Direct thrombin inhibitor

Overview
Direct thrombin inhibitors (DTIs) are a class of medication that act as anticoagulants (delaying blood clotting) by directly inhibiting the enzyme thrombin. Some are in clinical use, while others are undergoing clinical development. Several members of the class are expected to replace heparin (and derivatives) and warfarin in various clinical scenarios.

Types
There are two types of DTIs, dependent on their interaction with the thrombin molecule. Bivalent DTIs (hirudin and analogs) bind both to the active site and exosite 1, while univalent DTIs bind only to the active site.

Bivalent
Hirudin and derivatives were originally discovered in Hirudo medicinalis:
 * Hirudin
 * Bivalirudin (transient inhibition - is cleaved by thrombin)
 * Lepirudin
 * Desirudin

Univalent
Univalent DTIs include:
 * Argatroban
 * Melagatran (and its prodrug ximelagatran)
 * Dabigatran

Uses
Bivalent DTIs enjoy limited use in circumstances where heparin would be indicated but cannot be used, such as the acute coronary syndrome ("unstable angina"). As they are administered by injection (intravenous, intramuscular or subcutaneous), they are less suitable for long-term treatment.

Argatroban (as well as the hirudins) are used for heparin-induced thrombocytopenia, a rare but serious complication of heparin treatment that requires anticoagulation (as it increases both arterial and venous thrombosis risk) but not with the putative agent, heparin.

Ximelagatran showed good efficacy compared with warfarin in several trials in prevention and treatment of deep vein thrombosis and as thromboprophylaxis in atrial fibrillation. Development was stopped by manufacturer AstraZeneca, however, because of reports of liver enzyme derangements and liver failure. Dabigatran is under development for similar indications.

Monitoring
There is no therapeutic drug monitoring widely available for DTIs, in contrast with warfarin (INR) and heparin (APTT). The ecarin clotting time, although not in general clinical use, would be the most appropriate monitoring test.