Direct Thrombin Inhibitors

How to Cite This Chapter: Douketis J, Undas A, Zawilska K. Direct Thrombin Inhibitors. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. Accessed July 07, 2020.
Last Updated: June 23, 2019
Last Reviewed: June 23, 2019
Chapter Information

1. Mechanism of action: Thrombin inhibitors block the catalytic site or the substrate recognition site in the thrombin molecule. Oral dabigatran is used for prevention of venous thromboembolism. Agents used for other indications include recombinant hirudin (lepirudin, IV desirudin) and synthetic analogues of hirudin (bivalirudin, IV argatroban).

2. Monitoring of the anticoagulant effect is not necessary in patients treated with dabigatran. Within 1 to 3 hours of the administration of dabigatran, corresponding to the peak anticoagulant effect, a slightly prolonged prothrombin time and a prolonged activated partial thromboplastin time (aPTT) (up to 50-65 seconds) can be seen in the majority of patients; the thrombin time is markedly prolonged, frequently beyond the limit of quantification. In patients planned for urgent invasive procedures, determine the aPTT; values >40 seconds suggest a sustained anticoagulant effect. More reliable and precise methods of measuring the anticoagulant effect of dabigatran include the dilute thrombin time (using the Hemoclot assay that is approved for use in the European Union) and ecarin clotting time. The anticoagulant effects of bivalirudin can be monitored using the activated clotting time (this is used in patients with an acute coronary syndrome) or aPTT.

3. Contraindications are the same as in the case of heparins (except for heparin-induced thrombocytopenia) and additionally include pregnancy and breastfeeding. Dabigatran is contraindicated in patients with a glomerular filtration rate (GFR) <30 mL/min, patients with severe liver failure, as well as in patients treated with dronedarone, azole antifungal agents (ketoconazole, itraconazole, voriconazole, posaconazole), rifampin (INN rifampicin), phenobarbital, carbamazepine, phenytoin, and hypericum (St John’s wort). The dose of dabigatran should be reduced in patients >80 years, patients with renal failure and a GFR 30 to 50 mL/min, and in patients treated with amiodarone or verapamil. The concomitant use of dabigatran and other anticoagulants (except for unfractionated heparin at doses used to maintain the patency of a central venous or arterial catheter), antiplatelet agents, thrombolytic agents, or dextran may be associated with an increased risk of bleeding.

4. Discontinuation of treatment before surgical procedures: see Periprocedural Direct Oral Anticoagulant (DOAC) Management.

5. Complications: Mainly bleeding, dyspepsia (in the case of dabigatran). Idarucizumab is an antidote that neutralizes the anticoagulant effect of dabigatran; it should be considered in selected patients who have serious or life-threatening bleeding or who require an emergency (ie, within 6 hours) surgery or procedure. Administer 5 IV in two 2.5 g doses over 15 minutes. The anticoagulant effect of dabigatran may be neutralized by a prothrombin complex concentrate (PCC) 25 IU/kg (the dose may be repeated twice) or activated PCC 50 IU/kg (maximum, 200 IU/kg/d). Bivalirudin, argatroban, and dabigatran can be eliminated from blood by hemodialysis (without an anticoagulant) or hemoperfusion.

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