heparin - Heparin structure, Medical use, Other uses/information

A chemical substance (a polysaccharide) found in the mast cells of the liver, lungs, and intestinal mucosa, which prevents blood clotting. Its physiological importance is controversial, but its extracted and purified form is used as an anti-coagulant drug in medicine (eg in the prevention of thrombosis).

Heparin structure

Native heparin is a polymer with a molecular weight ranging from 3 kDa to 40 kDa although the average molecular weight of most commercial heparin preparations is in the range of 12 kDa to 15 kDa. Heparin is a member of the glycosaminoglycan family of carbohydrates (which includes the closely related molecule heparan sulfate) and consists of a variably sulfated repeating disaccharide unit. It is in this form that heparin is usually administered as an anticoagulant.

GlcA-GlcNAc	GlcA-GlcNS	IdoA-GlcNS	IdoA(2S)-GlcNS
IdoA-GlcNS(6S)	IdoA(2S)-GlcNS(6S)

Abbreviations

GlcA = β-L-glucuronic acid IdoA = α-L-iduronic acid IdoA(2S) = 2-O-sulfo-α-L-iduronic acid GlcNAc = 2-deoxy-2-acetamido-α-D-glucopyranosyl GlcNS = 2-deoxy-2-sulfamido-α-D-glucopyranosyl GlcNS(6S) = 2-deoxy-2-sulfamido-α-D-glucopyranosyl-6-O-sulfate

Three-dimensional structure

The three dimensional structure of heparin is complicated by the fact that iduronic acid may be present in either of two low energy conformations when internally positioned within an oligosaccharide. These models correspond to the protein data bank code 1HPN

In the image above:

A = 1HPN (all IdoA(2S) residues in 2S0 conformation) Jmol viewer B = van der Waals radius space filling model of A C = 1HPN (all IdoA(2S) residues in 1C4 conformation) Jmol viewer D = van der Waals radius space filling model of C

In these models heparin adopts a helical conformation, the rotation of which places clusters of sulfate groups at regular intervals of about 17 angstroms (1.7 nm) on either side of the helical axis.

Medical use

Heparin acts as an anticoagulant, preventing the formation of clots and extension of existing clots within the blood. While heparin does not break down clots that have already formed, it allows the body's natural clot lysis mechanisms to work normally to break down clots that have already formed.

History

Heparin is one of the oldest drugs currently still in widespread clinical use.

Administration

Heparin is given parenterally;

If long-term anticoagulation is required, heparin is often only used to commence anticoagulation therapy until the oral anticoagulant warfarin takes effect.

Adverse reactions

A serious side-effect of heparin is heparin-induced thrombocytopenia (HIT syndrome). HITS can (rarely) occur shortly after heparin is given, but also when a person has been on heparin for a long while. There is also a benign form of thrombocytopenia associated with early heparin use which resolves without stopping heparin.

As with many drugs, overdoses of Heparin can be fatal. In September 2006, Heparin received worldwide publicity when 3 prematurely-born infants died after they were mistakenly given adult-sized doses of Heparin at an Indianapolis hospital.

Treatment of overdose

In case of overdose, protamine sulfate can be given to counteract the action of heparin.

Mechanism of action

Heparin is a naturally occurring anticoagulant produced by basophils and mast cells. Heparin binds to the enzyme inhibitor antithrombin III (AT-III) causing a conformational change which results in its active site being exposed.

AT-III binds to a specific pentasaccharide sulfation sequence contained within the heparin polymer

GlcNAc/NS(6S)-GlcA-GlcNS(3S,6S)-IdoA(2S)-GlcNS(6S)

The conformational change in AT-III on heparin binding mediates its inhibition of factor Xa. For thrombin inhibition however, thrombin must also bind to the heparin polymer at a site proximal to the pentasacchride. The formation of a ternary complex between AT-III, thrombin and heparin results in the inactivation of thrombin. For this reason heparin's activity against thrombin is size dependent, the ternary complex requiring at least 18 sacchride units for efficient formation.

This size difference has led to the development of low molecular weight heparins and more recently to fondaparinux (a synthetic pentasacchride identical in structure to the AT-III binding pentasacchride) as pharmaceutical anticoagulants.

With these fractioned heparin alternatives, there is a reduced risk of osteoporosis and heparin-induced thrombocytopenia (HIT). Because danaparoid does not contain heparin or heparin fragments cross-reactivity of danaparoid with heparin-induced antibodies is reported as less than 10% (see here)

The effects of heparin are measured in the lab by the partial thromboplastin time (aPTT), (the time it takes the blood plasma to clot).

Heparin's exact physiological role is still unclear, because blood anti-coagulation is mostly achieved by endothelial cell-derived heparan sulfate proteoglycans.

Heparin gel

Heparin gel (topical) may sometimes be used to treat sports injuries. It is known that the diprotonated form of histamine binds site specifically to heparin.

Other uses/information

Test tubes, Vacutainers, and capillary tubes that use the lithium salt of heparin (lithium heparin) as an anticoagulant are usually marked with green stickers and green tops. Heparin has the advantage over EDTA as an anticoagulant, as it does not affect levels of ions (such as calcium). Common diagnostic procedures require PCR amplification of a patient's DNA, which is easily extracted from white blood cells treated with heparin.