Effects of PEG-Hirudin in Clotting Parameters and Platelet Function and its Interaction with Aspirin in Healthy Volunteers

• Published in: Clinical and applied thrombosis/hemostasis Vol. 9; no. 1; pp. 79 - 88
• Main Authors: Esslinger, Hans-Ulrich, Köhne, Stephan, Radziwon, Piotr, Walenga, Jeanine M., Breddin, Hans Klaus
• Format: Journal Article
• Language: English
• Published: Thousand Oaks, CA SAGE Publications 01.01.2003; SAGE PUBLICATIONS, INC
• Subjects: Anticoagulants; Aspirin - pharmacology; Bleeding Time; Blood Coagulation - drug effects; Blood Platelets - drug effects; Blood Platelets - physiology; Cross-Over Studies; Health risk assessment; Hirudins - analogs & derivatives; Hirudins - pharmacokinetics; Hirudins - pharmacology; Humans; Platelet Aggregation Inhibitors - pharmacology; Reference Values; R-hirudin; Aspirin; Heparin; Bleeding time
• ISSN: 1076-0296; 1938-2723
• DOI: 10.1177/107602960300900111

The purpose of this study was to investigate the pharmacodynamics of PEG-Hirudin and its potential interactions with acetylsalicylic acid (ASA 325 mg once daily from days 1-3). In a randomized, 2-way cross-over trial, 6 healthy volunteers received PEG-Hirudin (IV bolus of 0.2 mg/kg + 0.02 mg/kg/h for 24 hours) and placebo (IV bolus + 24-hour infusion). In a further randomized, 3way cross-over trial another 9 healthy volunteers received ASA (325 mg) or oral placebo from days 1 to 3 and PEG-Hirudin (0.2 mg/kg + 0.02 mg/kg/h for 24 h) or IV placebo on day 3. Assessments included bleeding time (BT), collagen (1 μg ml-1)-induced platelet aggregation (CIPA), platelet adhesion, ecarin clotting time (ECT), activated clotting time (ACT), plasma anti-factor Ila activity (aIla), and activated partial thromboplastin time (aPTT). Ten minutes after the PEG-Hirudin injection/starting the infusion, mean plasma concentration was 3.1 μg/mL and aPTT, ECT, and ACT were prolonged up to 80, 309, and 233 seconds, respectively. During the last 8 hours of the 24-hour infusion mean PEG-Hirudin plasma concentration was 1.3 μg/mL. In the interaction study, ASA significantly inhibited CIPA. At 6 hours after administration, on day 3 mean BT was 6.5 minutes after PEG-Hirudin alone, 18.2 minutes after ASA alone, and 32.9 minutes after combined administration of ASA and PEG-Hirudin. PEG-Hirudin (0.2 mg/kg + 0.02 mg/kg/h for 24 hours) administered alone or together with 325 mg ASA proved to be safe in healthy volunteers. Combined use of PEG-Hirudin and ASA significantly increased the mean bleeding time compared to ASA or PEG-Hirudin monodrug administration. None of the clotting parameters or platelet function tests correlated with the prolongation of the bleeding time.