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Systematic (IUPAC) name
see Heparin structure
Clinical data
  • C[1]
Legal status
  • Prescription (US)
Routes of
i.v., s.c.
Pharmacokinetic data
Bioavailability erratic
Metabolism hepatic
Biological half-life 1.5 hrs
Excretion urine[2]
CAS Registry Number  Y
ATC code B01 C05 S01
PubChem CID:
DrugBank  N
ChemSpider  Y
Chemical data
Formula C12H19NO20S3
Molecular mass 12000–15000 g/mol

Heparin (from Ancient Greek ἧπαρ (hêpar), "liver"), a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule.[3] 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.

Although it is used principally in medicine for anticoagulation, its true physiological role in the body remains unclear, because blood anticoagulation is achieved mostly by heparan sulfate proteoglycans derived from endothelial cells.[4] 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.[5] In addition, it is observed across a number of widely different species, including some invertebrates that do not have a similar blood coagulation system.

In health system.[6]


  • Medical use 1
  • Adverse effects 2
    • Antidote to heparin overdose 2.1
  • Mechanism of action 3
  • Heparin structure 4
    • Abbreviations 4.1
    • Three-dimensional structure 4.2
    • Administration 4.3
    • Production 4.4
    • History 4.5
    • Novel drug development opportunities 4.6
  • Natural degradation or clearance 5
  • Depolymerisation techniques 6
    • Enzymatic 6.1
    • Chemical 6.2
  • Evolutionary conservation 7
  • Other uses and information 8
  • Heparin impurities and contamination recalls 9
  • Deaths 10
    • 2008 recall due to contamination 10.1
    • Use in homicide 10.2
    • Overdose issues 10.3
  • Toxicology 11
    • Detection in body fluids 11.1
  • Shelf life 12
  • See also 13
  • References 14
  • External links 15

Medical use

A vial of heparin sodium for injection

Heparin is a naturally occurring anticoagulant produced by basophils and mast cells.[7] 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:

Adverse effects

A serious side-effect of heparin is heparin-induced thrombocytopenia (HIT), caused by an immunological reaction that makes platelets a target of immunological response, resulting in the degradation of platelets, which causes thrombocytopenia. This condition is usually reversed on discontinuation, and in general can be avoided with the use of synthetic heparins. Also, a benign form of thrombocytopenia is associated with early heparin use, which resolves without stopping heparin.

Two nonhemorrhagic side-effects of heparin treatment are known. 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. More rarely, the side-effects alopecia and osteoporosis can occur with chronic use.

As with many drugs, overdoses of heparin can be fatal. In September 2006, heparin received worldwide publicity when three prematurely born infants died after they were mistakenly given overdoses of heparin at an Indianapolis hospital.[10]

Antidote to heparin overdose

Protamine sulfate (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.[11]

Mechanism of action

Heparin 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,[12][13] but no evidence indicates any one is more effective than the other in preventing mortality.[14] 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.[15] 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.[16]

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.[3] 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.[17] In contrast, antifactor Xa activity requires only the pentasaccharide-binding site.

Chemical structure of fondaparinux

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%.[18]

The effects of heparin are measured in the lab by the partial thromboplastin time (aPTT), one of the measures of the time it takes the blood plasma to clot. Partial thromboplastin time should not be confused with prothrombin time, or PT, which measures blood clotting time through a different pathway of the coagulation cascade.

Heparin enhances ATIII activity and neutralizes "activated serine protease coagulation factors."[19]

Heparin structure

Native heparin is a polymer with a molecular weight ranging from 3 to 30 kDa, although the average molecular weight of most commercial heparin preparations is in the range of 12 to 15 kDa.[20] Heparin is a member of the glycosaminoglycan family of carbohydrates (which includes the closely related molecule heparan sulfate) and consists of a variably sulfated repeating disaccharide unit.[21] 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 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.[22] 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 and amide sulfate groups are deprotonated and attract positively charged counterions to form a heparin salt. Heparin is usually administered in this form as an anticoagulant.

One 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.[23]


  • GlcA = β-D-glucuronic acid
  • IdoA = α-L-iduronic 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

Three-dimensional structure

The three-dimensional structure of heparin is complicated because iduronic 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.[24] 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.[25] 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, no evidence suggests that changes between these conformations occur in a concerted fashion. These models correspond to the protein data bank code 1HPN.

Two different structures of heparin

In the image above:

  • A = 1HPN (all IdoA(2S) residues in 2S0 conformation) Jmol viewer
  • B = van der Waals radius 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 angstroms (1.7 nm) on either side of the helical axis.


Heparin 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,[26] whereas LMWH has a half-life of four to five hours.[27] 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.

Details of administration are available in clinical practice guidelines by the American College of Chest Physicians:[28]

  • Non-weight-based heparin dose adjustment
  • Weight-based-heparin dose adjustment


Pharmaceutical-grade heparin is derived from mucosal tissues of slaughtered meat animals such as porcine (pig) intestines or bovine (cattle) lungs.[29] Advances to produce heparin synthetically have been made in 2003 and 2008.[30] In 2011, a chemoenzymatic process of synthesizing low molecular weight heparins from simple disaccharides was reported.[31]


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.[32] It was originally isolated from canine liver cells, hence its name (hepar or "ήπαρ" is Greek for "liver"). Heparin was discovered by Jay McLean and William Henry Howell in 1916.[33]

In 1916, McLean, a second-year medical student at Johns Hopkins University, was working under the guidance of Howell investigating procoagulant preparations, when he isolated a fat-soluble phosphatide anticoagulant in canine liver tissue.[34] In 1918, Howell coined the term 'heparin' for this type of fat-soluble anticoagulant. 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. McLean's work as a surgeon probably 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 published his research on the structure of heparin in 1935,[35] 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, nontoxic heparin that could be administered to patients, in a saline 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 as a blood anticoagulant. Prior to 1933, heparin was available in small amounts, was extremely expensive and toxic, and, as a consequence, of no medical value.[36]

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

Novel drug development opportunities

As detailed in the table below, the potential is great for the development of heparin-like structures as drugs to treat a wide range of diseases, in addition to their current use as anticoagulants.[37][38]

Disease states sensitive to heparin Heparin's effect in experimental models Clinical status
Acquired immunodeficiency syndrome Reduces the ability of human immunodeficiency virus types 1 and 2 to adsorb to cultured T4 cells.[39] -
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 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.[37]

Drug molecule Effect of new drug compared to heparin Biological activities
Heparin tetrasaccharide Nonanticoagulant, nonimmunogenic, orally active Antiallergic
Pentosan polysulfate Plant derived, little anticoagulant activity, anti-inflammatory, orally active Anti-inflammatory, antiadhesive, antimetastatic
Phosphomannopentanose sulfate Potent inhibitor of heparanase activity Antimetastatic, antiangiogenic, anti-inflammatory
Selectively chemically O-desulphated heparin Lacks anticoagulant activity Anti-inflammatory, antiallergic, antiadhesive

Natural degradation or clearance

Unfractionated heparin has a half-life of about one to two hours after infusion,[26] whereas low-molecular-weight heparin's half-life is about four times longer. Lower doses of heparin have a much shorter half-life than larger ones. Heparin binding to macrophage cells is internalized and depolymerized by the macrophages. It also rapidly binds to endothelial cells, which precludes the binding to antithrombin that results in anticoagulant action. For higher doses of heparin, endothelial cell binding will be saturated, such that clearance of heparin from the bloodstream by the kidneys will be a slower process.[40]

Depolymerisation techniques

Either chemical or enzymatic depolymerisation 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 (HS).


The enzymes traditionally used to digest heparin or HS are naturally produced by the soil bacterium Pedobacter heparinus (formerly named Flavobacterium heparinum).[41] This bacterium is capable of using either heparin or HS as its sole carbon and nitrogen source. To do so, it produces a range of enzymes such as lyases, glucuronidases, sulfoesterases, and sulfamidases.[42] The lyases have mainly been used in heparin/HS studies. The bacterium produces three lyases, heparinases I (EC, II (no EC number assigned) and III (EC and each has distinct substrate specificities as detailed below.[43][44]

Heparinase enzyme Substrate specificity
Heparinase I GlcNS(±6S)-IdoA(2S)
Heparinase II GlcNS/Ac(±6S)-IdoA(±2S)
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.[45][46] The C4-C5 unsaturated uronate is termed ΔUA or UA. It is a sensitive UV chromophore (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.


Nitrous acid

can be used to chemically depolymerise 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.[47]

IdoA(2S)-aMan: The anhydromannose can be reduced to an anhydromannitol

At both 'high' (4) and 'low' (1.5) pH, deaminative cleavage occurs between GlcNS-GlcA and GlcNS-IdoA, albeit 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 not being susceptible to nitrous acid cleavage.

Evolutionary conservation

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

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 phyla.

Other uses and information

  • Heparin gel (topical) may sometimes be used to treat sports injuries. The diprotonated form of histamine binds site-specifically to heparin.[58] 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 when its copper salt is formed. Copper-free molecules are not angiogenic.[59][60] In contrast heparin may inhibit angiogenesis when it is administered in the presence of corticosteroids.[61] This anti-angiogenic effect is independent of heparin's anticoagulant activity.[62]
  • Test tubes, Vacutainers, and capillary tubes that use the lithium salt of heparin (lithium heparin) as an anticoagulant are usually marked with green stickers and green tops. Heparin has the advantage over EDTA of not affecting levels of most ions. However, the levels of ionized calcium may be decreased if the concentration of heparin in the blood specimen is too high.[63] Heparin can interfere with some immunoassays, 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 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 and host homeostasis by providing characteristics similar to those of native endothelium.
  • The DNA binding sites on RNA polymerase can be occupied by heparin, preventing the polymerase from 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.[64]
  • Immobilized heparin can be used as an affinity ligand in protein purification. 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 factors or other types of heparin-binding proteins from a complex mixture of nonheparin-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.

Heparin impurities and contamination recalls

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.[65]

In December 2007, the US Food and Drug Administration (FDA) recalled a shipment of heparin because of bacterial growth (Serratia marcescens) in several unopened syringes of this product. S. marcescens can lead to life-threatening injuries and/or death.[66]

In March 2008, major recalls of heparin were announced by the FDA due to contamination of the raw heparin stock imported from China.[67][68] 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, a popular shellfish-derived supplement often used for arthritis, which was intended to substitute for actual heparin in potency tests.[69]


2008 recall due to contamination

In March 2008, major recalls of heparin were announced by pharmaceutical companies due to a suspected and unknown contamination of the raw heparin stock imported from China.[70][71] The contaminant was later found to be a compound called oversulfated chondroitin sulfate.[72] The US Food and Drug Administration was quoted as stating at least 19 deaths were believed linked to a raw heparin ingredient imported from the People's Republic of China, and 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'.

Use in homicide

In 2006, Petr Zelenka, a nurse in the Czech Republic, deliberately administered large doses to patients, killing seven, and attempting to kill 10 others.[73]

Overdose issues

In 2007, a nurse at Cedars-Sinai Medical Center mistakenly gave the 12-day-old twins of actor Dennis Quaid a dose of heparin that was 1,000 times the recommended dose for infants.[74] 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.,[75][76] and settled with the hospital for $750,000.[77] 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.[78]

In July 2008, another set of twins born at Christus Spohn Hospital South, in Corpus Christi, Texas, 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.[79] As of July 2008, the exact cause of the twins' death was under investigation.[80][81]

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.[82]


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 antifactor Xa activity. The specimen of choice is usually fresh, nonhemolyzed plasma from blood that has been anticoagulated with citrate, fluoride, or oxalate.[83][84]

Shelf life

Shelf life estimates range from 18 months to three years, depending upon the manufacturer.

See also



  1. ^ Heparin Sodium injection
  2. ^ heparin. In: Lexi-Drugs Online [database on the Internet]. Hudson (OH): Lexi-Comp, Inc.; 2007 [cited 2/10/12]. Available from: subscription required to view.
  3. ^ a b Cox, M.; Nelson D. (2004). Lehninger, Principles of Biochemistry (4). Freeman. p. 254.  
  4. ^ Marcum JA, McKenney JB, et al. (1986). "Anticoagulantly active heparin-like molecules from mast cell-deficient mice". Am. J. Physiol. 250 (5 Pt 2): H879–888.  
  5. ^ Nader, H.B.; Chavante, S.F.; Dos-Santos, E.A.; Oliveira, F.W.; De-Paiva, J.F.; Jerônimo, S.M.B.; Medeiros, G.F.; De-Abreu, L.R.D.; et al. (1999). "Heparan sulfates and heparins: similar compounds performing the same functions in vertebrates and invertebrates?". Braz. J. Med. Biol. Res. 32 (5): 529–538.  
  6. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  7. ^ Guyton, A. C.; Hall, J. E. (2006). Textbook of Medical Physiology (11). Elsevier Saunders. p. 464.  
  8. ^  
  9. ^  
  10. ^ Kusmer, Ken (20 September 2006). "3rd Ind. preemie infant dies of overdose". Fox News (Associated Press). Retrieved 2007-01-08. 
  11. ^ Internal medicine, Jay H. Stein, page 635
  12. ^ Agnelli G, Piovella F, Buoncristiani P, et al. (1998). "Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery". N Engl J Med 339 (2): 80–5.  
  13. ^ Bergqvist D, Agnelli G, Cohen AT, et al. (2002). "Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer". N Engl J Med 346 (13): 975–980.  
  14. ^ Handoll HHG, Farrar MJ, McBirnie J, Tytherleigh-Strong G, Milne AA, Gillespie WJ; Farrar; McBirnie; Tytherleigh-Strong; Milne; Gillespie (2002). Handoll, Helen HG, ed. "Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures". Cochrane Database Syst Rev 4 (4): CD000305.  
  15. ^ Chuang YJ, Swanson R., et al. (2001). "Heparin enhances the specificity of antithrombin for thrombin and factor Xa independent of the reactive center loop sequence. Evidence for an exosite determinant of factor Xa specificity in heparin-activated antithrombin". J. Biol. Chem. 276 (18): 14961–14971.  
  16. ^ Bjork I, Lindahl U.; Lindahl (1982). "Mechanism of the anticoagulant action of heparin". Mol. Cell. Biochem. 48 (3): 161–182.  
  17. ^ Petitou M, Herault JP, Bernat A, Driguez PA, et al. (1999). "Synthesis of Thrombin inhibiting Heparin mimetics without side effects". Nature 398 (6726): 417–422.  
  18. ^ Shalansky, Karen. DANAPAROID (Orgaran) for Heparin-Induced Thrombocytopenia. Vancouver Hospital & Health Sciences Centre, February 1998 Drug & Therapeutics Newsletter. Retrieved on 8 January 2007.
  19. ^  
  20. ^ Francis CW, Kaplan KL (2006). "Chapter 21. Principles of Antithrombotic Therapy". In Lichtman MA, Beutler E, Kipps TJ; et al. Williams Hematology (7th ed.).  
  21. ^ Bentolila, A.; et al. "Synthesis and heparin-like biological activity of amino acid-based polymers". Wiley InterScience. Retrieved 2008-03-10. (subscription required (help)). 
  22. ^ Gatti, G., Casu, B.; et al. (1979). C NMR Spectroscopy"13H and l"Studies on the Conformation of Heparin by (PDF). Macromolecules 12 (5): 1001–1007.  
  23. ^ "Online Medical Dictionary". Centre for Cancer Education. 2000. Retrieved 2008-07-11. 
  24. ^ Ferro D, Provasoli A; et al. (1990). "Conformer populations of L-iduronic acid residues in glycosaminoglycan sequences". Carbohydr. Res. 195 (2): 157–167.  
  25. ^ Mulloy B, Forster MJ, Jones C, Davies DB.; Forster; Jones; Davies (1 January 1993). "N.m.r. and molecular-modelling studies of the solution conformation of heparin". Biochem. J. 293 (Pt 3): 849–858.  
  26. ^ a b Eikelboom JW, Hankey GJ; Hankey (2002). "Low molecular weight heparins and heparinoids". The Medical Journal of Australia 177 (7): 379–383.  
  27. ^ Weitz JI (2004). "New anticoagulants for treatment of venous thromboembolism". Circulation 110 (9 Suppl 1): I19–26.  
  28. ^ Hirsh J, Raschke R; Raschke (2004). "Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy". Chest 126 (3 Suppl): 188S–203S.  
  29. ^ Linhardt RJ, Gunay NS.; Gunay (1999). "Production and Chemical Processing of Low Molecular Weight Heparins". Sem. Thromb. Hem. 3: 5–16.  
  30. ^ Bhattacharya, Ananyo (August 2008). "Flask synthesis promises untainted heparin". Chemistry World. Royal Society of Chemistry. Retrieved 6 February 2011. 
  31. ^ Xu, Y.; Masuko, S.; Takieddin, M.; Xu, H.; Liu, R.; Jing, J.; Mousa, S. A.; Linhardt, R. J.; Liu, J. (2011). "Chemoenzymatic Synthesis of Homogeneous Ultralow Molecular Weight Heparins". Science 334 (6055): 498–501.  
  32. ^ Linhardt RJ. (1991). "Heparin: An important drug enters its seventh decade". Chem. Indust. 2: 45–50. 
  33. ^ "Heparin used as an anticoagulant". 
  34. ^ MCLEAN, J. (1 January 1959). "The Discovery of Heparin". Circulation 19 (1): 75–78.  
  35. ^ Jorpes E (August 1935). "The chemistry of heparin". The Biochemical Journal 29 (8): 1817–30.  
  36. ^ Rutty, CJ. "Miracle Blood Lubricant: Connaught and the Story of Heparin, 1928–1937". Health Heritage Research Services. Archived from the original on August 23, 2007. Retrieved 2007-05-21. 
  37. ^ a b Lever R. and Page C.P. (2002). "Novel drug opportunities for heparin". Nature Reviews Drug Discovery 1 (2): 140–148.  
  38. ^ Coombe D.R. and Kett W.C. (2005). "Heparan sulfate-protein interactions: therapeutic potential through structure-function insights". Cell. Mol. Life Sci. 62 (4): 410–424.  
  39. ^ Baba M, Pauwels R, Balzarini J, Arnout J, Desmyter J, De Clercq E; Pauwels; Balzarini; Arnout; Desmyter; De Clercq (1988). "Mechanism of inhibitory effect of dextran sulfate and heparin on replication of human immunodeficiency virus in vitro". PNAS 85 (16): 6132–6.  
  40. ^ Weitz DS, Weitz JI; Weitz (2010). "Update on heparin: what do we need to know?". Journal of Thrombosis and Thrombolysis 29 (2): 199–207.  
  41. ^ Shaya D, Tocilj A., et al. (2006). "Crystal structure of heparinase II from Pedobacter heparinus and its complex with a disaccharide product". J. Biol. Chem. 281 (22): 15525–15535.  
  42. ^ Galliher PM, Cooney CL., et al. (1981). "Heparinase production by Flavobacterium heparinum". Appl. Environ. Microbiol. 41 (2): 360–365.  
  43. ^ Linhardt RJ, Turnbull JE., et al. (1990). "Examination of the substrate specificity of heparin and heparan sulfate lyases". Biochemistry 29 (10): 2611–2617.  
  44. ^ Desai UR, Wang HM. and Linhardt RJ. (1993). "Specificity studies on the heparin lyases from Flavobacterium heparinum". Biochemistry 32 (32): 8140–8145.  
  45. ^ Linker A, Hovingh P.; Hovingh (1972). "Isolation and characterization of oligosaccharides obtained from heparin by the action of heparinase". Biochemistry 11 (4): 563–568.  
  46. ^ Linhardt RJ, Rice KG., et al. (1988). "Mapping and quantification of the major oligosaccharide components of heparin". Biochem. J. 254 (3): 781–787.  
  47. ^ Shively JE, Conrad HE.; Conrad (1976). "Formation of anhydrosugars in the chemical depolymerization of heparin". Biochemistry 15 (18): 3932–3942.  
  48. ^ Warda M, Mao W., et al. (2003). "Turkey intestine as a commercial source of heparin? Comparative structural studies of intestinal avian and mammalian glycosaminoglycans". Comp. Biochem. Physiol. B Biochem. Mol. Biol. 134 (1): 189–197.  
  49. ^ Ototani N, Kikuchi M, Yosizawa Z.; Kikuchi; Yosizawa (1981). "Comparative studies on the structures of highly active and relatively inactive forms of whale heparin". J Biochem (Tokyo) 90 (1): 241–246.  
  50. ^ Warda M, Gouda EM., et al. (2003). "Isolation and characterization of raw heparin from dromedary intestine: evaluation of a new source of pharmaceutical heparin". Comp. Biochem. Physiol. C Toxicol. Pharmacol. 136 (4): 357–365.  
  51. ^ Bland CE, Ginsburg H., et al. (1982). "Mouse heparin proteoglycan. Synthesis by mast cell-fibroblast monolayers during lymphocyte-dependent mast cell proliferation". J. Biol. Chem. 257 (15): 8661–8666.  
  52. ^ Linhardt RJ, Ampofo SA., et al. (1992). "Isolation and characterization of human heparin". Biochemistry 31 (49): 12441–12445.  
  53. ^ Hovingh P, Linker A.; Linker (1982). "An unusual heparan sulfate isolated from lobsters (Homarus americanus)". J. Biol. Chem. 257 (16): 9840–9844.  
  54. ^ Hovingh P, Linker A.; Linker (1993). , a freshwater mussel"Anodonta californiensis"Glycosaminoglycans in . Biol. Bull 185 (2): 263–276.  
  55. ^ Pejler G, Danielsson A., et al. (1987). "Structure and antithrombin-binding properties of heparin isolated from the clams Anomalocardia brasiliana and Tivela mactroides". J. Biol. Chem. 262 (24): 11413–11421.  
  56. ^ Dietrich CP, Paiva JF., et al. (1999). "Structural features and anticoagulant activities of a novel natural low-molecular-weight heparin from the shrimp Penaeus brasiliensis". Biochim. Biophys. Acta. 1428 (2–3): 273–283.  
  57. ^ a b Medeiros GF, Mendes, A., et al. (2000). "Distribution of sulfated glycosaminoglycans in the animal kingdom: widespread occurrence of heparin-like compounds in invertebrates". Biochim. Biophys. Acta. 1475 (3): 287–294.  
  58. ^ Chuang W, Christ MD, Peng J, Rabenstein DL.; Christ; Peng; Rabenstein (2000). "An NMR and molecular modeling study of the site-specific binding of histamine by heparin, chemically modified heparin, and heparin-derived oligosacchrides". Biochemistry. 39 (13): 3542–3555.  
  59. ^ Alessandri, G. Raju, K. and Gullino, PM. (1983). "Mobilization of capillary endothelium in-vitro induced by effectors of angiogenesis in-vivo". Cancer. Res. 43 (4): 1790–1797.  
  60. ^ Raju, K. Alessandri, G. Ziche, M. and Gullino, PM. (1982). "Ceruloplasmin, copper ions, and angiogenesis". J. Natl. Cancer. Inst. 69 (5): 1183–1188.  
  61. ^ Folkman J. (1985). "Regulation of angiogenesis: a new function of heparin". Biochem. Pharmacol. 34 (7): 905–909.  
  62. ^ Folkman J. and Ingber DE. (1987). "Angiostatic steroids. Method of discovery and mechanism of action". Ann. Surg. 206 (3): 374–383.  
  63. ^ Higgins, C. (October 2007). "The use of heparin in preparing samples for blood-gas analysis" (PDF). Medical Laboratory Observer. 
  64. ^ Yokota M, Tatsumi N, Nathalang O, Yamada T, Tsuda I.; Tatsumi; Nathalang; Yamada; Tsuda (1999). "Effects of Heparin on Polymerase Chain Reaction for Blood White Cells". J. Clin. Lab. Anal. 13 (3): 133–140.  
  65. ^ Szabolcs Beni, John F. K. Limtiaco, Cynthia K. Larive; Limtiaco; Larive (September 2011). "Analysis and characterization of heparin impurities". Analytical and Bioanalytical Chemistry 399 (2): 527–539.  
  66. ^ AM2 PAT, Inc. Issues Nationwide Recall of Pre-Filled Heparin Lock Flush Solution USP (5 mL in 12 mL Syringes), Am2pat, Inc. Press release, December 20, 2007
  67. ^ CBS News, Blood-thinning drug under suspicion
  68. ^ FDA informational page with information and links about FDA investigation.
  69. ^ Zawisza, Julie (29 March 2008). "FDA Media Briefing on Heparin" (PDF).  
  70. ^ New York Times, March 6, 2008 Drug Tied to China Had Contaminant, F.D.A. Says, retrieved 2008-03-07
  71. ^ New York Times, March 7, 2008 German Authorities Report Problems With Blood Thinner, retrieved 2008-03-07
  72. ^ Blossom, DB; Kallen, AJ; Patel, PR; Elward, A; Robinson, L; Gao, G; Langer, R; Perkins, KM; et al. (2008). "Outbreak of adverse reactions associated with contaminated heparin". N Engl J Med. 359 (25): 2674–84.  
  73. ^ Nurse committed murders to "test" doctors, Radio Praha, May 12, 2006
  74. ^ Ornstein, Charles; Gorman, Anna. (November 21, 2007) Los Angeles Times Report: Dennis Quaid's twins get accidental overdose. Archived March 7, 2008 at the Wayback Machine
  75. ^ Dennis Quaid and wife sue drug maker, USA Today, December 4, 2007
  76. ^ Dennis Quaid files suit over drug mishap, Los Angeles Times, December 5, 2007
  77. ^ Quaid Awarded $750,000 Over Hospital Negligence,, December 16, 2008
  78. ^ WTHR story about Methodist Hospital overdose
  79. ^ Statement by Dr. Richard Davis, Chief Medical Officer, CHRISTUS Spohn Health System, July 10, 2008
  80. ^ At a Glance Heparin Overdose at Hospital, Dallas Morning News, July 11. 2008
  81. ^ "Officials Investigate Infants' Heparin OD at Texas Hospital." ABC News. July 11, 2008. Retrieved on July 24, 2008.
  82. ^ "Heparin Overdose Kills Toddler At Hospital, Staff Investigated." "KETV Omaha." March 31, 2010.
  83. ^ Hansen R, Koster A, Kukucka M, et al. A quick anti-Xa-activity-based whole blood coagulation assay for monitoring unfractionated heparin during cardiopulmonary bypass: a pilot investigation. Anesth. Analg. 91: 533-853, 2000.
  84. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 728-729.

Further reading

  • Marcum JA (January 2000). "The origin of the dispute over the discovery of heparin". Journal of the History of Medicine and Allied Sciences 55 (1): 37–66.  

External links

  • History of heparin
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