Heparin (T3D2566)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (14)XML
Targets (14)
Record Information
Version2.0
Creation Date2009-07-05 03:16:06 UTC
Update Date2014-12-24 20:25:42 UTC
Accession NumberT3D2566
Identification
Common NameHeparin
ClassSmall Molecule
DescriptionHeparin 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.
Compound Type
  • Animal Toxin
  • Anticoagulant
  • Drug
  • Ester
  • Fibrinolytic Agent
  • Food Toxin
  • Heparin
  • Metabolite
  • Natural Compound
  • Organic Compound
Chemical Structure
Thumb
MOLSDF3D-SDFPDBSMILESInChI View 3D Structure
Synonyms
Synonym
alpha-Heparin
Arteven
Bemiparin
Calcilean
Calciparine
Certoparin
Clexane
Clivarine
Dalteparin
Enoxaparin
Eparina
Fraxiparin
Hep-lock
Hepalean
Heparin LEO
Heparin Lock Flush
Heparin sodium
Heparin sulfate
Heparin sulphate
Heparinate
Heparinic acid
Heparinsodiumsalt
Liquaemin
Liquemin
Multiparin
Novoheparin
Panheprin
Thromboliquine
Chemical FormulaC26H41NO34S4
Average Molecular Mass1039.850 g/mol
Monoisotopic Mass1039.039 g/mol
CAS Registry Number9005-49-6
IUPAC NameNot Available
Traditional NameNot Available
SMILES[H][C@]1(O)O[C@]([H])(O[C@@]2([H])[C@]([H])(O)[C@@]([H])(OS(O)(=O)=O)C([H])(O)O[C@@]2([H])C(O)=O)[C@]([H])(OS(O)(=O)=O)[C@@]([H])(CS(O)(=O)=O)[C@]1([H])O[C@]1([H])O[C@]([H])(C(O)=O)[C@@]([H])(O[C@@]2([H])O[C@]([H])(COS(O)(=O)=O)[C@@]([H])(O)[C@]([H])(O)[C@@]2([H])N=C(C)O)[C@]([H])(O)[C@@]1([H])O
InChI IdentifierInChI=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 KeyInChIKey=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.
KingdomOrganic compounds
Super ClassOrganic oxygen compounds
ClassOrganooxygen compounds
Sub ClassCarbohydrates and carbohydrate conjugates
Direct ParentDisaccharide 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 FrameworkAliphatic heteromonocyclic compounds
External DescriptorsNot Available
Biological Properties
StatusDetected and Not Quantified
OriginEndogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot 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
PathwaysNot Available
Applications
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
SolubilitySoluble
LogP-13.2
Predicted Properties
PropertyValueSource
Water Solubility6.57 g/LALOGPS
logP-2.4ALOGPS
logS-2ALOGPS
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-002b-0345970000-312d52dd4db42cd5c8912019-02-23View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0597-0197730000-6632a535e1b1532284b82019-02-23View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0a4u-1892000000-280004d4d5dee6884f952019-02-23View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-00di-0223910000-07995d24a76c0396a7b62019-02-23View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-014v-5478690000-6170b2b390a60a9d9f922019-02-23View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-002k-9343000000-bb02a79ec256fcfac6d92019-02-23View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-002b-0000090000-1802fdd4e84da9aeb7352021-09-22View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-000t-8040940000-fdd6d51810092578d8f12021-09-22View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0059-4190000000-1ef31839f6be16941adb2021-09-22View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0006-0000090000-50c066d3b3dc031eee002021-09-23View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0002-9320350000-b67f53cd25d0a531b7f72021-09-23View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-052b-9141300000-4839c7b06f4cddd9e6462021-09-23View Spectrum
1D NMR1H NMR Spectrum (1D, 600 MHz, H2O, experimental)Not Available2018-05-25View Spectrum
1D NMR1H NMR Spectrum (1D, 100 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 100 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 1000 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 1000 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 200 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 200 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 300 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 300 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 400 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 400 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 500 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 600 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 600 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 700 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 700 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 800 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 800 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 900 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 900 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
2D NMR[1H, 13C]-HSQC NMR Spectrum (2D, 600 MHz, H2O, experimental)Not Available2018-05-25View Spectrum
Toxicity Profile
Route of ExposureIntravenous, 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 ToxicityHeparin-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 (32). 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 (33).
MetabolismLiver 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 ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesUnfractionated 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 LevelNot Available
Health EffectsA 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)
SymptomsHeparin 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
TreatmentProtamine 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)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01109
HMDB IDHMDB01394
PubChem Compound ID46507594
ChEMBL IDCHEMBL1909300
ChemSpider ID751
KEGG IDC00374
UniProt IDNot Available
OMIM ID107300142360142640176860
ChEBI ID28304
BioCyc IDHEPARIN
CTD IDD006493
Stitch IDHeparin
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkHeparin
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.

MSDSLink
General References
  1. Linhardt RJ, Gunay NS: Production and chemical processing of low molecular weight heparins. Semin Thromb Hemost. 1999;25 Suppl 3:5-16. [10549711 ]
  2. Ferro DR, Provasoli A, Ragazzi M, Casu B, Torri G, Bossennec V, Perly B, Sinay P, Petitou M, Choay J: Conformer populations of L-iduronic acid residues in glycosaminoglycan sequences. Carbohydr Res. 1990 Jan 15;195(2):157-67. [2331699 ]
  3. Mulloy B, Forster MJ, Jones C, Davies DB: N.m.r. and molecular-modelling studies of the solution conformation of heparin. Biochem J. 1993 Aug 1;293 ( Pt 3):849-58. [8352752 ]
  4. Hirsh J, Raschke R: Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep;126(3 Suppl):188S-203S. [15383472 ]
  5. Petitou M, Herault JP, Bernat A, Driguez PA, Duchaussoy P, Lormeau JC, Herbert JM: Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature. 1999 Apr 1;398(6726):417-22. [10201371 ]
  6. Spruill WJ, Wade WE, Huckaby WG, Leslie RB: Achievement of anticoagulation by using a weight-based heparin dosing protocol for obese and nonobese patients. Am J Health Syst Pharm. 2001 Nov 15;58(22):2143-6. [11760916 ]
  7. McDonald MM, Jacobson LJ, Hay WW Jr, Hathaway WE: Heparin clearance in the newborn. Pediatr Res. 1981 Jul;15(7):1015-8. [7254945 ]
  8. 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. [11576777 ]
  9. 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. [12175393 ]
  10. Kandrotas RJ: Heparin pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 1992 May;22(5):359-74. [1505142 ]
  11. 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. [8294632 ]
  12. 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. [8891437 ]
  13. 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. [16639677 ]
  14. 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. [16044416 ]
  15. Haram K, Bjorge L, Sandset PM: Successful preconceptional prophylactic treatment with combined acetyl salicylic acid and low-molecular heparin (Fragmin) in a case of antiphospholipid-antibody syndrome with prior life-threatening hemolysis, elevated liver enzymes and low-platelet syndrome: a case report. Acta Obstet Gynecol Scand. 2005 Dec;84(12):1213-4. [16305714 ]
  16. Harding SA, Din JN, Sarma J, Josephs DH, Fox KA, Newby DE: Promotion of proinflammatory interactions between platelets and monocytes by unfractionated heparin. Heart. 2006 Nov;92(11):1635-8. Epub 2006 May 18. [16709700 ]
  17. Christensen K, Larsson R, Emanuelsson H, Elgue G, Larsson A: Effects on blood compatibility in vitro by combining a direct P2Y12 receptor inhibitor and heparin coating of stents. Platelets. 2006 Aug;17(5):318-27. [16928604 ]
  18. Applebaum DM, Goldberg AP, Pykalisto OJ, Brunzell JD, Hazzard WR: Effect of estrogen on post-heparin lipolytic activity. Selective decline in hepatic triglyceride lipase. J Clin Invest. 1977 Apr;59(4):601-8. [845252 ]
  19. Yeh RW, Everett BM, Foo SY, Dorer DJ, Laposata M, Van Cott EM, Jang IK: Predictors for the development of elevated anti-heparin/platelet factor 4 antibody titers in patients undergoing cardiac catheterization. Am J Cardiol. 2006 Aug 1;98(3):419-21. Epub 2006 Jun 12. [16860036 ]
  20. Harel A, Fainaru M, Rubinstein M, Tal N, Schwartz M: Fish apolipoprotein-A-I has heparin binding activity: implication for nerve regeneration. J Neurochem. 1990 Oct;55(4):1237-43. [2118944 ]
  21. Bengtsson E, Aspberg A, Heinegard D, Sommarin Y, Spillmann D: The amino-terminal part of PRELP binds to heparin and heparan sulfate. J Biol Chem. 2000 Dec 29;275(52):40695-702. [11007795 ]
  22. 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. [9208186 ]
  23. Weaver JC, Vanbever R, Vaughan TE, Prausnitz MR: Heparin alters transdermal transport associated with electroporation. Biochem Biophys Res Commun. 1997 May 29;234(3):637-40. [9175766 ]
  24. Williams MS, Ng'alla LS: Heparin therapy leads to platelet activation and prolongation of PFA-100 closure time. J Cardiovasc Pharmacol Ther. 2005 Dec;10(4):273-80. [16382263 ]
  25. Oster JR, Singer I, Fishman LM: Heparin-induced aldosterone suppression and hyperkalemia. Am J Med. 1995 Jun;98(6):575-86. [7778574 ]
  26. Sarris E, Tsele E, Bagiatoudi G, Salpigidis K, Stavrianaki D, Kaklamanis L, Siakotos M: Diffuse alopecia in a hemodialysis patient caused by a low-molecular-weight heparin, tinzaparin. Am J Kidney Dis. 2003 May;41(5):E15. [12778433 ]
  27. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics. 1983; 72:356-8. [PubMed] [IDIS 175725]
  28. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull. 1982; 12:10-1. [PubMed]
  29. Anon. Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982; 31:290-1. [PubMed] [IDIS 150868]
  30. Abbott Laboratories. Heparin lock flush solution, USP 100 USP units/mL prescribing information. North Chicago, IL; 1998 Jul.
  31. Drugs.com [Link]
  32. LiverTox - Heparin [Link]
  33. UpToDate - Drugs that affect bone metabolism [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

Target Details
1. Prothrombin
General Function:
Thrombospondin receptor activity
Specific Function:
Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing.
Gene Name:
F2
Uniprot ID:
P00734
Molecular Weight:
70036.295 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Fuster V: [Oral antithrombins and the future of antithrombotic therapy]. Rev Esp Cardiol. 2004;57 Suppl 1:2-8. [15511384 ]
  3. Hansen PR: [Bivalirudin: a direct thrombin inhibitor in percutaneous coronary interventions]. Ugeskr Laeger. 2006 Sep 18;168(38):3207-9. [17026893 ]
  4. Grudzinski L, Quinan P, Kwok S, Pierratos A: Sodium citrate 4% locking solution for central venous dialysis catheters--an effective, more cost-efficient alternative to heparin. Nephrol Dial Transplant. 2007 Feb;22(2):471-6. Epub 2006 Oct 25. [17065193 ]
  5. Keller TT, van der Sluijs KF, de Kruif MD, Gerdes VE, Meijers JC, Florquin S, van der Poll T, van Gorp EC, Brandjes DP, Buller HR, Levi M: Effects on coagulation and fibrinolysis induced by influenza in mice with a reduced capacity to generate activated protein C and a deficiency in plasminogen activator inhibitor type 1. Circ Res. 2006 Nov 24;99(11):1261-9. Epub 2006 Oct 26. [17068293 ]
  6. Li N, He S, Blomback M, Hjemdahl P: Platelet activity, coagulation, and fibrinolysis during exercise in healthy males: effects of thrombin inhibition by argatroban and enoxaparin. Arterioscler Thromb Vasc Biol. 2007 Feb;27(2):407-13. Epub 2006 Nov 30. [17138937 ]
Target Details
2. Antithrombin-III
General Function:
Serine-type endopeptidase inhibitor activity
Specific Function:
Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade. AT-III inhibits thrombin, matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa. Its inhibitory activity is greatly enhanced in the presence of heparin.
Gene Name:
SERPINC1
Uniprot ID:
P01008
Molecular Weight:
52601.935 Da
References
  1. Lee S, Gibson CM: Enoxaparin in acute coronary syndromes. Expert Rev Cardiovasc Ther. 2007 May;5(3):387-99. [17489664 ]
  2. Mirow N, Zimmermann B, Maleszka A, Knobl H, Tenderich G, Koerfer R, Herberg FW: Plasma protein binding properties to immobilized heparin and heparin-albumin conjugate. Artif Organs. 2007 Jun;31(6):466-71. [17537059 ]
  3. Sun W, Bandmann H, Schrader T: A fluorescent polymeric heparin sensor. Chemistry. 2007;13(27):7701-7. [17600786 ]
  4. Pappalardo F, Franco A, Crescenzi G, De Simone F, Torracca L, Zangrillo A: Anticoagulation management in patients undergoing open heart surgery by activated clotting time and whole blood heparin concentration. Perfusion. 2006 Dec;21(5):285-90. [17201083 ]
  5. Kaiserman D, Whisstock JC, Bird PI: Mechanisms of serpin dysfunction in disease. Expert Rev Mol Med. 2006 Dec 11;8(31):1-19. [17156576 ]
Target Details
3. Coagulation factor X
General Function:
Serine-type endopeptidase activity
Specific Function:
Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.
Gene Name:
F10
Uniprot ID:
P00742
Molecular Weight:
54731.255 Da
References
  1. Graff J, Picard-Willems B, Harder S: Monitoring effects of direct FXa-inhibitors with a new one-step prothrombinase-induced clotting time (PiCT) assay: comparative in vitro investigation with heparin, enoxaparin, fondaparinux and DX 9065a. Int J Clin Pharmacol Ther. 2007 Apr;45(4):237-43. [17474542 ]
  2. Berges A, Laporte S, Epinat M, Zufferey P, Alamartine E, Tranchand B, Decousus H, Mismetti P: Anti-factor Xa activity of enoxaparin administered at prophylactic dosage to patients over 75 years old. Br J Clin Pharmacol. 2007 Oct;64(4):428-38. Epub 2007 May 17. [17509040 ]
  3. Paige JT, Gouda BP, Gaitor-Stampley V, Scalia PG, Klainer TE, Raum WJ, Martin LF: No correlation between anti-factor Xa levels, low-molecular-weight heparin, and bleeding after gastric bypass. Surg Obes Relat Dis. 2007 Jul-Aug;3(4):469-75. Epub 2007 Jun 12. [17567541 ]
  4. Ignjatovic V, Summerhayes R, Gan A, Than J, Chan A, Cochrane A, Bennett M, Horton S, Shann F, Lane G, Ross-Smith M, Monagle P: Monitoring Unfractionated Heparin (UFH) therapy: which Anti-Factor Xa assay is appropriate? Thromb Res. 2007;120(3):347-51. Epub 2006 Nov 21. [17118432 ]
  5. Patey SJ, Edwards EA, Yates EA, Turnbull JE: Heparin derivatives as inhibitors of BACE-1, the Alzheimer's beta-secretase, with reduced activity against factor Xa and other proteases. J Med Chem. 2006 Oct 5;49(20):6129-32. [17004727 ]
Target Details
4. Heparanase
General Function:
Syndecan binding
Specific Function:
Endoglycosidase that cleaves heparan sulfate proteoglycans (HSPGs) into heparan sulfate side chains and core proteoglycans. Participates in extracellular matrix (ECM) degradation and remodeling. Selectively cleaves the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo group. Can also cleave the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying a 2-O-sulfo group, but not linkages between a glucuronic acid unit and a 2-O-sulfated iduronic acid moiety. It is essentially inactive at neutral pH but becomes active under acidic conditions such as during tumor invasion and in inflammatory processes. Facilitates cell migration associated with metastasis, wound healing and inflammation. Enhances shedding of syndecans, and increases endothelial invasion and angiogenesis in myelomas. Acts as procoagulant by increasing the generation of activation factor X in the presence of tissue factor and activation factor VII. Increases cell adhesion to the extacellular matrix (ECM), independent of its enzymatic activity. Induces AKT1/PKB phosphorylation via lipid rafts increasing cell mobility and invasion. Heparin increases this AKT1/PKB activation. Regulates osteogenesis. Enhances angiogenesis through up-regulation of SRC-mediated activation of VEGF. Implicated in hair follicle inner root sheath differentiation and hair homeostasis.
Gene Name:
HPSE
Uniprot ID:
Q9Y251
Molecular Weight:
61148.17 Da
References
  1. Zhao H, Liu H, Chen Y, Xin X, Li J, Hou Y, Zhang Z, Zhang X, Xie C, Geng M, Ding J: Oligomannurarate sulfate, a novel heparanase inhibitor simultaneously targeting basic fibroblast growth factor, combats tumor angiogenesis and metastasis. Cancer Res. 2006 Sep 1;66(17):8779-87. [16951194 ]
  2. Waterman M, Ben-Izhak O, Eliakim R, Groisman G, Vlodavsky I, Ilan N: Heparanase upregulation by colonic epithelium in inflammatory bowel disease. Mod Pathol. 2007 Jan;20(1):8-14. Epub 2006 Oct 13. [17041566 ]
  3. Hostettler N, Naggi A, Torri G, Ishai-Michaeli R, Casu B, Vlodavsky I, Borsig L: P-selectin- and heparanase-dependent antimetastatic activity of non-anticoagulant heparins. FASEB J. 2007 Nov;21(13):3562-72. Epub 2007 Jun 8. [17557930 ]
  4. Han J, Woytowich AE, Mandal AK, Hiebert LM: Heparanase upregulation in high glucose-treated endothelial cells is prevented by insulin and heparin. Exp Biol Med (Maywood). 2007 Jul;232(7):927-34. [17609509 ]
  5. Bisio A, Mantegazza A, Urso E, Naggi A, Torri G, Viskov C, Casu B: High-performance liquid chromatographic/mass spectrometric studies on the susceptibility of heparin species to cleavage by heparanase. Semin Thromb Hemost. 2007 Jul;33(5):488-95. [17629845 ]
Target Details
5. P-selectin
General Function:
Sialic acid binding
Specific Function:
Ca(2+)-dependent receptor for myeloid cells that binds to carbohydrates on neutrophils and monocytes. Mediates the interaction of activated endothelial cells or platelets with leukocytes. The ligand recognized is sialyl-Lewis X. Mediates rapid rolling of leukocyte rolling over vascular surfaces during the initial steps in inflammation through interaction with PSGL1.
Gene Name:
SELP
Uniprot ID:
P16109
Molecular Weight:
90833.105 Da
References
  1. Monzavi-Karbassi B, Stanley JS, Hennings L, Jousheghany F, Artaud C, Shaaf S, Kieber-Emmons T: Chondroitin sulfate glycosaminoglycans as major P-selectin ligands on metastatic breast cancer cell lines. Int J Cancer. 2007 Mar 15;120(6):1179-91. [17154173 ]
  2. Simonis D, Fritzsche J, Alban S, Bendas G: Kinetic analysis of heparin and glucan sulfates binding to P-selectin and its impact on the general understanding of selectin inhibition. Biochemistry. 2007 May 22;46(20):6156-64. Epub 2007 Apr 26. [17458940 ]
  3. Maugeri N, Di Fabio G, Barbanti M, de Gaetano G, Donati MB, Cerletti C: Parnaparin, a low-molecular-weight heparin, prevents P-selectin-dependent formation of platelet-leukocyte aggregates in human whole blood. Thromb Haemost. 2007 Jun;97(6):965-73. [17549299 ]
  4. Simonis D, Christ K, Alban S, Bendas G: Affinity and kinetics of different heparins binding to P- and L-selectin. Semin Thromb Hemost. 2007 Jul;33(5):534-9. [17629851 ]
  5. Asberg AE, Videm V: Inhibition of platelet receptors involved in neutrophil-platelet interaction in model cardiopulmonary bypass. Artif Organs. 2007 Aug;31(8):617-26. [17651117 ]
Target Details
6. Coagulation factor IX
General Function:
Serine-type endopeptidase activity
Specific Function:
Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa.
Gene Name:
F9
Uniprot ID:
P00740
Molecular Weight:
51778.11 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
Target Details
7. Fibroblast growth factor 19
General Function:
Fibroblast growth factor receptor binding
Specific Function:
Involved in the suppression of bile acid biosynthesis through down-regulation of CYP7A1 expression, following positive regulation of the JNK and ERK1/2 cascades. Stimulates glucose uptake in adipocytes. Activity requires the presence of KLB and FGFR4.
Gene Name:
FGF19
Uniprot ID:
O95750
Molecular Weight:
24002.345 Da
References
  1. Harmer NJ, Pellegrini L, Chirgadze D, Fernandez-Recio J, Blundell TL: The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity. Biochemistry. 2004 Jan 27;43(3):629-40. [14730967 ]
Target Details
8. Fibroblast growth factor 2
General Function:
Ligand-dependent nuclear receptor transcription coactivator activity
Specific Function:
Plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and cell migration. Functions as potent mitogen in vitro.
Gene Name:
FGF2
Uniprot ID:
P09038
Molecular Weight:
30769.715 Da
References
  1. Rose K, Kriha D, Pallast S, Junker V, Klumpp S, Krieglstein J: Basic fibroblast growth factor: lysine 134 is essential for its neuroprotective activity. Neurochem Int. 2007 Jul;51(1):25-31. Epub 2007 Apr 19. [17524524 ]
Target Details
9. Fibroblast growth factor 4
General Function:
Heparin binding
Specific Function:
Plays an important role in the regulation of embryonic development, cell proliferation, and cell differentiation. Required for normal limb and cardiac valve development during embryogenesis.
Gene Name:
FGF4
Uniprot ID:
P08620
Molecular Weight:
22047.355 Da
References
  1. Bellosta P, Iwahori A, Plotnikov AN, Eliseenkova AV, Basilico C, Mohammadi M: Identification of receptor and heparin binding sites in fibroblast growth factor 4 by structure-based mutagenesis. Mol Cell Biol. 2001 Sep;21(17):5946-57. [11486033 ]
Target Details
10. Fibroblast growth factor receptor 1
General Function:
Protein tyrosine kinase activity
Specific Function:
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation.
Gene Name:
FGFR1
Uniprot ID:
P11362
Molecular Weight:
91866.935 Da
References
  1. Ibrahimi OA, Zhang F, Hrstka SC, Mohammadi M, Linhardt RJ: Kinetic model for FGF, FGFR, and proteoglycan signal transduction complex assembly. Biochemistry. 2004 Apr 27;43(16):4724-30. [15096041 ]
Target Details
11. Fibroblast growth factor receptor 2
General Function:
Protein tyrosine kinase activity
Specific Function:
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosis, and in the regulation of embryonic development. Required for normal embryonic patterning, trophoblast function, limb bud development, lung morphogenesis, osteogenesis and skin development. Plays an essential role in the regulation of osteoblast differentiation, proliferation and apoptosis, and is required for normal skeleton development. Promotes cell proliferation in keratinocytes and immature osteoblasts, but promotes apoptosis in differentiated osteoblasts. Phosphorylates PLCG1, FRS2 and PAK4. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. FGFR2 signaling is down-regulated by ubiquitination, internalization and degradation. Mutations that lead to constitutive kinase activation or impair normal FGFR2 maturation, internalization and degradation lead to aberrant signaling. Over-expressed FGFR2 promotes activation of STAT1.
Gene Name:
FGFR2
Uniprot ID:
P21802
Molecular Weight:
92024.29 Da
References
  1. Robinson CJ, Harmer NJ, Goodger SJ, Blundell TL, Gallagher JT: Cooperative dimerization of fibroblast growth factor 1 (FGF1) upon a single heparin saccharide may drive the formation of 2:2:1 FGF1.FGFR2c.heparin ternary complexes. J Biol Chem. 2005 Dec 23;280(51):42274-82. Epub 2005 Oct 11. [16219767 ]
Target Details
12. Fibroblast growth factor receptor 4
General Function:
Protein tyrosine kinase activity
Specific Function:
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling.
Gene Name:
FGFR4
Uniprot ID:
P22455
Molecular Weight:
87953.535 Da
References
  1. Loo BM, Kreuger J, Jalkanen M, Lindahl U, Salmivirta M: Binding of heparin/heparan sulfate to fibroblast growth factor receptor 4. J Biol Chem. 2001 May 18;276(20):16868-76. Epub 2001 Feb 21. [11278860 ]
Target Details
13. Platelet factor 4
General Function:
Heparin binding
Specific Function:
Released during platelet aggregation. Neutralizes the anticoagulant effect of heparin because it binds more strongly to heparin than to the chondroitin-4-sulfate chains of the carrier molecule. Chemotactic for neutrophils and monocytes. Inhibits endothelial cell proliferation, the short form is a more potent inhibitor than the longer form.
Gene Name:
PF4
Uniprot ID:
P02776
Molecular Weight:
10844.78 Da
References
  1. Visentin GP, Ford SE, Scott JP, Aster RH: Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. J Clin Invest. 1994 Jan;93(1):81-8. [8282825 ]
Target Details
14. Vascular endothelial growth factor A
General Function:
Vascular endothelial growth factor receptor binding
Specific Function:
Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan sulfate and heparin. NRP1/Neuropilin-1 binds isoforms VEGF-165 and VEGF-145. Isoform VEGF165B binds to KDR but does not activate downstream signaling pathways, does not activate angiogenesis and inhibits tumor growth.
Gene Name:
VEGFA
Uniprot ID:
P15692
Molecular Weight:
27042.205 Da
References
  1. Lee TY, Folkman J, Javaherian K: HSPG-binding peptide corresponding to the exon 6a-encoded domain of VEGF inhibits tumor growth by blocking angiogenesis in murine model. PLoS One. 2010 Apr 1;5(4):e9945. doi: 10.1371/journal.pone.0009945. [20376344 ]