Heparin

 

Heparin was discovered in 1916 and has been used for nearly a century as an anticoagulant which thus makes it one of the oldest pharmaceuticals still in use. It is routinely prescribed before most major surgeries, to people who are immobile for long periods and to patients on kidney dialysis. Besides its major property as an inhibitor of key steps in the blood coagulation cascade, this intriguing molecule interacts with a large variety of biologically important proteins in humans.
 
The vast unexploited therapeutic potential of this molecule is mainly due to the structural complexity and heterogeneity. Heparin is also special because it has the highest negative charge density of any known biological molecule.
 
 It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.
 
 The main source of heparin is pig intestine and most of it is produced in China. The annual worldwide consumption of crude heparin is over 200 tons. Approximately, 10 to12 million Americans are treated with heparin each year and sales revenues are in excess of $5.0 billion per year((ChinaInsider, China’s  Heparin  Revisited:  What  Went  Wrong  and  Has  Anything  Changed? Clifford S. Mintz, PhD and John Liu, MD, MS )) .
 
 

Structure:

 
Heparin and heparan sulfate (H/HS) are naturally occurring polysaccharides characterised by a large number of negatively charged functionalities such as sulphates and carboxylates. The backbone structure is defined by linear repeating disaccharide units containing D-glucosamine and L-iduronic acid (or D-glucuronic acid).
 

Medical use:

Heparin1 is a naturally occurring anticoagulant produced by basophils and mast cells. 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 (unlike tissue plasminogen activator), it allows the body's natural clot lysis mechanisms to work normally to break down clots that have formed. Heparin is generally 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
• Hemofiltration
• Indwelling central or peripheral venous catheters
 
 
 

Mechanism of action

 
Heparin2 and its low-molecular-weight derivatives (e.g., enoxaparin, dalteparin, tinzaparin) are effective at preventing deep vein thromboses and pulmonary emboli in patients at risk but no evidence indicates any one is more effective than the other in preventing mortality. Heparin binds to the enzyme inhibitor antithrombin III (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(6S)-GlcA-GlcNS(3S,6S)-IdoA(2S)-GlcNS(6S)
 
The conformational change in AT 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, with the ternary complex requiring at least 18 saccharide units for efficient formation. In contrast, antifactor Xa activity requires only the pentasaccharide binding site.
 
This size difference has led to the development of low-molecular-weight heparins (LMWHs) and, more recently, to fondaparinux as pharmaceutical anticoagulants. LMWHs and fondaparinux target antifactor Xa activity rather than antithrombin activity, with the aim of facilitating a more subtle regulation of coagulation and an improved therapeutic index.
 
The chemical structure of fondaparinux is shown above. It is a synthetic pentasaccharide, whose chemical structure is almost identical to the AT binding pentasaccharide sequence that can be found within polymeric heparin and heparan sulfate.
With LMWH and fondaparinux, the risk of osteoporosis and heparin-induced thrombocytopenia (HIT) is reduced. Monitoring of the activated partial thromboplastin time is also not required and does not reflect the anticoagulant effect, as APTT is insensitive to alterations in factor Xa.
Danaparoid, a mixture of heparan sulfate, dermatan sulfate, and chondroitin sulfate can be used as an anticoagulant in patients having developed HIT. Because danaparoid does not contain heparin or heparin fragments, cross-reactivity of danaparoid with heparin-induced antibodies is reported as less than 10%.
 
 
 

Administration:

 
Heparin3 is given parenterally because it is not absorbed from the gut, due to its high negative charge and large size. It can be injected intravenously or subcutaneously (under the skin); intramuscular injections (into muscle) are avoided because of the potential for forming hematomas. Because of its short biologic half-life of about one hour, heparin must be given frequently or as a continuous infusion. Unfractionated heparin has a half-life of about one to two hours after infusion, whereas LMWH has a half-life of four to five hours. The use of LMWH has allowed once-daily dosing, thus not requiring a continuous infusion of the drug. If long-term anticoagulation is required, heparin is often used only to commence anticoagulation therapy until an oral anticoagulant e.g. warfarin takes effect.
 
 
 

Adulterated Chinese Heparin:

 
 
In late 2007 and early 2008 the US Food and Drug Administration (FDA) and the Centers for Disease Control (CDC) in Atlanta began receiving reports of serious adverse reactions and deaths in patients undergoing dialysis4. These reports triggered a series of investigations by the US FDA which linked the adverse events and deaths to heparin products manufactured by Baxter International Inc.
Analyses of Baxter’s adulterated heparin products revealed the presence of oversulfated chondroitin sulfate (OSCS); a contaminant that was ultimately linked to the reported adverse reactions and deaths among dialysis patients. OSCS, a heparin-like molecule, is not a byproduct of the heparin production process nor is it a natural product. It is a synthetic material that is produced by chemically modifying chondroitin sulfate, a nutritional supplement that if frequently used to control joint pain.
OSCS can be 100 times less expensive to produce than heparin. Recent estimates suggest that OSCS cost as little as $20/kg to manufacture as compared with a price of roughly $2,000/kg to produce crude heparin.
The amount of OSCS found in adulterated heparin lots ranged from 2% to 50% by dry weight.
After several years investigation it was widely concluded that the OSCS was intentionally added to crude heparin preparations that were exported to the US and other countries for economical gain.
 
This incident among others can move the market towards more pure and secure synthetic alternative products.
 
 
References
 
1,2,3 : ((http://en.wikipedia.org/wiki/Heparin))
 
4 : ((ChinaInsider, China’s  Heparin  Revisited:  What  Went  Wrong  and  Has  Anything  Changed? Clifford S. Mintz, PhD and John Liu, MD, MS))