Naturally occurring mixture of organic compounds used as a short-term anticoagulant to prevent thrombosis during and after surgery and for initial treatment of various heart, lung, and circulatory disorders in which there is increased risk of blood clotting. Comprising complex carbohydrate molecules called mucopolysaccharides, it normally is present in the human body in liver and lung tissues. It was discovered in 1922 and originally used to prevent clotting in blood taken for laboratory tests.
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Although used principally in medicine for anticoagulation, the true physiological role in the body remains unclear, because blood anti-coagulation is achieved mostly by endothelial cell-derived heparan sulfate proteoglycans. Heparin is usually stored within the secretory granules of mast cells and released only into the vasculature at sites of tissue injury. It has been proposed that, rather than anticoagulation, the main purpose of heparin is in a defensive mechanism at sites of tissue injury against invading bacteria and other foreign materials. In addition, it is preserved across a number of widely different species, including some invertebrates which lack a similar blood coagulation system.
1 unit of heparin (the "Howell Unit") is an amount approximately equivalent to 0.002 mg of pure heparin, which is the quantity required to keep 1 mL of cat's blood fluid for 24 hours at 0°C.
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. The conformational equilibrium being influenced by sulfation state of adjacent glucosamine sugars. Nevertheless, the solution structure of a heparin dodecasacchride composed solely of six GlcNS(6S)-IdoA(2S) repeat units has been determined using a combination of NMR spectroscopy and molecular modeling techniques. Two models were constructed, one in which all IdoA(2S) were in the 2S0 conformation (A and B below), and one in which they are in the 1C4 conformation (C and D below). However there is no evidence to suggest that changes between these conformations occur in a concerted fashion. These models correspond to the protein data bank code 1HPN.
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Heparin and its derivatives (enoxaparin, dalteparin, and so forth) are effective at preventing deep-vein thromboses and pulmonary emboli in patients at risk, but there is no evidence that they are effective at preventing death. Current guidelines recommend aspirin and leg stockings instead.
AT binds to a specific pentasaccharide sulfation sequence contained within the heparin polymer
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, 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 (LMWHs) 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. The chemical structure of fondaparinux is shown to the left. 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, there is a reduced risk of osteoporosis and heparin-induced thrombocytopenia (HIT). Monitoring of the APTT is also not required and indeed 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 who have 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%.
Heparin is given parenterally, as it is degraded when taken by mouth. 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 approximately one hour, heparin must be given frequently or as a continuous infusion. However, the use of low molecular weight heparin (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 the oral anticoagulant warfarin takes effect.
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 overdoses of heparin at an Indianapolis hospital.
In 1916, McLean, a second-year medical student at Johns Hopkins University, was working under the guidance of Howell investigating pro-coagulant preparations, when he isolated a fat-soluble phosphatide anti-coagulant. It was Howell who coined the term heparin for this type of fat-soluble anticoagulant in 1918. In the early 1920s, Howell isolated a water-soluble polysaccharide anticoagulant, which was also termed heparin, although it was distinct from the phosphatide preparations previously isolated. It is probable that the work of McLean changed the focus of the Howell group to look for anticoagulants, which eventually led to the polysaccharide discovery.
Between 1933 and 1936, Connaught Medical Research Laboratories, then a part of the University of Toronto, perfected a technique for producing safe, non-toxic heparin that could be administered to patients in a salt solution. The first human trials of heparin began in May 1935, and, by 1937, it was clear that Connaught's heparin was a safe, easily-available, and effective blood anticoagulant. Prior to 1933, heparin was available, but in small amounts, and was extremely expensive, toxic, and, as a consequence, of no medical value.
For a full discussion of the events surrounding heparin's discovery see Marcum J. (2000).
|Disease states sensitive to heparin||Heparins effect in experimental models||Clinical status|
|Adult respiratory distress syndrome||Reduces cell activation and accumulation in airways, neutralizes mediators and cytotoxic cell products, and improves lung function in animal models||Controlled clinical trials|
|Allergic encephalomyelitis||Effective in animal models||-|
|Allergic rhinitis||Effects as for adult respiratory distress syndrome, although no specific nasal model has been tested||Controlled clinical trial|
|Arthritis||Inhibits cell accumulation, collagen destruction and angiogenesis||Anecdotal report|
|Asthma||As for adult respiratory distress syndrome, however it has also been shown to improve lung function in experimental models||Controlled clinical trials|
|Cancer||Inhibits tumour growth, metastasis and angiogenesis, and increases survival time in animal models||Several anecdotal reports|
|Delayed type hypersensitivity reactions||Effective in animal models||-|
|Inflammatory bowel disease||Inhibits inflammatory cell transport in general. No specific model tested||Controlled clinical trials|
|Interstitial cystitis||Effective in a human experimental model of interstitial cystitis||Related molecule now used clinically|
|Transplant rejection||Prolongs allograph survival in animal models||-|
As a result of heparin's effect on such a wide variety of disease states a number of drugs are indeed in development whose molecular structures are identical or similar to those found within parts of the polymeric heparin chain.
|Drug molecule||Effect of new drug compared to heparin||Biological activities|
|Heparin tetrasaccharide||Non-anticoagulant, non-immunogenic, orally active||Anti-allergic|
|Pentosan polysulfate||Plant derived, little anticoagulant activity, Anti-inflammatory, orally active||Anti-inflammatory, anti-adhesive, anti-metastatic|
|Phosphomannopentanose sulfate||Potent inhibitor of heparanase activity||Anti-metastatic, anti-angiogenic, anti-inflammatory|
|Selectively chemically O-desulphated heparin||Lacks anticoagulant activity||Anti-inflammatory, anti-allergic, anti-adhesive|
|Heparinase enzyme||Substrate specificity|
|Heparinase II|| GlcNS/Ac(±6S)-IdoA(±2S)|
|Heparinase III||GlcNS/Ac(±6S)-GlcA/IdoA (with a preference for GlcA)|
At low pH deaminative cleavage results in the release of inorganic SO4, and the conversion of GlcNS into anhydromannose (aMan). Low pH nitrous acid treatment is an excellent method to distinguish N-sulfated polysaccharides such as heparin and HS from non N-sulfated polysacchrides such as chondroitin sulfate and dermatan sulfate; chondroitin sulfate and dermatan sulfate being un-susceptable to nitrous acid cleavage.
In March 2008, major recalls of heparin were announced by the FDA due to contamination of the raw heparin stock imported from China. The FDA admitted that it had violated its own policies by failing to inspect the American pharmaceutical firm Scientific Protein’s plant in China before approving the drug for sale. The U.S. Food and Drug Administration was quoted as stating that at least 81 deaths were believed linked to a raw heparin ingredient imported from the People's Republic of China, and that they had also received 785 reports of serious injuries associated with the drug’s use. According to the New York Times, "Problems with heparin reported to the agency include difficulty breathing, nausea, vomiting, excessive sweating and rapidly falling blood pressure that in some cases led to life-threatening shock."
The contaminant has been identified as an "over-sulphated" derivative of chondroitin sulfate, a popular shellfish-derived supplement often used for arthritis. Since this "over-sulphated" variant is not naturally occurring and mimics the properties of heparin,the counterfeit is almost certainly intentional as opposed to an accidental lapse in manufacturing. The heparin was cut from anywhere from 2-60% with a counterfeit substance due to cost effectiveness, and a shortage of suitable pigs in China.
When the FDA finally did conduct an inspection of Baxter's Chinese Heparin supplier, it found serious deficiencies at the facility which the FDA detailed in a letter to the Chinese company. The FDA has stated that it does not have the funds nor bear the responsibility to inspect on a regular basis overseas manufacturers of active pharmaceutical ingredients such as heparin.
In July 2008, another set of twins born at Christus Spohn Hospital South, a Texas hospital, died after an accidentally administered overdose of the drug. The overdose was due to a mixing error at the hospital pharmacy and, unlike the Quaid case, was unrelated to the product's packaging or labeling. , whether the deaths were due to the overdose is under investigation.
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