Vascular Pharmacology
MRCS Part A & B — Comprehensive Study Notes
Heparin (UFH & LMWH)
Unfractionated Heparin (UFH)
Chemistry: Heterogeneous mixture of sulphated polysaccharide chains, molecular weight (MW) 3000–30,000 Da (mean ~15,000 Da). Extracted from porcine intestinal mucosa or bovine lung. Highly variable composition → variable pharmacokinetics.
Mechanism: Binds to Antithrombin III (ATIII) via a specific pentasaccharide sequence → conformational change in ATIII → 1000-fold potentiation of ATIII’s inhibitory activity. The UFH-ATIII complex irreversibly inactivates: Thrombin (IIa) — requires UFH chain ≥18 saccharides to bind both thrombin and ATIII simultaneously; Factor Xa — smaller UFH chains sufficient; also IXa, XIa, XIIa. UFH also releases TFPI (tissue factor pathway inhibitor) from endothelial cells → additional anticoagulation effect.
Anti-IIa:Anti-Xa ratio of UFH: Approximately 1:1 (equal thrombin and factor Xa inhibition). Kinetics: Highly protein-bound (to acute-phase reactants, platelet factor 4, macrophages) → non-linear kinetics → unpredictable dose-response → requires monitoring. Half-life dose-dependent: 25 min at low doses, 90–150 min at high doses.
Monitoring: APTT (target 1.5–2.5× control for therapeutic anticoagulation). Anti-Xa level (target 0.3–0.7 IU/mL for therapeutic) used when APTT unreliable (lupus anticoagulant, factor deficiencies). Dosing: Therapeutic (acute VTE/ACS): 80 units/kg IV bolus + 18 units/kg/hr infusion; adjust by APTT-based nomogram. Prophylactic: 5000 units SC BID or TDS.
Reversal: Protamine sulphate — positively charged protein derived from salmon sperm; electrostatically binds heparin → neutralisation. Dose: 1 mg per 100 units UFH given in last 2–3 hours (maximum 50 mg). Administer SLOWLY IV over 10 minutes — rapid injection causes hypotension, bradycardia, pulmonary vasoconstriction, anaphylaxis. Side effects: anaphylaxis (higher risk in fish allergy, prior protamine exposure, vasectomy — anti-sperm antibodies cross-react), pulmonary hypertension, myocardial depression.
Complications: HIT Type II (immune-mediated thrombocytopaenia + paradoxical thrombosis), osteoporosis (prolonged use inhibits osteoblasts, activates osteoclasts), hypoaldosteronism → hyperkalaemia (UFH inhibits aldosterone synthesis → K+ retention; rare but clinically significant), alopecia (rare), elevated liver enzymes.
Low Molecular Weight Heparin (LMWH)
Chemistry: Produced by enzymatic (heparinase) or chemical depolymerisation of UFH → shorter chains, mean MW 4000–6000 Da. More uniform composition than UFH → more predictable pharmacokinetics.
Mechanism: Predominantly inhibits Factor Xa (anti-Xa activity dominant). Shorter chains cannot simultaneously bridge ATIII and thrombin (requires ≥18 saccharides) → markedly reduced anti-IIa activity vs UFH. Anti-Xa:Anti-IIa ratio ≈ 4:1 (compared to 1:1 for UFH). Clinical significance: LMWH is more selective for factor Xa, less able to inhibit thrombin directly.
Products and dosing: Enoxaparin (Clexane) — treatment 1.5 mg/kg OD or 1 mg/kg BID SC; prophylaxis 40 mg OD. Dalteparin (Fragmin) — treatment 200 units/kg OD; prophylaxis 5000 units OD. Tinzaparin (Innohep) — treatment 175 units/kg OD. Fondaparinux (Arixtra) — synthetic pentasaccharide; selective anti-Xa ONLY; no anti-IIa activity; no HIT risk; treatment 7.5 mg OD; prophylaxis 2.5 mg OD.
Advantages over UFH: Predictable dose-response (no routine monitoring needed in most patients), once/twice daily SC dosing (outpatient treatment), lower HIT incidence, less non-specific protein binding, no need for APPT monitoring, proven in multiple VTE treatment/prophylaxis trials.
Monitoring: NOT routinely required. Anti-Xa levels used in: renal failure (eGFR <30), extremes of body weight (<40 kg or >100 kg), pregnancy, paediatrics. Therapeutic peak anti-Xa for BID dosing: 0.6–1.0 IU/mL; OD: 1.0–1.5 IU/mL.
Reversal: Protamine partially reverses LMWH (neutralises anti-IIa activity completely; anti-Xa activity only 60–80% reversed). Dose: 1 mg protamine per 100 anti-Xa units LMWH. If LMWH given >8h: 0.5 mg per 100 units. Andexanet alfa also reverses LMWH.
Renal dose adjustment: LMWH renally excreted → accumulates in CKD → increased bleeding risk. Use UFH (renal-independent) or reduce LMWH dose with anti-Xa monitoring in severe CKD (eGFR <30).
Clinical Vignette: Anticoagulation in Vascular Surgery
Scenario: 68-year-old on warfarin (mechanical mitral valve) presents with acute lower limb ischaemia (23h onset). Needs emergent angiography/intervention. Exam: absent distal pulses, mottled skin, pain, sensory loss (Category 2a). Anticoagulation decision: Cannot wait 5–7 days for warfarin bridge. INR currently 2.5 (therapeutic). Reverse immediately with 4-factor PCC 25–50 units/kg IV + 10 mg vitamin K IV (onset ~4h). Achieve INR <1.5 within minutes. Proceed to angiosuite immediately. Thrombectomy/thrombolysis performed. Post-op: restart LMWH 1.5 mg/kg BID evening (parenteral). 5 days later, when oral intake stable, bridge warfarin (5 mg daily, monitor INR closely given high protein C depletion risk from mechanical valve + prior reversal). Continue LMWH overlap until INR >2.0 on two consecutive days. Restart mechanical valve anticoagulation. Key learning: Warfarin reversal in emergency vascular situations requires IMMEDIATE PCC (not relying on vitamin K onset); bridging strategy differs from elective management; mechanical valves require indefinite anticoagulation (not DOACs).