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Systematic (IUPAC) name
see Heparin structure
Clinical data AHFS/Drugs.com monograph  Pregnancy cat. Legal status Routes C Prescription (US) i.v., s.c. Pharmacokinetic data Bioavailability Metabolism Half-life Excretion erratic hepatic 1.5 hrs urine 
Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII ChEMBL 9005-49-6 B01AB01 CID 772   C05BA03  S01XA14 
   
CHEMBL526514 Chemical data
Formula Mol. mass
C12H19NO20S3 12000–15000 g/mol 
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 Not shown below are the rare disaccharides containing a 3-O-sulfated glucosamine (GlcNS(3S. 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. The main disaccharide units that occur in heparin are shown below. One unit of heparin (the "Howell Unit") is an amount approximately equivalent to 0. 2 Heparin structure Native heparin is a polymer with a molecular weight ranging from 3 kDa to 30 kDa. which is the quantity required to keep 1 mL of cat's blood fluid for 24 hours at 0 °C. the ester and amide sulfate groups are deprotonated and attract positively charged counterions to form a heparin salt. In addition.Heparin Heparin (from Ancient Greek ηπαρ (hepar). although the average molecular weight of most commercial heparin preparations is in the range of 12 kDa to 15 kDa. Heparin is usually stored within the secretory granules of mast cells and released only into the vasculature at sites of tissue injury. the main purpose of heparin is defense at such sites against invading bacteria and other foreign materials. liver). is widely used as an injectable anticoagulant. IdoA(2S)-GlcNS(6S). including some invertebrates that do not have a similar blood coagulation system. a highly sulfated glycosaminoglycan. It has been proposed that. it is conserved across a number of widely different species. 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.002 mg of pure heparin.6S)) or a free amine group (GlcNH3+). because blood anti-coagulation is achieved mostly by heparan sulfate proteoglycans derived from endothelial cells. and has the highest negative charge density of any known biological molecule. its true physiological role in the body remains unclear. GlcA-GlcNAc GlcA-GlcNS IdoA-GlcNS IdoA(2S)-GlcNS . also known as unfractionated heparin. this makes up 85% of heparins from beef lung and about 75% of those from porcine intestinal A sample of Heparin Sodium for injection mucosa. Under physiological conditions. N-sulfated glucosamine. The most common disaccharide unit is composed of a 2-O-sulfated iduronic acid and 6-O-sulfated. For example. rather than anticoagulation. Although it is used principally in medicine for anticoagulation. It is in this form that heparin is usually administered as an anticoagulant.
Heparin 3 IdoA-GlcNS(6S) IdoA(2S)-GlcNS(6S) Abbreviations • • • • • • 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 by the fact that iduronic acid may be present in either of two low-energy conformations when internally positioned within an oligosaccharide. and one in which they are in the 1C4 conformation (C and D below). Nevertheless.  . However there is no evidence to suggest that changes between these conformations occur in a concerted fashion. 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. one in which all IdoA(2S) were in the 2S0 conformation (A and B below). Two models were constructed. The conformational equilibrium is influenced by sulfation state of adjacent glucosamine sugars. These models correspond to the protein data bank code 1HPN.
NSTEMI Atrial fibrillation Deep-vein thrombosis and pulmonary embolism Cardiopulmonary bypass for heart surgery. Medical use Heparin is a naturally occurring anticoagulant produced by basophils and mast cells. Heparin acts as an anticoagulant. it allows the body's natural clot lysis mechanisms to work normally to break down clots that have formed. preventing the formation of clots and extension of existing clots within the blood. Heparin is generally used for anticoagulation for the following conditions: • • • • • • Acute coronary syndrome.7 nm) on either side of the helical axis. While heparin does not break down clots that have already formed (unlike tissue plasminogen activator)..Heparin 4 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. ECMO circuit for extracorporeal life support Hemofiltration • Indwelling central or peripheral venous catheters . e. the rotation of which places clusters of sulfate groups at regular intervals of about 17 angstroms (1.g. heparin adopts a helical conformation.
 AT binds to a specific pentasaccharide sulfation sequence contained within the heparin polymer: GlcNAc/NS(6S)-GlcA-GlcNS(3S. heparin's activity against thrombin is size-dependent. more recently. The formation of a ternary complex between AT. The chemical structure of fondaparinux is shown above. With LMWH and fondaparinux. and chondroitin sulfate. thrombin. For this reason. Danaparoid. cross-reactivity of danaparoid with heparin-induced antibodies is reported as less than 10%. Because danaparoid does not contain heparin or heparin fragments. but there is no evidence that any one is more effective than the other in preventing mortality. one of the measures of the time it takes the blood plasma to clot. with the aim of facilitating a Chemical structure of fondaparinux more subtle regulation of coagulation and an improved therapeutic index. most notably factor Xa. can be used as an anticoagulant in patients that have developed HIT. In contrast. and heparin results in the inactivation of thrombin. thrombin must also bind to the heparin polymer at a site proximal to the pentasaccharide. which measures blood clotting time through a different pathway of the coagulation cascade. the ternary complex requiring at least 18 saccharide units for efficient formation. or PT. however. 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. there is a reduced risk of osteoporosis and heparin-induced thrombocytopenia (HIT). as APTT is insensitive to alterations in factor Xa. dermatan sulfate.Heparin 5 Mechanism of action Heparin and its low molecular weight derivatives (e. For thrombin inhibition. The rate of inactivation of these proteases by AT can increase by up to 1000-fold due to the binding of heparin. Monitoring of the activated partial thromboplastin time is also not required and does not reflect the anticoagulant effect. to fondaparinux as pharmaceutical anticoagulants.6S)-IdoA(2S)-GlcNS(6S) The conformational change in AT on heparin-binding mediates its inhibition of factor Xa. . whose chemical structure is almost identical to the AT binding pentasaccharide sequence that can be found within polymeric heparin and heparan sulfate. This size difference has led to the development of low-molecular-weight heparins (LMWHs) and. The effects of heparin are measured in the lab by the partial thromboplastin time (aPTT). Low-molecular-weight heparins and fondaparinux target anti-factor Xa activity rather than anti-thrombin activity. anti-factor Xa activity requires only the pentasaccharide binding site. tinzaparin) are effective at preventing deep vein thromboses and pulmonary emboli in patients at risk. The activated AT then inactivates thrombin and other proteases involved in blood clotting. enoxaparin. dalteparin. The highly negative charge density of heparin contributes to its very strong electrostatic interaction with thrombin. a mixture of heparan sulfate.g. It is a synthetic pentasaccharide. Partial thromboplastin time should not be confused with Prothrombin time.
In 1916. 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. This abnormality is not associated with liver dysfunction. Adverse reactions A serious side-effect of heparin is heparin-induced thrombocytopenia (HIT). If long-term anticoagulation is required. History Heparin is one of the oldest drugs currently in widespread clinical use. heparin must be given frequently or as a continuous infusion. The other complication is hyperkalemia. thus not requiring a continuous infusion of the drug. McLean. The first is elevation of serum aminotransferase levels. The use of LMWH has allowed once-daily dosing. and it disappears after the drug is discontinued. a second-year medical student at Johns Hopkins University. Heparin can be injected intravenously or subcutaneously (under the skin). although it did not enter clinical trials until 1935. and can generally be avoided with the use of synthetic heparins. and is the result of heparin-induced aldosterone suppression. This is what causes thrombocytopenia. resulting in the degradation of platelets. HIT is caused by an immunological reaction that makes platelets a target of immunological response. when he isolated a fat-soluble phosphatide anti-coagulant in canine . The hyperkalemia can appear within a few days after the onset of heparin therapy. heparin is often used only to commence anticoagulation therapy until the oral anticoagulant warfarin takes effect. overdoses of heparin can be fatal. side-effects include alopecia and osteoporosis can occur with chronic use. There are two nonhemorrhagic side-effects of heparin treatment. Details of administration are available in clinical practice guidelines by the American College of Chest Physicians: • Non-weight-based heparin dose adjustment  • Weight-based-heparin dose adjustment  Production Pharmaceutical-grade heparin is derived from mucosal tissues of slaughtered meat animals such as porcine (pig) intestine or bovine (cow) lung. hence its name (hepar or "ήπαρ" is Greek for "liver"). Advances to produce heparin synthetically have been made in 2003 and 2008. More rarely.  whereas low-molecular-weight heparin (LMWH) has a half-life of four to five hours. There is also a benign form of thrombocytopenia associated with early heparin use. intramuscular injections (into muscle) are avoided because of the potential for forming hematomas. was working under the guidance of Howell investigating pro-coagulant preparations. As with many drugs. which has been reported in as many as 80% of patients receiving heparin.Heparin 6 Administration Heparin is given parenterally because it is not absorbed from the gut. Heparin's discovery can be attributed to the research activities of two men: Jay McLean and William Henry Howell. heparin received worldwide publicity when 3 prematurely born infants died after they were mistakenly given overdoses of heparin at an Indianapolis hospital. Its discovery in 1916 predates the establishment of the Food and Drug Administration of the United States. This condition is usually reversed on discontinuation. In September 2006. due to its high negative charge and large size. It was originally isolated from canine liver cells. Unfractionated heparin has a half-life of approximately one to two hours after infusion. which resolves without stopping heparin. Because of its short biologic half-life of approximately one hour. which occurs in 5 to 10% of patients receiving heparin.
as a consequence. Erik Jorpes at Karolinska Institutet published his research on the structure of heparin in 1935. collagen destruction and angiogenesis As for adult respiratory distress syndrome. In the early 1920s. Between 1933 and 1936. Disease states sensitive to heparin Acquired immunodeficiency syndrome Adult respiratory distress syndrome Allergic encephalomyelitis Allergic rhinitis Heparin's effect in experimental models Clinical status Reduces the ability of Human Immunodeficiency Virus types 1 and 2 to adsorb to  cultured T4 cells. No specific model tested Effective in a human experimental model of interstitial cystitis Controlled clinical trials Related molecule now used clinically - Transplant rejection Prolongs allograft survival in animal models . which eventually led to the polysaccharide discovery. it was clear that Connaught's heparin was a safe. Prior to 1933. easily available.Heparin liver tissue. and was extremely expensive. - Reduces cell activation and accumulation in airways. A posthumous attempt to nominate McLean for a Nobel Prize failed. which made it possible for the Swedish company Vitrum AB to launch the first heparin product for intravenous use in 1936. and improves lung function in animal models Effective in animal models Effects as for adult respiratory distress syndrome. although no specific nasal model has been tested Inhibits cell accumulation. non-toxic heparin that could be administered to patients in a salt solution. and increases survival time in animal models Controlled clinical trial Arthritis Asthma Anecdotal report Controlled clinical trials Cancer Several anecdotal reports - Delayed type hypersensitivity Effective in animal models reactions Inflammatory bowel disease Interstitial cystitis Inhibits inflammatory cell transport in general. 7 Novel drug development opportunities As detailed in the table below. then a part of the University of Toronto. by 1937. but in small amounts. and. perfected a technique for producing safe. however it has also been shown to improve lung function in experimental models Inhibits tumour growth. Connaught Medical Research Laboratories. of no medical value. It is probable that McLean's work as a surgeon changed the focus of the Howell group to look for anticoagulants. several researchers were investigating heparin. there is a great deal of potential for the development of heparin-like structures as drugs to treat a wide range of diseases. In the 1930s. metastasis and angiogenesis. It was Howell in 1918 who coined the term heparin for this type of fat-soluble anticoagulant in 1918. in addition to their current use as anticoagulants. . heparin was available. The first human trials of heparin began in May 1935. which was also termed heparin. although it was distinct from the phosphatide preparations previously isolated. neutralizes mediators and cytotoxic Controlled clinical trials cell products. and effective blood anticoagulant. toxic. and. Howell isolated a water-soluble polysaccharide anticoagulant.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.
orally active Potent inhibitor of heparanase activity Biological activities Anti-allergic Anti-inflammatory. non-immunogenic. It is the lyases that have mainly been used in heparin/HS studies. little anticoagulant activity. In order to do so. Lower doses of heparin have a much shorter half-life than larger doses of heparin. heparinases I (EC 4. This bacterium is capable of utilizing either heparin or HS as its sole carbon and nitrogen source.Heparin 8 Drug molecule Heparin tetrasaccharide Pentosan polysulfate Effect of new drug compared to heparin Non-anticoagulant. anti-adhesive Phosphomannopentanose sulfate Selectively chemically O-desulphated heparin Lacks anticoagulant activity Natural degradation or clearance Unfractionated heparin has a half-life of approximately one to two hours after infusion. it produces a range of enzymes such as lyases. endothelial cell binding will be saturated. which precludes the binding to antithrombin that results in anticoagulant action.7 ). The bacterium produces three lyases. Enzymatic The enzymes traditionally used to digest heparin or HS are naturally produced by the soil bacterium Pedobacter heparinus (formerly named Flavobacterium heparinum). anti-metastatic Anti-metastatic. Anti-inflammatory. Heparin binding to macrophage cells is internalized and depolymerized by the macrophages. II (no EC number assigned) and III (EC 4. Heparin also rapidly binds to endothelial cells.2. anti-adhesive. orally active Plant derived.2. sulfoesterases.2. For higher doses of heparin. anti-angiogenic. anti-inflammatory Anti-inflammatory. and sulfamidases.2.  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 (HS). anti-allergic. glucuronidases. such that clearance of heparin from the bloodstream by the kidneys will be a slower process. Heparinase enzyme Substrate specificity Heparinase I Heparinase II GlcNS(±6S)-IdoA(2S) GlcNS/Ac(±6S)-IdoA(±2S) GlcNS/Ac(±6S)-GlcA GlcNS/Ac(±6S)-GlcA/IdoA (with a preference for GlcA) Heparinase III .8 ) and each has distinct substrate specificities as detailed below. whereas low-molecular-weight heparin has a half-life that is about four times longer.
 The C4-C5 unsaturated uronate is termed ΔUA or UA. deaminative cleavage results in the release of inorganic SO4. 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. Fresh water mussel 8. UA(2S)-GlcNS(6S) Chemical Nitrous acid can be used to chemically de-polymerise heparin/HS. Evolutionary conservation In addition to the bovine and porcine tissue from which pharmaceutical-grade heparin is commonly extracted. Sand dollar 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. Clam 9. Mouse 5. and the conversion of GlcNS into anhydromannose (aMan). chondroitin sulfate and dermatan sulfate being un-susceptible to nitrous acid cleavage. Dromedary camel 4. Turkey 2. Lobster 7. Humans 6. heparin has also been extracted and characterised from the following species: 1. and therefore chain cleavage. IdoA(2S)-aMan: The anhydromannose can be Low-pH nitrous acid treatment is an excellent method to distinguish reduced to an anhydromannitol N-sulfated polysaccharides such as heparin and HS from non N-sulfated polysacchrides such as chondroitin sulfate and dermatan sulfate. This action generates an unsaturated double bond between C4 and C5 of the uronate residue. The above list also demonstrates how heparin has been highly evolutionarily conserved with molecules of a similar structure being produced by a broad range of organisms belonging to many different phyla. . These species do not possess any blood coagulation system similar to that present within the species listed 1–5. At low pH.Heparin 9 The lyases cleave heparin/HS by a beta elimination mechanism. is regardless of O-sulfation carried by either monosaccharide unit. all be it at a slower rate at the higher pH. Shrimp 10. deaminative cleavage occurs between GlcNS-GlcA and GlcNS-IdoA. Mangrove crab 11. At both 'high' (4) and 'low' (1.5) pH. Under both conditions nitrous acid effects deaminative cleavage of the chain.5 or at a higher pH of 4. The deamination reaction. Whale 3. Nitrous acid can be used at pH 1.
preventing the polymerase binding to promoter DNA. 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 use takes advantage of heparin's high number of anionic sulfate groups. • Common diagnostic procedures require PCR amplification of a patient's DNA. it only prevents conversion of fibrinogen to fibrin. This poses a potential problem. As lithium heparin is usually used. Specific proteins can then be selectively dissociated from heparin with the use of differing salt concentrations or by use of a salt gradient. proteins and DNA.Heparin 10 Other uses and information • Heparin gel (topical) may sometimes be used to treat sports injuries. being a negatively charged sugar-containing macromolecule. Heparin can interfere with some immunoassays. These groups will capture molecules or proteins with an overall positive charge. bacterial endotoxins. i. and it has been found to interfere with the PCR reaction at levels as low as 0. transmissible spongiform encephalopathy (TSE) agents. . a person's lithium levels cannot be obtained from these tubes. Only thrombolytics can break up a clot. heavy metals and extraneous cations can be introduced. However. since heparin may be extracted along with the DNA. This methodology takes advantage of heparin's structural similarity to RNA and DNA. royal-blue-topped Vacutainers containing sodium heparin are used. play no role in coagulation and do not bind nucleotides. This anti-angiogenic effect is independent of heparin's anticoagulant activity. 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. the numbers of potential impurities are relatively large compared with a wholly synthetic therapeutic agent. Heparin has the advantage over EDTA of not affecting levels of most ions. The format of immobilized heparin can vary widely from coated plastic surfaces for diagnostic purposes to chromatography resin. • Heparin-coated blood oxygenators are available for use in heart-lung machines.. the methods employed to minimize the occurrence and to identify and/or eliminate these contaminants are well established and listed in guidelines and pharmacopoeias. It is known that the diprotonated form of histamine binds site specifically to heparin. Most types of immobilized heparin can be used in three ways. The release of histamine from mast cells at a site of tissue injury contributes to an inflammatory response. However. Vacutainers. • Immobilized heparin can be used as an affinity ligand in protein purification. and so help to reduce inflammation. lipids.e. The second use is to use heparin as a high-capacity cation exchanger. these specialized oxygenators are thought to improve overall biocompatibility and host homeostasis by providing characteristics similar to native endothelium. • Test tubes. impurities such as solvents. In contrast heparin may inhibit angiogenesis when it is administered in the presence of corticosteroids. • Heparin does not break up fibrin. • The DNA binding sites on RNA polymerase can be occupied by heparin. Copper-free molecules are non-angiogenic. which is easily extracted from white blood cells treated with heparin. The range of possible biological contaminants includes viruses. for this purpose. Heparin impurities and contamination recalls Considering the animal source of pharmaceutical heparin. During the preparation of pharmaceutical-grade heparin from animal tissues. The major challenge in the analysis of heparin impurities is the detection and identification of structurally related impurities. • Heparin gains the capacity to initiate angiogenesis when its copper salt is formed. The first is to use heparin to select out specific coagulation factors or other types of heparin-binding proteins from a complex mixture of non-heparin-binding proteins. The rationale behind the use of such topical gels may be to block the activity of released histamine. This property is exploited in a range of molecular biological assays. and capillary tubes that use the lithium salt of heparin (lithium heparin) as an anticoagulant are usually marked with green stickers and green tops.002 U in a 50 μL reaction mixture. Among other things.
 In March 2010. A common natural contaminant.4 linkages to form the polymer. Prior to the Quaid accident. Food and Drug Administration (FDA) recalled a shipment of heparin because of bacterial growth (Serratia marcescens) in several unopened syringes of this product. Baxter Healthcare Corp. died after an accidentally administered overdose of the drug.Heparin The most prevalent impurity in heparin is dermatan sulfate (DS). Petr Zelenka. DS is present at levels of 1–7% in heparin API. the U. The adulterant was identified as an "over-sulphated" derivative of chondroitin sulfate. killing 7.000 times the recommended dose for infants. DS has a lower negative charge density overall compared to heparin. The Quaid family subsequently sued the manufacturer. the exact cause of the twins' death was under investigation. In December 2007. deliberately administered large doses to patients. Overdose issues In 2007. connected via 1. IdoA or IdoA2S) and four possible hexosamine (GalNAc. 11 Illegal use Use in homicide In 2006. Indiana were given an overdose.000. a popular shellfish-derived supplement often used for arthritis. a nurse at Cedars-Sinai Medical Center mistakenly gave actor Dennis Quaid's twelve-day-old twins a dose of heparin that was 1. but has no proven biological activity that influences the anticoagulation effect of heparin. a nurse in the Czech Republic. six newborn babies at Methodist Hospital in Indianapolis. major recalls of heparin were announced by the FDA due to contamination of the raw heparin stock imported from China. also known as chondroitin sulfate B. The bacterium Serratia marcescens can lead to life-threatening injuries and/or death. The building block of DS is a disaccharide composed of 1. The overdose allegedly arose because the labeling and design of the adult and infant versions of the product were similar.NAc4S. The presence of iduronic acid in DS distinguishes it from chrondroitin sulfate A and C and likens it to heparin and HS . . and settled with the hospital for $750. The exact circumstances surrounding her death are still under investigation. The overdose was due to a mixing error at the hospital pharmacy and was unrelated to the product's packaging or labeling.3-linked N-acetyl galactosamine (GalN) and a uronic acid residue. which was intended to substitute for actual heparin in potency tests. DS is composed of three possible uronic acid (GlcA. and attempting to kill 10 others.S. another set of twins born at Christus Spohn Hospital South. According to the FDA. Three of the babies died after the mistake. a two-year-old transplant patient from Texas was given a lethal dose of heparin at the University of Nebraska Medical Center. GalNAc6S or GalNAc4S6S) building blocks. the adulterated heparin killed 81 people in the United States. In July 2008. As of July 2008. a hospital located in Corpus Christi. In March 2008. Texas. Gal..
htm) Vancouver Hospital & Health Sciences Centre. ap/ index. The specimen of choice is usually fresh. 2008  WTHR story (http:/ / www. 2007 [cited 2/10/12]. whocc. no/ atc_ddd_index/ ?code=C05BA03  http:/ / www. Radio Praha. gov/ Drugs/ DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/ UCM112597) with information and links about FDA investigation.  http:/ / chestjournal.Heparin 12 Toxicology Contraindications: risk of bleeding (especially in patients with uncontrolled blood pressure. Gorman. com/ stories/ 2008/ 03/ 01/ eveningnews/ main3896578. expansion  Internal medicine. 2. rather than on a direct measure of its chemical presence. nlm. page 635  http:/ / enzyme. non-hemolyzed plasma from blood that has been anticoagulated with citrate. gov/ srs/ srsdirect. December 5. 2. 2007  Dennis Quaid files suit over drug mishap (http:/ / www. (http:/ / www. thrombocytopenia. cnn. html  heparin. expasy. December 16. expasy.1883436. latimes. asp?s=5418800) about Methodist Hospital overdose . gov/ summary/ summary. 2. December 20. html)  Dennis Quaid and wife sue drug maker (http:/ / www. org/ EC/ 4. rcsb. php/ User:K. liver disease and stroke). pdb  http:/ / wiki. Blood-thinning drug under suspicion (http:/ / www. gov/ cgi/ mesh/ 2009/ MB_cgi?term=9005-49-6& rn=1  http:/ / www. chestpubs. In: Lexi-Drugs Online [database on the Internet]. shtml)  FDA informational page (http:/ / www. whocc. Am2pat. usatoday. subscription required to view. org/ w/ index. severe hypertension. com/ Global/ story. severe liver disease. 7  http:/ / enzyme. com/ cgi-bin/ blogs/ dailydish/ detail?blogid=7& entry_id=33678). cbsnews. Karen. php/ compound/ inspect/ CHEMBL526514  http:/ / en. nlm. Retrieved on 8 January 2007. 2007  CBS News. jmol. no/ atc_ddd_index/ ?code=B01AB01  http:/ / www. jsp?regno=T2410KM04A  https:/ / www. Anna. fda. murphy  Shalansky. ebi. org/ index. February 1998 Drug & Therapeutics Newsletter.com. (http:/ / www. Inc. Inc. Issues Nationwide Recall of Pre-Filled Heparin Lock Flush Solution USP (5 mL in 12 mL Syringes) (http:/ / www. Notes and references  http:/ / www. fluoride or oxalate. org/ pdb/ files/ 1hpn. com/ monograph/ heparin-sodium. vhpharmsci. chestpubs. (November 21.1. html). htm). com. nlm. nih. ac. radio. Side effects: hemorrhage. fda.. com/ features/ health/ la-me-quaid5dec05. DANAPAROID (Orgaran) for Heparin-Induced Thrombocytopenia. cgi?cid=772  http:/ / www. Shelf life Shelf life estimates range from 18 months to 3 years. 2. nih. 17216115  http:/ / fdasis. whocc. 2007) Los Angeles Times Report: Dennis Quaid's twins get accidental overdose.000 Over Hospital Negligence (http:/ / www. com/ Newsletters/ 1990s-NEWS/ article6. com/ 2007/ SHOWBIZ/ Movies/ 11/ 21/ quaid. May 12. cz/ en/ article/ 85964). wthr. ncbi. These include activated partial thromboplastin time (APTT) and anti-factor Xa activity. Jay H.  http:/ / www. newborns. uk/ chembldb/ index. expansion  http:/ / chestjournal. December 4. Stein. com/ life/ people/ 2007-12-04-quaid-lawsuit_N. nih. chemspider. ca/ drugs/ DB01109  http:/ / www. Charles.  Nurse committed murders to "test" doctors (http:/ / www. org/ content/ 126/ 3_suppl/ 188S/ T5. lexi. 2007  Quaid Awarded $750. drugbank. 8  AM2 PAT. story). org/ content/ 126/ 3_suppl/ 188S/ T4. SFGate. drugs. Inc. Hudson (OH): Lexi-Comp. 2006  Ornstein. gov/ oc/ po/ firmrecalls/ am2pat12_07. org/ EC/ 4. no/ atc_ddd_index/ ?code=S01XA14  http:/ / pubchem. Press release. php?title=Special:ComparePages& rev1=407837023& page2=Heparin  http:/ / www. Available from: http:/ / online. sfgate. increased potassium levels and osteoporosis. Los Angeles Times. USA Today. com/ Chemical-Structure. Detection in body fluids Current clinical laboratory assays for heparin rely on an indirect measurement of the effect of the drug. depending upon the manufacturer. wikipedia.
CHRISTUS Spohn Health System (http:/ / christusspohn.nlm. 2008. 2008. "The origin of the dispute over the discovery of heparin" (http:/ / jhmas. com/ sharedcontent/ dws/ news/ texassouthwest/ stories/ DN-bloodthinner_11tex. go. aspx?id=b8250e15-c437-48f3-8345-edc85a47565a). wikipedia. PMID 10734720 (http:/ / www. 2008.1093/jhmas/55.Heparin  Statement by Dr. 2008  " Officials Investigate Infants' Heparin OD at Texas Hospital (http:/ / abcnews. et al.com/Heparin-Conntact9608. 4d4aa44. doi. Edition1. 37). Biomedical Publications. pp. 728-729. 13 Further reading Marcum JA (January 2000). Anesth. Chief Medical Officer. Koster A. Journal of the History of Medicine and Allied Sciences 55 (1): 37–66. 91: 533-853. php?title=Heparin& action=edit  At a Glance Heparin Overdose at Hospital (http:/ / www. biz/ NewsReleases/ Article_Detail. A quick anti-Xa-activity-based whole blood coagulation assay for monitoring unfractionated heparin during cardiopulmonary bypass: a pilot investigation. ketv. org/ 10. State. Baselt. ncbi. 1093/ jhmas/ 55. Staff Investigated (http:/ / www. External links • History of heparin (http://www. Retrieved on July 24. html). July 11. Foster City. ART.  Hansen R. netreturns. July 10. 2000." ABC News.html) ." March 31. dallasnews. Kukucka M. Analg. 2010. 8th edition.37 (http:/ / dx.  R. doi: 10.healthheritageresearch. com/ news/ 23020944/ detail. 1.nih.  " Heparin Overdose Kills Toddler At Hospital.gov/pubmed/10734720).1. Dallas Morning News. html). Richard Davis. org/ cgi/ pmidlookup?view=long& pmid=10734720). CA." "KETV Omaha. 2008  http:/ / en. org/ w/ index. July 11. oxfordjournals. Disposition of Toxic Drugs and Chemicals in Man. com/ GMA/ Parenting/ story?id=5346509& page=1).
Brazzbatch. Unyoyega.php?title=File:IdoA-GlcNS(6S). CDN99. Isoxyl.png License: Public Domain Contributors: K. Edward.png Source: http://en. Drubroughton. Ksheka.wikipedia Image:Heparin-3D-structures. 232 anonymous edits Image Sources.wikipedia. Waveguide2. Archiee777.svg License: Public Domain Contributors: Louisajb (talk) 09:54.wikipedia.Article Sources and Contributors 14 Article Sources and Contributors Heparin Source: http://en. Licenses and Contributors file:Heparin-3D-vdW.php?title=File:GlcA-GlcNAc. Yannis koulouridis. Theda. Louisajb. Preschooler. MarcoTolo. Jezhotwells.php?title=File:GlcA-GlcNS.mosh. Sheep2000.php?title=File:Heparin_Sodium_sample.0/ . Koavf. Dreadstar. Thatguyflint.murphy at en. Rjwilmsi. Anypodetos. LHcheM.wikipedia. Belg4mit. Dgfernig. Chodges.).png License: Public domain Contributors: User:Ronhjones License Creative Commons Attribution-Share Alike 3.murphy at en. Watermelon mang.svg Source: http://en.wikipedia. Uanfala. Allens. Lab-oratory. Terrace4. Pwthomas99. Benjah-bmm27. Edgar181. AxelBoldt.wikipedia Image:GlcA-GlcNS. Buliancube.wikipedia Image:IdoA(2S)-GlcNS.png Source: http://en.tan.png License: Public Domain Contributors: K.wikipedia. Ohnoitsjamie. DMacks. Scottalter.wikipedia. Wavelength.svg License: Public Domain Contributors: Anomie File:X mark. Nono64. Richard Arthur Norton (1958.0 Unported //creativecommons. Zaphraud.svg Source: http://en.0 Contributors: LHcheM Image:GlcA-GlcNAc. Brighterorange.org/w/index. Andrew73. MuanN. Diberri. Chowbok. Arcadian. BjarteSorensen. Ka296307. Narayanese. Anthonyhcole. 16 December 2011 (UTC) Image:reduction fig.murphy at en.php?title=File:Heparin-3D-vdW. Blainster.org/w/index. Clemondo.wikipedia.wikipedia. Gaius Cornelius.php?oldid=549384868 Contributors: AFD2608.heart. Kozuch. Salvadorjo. Ian Pitchford.php?title=File:Reduction_fig. Jmknox.t2. Swaraj29. LuxNevada. Teaktl17.png Source: http://en. Boghog.org/w/index.png Source: http://en.png License: Public Domain Contributors: K. HamburgerRadio.png Source: http://en. Public Menace.org/w/index.png Source: http://en.org/w/index. Derek. Weetoddid. Chocobomastr. Phil Wardle. Tartarus21. Darrkwings.php?title=File:UA(2S)-GlcNS(6S). Sanfranman59. Borgx.org/w/index.png License: Public Domain Contributors: Benjah-bmm27. Julesd.wikipedia Image:IdoA-GlcNS.php?title=File:Heparin-3D-structures. Jreferee. Ike9898.jpg License: Creative Commons Attribution-Sharealike 3.at.cashman.wikipedia. Fvasconcellos Image:Fondaparinux.org/w/index.php?title=File:Yes_check. ﺣﺴﻦ ﻋﻠﻲ ﺍﻟﺒﻂ.php?title=File:IdoA-GlcNS. Ground Zero. Capybara.wikipedia. Giftlite.org/w/index. Pelirojopajaro.png License: Public Domain Contributors: K. Blahdenoma.php?title=File:Fondaparinux. Mmoneypenny.wikipedia. Darklilac. Silje. Osm agha. Kosebamse. Obli. Fuzheado. Neelix.png License: Public Domain Contributors: Benjah-bmm27. Bender235. GregorB. Coralmizu. DrAlvi. Dcirovic. Geekish. Admnt. K. Neparis. Biosthmors. Niels Olson. Ebliss1. Gxcf1.png Source: http://en. Ccady. Brinerustle. Vivaldi.png Source: http://en. Fvasconcellos File:Yes check. Rmky87. Casforty.org/w/index. Beetstra. Chepry. Brianski. Tide rolls. Atif. Alan Liefting. Eug. Ashton1983. Sciurinæ.php?title=File:X_mark. Giraffedata. All Is One.png Source: http://en. Chris the speller. Paiamshadi.murphy at en. Rich Farmbrough. Rbaselt. Emory25. HazyM. Naerii.wikipedia.org/w/index. Mmalik.svg Source: http://en. Redpanda66.org/w/index. Chzz.wikipedia. Gene Nygaard.jpg Source: http://en. Snek01.org/licenses/by-sa/3.png License: Public Domain Contributors: K. Greg WS.png License: Public Domain Contributors: K. Bdub79. Someone else. Antandrus. Mrdeath5493. The Banner.svg License: Public Domain Contributors: User:Gmaxwell File:Heparin Sodium sample. Hex ten. Appraiser. Bcericksen. Benbest. GSMR.org/w/index. Miguel Andrade. Dextar2893. Bignoter. WolfmanSF. Eric119. WLU. Strom.org/w/index.php?title=File:IdoA(2S)-GlcNS. Kpjas. Shoy. Jfdwolff.murphy at en. Drphilharmonic. Wrichik.wikipedia Image:IdoA-GlcNS(6S). Ivan09193. Cburnett.murphy at en.svg License: Public Domain Contributors: NEUROtiker Image:UA(2S)-GlcNS(6S). Alex. SandyGeorgia.php?title=File:IdoA(2S)-GlcNS(6S). Cacycle.murphy. Chem-awb.wikipedia Image:IdoA(2S)-GlcNS(6S). Axl.org/w/index.wikipedia. TJRC. Peak. Postrach. TimVickers. Editore99. The JPS. Tristanb. Raine8m. DKqwerty. Gak.wikipedia.org/w/index.svg Source: http://en. Tomas e. UncleDouggie.
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