[Frontiers in Bioscience 11, 113-120, January 1, 2006]

Inhibition of thrombin: relevance to anti-thrombosis strategy

Garry X. Shen

Departments of Internal Medicine and Physiology, University of Manitoba, Winnipeg, Manitoba, Canada

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Leeches and hirudin
4. Inhibition of thrombin active site
5. Synthetic peptide thrombin inhibitors
6. Small molecular thrombin inhibitors
7. Orally active thrombin inhibitors
8. Non-peptide thrombin inhibitors
9. Clinical applications of thrombin-specific inhibitors
10. Statins on thrombin generation
11. Summary
12. Acknowledgments
13. References

1. ABSTRACT

Thromboembolism is a common cause of death and disability. Heparin or warfarin, the current standard management for thromboembolism may cause serious bleeding complications. Thrombin is the key enzyme of coagulation. Hirudin, the most potent natural thrombin-specific inhibitor, was first isolated from leech salivary fluid. Synthetic thrombin-specific inhibitors are rationally designed based on the knowledge on the structures of the activate site of thrombin. Thrombin-specific inhibitors are the current best choice for the treatment of heparin-induced thrombocytopenia (HIT). Recombinant hirudins (such as desirudin) were also approved for the prevention of thrombosis after hip or knee surgery. Bivalirudin (hirulog-1 or Angiomax), in adjunct to aspirin, was approved for prevention of thrombosis in patients with unstable angina following angioplasty. Argatroban has been used for the treatment of HIT, peripheral and cerebral thrombotic diseases. The benefit of using thrombin-specific inhibitors alone in acute myocardial infarction or unstable angina remains uncertain. Some of thrombin-specific inhibitors which are small molecules are orally active. The major concern for the use of thrombin-specific inhibitors is bleeding complication. The efficacy, safety, stability and oral bioavailability may be considerably improved through structural optimization. A growing line of evidence suggests that statins, the most commonly prescribed cholesterol lowering drug, may inhibit thrombin generation. Statins do not cause bleeding and have an outstanding safety profile. The findings suggest that further development of thrombin-specific inhibitors and exploration of the potential applications of non-specific thrombin inhibitors, including statins, may improve the prevention and management of thromboembotic events.