Unfractionated Heparin

Unfractionated heparin is a heterogeneous mixture of sulphated polysaccharides (3 to 30 kDa) that binds antithrombin, increasing its inhibition of thrombin and factor Xa up to 1000-fold. Its short half-life, full reversibility with protamine and independence from kidney clearance make it the preferred anticoagulant in acute care, renal failure and around procedures.

Mechanism. A specific pentasaccharide binds antithrombin and inhibits factor Xa. Chains of 18 saccharides or more also bind thrombin, forming a ternary complex that inhibits it. Heparin binds plasma proteins, endothelium and platelet factor 4, which causes variable response and heparin-induced thrombocytopenia.

Pharmacokinetics. Given intravenously (or subcutaneously for prophylaxis). Elimination is dose dependent, with a half-life of 30 minutes at low doses and 60 to 90 minutes at therapeutic doses. Onset is immediate intravenously. Anticoagulation after subcutaneous therapeutic doses begins within 1 to 2 hours.

Monitoring principle. Response varies between patients, so laboratory monitoring guides dosing.

• Unfractionated heparin: intravenous infusion, subcutaneous, and flush solutions.
• Compared with low molecular weight heparin: shorter acting, more monitoring, fully reversible, higher heparin-induced thrombocytopenia risk and osteoporosis risk, preferred in severe renal failure.

• Venous thromboembolism: 80 units/kg (or 5000 units) bolus, then 18 units/kg/hour (or 1300 units/hour), adjusted every 6 hours to aPTT 1.5 to 2.5 times control or anti-Xa 0.3 to 0.7 units/mL.
• Acute coronary syndrome: 60 units/kg bolus (maximum 4000 units), then 12 units/kg/hour (maximum 1000 units/hour) for 48 hours or until intervention, aPTT 50 to 70 seconds.
• Percutaneous coronary intervention: 70 to 100 units/kg bolus (50 to 70 units/kg with a glycoprotein IIb/IIIa inhibitor), activated clotting time 250 to 350 seconds (200 to 250 seconds with a glycoprotein IIb/IIIa inhibitor).
• Prophylaxis: 5000 units subcutaneously every 8 to 12 hours.
• Pregnancy and mechanical valves: used peripartum in some regimens because of reversibility.
• Cardiopulmonary bypass and dialysis: dosed to activated clotting time targets by specialist teams.
• Line patency: 10 units/mL flush solutions.
• Selection: use in renal failure (creatinine clearance under 30 mL/min), high bleeding risk, before surgery or procedures, and when reversibility matters.

Contraindications. Active major bleeding, history of heparin-induced thrombocytopenia, and severe thrombocytopenia (relative). Use with caution after recent surgery, in uncontrolled hypertension and with intracranial disease.

Adverse effects. Bleeding, heparin-induced thrombocytopenia (type II, 0.1% to 5%, at days 5 to 14, with paradoxical thrombosis), non-immune early platelet fall, osteoporosis with long-term use, hyperkalaemia (suppressed aldosterone), raised liver enzymes, skin reactions and alopecia.

Heparin-induced thrombocytopenia. Suspect with a platelet fall of over 50% or below 100 x 10^9/L from day 5 to 14, or earlier after recent exposure, particularly with new thrombosis. Stop all heparin including flushes, send antibody testing, and start a non-heparin anticoagulant (argatroban, bivalirudin, fondaparinux, or a direct oral anticoagulant in stable patients). Do not give platelet transfusions unless bleeding, and avoid warfarin until platelets recover.

Reversal. Protamine sulphate 1 mg for each 100 units of heparin given in the previous 2 to 3 hours (maximum 50 mg), slowly intravenously. Reactions include hypotension, bradycardia and anaphylaxis, especially after previous exposure to protamine-containing insulin or fish allergy.

Interactions. Antiplatelet drugs, NSAIDs, thrombolytics and glycoprotein IIb/IIIa inhibitors raise bleeding. Intravenous glyceryl trinitrate and antihistamines may reduce effect. Antithrombin deficiency causes heparin resistance.

Monitoring. aPTT or anti-Xa 6 hours after starting and after each change, then daily. Platelet count before starting, then every 2 to 3 days from day 4 to day 14. Haemoglobin and potassium.

Referral and escalation. Platelet fall, new thrombosis on heparin, or bleeding not controlled by stopping and protamine needs urgent haematology input.

Special groups. Pregnancy: safe and does not cross the placenta. Renal failure: preferred. Obesity: use actual body weight with caps. Children: age-adjusted dosing.