Antiplatelets, Anticoagulants & Fibrinolytics

Haemostasis is the arrest of blood loss from damaged vessels via clot formation. Thromboembolic diseases arise when pathological clots form in the vasculature. Virchow's triad describes the three contributors to venous thrombosis: endothelial injury, hypercoagulability, and blood flow stasis.

Endogenous anticoagulants include prostacyclin (PGI2 — produced by endothelial COX-2; inhibits platelet aggregation by increasing platelet cAMP; inhibits COX-1 → decreased TXA2); antithrombin (inhibits coagulation factors); and thrombomodulin/Protein C and S (thrombomodulin activates Protein C, which with Protein S inactivates factors Va and VIIIa).

Thrombus formation: endothelial injury → decreased PGI2 and NO → platelets adhere to ECM (vWF, collagen) → platelet activation → thrombin release → shape change → granule release (ADP activates P2Y receptors → decreased cAMP → platelet activation; TXA2 → vasoconstriction and platelet aggregation) → fibrin stabilises platelet plug.

Aspirin (acetylsalicylate): irreversibly acetylates platelet COX (COX-1) → reduces TXA2 for the platelet's lifetime (~7-9 days). At low doses acts in portal circulation; rapidly cleared by first-pass esterase metabolism to salicylate (inactive). Minimal effect on endothelial COX-2 PGI2 because endothelium can resynthesise COX (nucleated cells), while platelets cannot (anucleate). ADRs: haemorrhage, GI ulceration, Reye syndrome (with viral illness in children). Indicated for secondary prevention; contraindicated for primary prevention.

Clopidogrel: non-competitive P2Y receptor (ADP receptor) antagonist; prevents GPIIb/IIIa (fibrinogen receptor) activation; metabolised by multiple CYPs (CYP2C19, CYP3A4, etc.); used as monotherapy or with aspirin.

Anticoagulants: unfractionated heparin (UFH) binds antithrombin and both Factor Xa and Factor IIa (thrombin) → decreased fibrin. Given IV; T½ 0.5-1h; reversed by protamine sulphate. ADRs: haemorrhage, heparin-induced thrombocytopenia (HIT — IgG response causing paradoxical thrombosis and gangrene). LMWH (e.g. enoxaparin): binds antithrombin, potentiates action on Factor Xa only; given SC; longer T½ 4-6h; fewer ADRs; renal clearance; less readily reversed.

Warfarin (VKA): oral; competitively inhibits hepatic vitamin K epoxide reductase → prevents reduced vitamin K from activating Factors II, VII, IX, X and Proteins C and S. Very narrow therapeutic index; monitor INR (target 2-3). Metabolised by CYP2C9 (S-warfarin) and CYP1A2/CYP3A4 (R-warfarin); interacts with almost everything. ADRs: haemorrhage (most common), skin necrosis, paradoxical microvasculature thrombosis (Protein C/S inhibition), teratogenic. Reversal: withdraw → Vitamin K1 → prothrombinex-VF (PCC) or FFP.

DOACs/NOACs: dabigatran (direct thrombin inhibitor; oral; renal clearance; reversed by idarucizumab); rivaroxaban (Factor Xa inhibitor; oral; affected by CYP3A4 and P-gp). Fewer interactions than warfarin; no routine INR monitoring needed.

Fibrinolytics (rtPAs): alteplase and tenecteplase — mimic tissue plasminogen activator (tPA); convert plasminogen to plasmin to degrade fibrin. Given IV acutely post-MI or ischaemic stroke (within 6h for optimal outcome). ADR: bleeding. Contraindicated with concurrent anticoagulants.