Low-Molecular-Weight Heparins
Heparin has been successfully used in the prophylaxis and treatment of venous and arterial thrombotic disorders. Despite heparin's ability to prevent myocardial infarction (MI) and recurrent ischemia, uncommon but potentially serious side effects, and relative unpredictability have encouraged researchers to develop alternative therapies, including new anticoagulants and antithrombotics termed the low-molecular-weight heparins (LMWHs).

Pharmaceutical heparin is a variable mixture of saccharide polymers with molecular weights ranging from approximately 5,000-30,000 kDa. The anticoagulant activity of heparin is mediated by binding and amplifying the anticoagulant activity of antithrombin (AT). Polysaccharides shorter than 18 units but containing a specific "essential" pentasaccharide sequence increase the activity of AT to inhibit the activity of factor Xa. However, these short sequences cannot amplify AT activity against thrombin (factor IIa). The inactivation of thrombin requires that the polysaccharide contain a specific sequence of at least 18 units, in addition to the pentasaccharide unit. The distribution of these saccharide sequences in heparin appears to be random;4 only about 30% of heparin species contain the sequence necessary for anticoagulation.

LMWHs are obtained by the chemical or enzymatic depolymerization of heparin giving rise to mixtures of smaller polymers with weight ranges from 2,000-15,000 kDa. The pentasaccharide sequences are most commonly found in the low-molecular-weight fractions while the longer sequences are resident in the higher weight fractions. Thus, the LMWHs have greater anti-Xa:IIa ratios compared with unfractionated heparin (UFH).

When compared with unfractionated heparin, LMWHs have fewer serious side effects, such as heparin-induced osteopenia and heparin-induced thrombocytopenia (HIT). In contrast to UFH, the LMWHs appear not to be inactivated by platelet factor 4. After subcutaneous injection, LMWHs also exhibit less plasma protein binding (and therefore greater bioavailability) than UFH. Review of two models of heparin recovery using UFH versus LMWH reveals that the increase of recovery from heparin-binding proteins is much higher with UFH compared to LMWHs.

Heparin increases platelet aggregation and activation. This effect has been observed predominantly following bolus dosing of UFH. Heparin-induced platelet activation is reduced or absent in patients with LMWH. In studies by Mascelli et al. and Xiao et al., several measures of platelet activation and aggregability were examined during percutaneous coronary intervention (PCI) and in acute coronary syndromes (ACS). Platelet aggregation in response to low concentrations of ADP and a thrombin-receptor agonist peptide (TRAP) was enhanced less with LMWH than UFH.

Heparin-induced thrombocytopenia is an antibody-mediated reaction in which patients develop auto-immunity against a complex of heparin and platelet factor 4. Patients with HIT are at increased risk for arterial and venous thrombosis. As many as 5% of patients treated with UFH develop this syndrome; it appears to be much less common in patients treated with LMWH. However, it is important to note that LMWHs all cross-react with heparin; therefore, LMWH cannot be used as an alternative for patients who develop HIT.