Low Molecular Weight Heparins — Types, Indications, Benefits and Side-Effect Profile

Low molecular weight heparins (LMWHs) are produced by chemical or enzymatic depolymerisation of unfractionated heparin (UFH), giving fragments of mean molecular weight 4,000–6,000 daltons (versus 15,000 for UFH).

Like UFH, LMWH acts by potentiating antithrombin. However, the shorter chains cannot bridge antithrombin to thrombin.

Consequently LMWH has a much greater effect on factor Xa than on thrombin (IIa) — the anti-Xa : anti-IIa ratio is about 3:1 to 4:1, compared with 1:1 for UFH.

Because of this, LMWH cannot be monitored by the APTT — it requires an anti-factor Xa assay where monitoring is needed.

Enoxaparin — the most widely used; anti-Xa:anti-IIa ratio ~3.8:1.

Dalteparin — ratio ~2.7:1; the preferred agent in cancer-associated thrombosis in many protocols.

Tinzaparin — ratio ~1.9:1; the largest mean molecular weight, and therefore least dependent on renal clearance, which makes it useful in renal impairment.

Nadroparin, reviparin, parnaparin, bemiparin are other agents in use.

Fondaparinux is a synthetic pentasaccharide — a pure indirect factor Xa inhibitor with no anti-IIa activity. It is not strictly an LMWH but is used in the same clinical settings and is the agent of choice in heparin-induced thrombocytopenia.

Longer half-life (about 4 hours versus 1 hour), permitting once- or twice-daily dosing.

Increased bioavailability after subcutaneous injection (>90% versus about 30% for UFH).

More predictable pharmacokinetics, because LMWH binds far less to plasma proteins, endothelium and macrophages.

Therefore it can be given by subcutaneous injection without routine monitoring, even at treatment doses.

UFH’s binding to multiple plasma proteins explains its unpredictable kinetics, especially in the elderly, where variability in these determinants is greater.

UFH carries a higher bleeding risk in older adults — patients over 72 treated with UFH for VTE had bleeding in 14.1% versus 7.1%, and major bleeding in 11.1% versus 3.1%, compared with younger patients.

Standard, non-weight-adjusted heparin doses in older patients produce higher heparin levels and a tendency to higher APTT.

Unless there is an absolute contraindication, LMWH has generally replaced UFH and should be preferred because of its predictable pharmacokinetics, efficacy and safety.

Lower incidence of heparin-induced thrombocytopenia and of heparin-induced osteoporosis than UFH.

LMWH has a survival advantage in patients with malignancy and thrombosis and has traditionally been the anticoagulant of choice in this group.

Prophylaxis of venous thromboembolism in medical and surgical inpatients, and after major orthopaedic surgery.

Treatment of established DVT and pulmonary embolism.

Acute coronary syndromes — unstable angina and NSTEMI, and as adjunct to fibrinolysis in STEMI.

Bridging anticoagulation around surgery or procedures in patients on warfarin.

Cancer-associated thrombosis, pregnancy-associated VTE, and extracorporeal circuits (haemodialysis).

LMWH and UFH remain the preferred anticoagulants where surgery or clinical instability is involved — cancer, sepsis, inability to take oral medication, or malabsorption.

Bleeding is the principal adverse effect.

Renal clearance — LMWHs are predominantly eliminated by renal excretion, so kidney impairment leads to prolonged half-life and accumulation. Dose should be reduced or the dosing interval extended; current data are insufficient to establish definitive LMWH dose adjustment in older patients with renal impairment.

Heparin-induced thrombocytopenia (HIT) — immune-mediated, causing both thrombocytopenia and paradoxical arterial and venous thrombosis, with mortality around 30% if unrecognised. It is less common with LMWH than UFH but can occur with either. Treatment is immediate withdrawal of all heparin and substitution with argatroban (acute) or fondaparinux (subsequent treatment/prophylaxis). Warfarin can worsen acute HIT and must be withheld or reversed with vitamin K.

Other effects: hyperkalaemia (aldosterone suppression), elevated transaminases, injection-site haematoma and skin necrosis, osteoporosis with prolonged use, and spinal or epidural haematoma with neuraxial anaesthesia.

Reversal: protamine sulfate neutralises only about 60% of LMWH’s anti-Xa activity (it fully reverses UFH). In overdose, LMWH will prolong the APTT, and bleeding may require protamine.