Thrombin inhibitors

Definition and Clinical Role

Thrombin inhibitors, also known as direct thrombin inhibitors (DTIs), are a class of anticoagulant medications that specifically inhibit the activity of thrombin (factor IIa)—a central enzyme in the coagulation cascade responsible for converting fibrinogen to fibrin, activating platelets, and amplifying further clotting factor activation. Unlike indirect agents such as heparin (which acts via antithrombin III), thrombin inhibitors bind directly to thrombin, either at its active site, exosite, or both.

Thrombin inhibitors are used to prevent and treat thromboembolic disorders, including deep vein thrombosis (DVT), pulmonary embolism (PE), atrial fibrillation (AF)-associated stroke prevention, and during percutaneous coronary interventions (PCI). They are also critical in managing patients with heparin-induced thrombocytopenia (HIT).

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Classification of Thrombin Inhibitors

1. Parenteral Direct Thrombin Inhibitors

   • Bivalent DTIs (bind both active site and exosite I)

   • Univalent DTIs (bind only active site)

2. Oral Direct Thrombin Inhibitors

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1. Parenteral Direct Thrombin Inhibitors

These are administered intravenously or subcutaneously and are used mainly in hospital settings.

a. Bivalirudin

• Mechanism: Bivalent DTI (binds both catalytic site and exosite I of thrombin).

• Indications:

  • Anticoagulation during PCI (especially in patients at risk for HIT)

  • Alternative to heparin in unstable angina

• Administration: IV infusion

• Brands: Angiomax

• Half-life: ~25 minutes

• Clearance: Renal

• Adverse Effects: Bleeding, back pain, hypotension

• Monitoring: Activated clotting time (ACT) during PCI

b. Argatroban

• Mechanism: Univalent DTI (binds active site only).

• Indications:

  • Anticoagulation in patients with HIT

  • PCI in HIT patients

• Administration: IV continuous infusion

• Brands: Argatroban (generic)

• Half-life: ~45 minutes

• Clearance: Hepatic (preferred in renal impairment)

• Adverse Effects: Bleeding, elevation in INR

• Monitoring: aPTT; INR (note: falsely elevated during warfarin transition)

c. Lepirudin (withdrawn from many markets)

• Mechanism: Recombinant hirudin (from leech saliva)

• Indications: Previously used in HIT (now replaced by safer alternatives)

• Notes: High immunogenicity, rare anaphylaxis risk

d. Desirudin

• Mechanism: Recombinant hirudin derivative

• Indications: DVT prophylaxis post-hip replacement surgery

• Administration: Subcutaneous

• Clearance: Renal

• Brands: Iprivask (withdrawn in some regions)

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2. Oral Direct Thrombin Inhibitors

a. Dabigatran etexilate

• Mechanism: Prodrug converted to dabigatran, a reversible direct thrombin inhibitor (univalent)

• Indications:

  • Stroke prevention in non-valvular AF

  • Treatment and secondary prevention of DVT and PE

  • Post-orthopedic surgery VTE prophylaxis (outside U.S.)

• Brands: Pradaxa

• Dosing:

  • AF: 150 mg twice daily (adjusted for renal function)

  • DVT/PE: 150 mg BID after initial parenteral anticoagulant for 5–10 days

• Bioavailability: ~6.5%

• Clearance: 80% renal

• Adverse Effects: Bleeding (especially GI), dyspepsia, gastritis

• Monitoring: No routine monitoring required; thrombin time (TT) or dilute thrombin time can be used if needed

• Reversal agent: Idarucizumab (Praxbind) – a monoclonal antibody fragment that reverses dabigatran within minutes

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Mechanism Summary

Thrombin inhibitors block thrombin’s ability to:

• Convert fibrinogen to fibrin

• Activate clotting factors V, VIII, XI, and XIII

• Activate platelets via PAR-1 receptors

They work independently of antithrombin III and inhibit both free and clot-bound thrombin, offering an advantage over heparin, which only inhibits free thrombin.

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Therapeutic Indications

Indication	Preferred DTI Agent
HIT (Heparin-induced thrombocytopenia)	Argatroban, Bivalirudin
PCI in HIT or high bleeding risk	Bivalirudin
Non-valvular AF stroke prevention	Dabigatran
DVT/PE treatment	Dabigatran (after parenteral agent)
DVT prevention post-orthopedic surgery	Dabigatran, Desirudin
HIT with renal failure	Argatroban (hepatic clearance)

Adverse Effects

1. Hemorrhage

   • Common across all DTIs

   • Risk increased with renal impairment (especially with dabigatran)

2. Gastrointestinal Effects

   • Dabigatran: dyspepsia, GERD, abdominal pain

3. Hepatic Effects

   • Argatroban may cause transient increase in liver enzymes

4. Allergic Reactions

   • Lepirudin/desirudin may induce antibodies; anaphylaxis reported

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Drug Interactions

Dabigatran

• P-glycoprotein inhibitors (e.g., amiodarone, verapamil): increase exposure

• P-gp inducers (e.g., rifampin): reduce exposure

• NSAIDs and antiplatelets: increase bleeding risk

• Avoid with antacids or H2 blockers: reduce absorption

Argatroban

• Warfarin: artificially increases INR

• CYP3A4 interactions: minor relevance clinically

Bivalirudin

• Minimal drug–drug interactions; highly predictable pharmacokinetics

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Monitoring and Laboratory Considerations

Agent	Routine Monitoring Needed	Lab Tests for Overdose/Effect
Dabigatran	No	aPTT (prolonged), TT (sensitive), ecarin clotting time
Argatroban	Yes	aPTT (goal: 1.5–3× control)
Bivalirudin	Yes (during PCI)	ACT (target-dependent on procedure)
Lepirudin	Yes	aPTT, ECT (specialist setting)

Advantages of DTIs Over Heparin

• Inhibit both free and clot-bound thrombin

• No dependence on antithrombin III

• No risk of heparin-induced thrombocytopenia (HIT)

• Predictable pharmacokinetics (esp. dabigatran)

• No need for routine coagulation monitoring (oral DTIs)

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Limitations and Clinical Considerations

• Cost: More expensive than heparin or warfarin

• Renal clearance: Limits use in severe renal impairment (dabigatran, bivalirudin)

• Lack of universal reversal agents: Only dabigatran has a specific antidote (idarucizumab); others rely on supportive care or off-label agents (e.g., PCCs)

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Reversal Strategies

Agent	Reversal Option(s)
Dabigatran	Idarucizumab (Praxbind)
Argatroban	Stop infusion; supportive care
Bivalirudin	Stop infusion; short half-life
Lepirudin	No antidote; supportive care

Brand and Generic Names Summary

Generic Name	Brand Name	Route	Notes
Dabigatran	Pradaxa	Oral	First oral DTI, stroke prevention
Bivalirudin	Angiomax	IV	PCI use, HIT alternative
Argatroban	Generic	IV	HIT, hepatic metabolism
Desirudin	Iprivask	SubQ	Hip replacement DVT prophylaxis
Lepirudin	Refludan (discontinued)	IV	Withdrawn due to immunogenicity