8.3.3 Direct thrombin inhibitors

There are two distinct categories: intravenous inhibitors, which are possible alternatives to heparin in heparinduced thrombocytopenia (HIT), and oral inhibitors, which are alternatives to anti-vitamin K agents. With the exception of dabigatran, there is yet no antagonist for these substances (see Tables 8.1 , 8.2 and 8.3 , 8.11 and 8.12 ).

 Intravenous agents

Hirudin is a substance isolated from the saliva of leeches. It binds to thrombin at the fibrin binding site and forms an irreversible complex with thrombin. It is no longer used and is replaced by recombinant or synthetic preparations, mainly used in heparin-induced thrombocytopenia (specific assays for ECC: see HIT) [1,5,910,14]. These substances inhibit both circulating and fibrin-bound thrombin, whereas heparin has no impact on the latter.

• Bivalirudin (Angiox^® ): a synthetic, reversible thrombin inhibitor that does not generate antibodies or thrombocytopenia. Dose-dependent effect, achieved in 2-10 minutes. Half-life: 25 min; renal excretion. Dosage in HIT: 0.15-2.0 mg/kg/h without bolus. Ease of use for ECC. In PCI: infusion 1.75 mg/kg/h up to 4 hours after the procedure, reduced bleeding risk compared to heparin [8]. Test to measure effect: ecarin time (ECT); less reliable: ACT, PTT.
• Argatroban (Argatroban Injection^® ): small synthetic molecule that selectively and reversibly binds to thrombin. Half-life: 40-50 minutes; minimal renal excretion and predominantly hepatic metabolism. Dosage in HIT: 2.0 mcg/kg/min without bolus; decrease to 0.5-1.2 mcg/kg/min in liver disease or after heart surgery. Return to normal coagulation 2-4 hours after stopping the infusion.
• Danaparoid sodium (Orgaran^® ): a mixture of heparin, chondroitin sulphate and dermatan. Half-life of 7 hours for anti-IIa activity and 25 hours for anti-Xa activity; renal elimination. Dosage in case of HIT: bolus 2'250 U, then infusion 400 U/h for 4 hours, 300 U/h for 4 hours and maintenance with 150-200 U/h.
• Desirudin (Iprivask^® ): recombinant form of hirudin, specific thrombin inhibitor. Elimination half-life: 2-3 hours (renal pathway). In clinical use for postoperative antithrombotic prophylaxis (5-15 mg/d), limited experience in HIT (15-30 mg/12h). Subcutaneous administration according to aPTT. Not suitable for ECC.
• Lepirudin (Refludan^® ): recombinant form of hirudin that causes irreversible inhibition of thrombin. Serum half-life 10 min, elimination half-life 1-1.5 hours. It is contraindicated in renal failure. Best monitored by ECT (ecarin clotting time of citrated whole blood). Lepirudin production was discontinued in 2012 for commercial reasons.

Oral agents: dabigatran (Pradaxa^® )

Dabigatran etexilate (Pradaxa^® ) is the orally absorbable form of dabigatran; its bioavailability is 6.5%. It is a direct competitive thrombin inhibitor, active on circulating thrombin and on thrombin bound in the clot. Peak concentration is reached in 1.5-3 hours. The half-life is 9-11 hours in the young and 13-17 hours in the elderly [4]; it exceeds 28 hours when creatinine clearance is < 30 mL/min [2]; dabigatran is contraindicated in renal failure. Patients > 75 years of age and those with a Cl_créat of 30-50 mL/min should receive half dose. Protein binding is modest (35% of circulating substance). Dabigatran is rapidly metabolised by nonspecific serum esterases; residues are excreted renally. The drug is not recommended for use in patients with creatinine clearance below 30 mL/min, or in patients with hepatic impairment or pregnancy [2]. It is also contraindicated in combination with anti-HIV drugs, amiodarone, verapamil, rifampicin, conazoles, cyclosporine and tacrolimus [3,12,13]. There is a specific antidote for dabigatran: idarucizumab (Praxbind^® ) is a monoclonal antibody marketed since the end of 2015; intravenously, it has rapid activity and a duration of action of 6 hours (see Antagonism). On the other hand, haemodialysis can remove about 40-68% of the substance in 4 hours [11]. Dabigatran has a significant tendency (OR 1.33) to increase the incidence of myocardial infarction compared with AVKs [9,12].

Preoperatively, it is recommended that dabigatran be discontinued 48 hours, and preferably >48 hours before highly bleeding procedures. If creatinine clearance is < 50 mL/min, the delay is increased to 3-4 days for standard operations and ≥ 4 days for operations with high bleeding risk [7,11]. It is sensible to monitor the resitual effect by a thrombin time (TT) 6-12 hours before surgery.

Coagulation tests are differentially affected by dabigatran (150 mg twice daily) [2,6,9,11,15,19]. 

• The TT is hypersensitive to dabigatran; a normal TT excludes the presence of dabigatran. This excess sensitivity is corrected by diluted TT (dTT) and calibrated for dabigatran (Hemoclot™), which allows a quantitative determination with excellent correlation to plasma level (r² = 0.92-0.99) [6].
• The ecarin clotting time (ECT) > 5 measures thrombin activity via a derivative of viper venom and is suitable for quantitative assessment of dabigatran as it correlates well with serum levels (r² = 0.92-1.0) [6].
• The APTT (activated partial thromboplastin time) provides an approximate indication of the anticoagulant effect of dabigatran, but its sensitivity is limited.
• PT and INR are unpredictably altered (x 1.5-1.9); they are not usable for the assessment of the anticoagulant effect of dabigatran.
• The aPTT is sensitive to dabigatran, but non-linearly; it can be used to determine the likely presence or absence of an anticoagulant effect, but not to quantify it. A residual effect of the substance is possible even if the aPTT is normal.

The recognised clinical indications for dabigatran are as follows [2,4,9,16,17,18].

• Perioperative prophylaxis of deep vein thrombosis (150-220 mg/d);
• Treatment of acute venous thrombosis (150 mg 2x/d) ;
• Prevention of systemic embolism (stroke) in non-valvular atrial fibrillation (150 mg 2x/d);
• The dosage is halved when creatinine clearance is < 50 mL/min and in patients > 75 years of age.

Ximelagatran, an oral precursor of melagatran, was withdrawn from the market in 2006 due to liver toxicity.

 © CHASSOT PG, MARCUCCI Carlo, last update November 2019.

References

1. ADAMS RLC, BIRD RJ. Review article: Coagulation cascade and therapeutic update: Relevance to nephrology. Part I: Overview of coagulation, thrombophilia and history of anticoagulants. Nephrol 2009; 14:462-70
2. AGENO WA, GALLUS AS, WITTKOWSKY A, et al. Oral anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9^th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl 2):e44S-e88S
3. ARTANG R, ROME E, NIELSEN JD, et al. Meta-analysis of randomized controlled trials on risk of myocardial infarction from the use of oral direct thrombin inhibitor. Am J Cardiol 2013; 112:1973-9
4. BAUER KA. Recent progress in anticoagulant therapy: oral direct inhibitors of thrombin and factor Xa. J Thromb Haemost 2011; 9(suppl 1):12-19
5. COPPENS M, EIKELBOOM JW, GUSTAFSSON D, WEITZ JI. Translational success stories. Development of direct thrombin inhibitors. Circ Res 2012; 111:920-9
6. CUKER A, SIEGAL DM, CROWTHER MA, et al. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014; 64:1128-39
7. FARAONI D, LEVY JH, ALBALADEJO P, et al. Updates in the perioperative and emergency management of non-vitamin K antagonist oral anticoagulants. Critic Care 2015; 19:203
8. FRANCHI F, ROLLINI F, ANGIOLILLO DJ. Antithrombotic therapy for patients with STEMI undergoing primary PCI. Nat Rev Cardiol 2017; 14: 361-79
9. GALANIS T, THOMSON L, PALLADINO M, et al. New oral anticoagulants. J Thromb Thrombolysis 2011; 31:310-20
10. GARCIA DA, BAGLIN TP, WEITZ JI, et al. Parenteral anticoagulants: Antithrombotic therapy and prevention of thrombosis, 9^th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl 2):e24S-e43S
11. HANKEY GJ, EIKELBOOM JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation 2011; 123: 1436-50
12. HEIDBUCHEL H, VERHAMME P, ALINGS M, et al. European Heart Rythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015; 17:1467-507
13. HEIDBUCHEL H, VERHAMME P, ALINGS M, et al. Updated European Heart Rythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Executive summary. Eur Heart J 2017; 38:2137-49
14. KELTON JG, ARNOLD DM, BATES SM. Nonheparin anticoagulants for heparin-induced thrombocytopenia. N Engl J Med 2013; 368:737-44
15. MUECK W, SCHWERS S, STAMPFUSS J. Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subject, specific patient populations and relevance of coagulation monitoring. Thrombosis Journal 2013; 11: 10
16. SCHULMAN S, KEARON C, KAKKAR AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-52
17. SINAURIDZE EI, PANTELEEV MA, ATAULLAKHANOV FI. Anticoagulant therapy: basic principles, classic approaches and recent developments. Blood Coag Fibrinol 2012; 23:482-93
18. WALLENTIN L, YUSUF S, EZEKOWITZ MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalized ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010; 376:975-83
19. WEITZ JI, QUINLAN DJ, EIKELBOOM JW. Periprocedural management and approach to bleeding in patients taking dabigatran. Circulation 2012; 126:2428-32