rich plasma (PRP) from blood samples which had been collected using hirudin as anticoagulant (0.7 micrograms/ml), the platelet count was constantly higher than in citrate PRP which had been sampled at the same time. The recombinant hirudin IK-HIR02 inhibits platelet adhesion to glass and also PITT. Both effects which have not been described before are most likely due to a direct inhibition of thrombin-induced platelet activation. These effects may contribute to the antithrombotic action of hirudin and probably have to be considered when hirudin is used in higher doses as an antithrombotic agent together with platelet function inhibitors to avoid excessive bleeding.
Schenk
J F
JF
International Institute of Thrombosis and Vascular Diseases, Frankfurt a.M., Germany.
Glusa
E
E
Radziwon
P
P
Butti
A
A
Markwardt
F
F
Breddin
H K
HK
D000328:Adult; D004305:Dose-Response Relationship, Drug; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D005898:Glass; D006629:Hirudins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D010973:Platelet Adhesiveness / Q000187:drug effects*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013917:Thrombin / Q000096:biosynthesis*
D005343:Fibrinolytic Agents; D006629:Hirudins; D011994:Recombinant Proteins; D013917:Thrombin; C060225:desirudin