Heparin

What is Heparin?

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 can also be used to form an inner anticoagulant surface on various experimental and medical devices such as test tubes and renal dialysis machines. Pharmaceutical grade heparin is derived from mucosal tissues of slaughtered meat animals such as porcine (pig) intestine or bovine (cow) lung.

Although used principally in medicine for anticoagulation, the true physiological role in the body remains unclear, because blood anti-coagulation is achieved mostly by heparan sulfate proteoglycans derived from endothelial cells.

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 defense at such sites against invading bacteria and other foreign materials. In addition, it is conserved across a number of widely different species, including some invertebrates that do not have a similar blood coagulation system.

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Heparin History

Heparin is one of the oldest drugs currently still in widespread clinical use. Its discovery in 1916 predates the establishment of the Food and Drug Administration of the United States, although it did not enter clinical trials until 1935. It was originally isolated from canine liver cells, hence its name (''hepar'' or "ήπαρ" is Greek for "liver"). Heparin's discovery can be attributed to the research activities of two men, Jay McLean and William Henry Howell.

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 in canine liver tissue. It was Howell in 1918 who coined the term ''heparin'' (from hepar, Greek for liver) 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. McLean worked as a surgeon. He died of ischaemic heart disease at the age of 67. An attempt to nominate him posthumously for a Nobel Prize failed.

In the 1930s, several researchers were investigating heparin. Erik Jorpes at Karolinska Institutet published his research on the structure of heparin in 1935, which made it possible for the Swedish company Vitrum AB to launch the first heparin product for intravenous use in 1936. 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). Now the leading manufacturer of heparin is SPL a company owned by Oscar Meyer.

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Heparin Controversies

Contamination recalls

In December 2007, the U.S. Food and Drug Administration (FDA) recalled a shipment of heparin because of a growth of Serratia marcescens in several unopened syringes of this product. The bacteria Serratia marcescens can lead to life-threatening injuries and/or death.

In March 2008, major recalls of heparin were announced by the FDA due to contamination of the raw heparin stock imported from China. According to the FDA, the contaminated heparin killed 81 people in the United States. The contaminant was identified as an "over-sulphated" derivative of chondroitin sulfate, a popular shellfish-derived supplement often used for arthritis.

Use in homicide

In 2006, Petr Zelenka, a nurse in the Czech Republic, deliberately administered large doses to patients, killing 7, and attempting to kill 10 others.

Overdose issues

In 2007, a nurse at Cedars-Sinai Medical Center mistakenly gave actor Dennis Quaid's twelve-day-old twins a dose of heparin which was 1,000 times the recommended dose for infants. The overdose allegedly arose because the labeling and design of the adult and infant versions of the product were similar. The Quaid family subsequently sued the manufacturer, Baxter Healthcare Corp., and settled with the hospital for $750,000. Prior to the Quaid accident, six newborn babies at Methodist Hospital in Indianapolis, Indiana were given an overdose. Three of the babies died after the mistake.

In July 2008, another set of twins born at Christus Spohn Hospital South, a hospital located in Corpus Christi, died after an accidentally administered overdose of the drug. The overdose was due to a mixing error at the hospital pharmacy and was unrelated to the product's packaging or labeling. , whether the deaths were due to the overdose is under investigation.

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Heparin Drug Development

As detailed in the table below, there is a great deal of potential for the development of heparin-like structures as drugs to treat a wide range of diseases, in addition to their current use as anticoagulants.

Disease states sensitive to heparinHeparins effect in experimental modelsClinical status
Adult respiratory distress syndromeReduces cell activation and accumulation in airways, neutralizes mediators and cytotoxic cell products, and improves lung function in animal modelsControlled clinical trials
Allergic encephalomyelitisEffective in animal models-
Allergic rhinitisEffects as for adult respiratory distress syndrome, although no specific nasal model has been testedControlled clinical trial
ArthritisInhibits cell accumulation, collagen destruction and angiogenesisAnecdotal report
AsthmaAs for adult respiratory distress syndrome, however it has also been shown to improve lung function in experimental modelsControlled clinical trials
CancerInhibits tumour growth, metastasis and angiogenesis, and increases survival time in animal modelsSeveral anecdotal reports
Delayed type hypersensitivity reactionsEffective in animal models-
Inflammatory bowel diseaseInhibits inflammatory cell transport in general. No specific model testedControlled clinical trials
Interstitial cystitisEffective in a human experimental model of interstitial cystitisRelated molecule now used clinically
Transplant rejectionProlongs allograft survival in animal models-

- indicates no information available

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. This bacterium is capable of utilizing either heparin or HS as its sole carbon and nitrogen source. In order to do this it produces a range of enzymes such as lyases, glucuronidases, sulfoesterases and sulfamidases. It is the lyases that have mainly been used in heparin/HS studies. The bacterium produces three lyases, heparinases I, II and III and each has distinct substrate specificities as detailed below.

Heparinase enzymeSubstrate specificity
Heparinase IGlcNS(±6S)-IdoA(2S)
Heparinase IIGlcNS/Ac(±6S)-IdoA(±2S)
GlcNS/Ac(±6S)-GlcA
Heparinase IIIGlcNS/Ac(±6S)-GlcA/IdoA (with a preference for GlcA)

The lyases cleave heparin/HS by a beta elimination mechanism. This action generates an unsaturated double bond between C4 and C5 of the uronate residue. The C4-C5 unsaturated uronate is termed ΔUA or UA. It is a sensitive UV chromaphore (max absorption at 232 nm) and allows the rate of an enzyme digest to be followed as well as providing a convenient method for detecting the fragments produced by enzyme digestion.

Chemical

Nitrous acid can be used to chemically de-polymerise heparin/HS. Nitrous acid can be used at pH 1.5 or at a higher pH of 4. Under both conditions nitrous acid effects deaminative cleavage of the chain. At both 'high' (4) and 'low' (1.5) pH, deaminative cleavage occurs between GlcNS-GlcA and GlcNS-IdoA, all be it at a slower rate at the higher pH. The deamination reaction, and therefore chain cleavage, is regardless of O-sulfation carried by either monosaccharide unit.

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-susceptible to nitrous acid cleavage.

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