Unfractionated Heparin

Unfractionated heparin is a mixture of sulphated glycosaminoglycan chains that activates antithrombin and inactivates thrombin and factor Xa within minutes. It treats acute coronary syndromes, venous thromboembolism, pulmonary embolism, and clots on heart valves or extracorporeal circuits. It has a short half life, is fully reversible with protamine, and is safe in kidney failure and pregnancy. It needs laboratory monitoring. It is cheap and widely available in East African hospitals.

Classification. Parenteral anticoagulant; indirect thrombin and factor Xa inhibitor.

Mechanism. Binds antithrombin, causing a conformational change that speeds antithrombin inhibition of thrombin (needs 18 or more saccharide units) and factor Xa (needs the pentasaccharide sequence). It also releases the natural inhibitor of tissue factor from the vessel wall.

Pharmacodynamics. IV onset immediate; peak at the end of the bolus; subcutaneous onset 20 to 60 minutes. Prolongs aPTT and activated clotting time. The dose response is nonlinear and varies between patients.

Pharmacokinetics. Not absorbed orally. Dose dependent half life 30 to 90 minutes (shorter at low doses, longer at high doses). Cleared by cell binding and the reticuloendothelial system, and at higher doses by the kidneys. Does not cross the placenta or enter breast milk.

Venous thromboembolism and pulmonary embolism, treatment, adult.

• Bolus 80 units/kg IV (or 5000 units).

• Infusion 18 units/kg/hour, adjusted to aPTT 1.5 to 2.5 times control (or anti Xa 0.3 to 0.7 units/mL) every 6 hours until stable, then daily.

• Continue for at least 5 days and until the INR is 2.0 or more for 24 hours when warfarin is started; use a lower bolus (5000 units) when bleeding risk is high.

Unstable angina and non ST elevation myocardial infarction, adult. Bolus 60 to 70 units/kg IV (maximum 5000 units), then 12 units/kg/hour (maximum 1000 units/hour) for 48 hours or until intervention; aPTT target 1.5 to 2.5 times control.

ST elevation myocardial infarction with fibrinolysis, adult. Bolus 60 units/kg (maximum 4000 units), then 12 units/kg/hour (maximum 1000 units/hour) for 24 to 48 hours.

Percutaneous coronary intervention, adult. Bolus 70 to 100 units/kg IV (50 to 70 units/kg with a glycoprotein IIb/IIIa inhibitor), aiming for an activated clotting time of 250 to 300 seconds (200 to 250 seconds with a glycoprotein IIb/IIIa inhibitor).

Prophylaxis of venous thromboembolism, adult. 5000 units SC every 8 to 12 hours (every 12 hours in high bleeding risk, pregnancy and orthopaedic surgery); no monitoring needed.

Catheter and arterial line maintenance. Flush with 10 units/mL solution, 2 to 5 mL; do not use as treatment.

Children. Treatment: bolus 75 units/kg IV, then 28 units/kg/hour (under 1 year) or 20 units/kg/hour (over 1 year); aPTT target 1.5 to 2.5 times control or anti Xa 0.35 to 0.7 units/mL. Prophylaxis: 10 units/kg/hour.

Contraindications. Active major bleeding; history of heparin induced thrombocytopenia; severe thrombocytopenia (under 50 x 10^9/L before treatment); haemorrhagic stroke; uncontrolled severe hypertension; recent neurosurgery or eye surgery; bleeding disorders; hypersensitivity (including to pork products).

Warnings. Bleeding; heparin induced thrombocytopenia (platelet fall of 50% or more at days 5 to 14, with thrombosis); osteoporosis with long term use (over 3 months); hyperkalaemia from reduced aldosterone; raised liver enzymes; skin necrosis at injection sites; heparin resistance (low antithrombin). Confusion between 1000 units/mL and 5000 units/mL vials is a common cause of overdose.

Adverse effects. Bleeding, bruising at injection sites, thrombocytopenia, raised liver enzymes, hyperkalaemia, rarely allergic reaction or alopecia.

Interactions. Aspirin, clopidogrel, non steroidal anti-inflammatory drugs, warfarin, thrombolytics, glycoprotein IIb/IIIa inhibitors: bleeding. Glyceryl trinitrate infusion: may reduce effect (conflicting data). Antihistamines, digoxin, tetracyclines, nicotine: variable.

Reversal. Protamine sulphate 1 mg for each 100 units of heparin given in the last 2 to 3 hours (maximum 50 mg in a single dose), IV over 10 minutes or more; monitor for hypotension and anaphylaxis.

Special groups.

• Pregnancy: safe; does not cross the placenta; used for mechanical valves and thrombosis; stop 6 hours before epidural placement (aPTT normal).

• Breastfeeding: safe.

• Patients of African ancestry: no dose change.

• Older adults: lower starting doses; higher bleeding risk.

• Kidney impairment: no adjustment; drug of choice with creatinine clearance under 15 mL/min.

• Liver impairment: use with care; monitor aPTT more often.

Formulations. Injection 1000, 5000 and 25000 units/mL (5 mL vials); prefilled syringes 5000 units/0.2 mL; flush 10 and 100 units/mL.

Administration. IV bolus then continuous infusion by pump (25000 units in 500 mL of 0.9% sodium chloride or 5% glucose gives 50 units/mL); or deep SC injection into the abdomen. Never intramuscular. Check vial strength twice and use a second person check.

Baseline. Platelet count, haemoglobin, aPTT, PT, creatinine, liver function, pregnancy status, bleeding history.

Monitoring. aPTT at 6 hours after starting and 6 hours after each change, then daily (or anti Xa levels in resistance). Platelet count before starting and on days 4 to 14 (every 2 to 3 days). Haemoglobin daily. Potassium in long infusions.

Stopping. Stop the infusion (effect gone in 2 to 4 hours); overlap with warfarin for at least 5 days and until the INR is 2.0 or more for 24 hours.

Common prescribing errors. Mixing up 1000 units/mL and 5000 units/mL vials; not adjusting to weight; giving IM; omitting platelet counts; stopping heparin before the INR is therapeutic; giving the flush strength as treatment.