direct thrombin inhibitor

MECHANISM: DTIs bind thrombin's active site (and, for bivalent agents like bivalirudin/hirudins, also exosite 1), blocking thrombin-mediated conversion of fibrinogen to fibrin, activation of factors V, VIII, XI, XIII, and platelet activation (PAR-1). Unlike heparin, they do NOT require antithrombin III and inhibit both free and fibrin-bound thrombin. They do not bind platelet factor 4, so they do not cause HIT.

KEY AGENTS: - Argatroban (IV): synthetic, hepatic metabolism -> use in HIT with renal impairment; monitor aPTT. Dose-reduce in hepatic dysfunction. - Bivalirudin (IV): synthetic hirudin analog; short half-life, mainly proteolytic cleavage with some renal clearance; used in PCI, an alternative to heparin, including in HIT. - Lepirudin (recombinant hirudin; discontinued) and desirudin (SC; DVT prophylaxis after hip replacement): renally cleared. Derived from the medicinal leech (Hirudo medicinalis). - Dabigatran (PO; prodrug dabigatran etexilate): fixed dosing, no routine monitoring, ~80% renal clearance (avoid/adjust in renal impairment). Used for stroke prevention in nonvalvular AF, and for DVT/PE treatment and prophylaxis. P-gp substrate (avoid with strong P-gp inducers such as rifampin). Dyspepsia/GI upset and GI bleeding are common adverse effects. Not recommended in mechanical heart valves (RE-ALIGN: higher thrombosis and bleeding). Also not preferred in antiphospholipid syndrome (triple-positive).

MONITORING: aPTT (prolonged) for argatroban/bivalirudin/hirudins; ecarin clotting time or dilute thrombin time for more precise measurement; INR may be mildly elevated with argatroban (important when transitioning to warfarin). Dabigatran: thrombin time is sensitive (a normal TT essentially excludes significant drug effect).

CLINICAL USES: 1. Heparin-induced thrombocytopenia (HIT): type II, immune-mediated (IgG against heparin-PF4 complexes), causes platelet drop 5-10 days after heparin start, with paradoxical thrombosis. Stop all heparin and start a non-heparin anticoagulant (argatroban, bivalirudin; fondaparinux sometimes used). Do not give warfarin alone initially (risk of skin necrosis/venous limb gangrene from rapid protein C drop). 2. PCI/ACS anticoagulation (bivalirudin). 3. Nonvalvular AF stroke prevention, VTE treatment/prophylaxis (dabigatran).

ADVERSE EFFECTS: Bleeding (main toxicity); dabigatran also causes dyspepsia and GI bleeding.

REVERSAL: Dabigatran -> idarucizumab (Praxbind), a humanized monoclonal Fab fragment that binds dabigatran; alternatives are activated charcoal if recent ingestion, hemodialysis (dabigatran is dialyzable because of low protein binding), and PCC. Argatroban/bivalirudin have no specific antidote, but their short half-lives help (bivalirudin ~25 min). Contrast with andexanet alfa for factor Xa inhibitors (rivaroxaban, apixaban).

COMPARISON HIGH-YIELD: - Heparin/LMWH: indirect, via antithrombin; HIT risk; reversal with protamine. - Warfarin: inhibits vitamin K epoxide reductase (factors II, VII, IX, X, proteins C and S); reversal with vitamin K/PCC/FFP. - Factor Xa inhibitors (-xabans) bind Xa directly; DTIs (-gatran, -rudin) bind IIa. Mnemonic: "-gatran" = direct thrombin; "-xaban" = Xa. - Fondaparinux: indirect Xa inhibitor via antithrombin.

BOARD PEARLS: HIT + renal failure -> argatroban (hepatic clearance). HIT + liver failure -> bivalirudin (or other non-hepatic agent). Dabigatran in a patient with AF and CKD -> caution; apixaban often preferred. Post-hip arthroplasty DVT prophylaxis -> desirudin is an option.