Low Molecular Weight Heparins

Low molecular weight heparins are fragments of unfractionated heparin (4 to 6 kDa) that inhibit factor Xa more than thrombin. They have predictable dose response, high subcutaneous bioavailability (90%), longer half-life and lower rates of heparin-induced thrombocytopenia and osteoporosis, so routine laboratory monitoring is not needed. They are used for prophylaxis and treatment of venous thromboembolism, in acute coronary syndrome and in pregnancy.

Members. Enoxaparin, dalteparin, tinzaparin and nadroparin. Products differ in molecular size and are not interchangeable at the same unit dose.

Mechanism. Short chains cannot bridge antithrombin and thrombin, so they inhibit factor Xa through antithrombin. Anti-Xa to anti-IIa ratio is about 3:1 to 4:1 for enoxaparin.

Pharmacokinetics. Peak anti-Xa activity 3 to 5 hours after subcutaneous injection, half-life 4 to 7 hours, and renal clearance that causes accumulation when creatinine clearance is under 30 mL/min. Weight, pregnancy and obesity change dosing needs.

• Enoxaparin: the most used; many indications.
• Dalteparin: cancer-associated thrombosis; dosing in renal impairment with anti-Xa monitoring.
• Tinzaparin: less renal accumulation; once daily.
• Nadroparin: prophylaxis and treatment in several regions.

• Prophylaxis (medical or surgical): enoxaparin 40 mg subcutaneously once daily (20 mg if creatinine clearance is under 30 mL/min), dalteparin 5000 units daily.
• Treatment of venous thromboembolism: enoxaparin 1 mg/kg every 12 hours or 1.5 mg/kg once daily; creatinine clearance under 30 mL/min: 1 mg/kg once daily. Dalteparin 200 units/kg once daily.
• Acute coronary syndrome: enoxaparin 1 mg/kg every 12 hours, with an initial 30 mg intravenous bolus in STEMI treated with thrombolysis (and 0.75 mg/kg every 12 hours without bolus if aged 75 years or over).
• Pregnancy: prophylactic or weight-adjusted dosing, with anti-Xa monitoring in extremes of weight or renal function, and switching to unfractionated heparin near delivery. Stop prophylactic dosing 12 hours and treatment dosing 24 hours before neuraxial anaesthesia.
• Cancer-associated thrombosis: full dose for the first month, then 75% to 80% dose in some regimens.
• Bridging: reserved for mechanical valves and very high thrombosis risk.
• Selection: preferred over unfractionated heparin in most patients with normal renal function.

Contraindications. Active major bleeding, history of heparin-induced thrombocytopenia, and severe thrombocytopenia. Use with caution in creatinine clearance under 30 mL/min, low body weight and obesity.

Adverse effects. Bleeding, injection site haematoma, heparin-induced thrombocytopenia (lower risk than unfractionated heparin), hyperkalaemia, osteoporosis with prolonged use, and spinal or epidural haematoma with neuraxial procedures.

Reversal. Protamine neutralises about 60% of anti-Xa activity. Dose 1 mg per 1 mg enoxaparin given within 8 hours, and 0.5 mg per 1 mg between 8 and 12 hours.

Interactions. Antiplatelet drugs, NSAIDs, other anticoagulants and thrombolytics raise bleeding.

Monitoring. Platelet count at baseline and every 2 to 4 days from day 4 to 14 if the risk of heparin-induced thrombocytopenia is not low, creatinine, haemoglobin, and anti-Xa (peak 4 hours after the third dose, target 0.6 to 1.0 units/mL for twice-daily and 1.0 to 2.0 units/mL for once-daily dosing) in pregnancy, renal impairment, extremes of weight and prolonged use.

Referral and escalation. Back pain or new neurological deficit after neuraxial anaesthesia on heparin is a spinal haematoma until excluded.

Special groups. Pregnancy: preferred anticoagulant. Breastfeeding: compatible. Renal impairment: dose reduce or switch to unfractionated heparin. Obesity: dose by actual weight. Children: age-specific dosing.