10.1 Anticoagulant, Antiplatelet and Haemostatic Drugs and Their Reversal

10.1 Anticoagulant, Antiplatelet and Haemostatic Drugs and Their Reversal

Why This Topic Matters

Anticoagulant and antiplatelet drugs affect timing of surgery, choice of neuraxial or regional techniques, transfusion strategy and the management of bleeding. EDAIC questions test mechanisms, pharmacokinetics, laboratory monitoring and reversal.

Heparins

Unfractionated Heparin (UFH)

• Mechanism: A mixture of sulphated glycosaminoglycans (mean molecular weight about 15 kDa). A specific pentasaccharide sequence binds antithrombin and accelerates its action about 1,000-fold. Chains longer than 18 saccharides can bridge antithrombin and thrombin, so UFH inhibits thrombin (IIa) and factor Xa equally.
• Pharmacokinetics: Binds plasma proteins, endothelium and macrophages, so the dose-response is unpredictable. Half-life is about 1-2 hours, increasing with dose. Clearance is mainly by the reticuloendothelial system, so it is suitable in renal failure.
• Monitoring: aPTT (therapeutic ratio about 1.5-2.5) or activated clotting time (ACT) during cardiopulmonary bypass (target above about 400-480 seconds).
• Reversal: Protamine sulphate, a basic protein that forms a stable salt with heparin; 1 mg neutralises about 100 units of heparin. Give slowly to avoid hypotension; severe reactions include catastrophic pulmonary vasoconstriction.
• Adverse effects: Heparin-induced thrombocytopenia (HIT), osteoporosis with long-term use, hyperkalaemia through aldosterone suppression, and heparin resistance from antithrombin deficiency.

Low Molecular Weight Heparin (LMWH)

• Shorter chains (mean about 4-5 kDa) cannot bridge thrombin, so activity is mainly anti-Xa (anti-Xa:anti-IIa ratio about 2-4:1 for enoxaparin).
• Predictable subcutaneous absorption, half-life about 4-6 hours, renal excretion: reduce the dose when creatinine clearance is below 30 mL/min.
• Monitored by anti-Xa activity (for example in renal failure, pregnancy or obesity).
• Protamine reverses only about 60% of the anti-Xa activity.
• Lower risk of HIT than UFH.

Fondaparinux

A synthetic pentasaccharide that binds antithrombin and inhibits only factor Xa. Half-life about 17-21 hours, renally excreted, not reversed by protamine, and does not cross-react with HIT antibodies.

Vitamin K Antagonists

Warfarin inhibits vitamin K epoxide reductase (VKORC1), preventing regeneration of reduced vitamin K needed for gamma-carboxylation of factors II, VII, IX and X and proteins C and S.

• Highly protein-bound (about 99%), metabolised by CYP2C9; genetic variants of CYP2C9 and VKORC1 alter dose requirements.
• Many interactions: enzyme inhibitors (amiodarone, metronidazole, fluconazole) raise the INR; enzyme inducers (rifampicin, carbamazepine) lower it.
• Elective surgery: stop about 5 days before; bridge with LMWH only in high thrombotic risk (for example mechanical mitral valve).
• Emergency reversal: four-factor prothrombin complex concentrate (PCC) (about 25-50 units/kg depending on INR and product) plus vitamin K 5-10 mg intravenously. Vitamin K takes 6-12 hours to act; fresh frozen plasma is a slower, larger-volume alternative.

Direct Oral Anticoagulants (DOACs)

• Routine tests are unreliable: dabigatran prolongs the thrombin time (a normal thrombin time excludes significant levels); anti-Xa assays calibrated for the specific drug measure factor Xa inhibitors.
• Elective interruption depends on bleeding risk and renal function: for factor Xa inhibitors, usually at least 24 hours for low-risk and 48 hours for high-risk surgery; dabigatran needs longer intervals when creatinine clearance falls (see the preoperative assessment section).
• Andexanet alfa is a modified recombinant factor Xa decoy that binds factor Xa inhibitors. It also binds heparin-antithrombin complexes, which can cause heparin resistance if cardiopulmonary bypass is needed.

Antiplatelet Drugs

• Clopidogrel needs activation by CYP2C19; poor metabolisers and patients taking inhibitors (such as omeprazole) have a reduced effect.
• After coronary stenting, dual antiplatelet therapy should not be interrupted without cardiology advice; elective surgery is usually deferred until the minimum duration has been completed.
• Reversal: platelet transfusion restores function for irreversible inhibitors once the drug has been cleared from plasma; with ticagrelor the active drug inhibits transfused platelets, so transfusion is less effective in the first day after the last dose. Desmopressin may improve platelet function in some cases.

Thrombolytics

Alteplase, tenecteplase and reteplase convert plasminogen to plasmin. They are used for acute ischaemic stroke (alteplase 0.9 mg/kg, maximum 90 mg, within 4.5 hours of onset), massive pulmonary embolism and, less often now, myocardial infarction. Recent major surgery is a contraindication. Life-threatening bleeding after thrombolysis is treated with cryoprecipitate or fibrinogen and tranexamic acid.

Haemostatic Drugs