ContaminantDB: Heparin

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Targets (16)XML

Record Information

Version

1.0

Creation Date

2009-07-05 03:16:06 UTC

Update Date

2016-11-09 01:08:40 UTC

Accession Number

CHEM002092

Identification

Common Name

Heparin

Class

Small Molecule

Description

Heparin is a highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. Unfractionated heparin (UH) is a heterogenous preparation of anionic, sulfated glycosaminoglycan polymers with weights ranging from 3000 to 30,000 Da. It is a naturally occurring anticoagulant released from mast cells. It binds reversibly to antithrombin III (ATIII) and greatly accelerates the rate at which ATIII inactivates coagulation enzymes thrombin (factor IIa) and factor Xa. UH is different from low molecular weight heparin (LMWH) in the following ways: the average molecular weight of LMWH is about 4.5 kDa whereas it is 15 kDa for UH; UH requires continuous infusions; activated partial prothrombin time (aPTT) monitoring is required when using UH; and UH has a higher risk of bleeding and higher risk of osteoporosis in long term use. Unfractionated heparin is more specific than LMWH for thrombin. Furthermore, the effects of UH can typically be reversed by using protamine sulfate.

Contaminant Sources

FooDB Chemicals
STOFF IDENT Compounds
T3DB toxins

Contaminant Type

Animal Toxin
Anticoagulant
Drug
Ester
Fibrinolytic Agent
Food Toxin
Heparin
Metabolite
Natural Compound
Organic Compound

Chemical Structure

MOL SDF 3D-SDF PDB SMILES InChI View 3D Structure

Synonyms

Value	Source
alpha-Heparin	HMDB
Clivarine	HMDB
Heparin sodium	HMDB
Arteven	HMDB
Bemiparin	HMDB
Certoparin	HMDB
Clexane	HMDB
Dalteparin	HMDB
Enoxaparin	HMDB
Eparina	HMDB
Fraxiparin	HMDB
Heparin sulfate	HMDB
Heparin sulphate	HMDB
Heparinate	HMDB
Heparinic acid	HMDB
Heparinsodiumsalt	HMDB
Thromboliquine	HMDB

Chemical Formula

C₂₆H₄₁NO₃₄S₄

Average Molecular Mass

1039.850 g/mol

Monoisotopic Mass

1039.039 g/mol

CAS Registry Number

9005-49-6

IUPAC Name

Not Available

Traditional Name

Not Available

SMILES

CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@@H]2[C@@H](O)O[C@H](O[C@H]3[C@H](O)[C@@H](OS(O)(=O)=O)C(O)O[C@H]3C(O)=O)[C@H](OS(O)(=O)=O)[C@H]2CS(O)(=O)=O)O[C@@H]1C(O)=O

InChI Identifier

InChI=1S/C26H41NO34S4/c1-4(28)27-7-9(30)8(29)6(2-52-63(43,44)45)53-24(7)56-15-10(31)11(32)25(58-19(15)21(36)37)55-13-5(3-62(40,41)42)14(60-64(46,47)48)26(59-22(13)38)57-16-12(33)17(61-65(49,50)51)23(39)54-18(16)20(34)35/h5-19,22-26,29-33,38-39H,2-3H2,1H3,(H,27,28)(H,34,35)(H,36,37)(H,40,41,42)(H,43,44,45)(H,46,47,48)(H,49,50,51)/t5-,6+,7+,8+,9+,10+,11+,12-,13-,14+,15-,16-,17+,18+,19-,22-,23?,24+,25+,26-/m0/s1

InChI Key

ZFGMDIBRIDKWMY-PASTXAENSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as disaccharide sulfates. These are disaccharides carrying one or more sulfate group on a sugar unit.

Kingdom

Organic compounds

Super Class

Organic oxygen compounds

Class

Organooxygen compounds

Sub Class

Carbohydrates and carbohydrate conjugates

Direct Parent

Disaccharide sulfates

Alternative Parents

Substituents

Disaccharide sulfate
1-o-glucuronide
O-glucuronide
Glucuronic acid or derivatives
Glycosyl compound
O-glycosyl compound
Beta-hydroxy acid
Hydroxy acid
Sulfuric acid monoamide
Oxane
Pyran
Sulfuric acid monoester
Sulfate-ester
Sulfuric acid ester
Alkyl sulfate
Organic sulfuric acid or derivatives
Hemiacetal
Secondary alcohol
Carboxylic acid
Organoheterocyclic compound
Oxacycle
Carboxylic acid derivative
Monocarboxylic acid or derivatives
Acetal
Organopnictogen compound
Organonitrogen compound
Organic nitrogen compound
Organic oxide
Carbonyl group
Hydrocarbon derivative
Alcohol
Aliphatic heteromonocyclic compound

Molecular Framework

Aliphatic heteromonocyclic compounds

External Descriptors

Not Available

Biological Properties

Status

Detected and Not Quantified

Origin

Endogenous

Cellular Locations

Cytoplasm
Extracellular
Membrane

Biofluid Locations

Not Available

Tissue Locations

Adipose Tissue
Adrenal Cortex
Adrenal Gland
Bladder
Epidermis
Fibroblasts
Intestine
Kidney
Liver
Lung
Mast Cell
Muscle
Nerve Cells
Neuron
Pancreas
Placenta
Platelet
Prostate
Skeletal Muscle
Spleen
Stratum Corneum
Testes
Thyroid Gland

Pathways

Not Available

Applications

anticoagulant

Biological Roles

Not Available

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	Not Available
Boiling Point	Not Available
Solubility	Soluble

Predicted Properties

Property	Value	Source
Water Solubility	6.57 g/L	ALOGPS
logP	-2.4	ALOGPS
logS	-2	ALOGPS
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	View
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-002b-0345970000-312d52dd4db42cd5c891	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0597-0197730000-6632a535e1b1532284b8	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0a4u-1892000000-280004d4d5dee6884f95	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-00di-0223910000-07995d24a76c0396a7b6	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-014v-5478690000-6170b2b390a60a9d9f92	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-002k-9343000000-bb02a79ec256fcfac6d9	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-002b-0000090000-1802fdd4e84da9aeb735	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-000t-8040940000-fdd6d51810092578d8f1	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0059-4190000000-1ef31839f6be16941adb	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0006-0000090000-50c066d3b3dc031eee00	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0002-9320350000-b67f53cd25d0a531b7f7	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-052b-9141300000-4839c7b06f4cddd9e646	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
2D NMR	[1H,13C] 2D NMR Spectrum	Not Available	Spectrum

Toxicity Profile

Route of Exposure

Intravenous, Irrigation, Subcutaneous, Intraperitoneal injection Heparin must be given parenterally as it is not absorbed through the gastrointestinal mucosa. It is usually given by iv infusion or deep sc injection. The onset of action is immediate after iv injection but can be delayed 20 to 60 minutes following sc injection. Plasma heparin concentrations may be increased and activated partial thromboplastin times (aPTTs) may be more prolonged in geriatric adults (older than 60 years of age) compared with younger adults.

Mechanism of Toxicity

Heparin-induced thrombocytopenia (HIT) is caused by the formation of abnormal antibodies that activate platelets. Heparin occurs naturally in the human body, but the development of HIT antibodies suggests heparin sulfate may act as a hapten, and thus be targeted by the immune system. In HIT, the immune system forms antibodies against heparin when it is bound to a protein called platelet factor 4 (PF4). These antibodies are usually of the IgG class and their development usually takes about five days. However, those who have been exposed to heparin in the last few months may still have circulating IgG, as IgG-type antibodies generally continue to be produced even when their precipitant has been removed. This is similar to immunity against certain microorganisms, with the difference that the HIT antibody does not persist more than three months. HIT antibodies have been found in individuals with thrombocytopenia and thrombosis who had no prior exposure to heparin sulfate, but the majority are found in people who are receiving heparin. The IgG antibodies form a complex with heparin and PF4 in the bloodstream. The tail of the antibody then binds to the FcγIIa receptor, a protein on the surface of the platelet. This results in platelet activation and the formation of platelet microparticles, which initiate the formation of blood clots; the platelet count falls as a result, leading to thrombocytopenia. (Wikipedia) The cause of the serum aminotransferase elevations during heparin therapy is not known, but it is likely due to a direct hepatotoxic effect on the liver (28). Heparin-induced hyperkalemia is the result of heparin-induced aldosterone suppression (Wikipedia). The most important, but probably not the only mechanism of aldosterone inhibition appears to involve reduction in both the number and affinity of the angiotensin-II receptors in the zona glomerulosa (25). Alopecia connected to chronic heparin use may be due to the antimitotic effect of heparin on the epithelial cells (26). Heparin causes bone loss by decreasing bone formation. The few studies of the mechanism of bone loss have revealed decreased bone formation, increasing bone resorption, or both (29).

Metabolism

Liver and the reticulo-endothelial system are the sites of biotransformation. The metabolic fate of heparin is not well understood. Route of Elimination: The drug appears to be removed mainly by the reticuloendothelial system. A small fraction of unchanged heparin also appears to be excreted in urine. Heparin cannot be eliminated by hemodialysis. Half Life: 1.5 hours. The plasma half-life of heparin increases from about 60 minutes with a 100 unit/kg dose to about 150 minutes with a 400 unit/kg dose.

Toxicity Values

Not Available

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

Unfractionated heparin is indicated for prophylaxis and treatment of venous thrombosis and its extension, prevention of post-operative deep venous thrombosis and pulmonary embolism and prevention of clotting in arterial and cardiac surgery. In cardiology, it is used to prevent embolisms in patients with atrial fibrillation and as an adjunct antithrombin therapy in patients with unstable angina and/or non-Q wave myocardial infarctions (i.e. non-ST elevated acute coronary artery syndrome) who are on platelet glycoprotein (IIb/IIIa) receptor inhibitors. Additionally, it is used to prevent clotting during dialysis and surgical procedures, maintain the patency of intravenous injection devices and prevent in vitro coagulation of blood transfusions and in blood samples drawn for laboratory values.

Minimum Risk Level

Not Available

Health 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. (Wikipedia)

Symptoms

Heparin sodium - Mouse, median lethal dose greater than 5000 mg/kg. Another side effect is heparin induced thrombocytopenia (HIT syndrome). HIT is caused by an immunological reaction that makes platelets form clots within the blood vessels, thereby using up coagulation factors

Treatment

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. (Wikipedia)

Concentrations

Not Available

External Links

DrugBank ID

Not Available

HMDB ID

HMDB0001394

FooDB ID

FDB022599

Phenol Explorer ID

Not Available

KNApSAcK ID

Not Available

BiGG ID

Not Available

BioCyc ID

Not Available

METLIN ID

Not Available

PDB ID

Not Available

Wikipedia Link

Chemspider ID

ChEBI ID

PubChem Compound ID

Kegg Compound ID

YMDB ID

Not Available

ECMDB ID

Not Available

References

Synthesis Reference

Fernando Fussi, Gianfranco Fedeli, “Oligo-heteropolysaccharides having a heparin-like activity method for their preparation and pharmaceutical compositions based thereon.” U.S. Patent US4757057, issued June, 1952.

MSDS

Link

General References

1. Kuberan, Balagurunathan; Beeler, David L.; Lawrence, Roger; Lech, Miroslaw; Rosenberg, Robert D. Rapid Two-Step Synthesis of Mitrin from Heparosan: A Replacement for Heparin. Journal of the American Chemical Society (2003), 125(41), 12424-12425.

2. Brunnee T, Reddigari SR, Shibayama Y, Kaplan AP, Silverberg M: Mast cell derived heparin activates the contact system: a link to kinin generation in allergic reactions. Clin Exp Allergy. 1997 Jun;27(6):653-63.

3. Betz G, Nowbakht P, Imboden R, Imanidis G: Heparin penetration into and permeation through human skin from aqueous and liposomal formulations in vitro. Int J Pharm. 2001 Oct 9;228(1-2):147-59.

4. Sun Y, Chai TC: Effects of dimethyl sulphoxide and heparin on stretch-activated ATP release by bladder urothelial cells from patients with interstitial cystitis. BJU Int. 2002 Sep;90(4):381-5.

5. Kandrotas RJ: Heparin pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 1992 May;22(5):359-74.

6. Delhumeau A, Moreau X, Chapotte C, Houi N, Bigorgne JC: Heparin-associated thrombocytopenia syndrome: an underestimated etiology of adrenal hemorrhage. Intensive Care Med. 1993;19(8):475-7.

7. Lortat-Jacob H, Brisson C, Guerret S, Morel G: Non-receptor-mediated tissue localization of human interferon-gamma: role of heparan sulfate/heparin-like molecules. Cytokine. 1996 Jul;8(7):557-66.

8. Harig F, Meier C, Hakami L, Strasser R, Bretzger J, Munch F, Vestweber-Wilmes E, Singer H, Weyand M, Cesnjevar R: Does the additional use of heparin-coated extracorporeal circuits (ECC) optimize the effect of modified ultrafiltration (MUF) in pediatric perfusion? Thorac Cardiovasc Surg. 2006 Apr;54(3):168-72.

9. Tonda R, Galan AM, Pino M, Hernandez MR, Ayats C, Pomar JL, Ordinas A, Escolar G: In vitro evaluation of platelet reactivity toward annuloplasty devices treated with heparin coating: studies under flow conditions. J Biomed Mater Res A. 2005 Oct 1;75(1):192-8.