Heparin, a highly-sulfated glycosaminoglycan, is widely used as an injectable anticoagulant and has the highest negative charge density of any known biological molecule; it consists of a variably-sulfated repeating disaccharide unit: The most common disaccharide unit is composed of a 2-O-sulfated iduronic acid and 6-O-sulfated, N-sulfated glucosamine, IdoA-GlcNS
Heparin is a naturally-occurring anticoagulant produced by basophils and mast cells; pharmaceutical grade heparin is derived from mucosal tissues of slaughtered meat animals such as porcine intestine or bovine lung. Heparin allows the body's natural clot lysis mechanisms to work normally to break down clots that have already formed.
Heparin binds to the enzyme inhibitor antithrombin (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop. The activated AT then inactivates thrombin and other proteases involved in blood clotting, most notably factor Xa. The rate of inactivation of these proteases by AT can increase by up to 1000-fold due to the binding of heparin.
AT binds to a specific pentasaccharide sulfation sequence contained within the heparin polymer
GlcNAc/NS-GlcA-GlcNS-IdoA-GlcNS
The conformational change inAT 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 pentasaccharide. The highly-negative charge density of heparin contributes to its very strong electrostatic interaction with thrombin The formation of a ternary complex between AT, 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 saccharide units for efficient formation. In contrast anti factor Xa activity only requires the pentasaccharide binding site
This size difference has led to the development of low-molecular-weight heparins and more recently to fondaparinux as pharmaceutical anticoagulants. Low-molecular-weight heparins and fondaparinux target anti-factor Xa activity rather than anti-thrombin (IIa) activity, with the aim of facilitating a more subtle regulation of coagulation and an improved therapeutic index
Heparin is used for anticoagulation for the following conditions:
- Acute coronary syndrome e.g., NSTEMI
- Atrial fibrillation
- Deep-vein thrombosis and pulmonary embolism
- Cardiopulmonary bypass for heart surgery.
- ECMO circuit for extracorporeal life support
Adverse reactions
A serious side-effect of heparin is heparin-induced thrombocytopenia (HIT syndrome).
This condition is usually reversed on discontinuation, and can generally be avoided with the use of synthetic heparins. There is also a benign form of thrombocytopenia associated with early heparin use, which resolves without stopping heparin.
There are two nonhemorrhagic side effects of heparin treatment. The first is elevation of serum aminotransferase levels, which has been reported in as many as 80% of patients receiving heparin. This abnormality is not associated with liver dysfunction, and it disappears after the drug is discontinued. The other complication is hyperkalemia, which occurs in 5 to 10% of patients receiving heparin, and is the result of heparin-induced aldosterone suppression. The hyperkalemia can appear within a few days after the onset of heparin therapy.
Rare side-effects include alopecia and osteoporosis with chronic use.
