Anticoagulants & Antiplatelets

Antithrombotic therapy encompasses anticoagulants (targeting the clotting cascade) and antiplatelets (targeting platelet activation) — essential in managing venous thromboembolism, atrial fibrillation, and acute coronary syndromes.

Warfarin is a vitamin K antagonist. It inhibits vitamin K epoxide reductase (VKOR), preventing recycling of vitamin K to its active hydroquinone form, which is required as a cofactor for gamma-carboxylation of clotting factors II, VII, IX, X (and anticoagulants protein C and S). This reduces production of functional clotting factors. The anticoagulant effect is delayed until existing factors are cleared (factor VII has the shortest half-life ~6 hours — INR rises first; full effect takes 3–5 days). Monitoring: INR (International Normalised Ratio). Therapeutic range is 2.0–3.0 for most indications (2.5–3.5 for mechanical heart valves). Warfarin has enormous pharmacokinetic and pharmacodynamic variability due to: CYP2C9 polymorphisms (metabolises S-warfarin), VKOR polymorphisms, and hundreds of drug interactions. Drugs that inhibit CYP2C9 (fluconazole, amiodarone, metronidazole) increase warfarin effect; inducers (rifampicin, carbamazepine) reduce it. Dietary vitamin K (green vegetables) antagonises warfarin effect. Reversal: vitamin K (slow, 12–24 hours for oral; 4–6 hours for IV), or 4-factor prothrombin complex concentrate (4F-PCC — rapid reversal for major bleeding or emergency surgery).

Heparin is an indirect thrombin inhibitor: it binds and activates antithrombin III (AT-III), which then rapidly inhibits thrombin (factor IIa) and factor Xa. Unfractionated heparin (UFH) inhibits both thrombin and Xa; monitoring via APTT (1.5–2.5× normal). UFH is reversible with protamine sulphate. Low molecular weight heparins (LMWH — enoxaparin, dalteparin) predominantly inhibit factor Xa, have more predictable pharmacokinetics, longer half-life, and do not require routine monitoring. They are renally cleared — avoid or reduce dose in severe CKD. Dose-adjusted enoxaparin via anti-Xa levels in obesity and renal impairment.

Direct oral anticoagulants (DOACs) target single clotting factors directly without requiring AT-III. Factor Xa inhibitors: apixaban and rivaroxaban bind directly to factor Xa. Rivaroxaban is once-daily for most indications; apixaban is twice-daily with lower GI bleeding rates. Direct thrombin inhibitors: dabigatran inhibits thrombin directly, twice-daily, with dabigatran etexilate as the prodrug. DOACs have predictable pharmacokinetics, no routine monitoring requirement, fewer drug interactions than warfarin, and demonstrated non-inferiority or superiority in clinical trials (RE-LY, ROCKET-AF, ARISTOTLE). Reversal: idarucizumab for dabigatran; andexanet alfa for factor Xa inhibitors (or 4F-PCC as alternative).

Aspirin irreversibly inhibits COX-1 in platelets, preventing thromboxane A2 synthesis and platelet aggregation. Because platelets have no nucleus, this effect lasts the platelet's lifespan (~7–10 days). Low-dose aspirin (75–100 mg) achieves maximal COX-1 inhibition with minimal GI effects. Used for secondary prevention of cardiovascular events.

Clopidogrel (and prasugrel, ticagrelor) are ADP receptor (P2Y12) antagonists. Clopidogrel is a prodrug requiring CYP2C19 activation — poor metabolisers (up to 30% of East Asians) have reduced efficacy. Ticagrelor is directly active and reversible. Dual antiplatelet therapy (DAPT — aspirin + P2Y12 inhibitor) is standard after acute coronary syndrome or coronary stent implantation for 12 months.