Clinical Utility of Subcutaneous Hirudins

Steven R. Deitcher

Disclosures

Am J Health Syst Pharm. 2003;60(20) 

In This Article

Abstract and Introduction

The clinical utility of subcutaneous hirudins is discussed.

The term "hirudins" refers to a class of antithrombotic agents structurally derived from the medicinal leech salivary protein hirudin. Breakthroughs in biotechnology over the past 20 years have resulted in the development of recombinant versions of hirudin (r-hirudin). Lepirudin is one such r-hirudin that is identical to natural hirudin except for the substitution of leucine for isoleucine at the N-terminus and the elimination of a sulfate group on the tyrosine at position 63. Another r-hirudin, desirudin, is identical to hirudin except for a valine-valine in the N-terminus and the absence of the sulfate group on tyrosine at position 63. Both r-hirudins are bivalent and tightly bind to both the catalytic site and the exosite of thrombin to exert their inhibitory effects on thrombin.

Unfractionated heparin (UF) and low-molecular-weight heparins (LMWHs) are widely used in medical and surgical patients to prevent and treat arterial and venous thrombotic events. Besides bleeding, the major adverse effect of heparins is heparin-induced thrombocytopenia (HIT). HIT is associated with a paradoxical hypercoagulable state and marked risk of clinical thrombosis. Management of HIT requires the immediate cessation of all heparin exposure, and the initiation of an alternative anticoagulant.

Because r-hirudins are effective agents and do not cross-react with HIT-associated antibodies, they are excellent anticoagulants in patients with past or current HIT. Clinical trials have also demonstrated the efficacy and safety of subcutaneous (s.c.) r-hirudins compared to heparins in non-HIT settings. Results of these trials support the use of r-hirudin therapy in patients with HIT or at risk of developing HIT. Additionally, case reports have described safe and effective use of s.c. r-hirudin therapy in the outpatient setting in both HIT and non-HIT patients.

Since ancient times medicinal leeches (Hirudo medicinalis) have prevented blood from clotting, as demonstrated by prolonged bleeding at sites of leech wounds following animal detachment. Very early in the twentieth century, extracts from leech heads with anticoagulant activity were prepared for which the name "hirudin" was suggested. It was not until the 1950s that the actual hirudin anticoagulant protein was isolated from leech peripharyngeal gland-derived saliva.[1] The term "hirudins" refers to a class of anti-thrombotic agents homologous with the original leech protein.[2] Advances in biotechnology over the past 20 years have resulted in the development of several recombinant versions of hirudin (r-hirudins) including lepirudin and desirudin.[1,2]

Point mutations and N-terminal modifications via recombinant DNA technology have resulted in the development of r-hirudin products that have been evaluated in clinical studies.[1] Lepirudin is identical to natural hirudin except for the substitution of leucine for isoleucine at the N-terminus and the lack of sulfation of the tyrosine at position 63.[3] Similarly, desirudin is identical to hirudin except for a valine-valine in the N-terminus and the absence of the sulfate group on tyrosine at position 63.[2] Similar to the parent protein, both r-hirudins are bivalent and tightly bind to both the catalytic site and the exosite of thrombin to exert their pharmacologic activity.[2]

Unfractionated heparin (UF) and low-molecular-weight heparins (LMWHs) are widely used in medical and surgical patients to both prevent and treat arterial and venous thrombotic events. Besides bleeding, the major adverse side effect of heparins is heparin-induced thrombocytopenia (HIT). HIT is an immune-mediated drug reaction associated with a paradoxical hypercoagulable state, marked risk of clinical thrombosis, and significant risk of limb loss.[4] Because r-hirudins are safe and effective agents and do not cross-react with HIT-associated antibodies, they are excellent anticoagulants in patients with past or current HIT and those at risk for HIT. Several clinical trials have been published evaluating the efficacy and safety of subcutaneously (s.c.) administered r-hirudins where heparin is typically the treatment of choice. The following is a review of these clinical trials, as well as published case reports.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....