Anticoagulants and antiplatelets

Antiplatelet drugs

• Stop clopidogrel or ticagrelor about 5–7 days before elective surgery (prasugrel 7), unless there is a recent stent.

Heparins

Heparin is a natural anticoagulant stored with histamine in mast cells and basophils. It also releases lipoprotein lipase from endothelium, which clears lipaemic plasma.

• Heparin prolongs the APTT within hours because it speeds antithrombin's inactivation of thrombin (and IXa, Xa). Patients with antithrombin deficiency respond poorly.
• Protamine is strongly basic and binds the acidic heparin directly to form an inactive salt: chemical antagonism. It binds the short LMWH chains poorly, so LMWH reversal is only partial. Dose: 1 mg per 100 units of heparin given in the last 15 minutes, maximum 50 mg; so 5,000 units given 10 minutes ago needs 50 mg. Protamine can cause hypotension and anaphylaxis (fish allergy, vasectomy, prior protamine insulin).
• Heparin-induced thrombocytopenia (HIT): IgG against heparin–platelet factor 4 complexes activates platelets, so the count falls by more than 50% at 5–10 days with new thrombosis. Confirm with the anti-PF4/heparin antibody assay. Stop all heparin; use a non-heparin anticoagulant such as argatroban or bivalirudin (direct thrombin inhibitors, which do not need antithrombin), fondaparinux or a DOAC. Do not transfuse platelets routinely; delay warfarin until platelets recover.
• Fondaparinux: synthetic pentasaccharide; antithrombin-dependent anti-Xa; no HIT.

Warfarin

• Inhibits vitamin K epoxide reductase (VKORC1), so factors II, VII, IX, X and proteins C and S are not γ-carboxylated.
• Monitor by PT expressed as INR (target 2.5 for VTE and AF; 3.0–3.5 for mechanical mitral valves and recurrent VTE). Heparin is monitored by APTT.
• Onset takes days; protein C falls first (short half-life), giving an early procoagulant state, so overlap with heparin for at least 5 days and until INR is 2 or more for 24 hours. Protein C deficiency predisposes to warfarin skin necrosis.
• Teratogenic in weeks 6–12: nasal hypoplasia and stippled epiphyses (chondrodysplasia punctata); later fetal CNS bleeding. Use LMWH in pregnancy (DVT in pregnancy is treated with LMWH). Warfarin is safe in breastfeeding.
• In cancer, LMWH or a DOAC is preferred: warfarin works less well and the INR is unstable with chemotherapy, vomiting and interactions.

• Dental extraction with INR below 4: continue warfarin with local haemostasis (tranexamic mouthwash); avoid NSAIDs and interacting antibiotics. Major elective surgery: stop 5 days before; bridge only high-risk patients.

Direct oral anticoagulants

• Because most dabigatran is cleared by the kidney, it is stopped longer before surgery in renal impairment than apixaban. Check creatinine clearance first.
• Not for mechanical valves, triple-positive antiphospholipid syndrome, or moderate to severe mitral stenosis; avoid in pregnancy.

VTE prevention and special situations

• All adult admissions have a VTE and bleeding risk assessment. Mechanical (early mobilisation, stockings, intermittent pneumatic compression) and pharmacological (LMWH starting 6–12 hours post-op; extended 28 days after major cancer surgery; 14 days knee and 28–35 days hip replacement) prophylaxis.
• No spinal or epidural within 12 hours of prophylactic LMWH (24 hours after a treatment dose).
• Proximal DVT with major bleeding, when anticoagulation is impossible: a retrievable IVC filter; remove it once anticoagulation is possible.
• Superficial thrombophlebitis within 3 cm of the saphenofemoral junction is treated like a DVT with anticoagulation; recurrent migratory thrombophlebitis suggests malignancy.

Thrombolytics and antifibrinolytics

• Alteplase, tenecteplase (fibrin-specific) and streptokinase convert plasminogen to plasmin, which digests fibrin.
• Uses: ischaemic stroke within 4.5 hours after CT excludes haemorrhage; STEMI when primary PCI is unavailable within 120 minutes; massive PE with shock.
• Streptokinase is a bacterial protein: it induces neutralising antibodies, so it is not repeated after 5 days (allergy and inefficacy). During infusion hypotension is common, caused by plasmin-generated bradykinin dilating vessels; slow the infusion rather than labelling allergy.
• Absolute contraindications: previous intracranial bleed, recent ischaemic stroke, CNS tumour, recent major trauma or surgery, active bleeding, aortic dissection.
• Tranexamic acid blocks the lysine-binding sites on plasminogen and inhibits fibrinolysis: trauma (within 3 hours), postpartum haemorrhage, menorrhagia, mouth and nose bleeds in haemophilia. Avoid in upper urinary tract bleeding: stabilised clots cause clot retention and ureteric obstruction.

Exam trap Never treat HIT with warfarin alone or platelet transfusion; switch to a direct thrombin inhibitor or other non-heparin anticoagulant.

Haematinics

• Oral iron: one tablet daily or on alternate days. Each dose raises hepcidin for about 24 hours, blocking ferroportin and next-day absorption; spacing doses lets hepcidin fall, so fractional absorption improves and unabsorbed iron (the cause of nausea and constipation) is less. Take with vitamin C (orange juice), away from tea, antacids, PPIs, tetracyclines and quinolones. Black stools are expected.
• Expected Hb rise about 10 g/L (1 g/dL) per week; continue 3 months after Hb normalises. Failure after 2 months suggests non-adherence, ongoing loss, malabsorption (coeliac disease) or a wrong diagnosis such as thalassaemia trait.
• IV iron: intolerance or malabsorption, CKD, and late pregnancy with severe anaemia (avoid in the first trimester and active infection).
• Vitamin B12: IM hydroxocobalamin. In severe megaloblastic anaemia, the burst of new cell production in the first days pulls potassium into the new cells, causing hypokalaemia; monitor and replace. The same happens with folate replacement.
• Folic acid 5 mg daily, after B12 deficiency is excluded or treated.
• Erythropoietin is made by peritubular interstitial fibroblasts of the renal cortex and acts through the JAK2–STAT pathway. In dialysis patients with anaemia and adequate iron, EPO injections are the treatment; adverse effects are hypertension, thrombosis, red cell aplasia.
• Hydroxyurea (hydroxycarbamide) reduces sickle crises and acute chest syndrome by raising fetal haemoglobin (HbF), which does not polymerise with HbS.

Remember Heparin needs antithrombin; argatroban and dabigatran hit thrombin directly.

How FCPS asks about this

• Monitoring: IV heparin by APTT; warfarin by PT/INR; LMWH usually none.
• Warfarin with metronidazole or clarithromycin: INR rises (CYP inhibition).
• Clopidogrel failure in a CYP2C19 poor metaboliser: prodrug not activated.
• Protamine type of antagonism and dose: chemical; 1 mg per 100 units, 50 mg after 5,000 units.
• HIT drug that needs no antithrombin: argatroban or bivalirudin; confirm with anti-PF4 antibodies.
• Why streptokinase is not repeated: neutralising antibodies; hypotension during infusion is bradykinin-mediated.
• Alternate-day iron: a dose raises hepcidin, blocking next-day absorption; take with orange juice, not tea.