Low molecular weight heparin

In medicine, low-molecular-weight heparin (LMWH) is a class of medication used as an anticoagulant in diseases that feature thrombosis, as well as for prophylaxis in situations that lead to a high risk of thrombosis.

Heparin is a naturally occurring polysaccharide that inhibits coagulation, the process whereby thrombosis occurs (see Heparin: Mechanisms of action). Natural heparin consists of molecular chains of varying lengths, or molecular weights. Chains of molecular weight from 5000 to over 40,000 Daltons, making up polydisperse pharmaceutical-grade heparin.

Heparin derived from natural sources, mainly porcine intestine or bovine lung, can be administered therapeutically to prevent thrombosis (see anticoagulation). However, the effects of natural, or unfractionated heparin can be difficult to predict. After a standard dose of unfractionated heparin, coagulation parameters must be monitored very closely to prevent over- or under-anticoagulation.

Low-molecular-weight heparins (LMWHs), in contrast, consist of only short chains of polysaccharide. LMWHs are defined as heparin salts having an average molecular weight of less than 8000 Da and for which at least 60% of all chains have a molecular weight less than 8000 Da. These are obtained by various methods of fractionation or depolymerisation of polymeric heparin.

Anti-factor Xa activity
The effects of LMWHs cannot be acceptably measured using the partial thromboplastin time (PTT) or activated clotting time (ACT) tests. Rather, LMWH therapy is monitored by the anti-factor Xa assay, measuring anti-factor Xa activity. The methodology of an anti-factor Xa assay is that patient plasma is added to a known amount of excess factor Xa and excess antithrombin. If heparin or LMWH is present in the patient plasma, it will bind to antithrombin and form a complex with factor Xa, inhibiting it. The amount of residual factor Xa is inversely proportional to the amount of heparin/LMWH in the plasma. The amount of residual factor Xa is detected by adding a chromogenic substrate that mimics the natural substrate of factor Xa, making residual factor Xa cleave it, releasing a colored compound that can be detected by a spectrophotometer. Antithrombin deficiencies in the patient do not affect the assay, because excess amounts of antithrombin is provided in the reaction. Results are given in anticoagulant concentration in units/mL of antifactor Xa, such that high values indicate high levels of anticoagulation and low values indicate low levels of anticoagulation.

LMWHs have a potency of greater than 70 units/mg of anti-factor Xa activity and a ratio of anti-factor Xa activity to anti-thrombin activity of >1.5.

Low-molecular-weight heparin products
Various methods of heparin depolymerisation are used in the manufacture of low-molecular-weight heparin. These are listed below:
 * Oxidative depolymerisation with hydrogen peroxide. Used in the manufacture of ardeparin (Normiflo)
 * Deaminative cleavage with isoamyl nitrite. Used in the manufacture of certoparin (Sandoparin)
 * Alkaline beta-eliminative cleavage of the benzyl ester of heparin. Used in the manufacture of enoxaparin (Lovenox and Clexane)
 * Oxidative depolymerisation with Cu2+ and hydrogen peroxide. Used in the manufacture of parnaparin (Fluxum)
 * Beta-eliminative cleavage by the heparinase enzyme. Used in the manufacture of tinzaparin (Innohep and Logiparin)
 * Deaminative cleavage with nitrous acid. Used in the manufacture of dalteparin (Fragmin), reviparin (Clivarin) and nadroparin (Fraxiparin)

Deaminative cleavage with nitrous acid results in the formation of an unnatural anhydromannose residue at the reducing terminal of the oligosaccharides produced. This can subsequently be converted to anhydromannitol using a suitable reducing agent as shown to the left.

Likewise both chemical and enzymatic beta-elimination result in the formation of an unnatural unsaturated uronate residue(UA) at the non-reducing terminal, as shown to the left.

Differences between low molecular weight heparin products
Comparisons between LMWHs prepared by similar processes vary. For example, a comparison of Dalteparin and Nadroparin suggests they are more similar than products produced by different processes. However, comparison of enoxaparin and tinzaparin shows they are very different from each other with respect to chemical, physical, and biological properties.

As might be expected, products prepared by distinctly different processes are dissimilar in physical, chemical, and biological properties.

Differences from unfractionated heparin
Its differences with heparin (i.e. "unfractioned heparin") include:
 * Average molecular weight: heparin is about 15 kDa and LMWH is about 4.5 kDa.
 * Once-daily dosing by subcutaneous injection, rather than a continuous infusion of unfractionated heparin.
 * No need for monitoring of the APTT coagulation parameter.
 * Possibly a smaller risk of bleeding.
 * Smaller risk of osteoporosis in long-term use.
 * Smaller risk of heparin-induced thrombocytopenia, a potential side effect of heparin.
 * The anticoagulant effects of heparin are typically reversible with protamine sulfate, while protamine's effect on LMWH is limited.
 * Has less of an effect on thrombin compared to heparin, but maintains the same effect on Factor Xa.

Clinical uses
Because it can be given subcutaneously and does not require APTT monitoring, LMWH permits outpatient treatment of conditions such as deep vein thrombosis or pulmonary embolism that previously mandated inpatient hospitalization for unfractionated heparin administration.

Because LMWH has more predictable pharmacokinetics and anticoagulant effect, LMWH is recommended over unfractionated heparin for patients with massive pulmonary embolism, and for initial treatment of deep vein thrombosis. Prophylactic treatment of hospitalized medical patients with LMWH and similar anticoagulants results in a 53% reduction of risk for symptomatic deep vein thrombosis.

The use of LMWH needs to be monitored closely in patients at extremes of weight or in-patients with renal dysfunction. An anti-factor Xa activity may be useful for monitoring anticoagulation. Given its renal clearance, LMWH may not be feasible in patients that have end-stage renal disease.

Use in venothromboembolic disease associated with cancer
The CLOT study, published in 2003, showed that, in patients with malignancy and acute venous thromboembolism, dalteparin was more effective than coumarin in reducing the risk of recurrent embolic events. Use of LMWH in cancer patients for at least the first 3 to 6 months of long-term treatment is recommended in numerous guidelines and is now regarded as a standard of care.