Anticoagulants

Introduction

Anticoagulants are drugs that inhibit various steps in the coagulation cascade to prevent the formation and propagation of blood clots. They are used in the prevention and treatment of venous thromboembolism (VTE), atrial fibrillation-related stroke, prosthetic heart valve thrombosis, myocardial infarction, and other thromboembolic conditions.

Unlike antiplatelet agents (which target platelet aggregation), anticoagulants primarily act on coagulation factors (either directly or indirectly). The therapeutic aim is to balance antithrombotic efficacy with bleeding risk.

---

Classification of Anticoagulants

1. Vitamin K Antagonists (VKAs)

• Mechanism: Inhibit vitamin K epoxide reductase → reduced synthesis of vitamin K–dependent clotting factors II, VII, IX, X, and proteins C & S.

• Generic: warfarin (most widely used VKA).

• Uses: Atrial fibrillation, prosthetic heart valves, prevention/treatment of DVT and PE.

• Adverse Effects: Bleeding, skin necrosis (rare), teratogenicity.

• Monitoring: INR (target typically 2.0–3.0; 2.5–3.5 in mechanical valves).

• Antidote: Vitamin K, fresh frozen plasma, prothrombin complex concentrate.

---

2. Heparins

a. Unfractionated Heparin (UFH)

• Mechanism: Binds antithrombin III, enhancing inactivation of thrombin (IIa), Xa, IXa, XIa, XIIa.

• Uses: DVT/PE treatment, acute coronary syndromes, VTE prophylaxis, bridging before warfarin.

• Adverse Effects: Bleeding, heparin-induced thrombocytopenia (HIT), osteoporosis (long-term).

• Monitoring: aPTT (activated partial thromboplastin time).

• Antidote: Protamine sulfate.

b. Low-Molecular-Weight Heparins (LMWHs)

• Generics: enoxaparin, dalteparin, tinzaparin.

• Mechanism: Preferentially inhibit factor Xa (via antithrombin), some activity against IIa.

• Uses: VTE treatment/prophylaxis, ACS.

• Adverse Effects: Lower HIT risk than UFH, bleeding.

• Monitoring: Usually not needed, anti-Xa levels in special populations (pregnant, renal impairment).

c. Fondaparinux

• Mechanism: Synthetic pentasaccharide, selective indirect factor Xa inhibitor via antithrombin.

• Uses: VTE prophylaxis and treatment.

• Advantages: No HIT risk.

---

3. Direct Oral Anticoagulants (DOACs / NOACs)

a. Direct Thrombin Inhibitors

• Generic: dabigatran etexilate.

• Mechanism: Directly inhibits thrombin (IIa).

• Uses: Stroke prevention in atrial fibrillation (non-valvular), VTE treatment/prophylaxis.

• Antidote: Idarucizumab (specific reversal agent).

b. Direct Factor Xa Inhibitors

• Generics: rivaroxaban, apixaban, edoxaban, betrixaban.

• Mechanism: Direct, reversible inhibition of factor Xa.

• Uses: Stroke prevention in non-valvular AF, treatment/prophylaxis of VTE, postoperative DVT prevention.

• Antidote: Andexanet alfa (for rivaroxaban, apixaban), prothrombin complex concentrate.

---

4. Parenteral Direct Thrombin Inhibitors

• Generics: argatroban, bivalirudin, desirudin.

• Mechanism: Directly inhibit thrombin (IIa).

• Uses: Heparin-induced thrombocytopenia (HIT), PCI in patients with HIT.

• Monitoring: aPTT.

• Adverse Effects: Bleeding.

---

Clinical Indications of Anticoagulants

1. Venous thromboembolism (VTE): Treatment and secondary prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE).

2. Atrial fibrillation: Prevention of cardioembolic stroke (DOACs preferred over warfarin for non-valvular AF).

3. Mechanical heart valves: Warfarin is the only oral option.

4. Acute coronary syndromes: UFH, LMWH, bivalirudin.

5. Prophylaxis in surgery/immobilization: LMWH, fondaparinux, DOACs.

6. HIT management: Argatroban, bivalirudin (non-heparin anticoagulants).

---

Contraindications

• Active major bleeding.

• Severe uncontrolled hypertension.

• Recent hemorrhagic stroke.

• Severe liver disease with coagulopathy.

• Pregnancy:

  • Warfarin: contraindicated (teratogenic).

  • LMWH/UFH: safe alternatives.

---

Adverse Effects

• All anticoagulants: Risk of bleeding (most significant).

• Heparins: HIT, osteoporosis (long-term UFH).

• Warfarin: Skin necrosis, teratogenicity, multiple drug–food interactions.

• DOACs: GI upset, increased GI bleeding risk with dabigatran and rivaroxaban.

---

Clinical Considerations

1. Drug–drug and drug–food interactions:

   • Warfarin highly sensitive to CYP450 interactions (e.g., antibiotics, antifungals, antiepileptics).

   • Vitamin K–rich foods reduce warfarin efficacy.

   • DOACs have fewer interactions but are affected by P-glycoprotein and CYP3A4 inhibitors/inducers.

2. Monitoring:

   • Warfarin: INR required.

   • UFH: aPTT monitoring.

   • LMWH and DOACs: routine monitoring generally unnecessary.

3. Reversal strategies:

   • Warfarin: Vitamin K, prothrombin complex concentrate, FFP.

   • Heparins: Protamine sulfate (less effective for LMWH).

   • Dabigatran: Idarucizumab.

   • Factor Xa inhibitors: Andexanet alfa or PCC.

4. Renal function:

   • DOACs require dose adjustment in renal impairment; contraindicated in severe renal failure.

   • Warfarin preferred in ESRD.

5. Bridging therapy:

• Patients on warfarin often require bridging with LMWH/UFH during initiation or perioperatively.