Heparin
Overview
 
Heparin also known as unfractionated heparin, a highly sulfated glycosaminoglycan
Glycosaminoglycan
Glycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...

, is widely used as an injectable anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...

, and has the highest negative charge density
Charge density
The linear, surface, or volume charge density is the amount of electric charge in a line, surface, or volume, respectively. It is measured in coulombs per meter , square meter , or cubic meter , respectively, and represented by the lowercase Greek letter Rho . Since there are positive as well as...

 of any known biological molecule
Biomolecule
A biomolecule is any molecule that is produced by a living organism, including large polymeric molecules such as proteins, polysaccharides, lipids, and nucleic acids as well as small molecules such as primary metabolites, secondary metabolites, and natural products...

. It can also be used to form an inner anticoagulant surface on various experimental and medical devices such as test tube
Test tube
A test tube, also known as a culture tube or sample tube, is a common piece of laboratory glassware consisting of a finger-like length of glass or clear plastic tubing, open at the top, usually with a rounded U-shaped bottom....

s and renal dialysis machines.

Although it is used principally in medicine for anticoagulation, its true physiological role in the body remains unclear, because blood anti-coagulation is achieved mostly by heparan sulfate
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...

 proteoglycans derived from endothelial
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...

 cells.
Encyclopedia
Heparin also known as unfractionated heparin, a highly sulfated glycosaminoglycan
Glycosaminoglycan
Glycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...

, is widely used as an injectable anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...

, and has the highest negative charge density
Charge density
The linear, surface, or volume charge density is the amount of electric charge in a line, surface, or volume, respectively. It is measured in coulombs per meter , square meter , or cubic meter , respectively, and represented by the lowercase Greek letter Rho . Since there are positive as well as...

 of any known biological molecule
Biomolecule
A biomolecule is any molecule that is produced by a living organism, including large polymeric molecules such as proteins, polysaccharides, lipids, and nucleic acids as well as small molecules such as primary metabolites, secondary metabolites, and natural products...

. It can also be used to form an inner anticoagulant surface on various experimental and medical devices such as test tube
Test tube
A test tube, also known as a culture tube or sample tube, is a common piece of laboratory glassware consisting of a finger-like length of glass or clear plastic tubing, open at the top, usually with a rounded U-shaped bottom....

s and renal dialysis machines.

Although it is used principally in medicine for anticoagulation, its true physiological role in the body remains unclear, because blood anti-coagulation is achieved mostly by heparan sulfate
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...

 proteoglycans derived from endothelial
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...

 cells. Heparin is usually stored within the secretory granules of mast cell
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...

s 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.

Heparin structure

Native heparin is a polymer with a molecular weight ranging from 3 kDa
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...

 to 30 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
Glycosaminoglycan
Glycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...

 family of carbohydrates (which includes the closely related molecule heparan sulfate
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...

) and consists of a variably sulfated repeating disaccharide
Disaccharide
A disaccharide or biose is the carbohydrate formed when two monosaccharides undergo a condensation reaction which involves the elimination of a small molecule, such as water, from the functional groups only. Like monosaccharides, disaccharides form an aqueous solution when dissolved in water...

 unit.
The main disaccharide units that occur in heparin are shown below. The most common disaccharide unit is composed of a 2-O-sulfated iduronic acid
Iduronic acid
L-Iduronic acid is the major uronic acid component of the glycosaminoglycans dermatan sulfate, and heparin. It is also present in heparan sulfate although here in a minor amount relative to its carbon-5 epimer glucuronic acid....

 and 6-O-sulfated, N-sulfated glucosamine, IdoA(2S)-GlcNS(6S). For example, this makes up 85% of heparins from beef lung and about 75% of those from porcine intestinal mucosa.
Not shown below are the rare disaccharides containing a 3-O-sulfated glucosamine (GlcNS(3S,6S)) or a free amine group (GlcNH3+). Under physiological conditions, the ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...

 and amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...

 sulfate groups are deprotonated and attract positively charged counterions to form a heparin salt. It is in this form that heparin is usually administered as an anticoagulant.

One unit of heparin (the "Howell
William Henry Howell
William Henry Howell, Ph.D., M.D., LL.D., Sc.D. was an American physiologist. He pioneered the use of heparin as a blood anti-coagulant....

 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.

Abbreviations

  • GlcA = β-D-glucuronic acid
    Glucuronic acid
    Glucuronic acid is a carboxylic acid. Its structure is similar to that of glucose. However, glucuronic acid's sixth carbon is oxidized to a carboxylic acid...

  • IdoA = α-L-iduronic acid
    Iduronic acid
    L-Iduronic acid is the major uronic acid component of the glycosaminoglycans dermatan sulfate, and heparin. It is also present in heparan sulfate although here in a minor amount relative to its carbon-5 epimer glucuronic 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

http://www.google.co.in/imgres?q=heparin&hl=en&safe=active&sa=X&biw=1440&bih=708&tbm=isch&prmd=imvns&tbnid=JEsjEcggntlQoM:&imgrefurl=http://www.stoptheclot.org/learn_more/blood_clot_treatment.htm&docid=8UPDy9Tr3pw5_M&imgurl=http://www.stoptheclot.org/images/natt_other_art/anim_hep.gif&w=530&h=442&ei=5UyeTsjtJoHVrQfe8rSqCQ&zoom=1&iact=rc&dur=366&sig=116398142964580690664&page=1&tbnh=170&tbnw=187&start=0&ndsp=16&ved=1t:429,r:0,s:0&tx=64&ty=2

Three-dimensional structure

The three-dimensional structure of heparin is complicated by the fact that iduronic acid
Iduronic acid
L-Iduronic acid is the major uronic acid component of the glycosaminoglycans dermatan sulfate, and heparin. It is also present in heparan sulfate although here in a minor amount relative to its carbon-5 epimer glucuronic acid....

 may be present in either of two low-energy conformations when internally positioned within an oligosaccharide. The conformational equilibrium is influenced by sulfation state of adjacent glucosamine sugars. Nevertheless, the solution structure of a heparin dodecasaccharide 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.
In the image above:
  • A = 1HPN (all IdoA(2S) residues in 2S0 conformation) Jmol viewer
  • B = van der Waals radius
    Van der Waals radius
    The van der Waals radius, r, of an atom is the radius of an imaginary hard sphere which can be used to model the atom for many purposes. It is named after Johannes Diderik van der Waals, winner of the 1910 Nobel Prize in Physics, as he was the first to recognise that atoms had a finite size and to...

     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 angstrom
Ångström
The angstrom or ångström, is a unit of length equal to 1/10,000,000,000 of a meter . Its symbol is the Swedish letter Å....

s (1.7 nm) on either side of the helical axis.

Medical use

Heparin is a naturally occurring anticoagulant produced by basophils and mast cell
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...

s. 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
Tissue plasminogen activator
Tissue plasminogen activator is a protein involved in the breakdown of blood clots. It is a serine protease found on endothelial cells, the cells that line the blood vessels. As an enzyme, it catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown...

), it allows the body's natural clot lysis
Fibrinolysis
Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. This process has two types: primary fibrinolysis and secondary fibrinolysis...

 mechanisms to work normally to break down clots that have formed. Heparin is generally used for anticoagulation for the following conditions:
  • Acute coronary syndrome
    Acute coronary syndrome
    Acute coronary syndrome is usually one of three diseases involving the coronary arteries: ST elevation myocardial infarction , non ST elevation myocardial infarction , or unstable angina ....

    , e.g., NSTEMI
  • Atrial fibrillation
    Atrial fibrillation
    Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...

  • Deep-vein thrombosis and pulmonary embolism
    Pulmonary embolism
    Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...

  • Cardiopulmonary bypass for heart surgery.
  • ECMO circuit for extracorporeal life support
  • Hemofiltration
    Hemofiltration
    In medicine, hemofiltration, also haemofiltration, is a renal replacement therapy similar to hemodialysis which is used almost exclusively in the intensive care setting...

  • Indwelling central or peripheral venous catheters

Mechanism of Action

Heparin and its low molecular weight derivatives (e.g. enoxaparin
Enoxaparin
Enoxaparin is a low molecular weight heparin marketed under the trade names Lovenox and Clexane, among others. It is an anticoagulant used to prevent and treat deep vein thrombosis or pulmonary embolism, and is given as a subcutaneous injection...

, dalteparin
Dalteparin
Dalteparin is a low molecular weight heparin. It is marketed as Fragmin by Pfizer Inc. Like other low molecular weight heparins, dalteparin is used for prophylaxis or treatment of deep vein thrombosis and pulmonary embolism....

, tinzaparin
Tinzaparin
Tinzaparin is an antithrombotic drug in the heparin group. It is a low molecular weight heparin marketed as Innohep worldwide. It has been approved by the U.S. Food and Drug Administration for once daily treatment and prophylaxis of deep vein thrombosis and pulmonary embolism...

) are effective at preventing deep vein thromboses and pulmonary emboli in patients at risk, but there is no evidence that any one is more effective than the other in preventing mortality. Heparin binds to the enzyme inhibitor antithrombin
Antithrombin
Antithrombin is a small protein molecule that inactivates several enzymes of the coagulation system. Antithrombin is a glycoprotein produced by the liver and consists of 432 amino acids. It contains three disulfide bonds and a total of four possible glycosylation sites...

 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
Thrombin
Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...

 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
Thrombin
Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...

. The formation of a ternary complex
Ternary complex
A Ternary complex refers to a protein complex containing three different molecules which are bound together. In structural biology ternary complex can be used to describe a crystal containing a protein with two small molecules bound, for example cofactor and substrate; or a complex formed between...

 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 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
Fondaparinux
Fondaparinux is an anticoagulant medication chemically related to low molecular weight heparins. It is marketed by GlaxoSmithKline.-Structure and mechanism:Fondaparinux is a synthetic pentasaccharide Factor Xa inhibitor...

 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 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
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...

.

With LMWH and fondaparinux, there is a reduced risk of osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...

 and heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia is the development of thrombocytopenia , due to the administration of various forms of heparin, an anticoagulant...

 (HIT). 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
Danaparoid
Danaparoid sodium is an anticoagulant that works by inhibiting activated factor X .Danaparoid is considered a "low molecular weight heparin" by some sources, but is chemically distinct from heparin and thus has little cross-reactivity in heparin-intolerant patients.It consists of a mixture of...

, a mixture of heparan sulfate
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...

, dermatan sulfate
Dermatan sulfate
Dermatan sulfate is a glycosaminoglycan found mostly in skin, but also in blood vessels, heart valves, tendons, and lungs....

, and chondroitin sulfate
Chondroitin sulfate
Chondroitin sulfate is a sulfated glycosaminoglycan composed of a chain of alternating sugars . It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have over 100 individual sugars, each of which can be sulfated in variable positions and quantities...

, can be used as an anticoagulant in patients that 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%.

The effects of heparin are measured in the lab by the partial thromboplastin time (aPTT), (the time it takes the blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 to clot).

Administration

Heparin is given parenteral
Parenteral
Parenteral is a route of administration that involves piercing the skin or mucous membrane. Parenteral nutrition refers to providing nutrition via the veins.-Etymology:...

ly because it is not absorbed from the gut, due to its high negative charge and large size. Heparin can be injected intravenously or subcutaneously (under the skin); intramuscular injections (into muscle) are avoided because of the potential for forming hematoma
Hematoma
A hematoma, or haematoma, is a localized collection of blood outside the blood vessels, usually in liquid form within the tissue. This distinguishes it from an ecchymosis, which is the spread of blood under the skin in a thin layer, commonly called a bruise...

s. Because of its short biologic half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...

 of approximately one hour, heparin must be given frequently or as a continuous infusion
Infusion
An infusion is the outcome of steeping plants with desired chemical compounds or flavors in water or oil.-History:The first recorded use of essential oils was in the 10th or 11th century by the Persian polymath Avicenna, possibly in The Canon of Medicine.-Preparation techniques:An infusion is very...

. 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
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...

 takes effect.

Details of administration are available in clinical practice guidelines by the American College of Chest Physicians
American College of Chest Physicians
The American College of Chest Physicians is a medical organization in the United States consisting of physicians and non-physician specialists in the field of chest medicine, which includes pulmonology, thoracic surgery, and critical care medicine....

:

Production

Pharmaceutical-grade heparin is derived from mucosal tissues of slaughtered
Slaughterhouse
A slaughterhouse or abattoir is a facility where animals are killed for consumption as food products.Approximately 45-50% of the animal can be turned into edible products...

 meat animals such as porcine (pig) intestine or bovine (cow) lung. Advances to produce heparin synthetically have been made in 2003 and 2008.

Adverse reactions

A serious side-effect of heparin is heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia is the development of thrombocytopenia , due to the administration of various forms of heparin, an anticoagulant...

 (HIT). HIT is caused by an immunological reaction that makes platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes.  The average lifespan of a platelet is normally just 5 to 9 days...

s a target of immunological response, resulting in the degradation of platelets. This is what causes thrombocytopenia. 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
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...

, 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. More rarely, side-effects include alopecia
Alopecia
Alopecia means loss of hair from the head or body. Alopecia can mean baldness, a term generally reserved for pattern alopecia or androgenic alopecia. Compulsive pulling of hair can also produce hair loss. Hairstyling routines such as tight ponytails or braids may induce Traction alopecia. Both...

 and osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...

 can occur with chronic use.

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.

Antidote to Heparin Overdose

Protamine sulfate
Protamine sulfate
Protamine sulfate is a drug that reverses the anticoagulant effects of heparin by binding to it.Protamine was originally isolated from the sperm of salmon and other species of fish but is now produced primarily through recombinant biotechnology. It is a highly cationic peptide...

 (1 mg per 100 units of heparin that had been given over the past four hours) has been given to counteract the anticoagulant effect of heparin.

History

Heparin is one of the oldest drugs currently 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
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

 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
William Henry Howell
William Henry Howell, Ph.D., M.D., LL.D., Sc.D. was an American physiologist. He pioneered the use of heparin as a blood anti-coagulant....

.

In 1916, McLean, a second-year medical student at Johns Hopkins University
Johns Hopkins University
The Johns Hopkins University, commonly referred to as Johns Hopkins, JHU, or simply Hopkins, is a private research university based in Baltimore, Maryland, United States...

, 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 for this type of fat-soluble anticoagulant in 1918. In the early 1920s, Howell isolated a water-soluble polysaccharide
Polysaccharide
Polysaccharides are long carbohydrate molecules, of repeated monomer units joined together by glycosidic bonds. They range in structure from linear to highly branched. Polysaccharides are often quite heterogeneous, containing slight modifications of the repeating unit. Depending on the structure,...

 anticoagulant, which was also termed heparin, although it was distinct from the phosphatide preparations previously isolated. It is probable that McLean's work as a surgeon changed the focus of the Howell group to look for anticoagulants, which eventually led to the polysaccharide discovery.

In the 1930s, several researchers were investigating heparin. Erik Jorpes at Karolinska Institutet
Karolinska Institutet
Karolinska institutet is a medical university in Solna within the Stockholm urban area, Sweden, and one of Europe's largest medical universities...

 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.

A posthumous attempt to nominate McLean for a Nobel Prize failed.

Novel drug development opportunities

As detailed in the table below, there is a great deal of potential for the development of heparin-like structures as drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...

s to treat a wide range of disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...

s, in addition to their current use as anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...

s.
Disease states sensitive to heparin Heparin's 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 trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

s
Allergic encephalomyelitis
Encephalomyelitis
Encephalomyelitis is a general term for inflammation of the brain and spinal cord, describing a number of disorders:* Acute disseminated encephalomyelitis or postinfectious encephalomyelitis, a demyelinating disease of the brain and spinal cord, possibly triggered by vaccination or viral...

 
Effective in animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...

s
-
Allergic rhinitis
Allergic rhinitis
Allergic rhinitis, also known as pollenosis or hay fever, is an allergic inflammation of the nasal airways.It occurs when an allergen, such as pollen, dust or animal dander is inhaled by an individual with a sensitized immune system...

 
Effects as for adult respiratory distress syndrome, although no specific nasal model has been tested Controlled clinical trial
Arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....

 
Inhibits cell accumulation, collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...

 destruction and angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...

 
Anecdotal report
Asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...

 
As for adult respiratory distress syndrome, however it has also been shown to improve lung function in experimental models Controlled clinical trials
Cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

 
Inhibits tumour growth, metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...

 and angiogenesis, and increases survival time in animal models
Several anecdotal reports
Delayed type hypersensitivity reactions  Effective in animal models -
Inflammatory bowel disease
Inflammatory bowel disease
In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...

 
Inhibits inflammatory cell transport in general. No specific model tested Controlled clinical trials
Interstitial cystitis
Interstitial cystitis
Interstitial cystitis or bladder pain syndrome is a chronic, oftentimes severely debilitating disease of the urinary bladder...

 
Effective in a human experimental model of interstitial cystitis Related molecule now used clinically
Transplant rejection
Transplant rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...

 
Prolongs 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.
Drug molecule Effect of new drug compared to heparin Biological activities
Heparin tetrasaccharide Non-anticoagulant, non-immunogenic, orally active Anti-allergic
Pentosan polysulfate
Pentosan polysulfate
Pentosan polysulfate is the only oral medication approved by the U.S. FDA for the treatment of interstitial cystitis, also known as painful bladder syndrome....

 
Plant derived, little anticoagulant activity, Anti-inflammatory, orally active Anti-inflammatory, anti-adhesive, anti-metastatic
Phosphomannopentanose sulfate Potent inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...

 of heparanase
Heparanase
Heparanase, also known as HPSE, is an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate molecules into shorter chain length oligosaccharides.-Synthesis and structure:...

 activity
Anti-metastatic, anti-angiogenic, anti-inflammatory
Selectively chemically O-desulphated heparin Lacks anticoagulant activity Anti-inflammatory, anti-allergic, anti-adhesive

De-polymerisation techniques

Either chemical or enzymatic de-polymerisation techniques or a combination of the two underlie the vast majority of analyses carried out on the structure and function of heparin and heparan sulfate
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...

 (HS).

Enzymatic

The enzymes traditionally used to digest heparin or HS are naturally produced by the soil bacterium Pedobacter heparinus (formerly named Flavobacterium heparinum). This bacterium is capable of utilizing either heparin or HS as its sole carbon and nitrogen source. In order to do so, it produces a range of enzymes such as lyase
Lyase
In biochemistry, a lyase is an enzyme that catalyzes the breaking of various chemical bonds by means other than hydrolysis and oxidation, often forming a new double bond or a new ring structure...

s, glucuronidase
Glucuronidase
Beta-glucuronidases are members of the glycosidase family of enzymes that catalyze breakdown of complex carbohydrates. Human β-glucuronidase is a type of glucuronidase that catalyzes hydrolysis of β-D-glucuronic acid residues from the non-reducing end of mucopolysaccharides such as heparan sulfate...

s, sulfoesterases, and sulfamidases. It is the lyases that have mainly been used in heparin/HS studies. The bacterium produces three lyases, heparinases I , II (no EC number
EC number
The Enzyme Commission number is a numerical classification scheme for enzymes, based on the chemical reactions they catalyze....

 assigned) and III and each has distinct substrate specificities as detailed below.
Heparinase enzyme Substrate specificity
Heparinase I  GlcNS(±6S)-IdoA(2S)
Heparinase II GlcNS/Ac(±6S)-IdoA(±2S)
GlcNS/Ac(±6S)-GlcA
Heparinase III  GlcNS/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 chromophore
Chromophore
A chromophore is the part of a molecule responsible for its color. The color arises when a molecule absorbs certain wavelengths of visible light and transmits or reflects others. The chromophore is a region in the molecule where the energy difference between two different molecular orbitals falls...

 (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
Nitrous acid
Nitrous acid is a weak and monobasic acid known only in solution and in the form of nitrite salts.Nitrous acid is used to make diazides from amines; this occurs by nucleophilic attack of the amine onto the nitrite, reprotonation by the surrounding solvent, and double-elimination of water...

 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
Chondroitin sulfate
Chondroitin sulfate is a sulfated glycosaminoglycan composed of a chain of alternating sugars . It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have over 100 individual sugars, each of which can be sulfated in variable positions and quantities...

 and dermatan sulfate
Dermatan sulfate
Dermatan sulfate is a glycosaminoglycan found mostly in skin, but also in blood vessels, heart valves, tendons, and lungs....

, chondroitin sulfate and dermatan sulfate being un-susceptible to nitrous acid cleavage.

Evolutionary conservation

In addition to the bovine and porcine tissue from which pharmaceutical-grade heparin is commonly extracted, heparin has also been extracted and characterised from the following species:

The biological activity of heparin within species 6–11 is unclear and further supports the idea that the main physiological role of heparin is not anticoagulation. These species do not possess any blood coagulation system similar to that present within the species listed 1–5. The above list also demonstrates how heparin has been highly evolutionarily conserved
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...

 with molecules of a similar structure being produced by a broad range of organisms belonging to many different phyla
Phylum
In biology, a phylum The term was coined by Georges Cuvier from Greek φῦλον phylon, "race, stock," related to φυλή phyle, "tribe, clan." is a taxonomic rank below kingdom and above class. "Phylum" is equivalent to the botanical term division....

.

Other uses/information

  • Heparin gel (topical) may sometimes be used to treat sports injuries. It is known that the diprotonated form of histamine
    Histamine
    Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...

     binds site specifically to heparin. The release of histamine from mast cells at a site of tissue injury contributes to an inflammatory response. The rationale behind the use of such topical gels may be to block the activity of released histamine, and so help to reduce inflammation.
  • Heparin gains the capacity to initiate angiogenesis
    Angiogenesis
    Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...

     when its copper salt is formed. Copper-free molecules are non-angiogenic. In contrast heparin may inhibit angiogenesis
    Angiogenesis
    Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...

     when it is administered in the presence of corticosteroids. This anti-angiogenic effect is independent of heparins anticoagulant activity.

  • Test tubes, Vacutainer
    Vacutainer
    Vacutainer is a brand of test tubes specifically designed for venipuncture, which was developed in 1947 by Joseph Kleiner.In phlebotomy the word “vacutainer” has come to be used as a genericized trademark to describe any vacuum-based blood collection vial, regardless of brand. Becton Dickinson...

    s, and capillary
    Capillary
    Capillaries are the smallest of a body's blood vessels and are parts of the microcirculation. They are only 1 cell thick. These microvessels, measuring 5-10 μm in diameter, connect arterioles and venules, and enable the exchange of water, oxygen, carbon dioxide, and many other nutrient and waste...

     tubes that use the lithium
    Lithium
    Lithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...

     salt of heparin (lithium heparin) as an anticoagulant are usually marked with green stickers and green tops. Heparin has the advantage over EDTA
    EDTA
    Ethylenediaminetetraacetic acid, widely abbreviated as EDTA , is a polyamino carboxylic acid and a colourless, water-soluble solid. Its conjugate base is named ethylenediaminetetraacetate. It is widely used to dissolve limescale. Its usefulness arises because of its role as a hexadentate ligand...

     of not affecting levels of most ion
    Ion
    An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...

    s. However, it has been shown that the levels of ionized calcium may be decreased if the concentration of heparin in the blood specimen is too high. Heparin can interfere with some immunoassay
    Immunoassay
    An immunoassay is a biochemical test that measures the presence or concentration of a substance in solutions that frequently contain a complex mixture of substances. Analytes in biological liquids such as serum or urine are frequently assayed using immunoassay methods...

    s, however. As lithium heparin is usually used, a person's lithium levels cannot be obtained from these tubes; for this purpose, royal-blue-topped Vacutainers containing sodium
    Sodium
    Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...

     heparin are used.

  • Heparin-coated blood oxygenators are available for use in heart-lung machines. Among other things, these specialized oxygenators are thought to improve overall biocompatibility
    Biocompatibility
    Biocompatibility is related to the behavior of biomaterials in various contexts. The term may refer to specific properties of a material without specifying where or how the material is used , or to more empirical clinical success of a whole device in...

     and host homeostasis by providing characteristics similar to native endothelium.

  • The DNA binding sites on RNA polymerase
    RNA polymerase
    RNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...

     can be occupied by heparin, preventing the polymerase binding to promoter DNA. This property is exploited in a range of molecular biological assays.

  • Common diagnostic procedures require PCR amplification of a patient's DNA, which is easily extracted from white blood cells treated with heparin. This poses a potential problem, since heparin may be extracted along with the DNA, and it has been found to interfere with the PCR reaction at levels as low as 0.002 U in a 50 μL reaction mixture.

  • Immobilized heparin can be used as an affinity ligand
    Ligand
    In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...

     in protein purification
    Protein purification
    Protein purification is a series of processes intended to isolate a single type of protein from a complex mixture. Protein purification is vital for the characterization of the function, structure and interactions of the protein of interest. The starting material is usually a biological tissue or...

    . The format of immobilized heparin can vary widely from coated plastic surfaces for diagnostic purposes to chromatography resin. Most types of immobilized heparin can be used in three ways. The first is to use heparin to select out specific coagulation
    Coagulation
    Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...

     factors or other types of heparin-binding proteins from a complex mixture of non-heparin-binding proteins. Specific proteins can then be selectively dissociated from heparin with the use of differing salt concentrations or by use of a salt gradient. The second use is to use heparin as a high-capacity cation exchanger. This use takes advantage of heparin's high number of anionic sulfate groups. These groups will capture molecules or proteins with an overall positive charge, i.e., play no role in coagulation and do not bind nucleotides. The third use for immobilized heparin is group-specific purification of RNA and DNA-binding proteins such as transcription factors and/or virus-coat proteins. This methodology takes advantage of heparin's structural similarity to RNA and DNA, being a negatively charged sugar-containing macromolecule.

  • Heparin does not break up fibrin, it only prevents conversion of fibrinogen to fibrin. Only thrombolytics can break up a clot.

Contamination recalls

In December 2007, the U.S. Food and Drug Administration (FDA) recalled a shipment of heparin because of bacterial growth (Serratia marcescens
Serratia marcescens
Serratia marcescens is a species of Gram-negative, rod-shaped bacterium in the family Enterobacteriaceae. A human pathogen, S. marcescens is involved in nosocomial infections, particularly catheter-associated bacteremia, urinary tract infections and wound infections, and is responsible for 1.4% of...

) in several unopened syringes of this product. The bacterium 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 adulterated heparin killed 81 people in the United States. The adulterant was identified as an "over-sulphated" derivative of chondroitin sulfate
Chondroitin sulfate
Chondroitin sulfate is a sulfated glycosaminoglycan composed of a chain of alternating sugars . It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have over 100 individual sugars, each of which can be sulfated in variable positions and quantities...

, a popular shellfish-derived supplement often used for arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....

, which was intended to substitute for actual heparin in potency tests.

Use in homicide

In 2006, Petr Zelenka
Petr Zelenka (serial killer)
Petr Zelenka is a Czech serial killer. Zelenka, a nurse in Havlíčkův Brod, southeast of Prague, murdered seven patients by lethal injection, and attempted to kill 10 others between May and December, 2006. He killed with a hidden vial of heparin — a blood-thinning drug causing internal bleeding...

, a nurse in the Czech Republic
Czech Republic
The Czech Republic is a landlocked country in Central Europe. The country is bordered by Poland to the northeast, Slovakia to the east, Austria to the south, and Germany to the west and northwest....

, 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
Cedars-Sinai Medical Center
Originally established as Kaspare Cohn Hospital in 1902, Cedars-Sinai Medical Center is a non-profit, tertiary 958-bed hospital and multi-specialty academic health science centre located in Los Angeles, California, US. Part of the Cedars-Sinai Health System, the hospital employs a staff of over...

 mistakenly gave actor Dennis Quaid
Dennis Quaid
Dennis William Quaid is an American actor known for his comedic and dramatic roles. First gaining widespread attention in the 1980s, his career rebounded in the 1990s after he overcame an addiction to drugs and an eating disorder...

's twelve-day-old twins a dose of heparin that 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, Texas
Corpus Christi, Texas
Corpus Christi is a coastal city in the South Texas region of the U.S. state of Texas. The county seat of Nueces County, it also extends into Aransas, Kleberg, and San Patricio counties. The MSA population in 2008 was 416,376. The population was 305,215 at the 2010 census making it the...

, 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. , the exact cause of the twins' death was under investigation.

In March 2010, a two year old transplant patient from Texas was given a lethal dose of heparin at the University of Nebraska Medical Center. The exact circumstances surrounding her death are still under investigation.

Toxicology

Contraindications: risk of bleeding (especially in patients with uncontrolled blood pressure, liver disease and stroke), severe liver disease, severe hypertension.

Side effects: hemorrhage, thrombocytopenia, increased potassium levels and osteoporosis.

Detection in body fluids

Current clinical laboratory assays for heparin rely on an indirect measurement of the effect of the drug, rather than on a direct measure of its chemical presence. These include activated partial thromboplastin time (APTT) and anti-factor Xa activity. The specimen of choice is usually fresh, non-hemolyzed plasma from blood that has been anticoagulated with citrate, fluoride or oxalate.

Heparin impurities

Considering the animal source of pharmaceutical heparin, the numbers of potential impurities are relatively large compared with a wholly synthetic therapeutic agent. The range of possible biological contaminants includes viruses, bacterial endotoxins, transmissible spongiform encephalopathy (TSE) agents, lipids, proteins and DNA. During the preparation of pharmaceutical-grade heparin from animal tissues, impurities such as solvents, heavy metals and extraneous cations can be introduced. However, the methods employed to minimize the occurrence and to identify and/or eliminate these contaminants are well established and listed in guidelines and pharmacopoeias. The major challenge in the analysis of heparin impurities is the detection and identification of structurally related impurities.The most prevalent impurity in heparin is dermatan sulfate (DS), also known as chondroitin sulfate B. The building block of DS is a disaccharide composed of 1,3-linked N-acetyl galactosamine (GalN) and a uronic acid residue, connected via 1,4 linkages to form the polymer. DS is composed of three possible uronic acid (GlcA, IdoA or IdoA2S) and four possible hexosamine (GalNAc, Gal- NAc4S, GalNAc6S or GalNAc4S6S) building blocks. The presence of iduronic acid in DS distinguishes it from chrondroitin sulfate A and C and likens it to heparin and HS . DS has a lower negative charge density overall compared to heparin. A common natural contaminant, DS
is present at levels of 1–7% in heparin API, but has no proven biological activity that influences the anticoagulation effect of heparin.

See also

  • Acceptable daily intake
    Acceptable daily intake
    Acceptable daily intake or ADI is a measure of the amount of a specific substance in food or drinking water that can be ingested on a daily basis over a lifetime without an appreciable health risk...

  • Protein allergy
  • Low molecular weight heparin
    Low molecular weight heparin
    In medicine, low-molecular-weight heparin is a class of medication used as an anticoagulant in diseases that feature thrombosis, as well as for prophylaxis in situations that lead to a high risk of thrombosis....


Further reading

External links

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