Persistent thrombin generation in humans during specific thrombin inhibition with hirudin

Area of Science:

• Thrombosis and Hemostasis
• Pharmacology
• Biochemistry

Background:

• The extent to which antithrombotic drugs inhibit thrombin generation remains unclear.
• Hirudin, a direct thrombin inhibitor, forms a stable complex with thrombin, offering a potential marker for thrombin generation.
• Understanding thrombin generation during anticoagulation is crucial for managing thrombotic disorders.

Purpose of the Study:

• To investigate the degree of thrombin generation suppression by intravenous hirudin in humans.
• To assess the dynamics of thrombin generation during and after hirudin anticoagulation.
• To evaluate the utility of thrombin-hirudin complex as a marker for thrombin generation.

Main Methods:

• Intravenous hirudin was administered to three groups of patients at varying doses (0.1, 0.2, 0.3 mg.kg-1.h-1) for 6 hours.
• Plasma levels of thrombin-hirudin complex were measured using ELISA throughout the infusion and for 18 hours post-infusion.
• Plasma concentrations of fragment 1.2 and thrombin-antithrombin III complex were also monitored.

Main Results:

• Thrombin-hirudin complex levels increased significantly during and after hirudin infusion, indicating ongoing thrombin generation.
• Plasma fragment 1.2 levels remained at or above baseline, with a transient increase during hirudin infusion.
• Plasma thrombin-antithrombin III complex levels decreased during hirudin infusion but returned to baseline levels afterward.

Conclusions:

• Measurement of thrombin-hirudin complex can serve as a marker for thrombin generation in humans.
• Hirudin anticoagulation, even at high doses, does not completely block thrombin generation.
• Persistent thrombin generation during and after hirudin therapy may contribute to rethrombosis risk.