What is low-molecular-weight heparin (LMWH) and how does it compare with and differ from standard heparin?
Standard, unfractionated heparin (UH) is a mixture of linear polysaccharide chains, with a molecular weight that ranges from 5,000 to 30,000. Heparin acts as an anticoagulant by binding to antithrombin III and potentiates the inhibition of factors IIa (thrombin), IXa, Xa, XIa, and XIIa. A specific pentasaccharide sequence on the heparin chain has a high-affinity binding site for antithrombin III, and only about 30% of the heparin molecule has this sequence. In order to catalyze inhibition of factor Xa, only the pentasaccharide binding sequence is necessary. However, to catalyze inhibition of factor IIa, a heparin molecule must contain both this high-affinity pentasaccharide sequence and an additional chain of at least 13 sugars. UH is highly sulfated and negatively charged. As a result, it has a great affinity for plasma and vas-cular matrix proteins, and has less than a 30% bioavailability.
LMWH is produced by chemical or enzymatic depoly-merization of standard heparin, which produces shorter polysaccharide chains of 13 to 22 sugars and a molecular weight of 4,000 to 6,000. LMWH has the same anti-Xa activity as standard heparin with less anti-IIa (thrombin) activity. The concentration of LMWH is referred to in international standards and expressed as anti-Xa units per millimeter. The reduced molecular size leads to lower bind-ing of plasma and endothelial cell proteins. This results in greater than 90% bioavailability after subcutaneous injec-tion, a longer plasma half-life (4–6 hours versus 0.5–1 hours for standard heparin), and a predictable and reproducible dose response. Laboratory monitoring is not required. The peak LMWH anti-Xa activity occurs 3–4 hours after subcutaneous injection, and 12-hour anti-Xa levels are approximately 50% of peak levels. LMWH excretion is accomplished almost solely by the kidneys. Protamine sul-fate is able to neutralize 100% of anti-IIa activity but only 60–70% of anti-Xa activity, and therefore is not effective at neutralizing LMWH effects.