Heparin: Difference between revisions
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{{Short description|Anticoagulant}} |
{{Short description|Anticoagulant}} |
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{{Use dmy dates|date=March 2024}} |
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{{cs1 config |name-list-style=vanc |display-authors=6}} |
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{{Drugbox |
{{Drugbox |
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| Verifiedfields = changed |
| Verifiedfields = changed |
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| verifiedrevid = 407837023 |
| verifiedrevid = 407837023 |
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| image = Heparin General Structure V.1.svg |
| image = Heparin General Structure V.1.svg |
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<!-- Clinical data --> |
<!-- Clinical data --> |
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| pronounce = {{IPAc-en|ˈ|h|ɛ|p|ər|ɪ|n}} {{respell|HEP|ər|in}} |
| pronounce = {{IPAc-en|ˈ|h|ɛ|p|ər|ɪ|n}} {{respell|HEP|ər|in}} |
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| tradename = |
| tradename = |
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| Drugs.com = {{drugs.com|monograph|heparin-sodium}} |
| Drugs.com = {{drugs.com|monograph|heparin-sodium}} |
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| MedlinePlus = |
| MedlinePlus = |
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| licence_EU = <!-- EMA uses INN (or special INN_EMA) --> |
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| DailyMedID = Heparin |
| DailyMedID = Heparin |
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| pregnancy_AU = |
| pregnancy_AU = C |
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| pregnancy_AU_comment = <ref name="Heparin Interpharma APMDS">{{cite web | title=Heparin Interpharma APMDS | website=Therapeutic Goods Administration (TGA) | date=7 December 2023 | url=https://www.tga.gov.au/resources/auspmd/heparin-interpharma | access-date=7 March 2024}}</ref> |
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| pregnancy_AU_comment = |
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| pregnancy_category= |
| pregnancy_category= |
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| routes_of_administration = [[Intravenous therapy]], [[subcutaneous injection]] |
| routes_of_administration = [[Intravenous therapy]], [[subcutaneous injection]] |
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| class = |
| class = |
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| ATC_prefix = B01 |
| ATC_prefix = B01 |
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| ATC_suffix = AB01 |
| ATC_suffix = AB01 |
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<!-- Legal status --> |
<!-- Legal status --> |
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| legal_AU = |
| legal_AU = S4 |
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| legal_AU_comment = |
| legal_AU_comment = <ref name="Heparin Interpharma APMDS" /> |
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| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> |
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> |
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| legal_BR_comment = |
| legal_BR_comment = |
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| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --> |
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_CA_comment = |
| legal_CA_comment = |
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| legal_DE = <!-- Anlage I, II, III or Unscheduled --> |
| legal_DE = <!-- Anlage I, II, III or Unscheduled --> |
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| legal_DE_comment = |
| legal_DE_comment = |
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| legal_NZ = <!-- Class A, B, C --> |
| legal_NZ = <!-- Class A, B, C --> |
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| legal_NZ_comment = |
| legal_NZ_comment = |
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| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C --> |
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C --> |
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| legal_UK_comment = |
| legal_UK_comment = |
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| legal_US = Rx-only |
| legal_US = Rx-only |
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| legal_US_comment = |
| legal_US_comment = |
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| legal_EU = |
| legal_EU = |
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| legal_EU_comment = |
| legal_EU_comment = |
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| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> |
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> |
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| legal_UN_comment = |
| legal_UN_comment = |
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| legal_status = Rx-only |
| legal_status = Rx-only |
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| metabolism = Liver |
| metabolism = Liver |
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| elimination_half-life = 1.5 hours |
| elimination_half-life = 1.5 hours |
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| excretion = Urine<ref>{{cite web|title=Heparin|url=http://online.lexi.com |archive-url=https://web.archive.org/web/20120214182216/http://online.lexi.com/crlsql/servlet/crlonline |archive-date=2012 |
| excretion = Urine<ref>{{cite web|title=Heparin|url=http://online.lexi.com |archive-url=https://web.archive.org/web/20120214182216/http://online.lexi.com/crlsql/servlet/crlonline |archive-date=14 February 2012 |date=10 February 2012|url-access=subscription}}</ref> |
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<!--Identifiers--> |
<!--Identifiers--> |
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| UNII_Ref = {{fdacite|correct|FDA}} |
| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = T2410KM04A |
| UNII = T2410KM04A |
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| KEGG = D02956 |
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| KEGG2 = D02112 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 526514 |
| ChEMBL = 526514 |
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<!-- Definition and medical uses --> |
<!-- Definition and medical uses --> |
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'''Heparin''', also known as '''unfractionated heparin''' ('''UFH'''), is a medication and naturally occurring [[glycosaminoglycan]].<ref name=AHFS2016/><ref name=UK2016>{{cite web|title=Heparin (Mucous) Injection BP{{snd}}Summary of Product Characteristics |url=https://www.medicines.org.uk/emc/medicine/8308|website=Electronic Medicines Compendium|access-date=15 December 2016|date=September 2016|url-status=live|archive-url=https://web.archive.org/web/20161220184640/https://www.medicines.org.uk/emc/medicine/8308|archive-date=20 December 2016}}</ref> |
'''Heparin''', also known as '''unfractionated heparin''' ('''UFH'''), is a medication and naturally occurring [[glycosaminoglycan]].<ref name=AHFS2016/><ref name=UK2016>{{cite web|title=Heparin (Mucous) Injection BP{{snd}}Summary of Product Characteristics |url=https://www.medicines.org.uk/emc/medicine/8308|website=Electronic Medicines Compendium|access-date=15 December 2016|date=September 2016|url-status=live|archive-url=https://web.archive.org/web/20161220184640/https://www.medicines.org.uk/emc/medicine/8308|archive-date=20 December 2016}}</ref> Heparin is a blood [[anticoagulant]] that increases the activity of [[antithrombin]].<ref>{{cite journal | vauthors = Alquwaizani M, Buckley L, Adams C, Fanikos J | title = Anticoagulants: A Review of the Pharmacology, Dosing, and Complications | journal = Current Emergency and Hospital Medicine Reports | volume = 1 | issue = 2 | pages = 83–97 | date = June 2013 | pmid = 23687625 | pmc = 3654192 | doi = 10.1007/s40138-013-0014-6 }}</ref> It is used in the treatment of [[myocardial infarction|heart attacks]] and [[unstable angina]].<ref name=AHFS2016/> It can be given [[intravenous]]ly or by [[subcutaneous injection|injection under the skin]].<ref name=AHFS2016>{{cite web|title=Heparin Sodium|url=https://www.drugs.com/monograph/heparin-sodium.html|publisher=The American Society of Health-System Pharmacists|access-date=1 January 2016|url-status=live|archive-url=https://web.archive.org/web/20160127144903/http://www.drugs.com/monograph/heparin-sodium.html|archive-date=27 January 2016}}</ref> Its anticoagulant properties make it useful to prevent blood clotting in blood specimen [[test tube]]s and [[kidney dialysis machines]].<ref name=UK2016/><ref>{{cite book| vauthors = McClatchey KD |title=Clinical Laboratory Medicine|date=2002|publisher=Lippincott Williams & Wilkins|isbn=978-0-683-30751-1|page=662|url=https://books.google.com/books?id=3PJVLH1NmQAC&pg=PA662|url-status=live|archive-url=https://web.archive.org/web/20170910183109/https://books.google.com/books?id=3PJVLH1NmQAC&pg=PA662|archive-date=10 September 2017}}</ref> |
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<!-- Side effects and mechanism--> |
<!-- Side effects and mechanism--> |
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Common side effects include bleeding, pain at the injection site, and [[thrombocytopenia|low blood platelets]].<ref name=AHFS2016/> Serious side effects include [[heparin-induced thrombocytopenia]].<ref name=AHFS2016/> Greater care is needed in those with [[poor kidney function]].<ref name=AHFS2016/> |
Common side effects include bleeding, pain at the injection site, and [[thrombocytopenia|low blood platelets]].<ref name=AHFS2016/> Serious side effects include [[heparin-induced thrombocytopenia]].<ref name=AHFS2016/> Greater care is needed in those with [[poor kidney function]].<ref name=AHFS2016/> |
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Heparin is contraindicated for suspected cases of [[Post-vaccination embolic and thrombotic events|vaccine-induced pro-thrombotic immune thrombocytopenia]] (VIPIT) secondary to [[SARS-CoV-2]] vaccination, as heparin may further increase the risk of bleeding in an anti-PF4/heparin complex autoimmune manner, in favor of alternative anticoagulant medications (such as [[argatroban]] or [[danaparoid]]).<ref>{{Cite web|title=AstraZeneca COVID-19-Vakzine Umgang mit dem Risiko von Gerinnungskomplikationen |url=https://www.dgho.de/publikationen/stellungnahmen/gute-aerztliche-praxis/coronavirus/astrazeneca-vakzine-gerinnungsstoerungen-20210330.pdf}}</ref><ref>{{cite journal | vauthors = Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S | title = Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination | journal = The New England Journal of Medicine | volume = 384 | issue = 22 | pages = 2092–2101 | date = June 2021 | pmid = 33835769 | pmc = 8095372 | doi = 10.1056/NEJMoa2104840 | doi-access = free }}</ref><ref>{{Cite journal|vauthors=Pai M, Grill A, Ivers N|title=Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) Following AstraZeneca COVID-19 Vaccination |
Heparin is contraindicated for suspected cases of [[Post-vaccination embolic and thrombotic events|vaccine-induced pro-thrombotic immune thrombocytopenia]] (VIPIT) secondary to [[SARS-CoV-2]] vaccination, as heparin may further increase the risk of bleeding in an anti-PF4/heparin complex autoimmune manner, in favor of alternative anticoagulant medications (such as [[argatroban]] or [[danaparoid]]).<ref>{{Cite web |title=AstraZeneca COVID-19-Vakzine Umgang mit dem Risiko von Gerinnungskomplikationen |url=https://www.dgho.de/publikationen/stellungnahmen/gute-aerztliche-praxis/coronavirus/astrazeneca-vakzine-gerinnungsstoerungen-20210330.pdf |access-date=3 April 2021 |archive-date=13 January 2024 |archive-url=https://web.archive.org/web/20240113035203/https://www.dgho.de/publikationen/stellungnahmen/gute-aerztliche-praxis/coronavirus/astrazeneca-vakzine-gerinnungsstoerungen-20210330.pdf |url-status=live }}</ref><ref>{{cite journal | vauthors = Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S | title = Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination | journal = The New England Journal of Medicine | volume = 384 | issue = 22 | pages = 2092–2101 | date = June 2021 | pmid = 33835769 | pmc = 8095372 | doi = 10.1056/NEJMoa2104840 | doi-access = free }}</ref><ref>{{Cite journal|vauthors=Pai M, Grill A, Ivers N|title=Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) Following AstraZeneca COVID-19 Vaccination|date=26 March 2021|publisher=The Ontario COVID-19 Science Advisory Table|url=https://covid19-sciencetable.ca/wp-content/uploads/2021/03/Science-Brief_AstraZeneca_General_20210326_published.pdf|doi=10.47326/ocsat.2021.02.17.1.0|s2cid=233663558|access-date=3 April 2021|archive-date=30 March 2021|archive-url=https://web.archive.org/web/20210330185752/https://covid19-sciencetable.ca/wp-content/uploads/2021/03/Science-Brief_AstraZeneca_General_20210326_published.pdf|url-status=live}}</ref> |
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Heparin appears to be relatively safe for use during [[pregnancy]] and [[breastfeeding]].<ref>{{cite web|title=Heparin Pregnancy and Breastfeeding Warnings|url=https://www.drugs.com/pregnancy/heparin.html|website=drugs.com|access-date=15 January 2016|url-status=live|archive-url=https://web.archive.org/web/20160127000923/http://www.drugs.com/pregnancy/heparin.html|archive-date=27 January 2016}}</ref> Heparin is produced by [[basophil]]s and [[mast cell]]s in all [[mammals]].<ref>{{cite book| vauthors = Guyton AC, Hall JE |title=Textbook of Medical Physiology |issue=11 |publisher=Elsevier Saunders |year=2006 |page=464 |isbn=978-0-7216-0240-0}}</ref> |
Heparin appears to be relatively safe for use during [[pregnancy]] and [[breastfeeding]].<ref>{{cite web|title=Heparin Pregnancy and Breastfeeding Warnings|url=https://www.drugs.com/pregnancy/heparin.html|website=drugs.com|access-date=15 January 2016|url-status=live|archive-url=https://web.archive.org/web/20160127000923/http://www.drugs.com/pregnancy/heparin.html|archive-date=27 January 2016}}</ref> Heparin is produced by [[basophil]]s and [[mast cell]]s in all [[mammals]].<ref>{{cite book| vauthors = Guyton AC, Hall JE |title=Textbook of Medical Physiology |issue=11 |publisher=Elsevier Saunders |year=2006 |page=464 |isbn=978-0-7216-0240-0}}</ref> |
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<!-- Society and culture --> |
<!-- Society and culture --> |
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The discovery of heparin was announced in 1916.<ref>{{cite book| vauthors = Li JL, Corey EJ |title=Drug Discovery: Practices, Processes, and Perspectives|date=2013|publisher=John Wiley & Sons|isbn= |
The discovery of heparin was announced in 1916.<ref>{{cite book| vauthors = Li JL, Corey EJ |title=Drug Discovery: Practices, Processes, and Perspectives|date=2013|publisher=John Wiley & Sons|isbn=978-1-118-35446-9|page=189|url=https://books.google.com/books?id=mIyxO5cLEAcC&pg=PA189|url-status=live|archive-url=https://web.archive.org/web/20170910183109/https://books.google.com/books?id=mIyxO5cLEAcC&pg=PA189|archive-date=10 September 2017}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref>{{cite book|vauthors=((World Health Organization)) |title=World Health Organization model list of essential medicines: 21st list 2019 |year=2019 |hdl=10665/325771 |author-link=World Health Organization |publisher=World Health Organization |location=Geneva |id=WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO |hdl-access=free}}</ref> A [[fractionated]] version of heparin, known as [[low molecular weight heparin]], is also available.<ref>{{cite book| vauthors = Rietschel RL, Fowler JF, Fisher AA |title=Fisher's Contact Dermatitis|date=2008|publisher=PMPH-USA|isbn=978-1-55009-378-0|page=142|url=https://books.google.com/books?id=dQBAzfyCeQ8C&pg=PA142|url-status=live|archive-url=https://web.archive.org/web/20170910183109/https://books.google.com/books?id=dQBAzfyCeQ8C&pg=PA142|archive-date=10 September 2017}}</ref> |
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{{TOC limit|3}} |
{{TOC limit|3}} |
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==History== |
==History== |
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Heparin was discovered by [[Jay McLean]] and [[William Henry Howell]] in 1916, although it did not enter clinical trials until 1935.<ref>{{cite web|title=Heparin used as an anticoagulant|publisher=AnimalResearch.info|url=http://animalresearch.info/en/medical-advances/145/heparin-used-as-an-anticoagulant/|url-status=live|archive-url=https://web.archive.org/web/20131023120406/http://animalresearch.info/en/medical-advances/145/heparin-used-as-an-anticoagulant/|archive-date= |
Heparin was discovered by [[Jay McLean]] and [[William Henry Howell]] in 1916, although it did not enter clinical trials until 1935.<ref>{{cite web|title=Heparin used as an anticoagulant|publisher=AnimalResearch.info|url=http://animalresearch.info/en/medical-advances/145/heparin-used-as-an-anticoagulant/|url-status=live|archive-url=https://web.archive.org/web/20131023120406/http://animalresearch.info/en/medical-advances/145/heparin-used-as-an-anticoagulant/|archive-date=23 October 2013}}</ref> It was originally isolated from dog [[liver]] cells, hence its name (ἧπαρ ''hēpar'' is Greek for 'liver'; ''hepar'' + ''[[wikt:-in#Suffix|-in]]''). |
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McLean was a second-year medical student at [[Johns Hopkins University]], and was working under the guidance of Howell investigating pro-coagulant preparations, when he isolated a fat-soluble phosphatide anticoagulant in canine liver tissue.<ref>{{cite journal | vauthors = McLEAN J | title = The discovery of heparin | journal = Circulation | volume = 19 | issue = 1 | pages = 75–8 | date = January 1959 | pmid = 13619023 | doi = 10.1161/01.CIR.19.1.75 | doi-access = free }}</ref> In 1918, Howell coined the term 'heparin' for this type of fat-soluble anticoagulant. In the early 1920s, Howell isolated a water-soluble [[polysaccharide]] anticoagulant, which he also termed 'heparin', although it was different from the previously discovered phosphatide preparations.<ref>{{cite journal | vauthors = Howell WH |title=Heparin, an anticoagulant |journal=American Journal of Physiology |year=1922 |volume=63 |pages=434–435}}</ref><ref>{{cite journal | vauthors = Mueller RL, Scheidt S | title = History of drugs for thrombotic disease. Discovery, development, and directions for the future | journal = Circulation | volume = 89 | issue = 1 | pages = 432–49 | date = January 1994 | pmid = 8281678 | doi = 10.1161/01.cir.89.1.432 | doi-access = free }}</ref> McLean's work as a surgeon probably changed the focus of the Howell group to look for anticoagulants, which eventually led to the polysaccharide discovery. |
McLean was a second-year medical student at [[Johns Hopkins University]], and was working under the guidance of Howell investigating pro-coagulant preparations, when he isolated a fat-soluble phosphatide anticoagulant in canine liver tissue.<ref>{{cite journal | vauthors = McLEAN J | title = The discovery of heparin | journal = Circulation | volume = 19 | issue = 1 | pages = 75–8 | date = January 1959 | pmid = 13619023 | doi = 10.1161/01.CIR.19.1.75 | doi-access = free }}</ref> In 1918, Howell coined the term 'heparin' for this type of fat-soluble anticoagulant. In the early 1920s, Howell isolated a water-soluble [[polysaccharide]] anticoagulant, which he also termed 'heparin', although it was different from the previously discovered phosphatide preparations.<ref>{{cite journal | vauthors = Howell WH |title=Heparin, an anticoagulant |journal=American Journal of Physiology |year=1922 |volume=63 |pages=434–435}}</ref><ref>{{cite journal | vauthors = Mueller RL, Scheidt S | title = History of drugs for thrombotic disease. Discovery, development, and directions for the future | journal = Circulation | volume = 89 | issue = 1 | pages = 432–49 | date = January 1994 | pmid = 8281678 | doi = 10.1161/01.cir.89.1.432 | doi-access = free }}</ref> McLean's work as a surgeon probably changed the focus of the Howell group to look for anticoagulants, which eventually led to the polysaccharide discovery. |
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In the 1930s, several researchers were investigating heparin. [[Erik Jorpes]] at [[Karolinska Institutet]] published his research on the structure of heparin in 1935,<ref>{{cite journal | vauthors = Jorpes E | title = The chemistry of heparin | journal = The Biochemical Journal | volume = 29 | issue = 8 | pages = 1817–30 | date = August 1935 | pmid = 16745848 | pmc = 1266692 | doi = 10.1042/bj0291817 }}</ref> which made it possible for the Swedish company [[Vitrum AB]] to launch the first heparin product for [[intravenous]] use in 1936. Between 1933 and 1936, [[Connaught Medical Research Laboratories]], then a part of the University of Toronto, perfected a technique for producing safe, nontoxic heparin that could be administered to patients, in a saline solution. The first human trials of heparin began in May 1935, and, by 1937, it was clear that Connaught's heparin was safe, easily available, and effective as a blood anticoagulant. Prior to 1933, heparin was available in small amounts, was extremely expensive and toxic, and, as a consequence, of no medical value.<ref>{{cite web| vauthors = Rutty CJ |title=Miracle Blood Lubricant: Connaught and the Story of Heparin, 1928–1937 |publisher=Health Heritage Research Services |url=http://www.healthheritageresearch.com/Heparin-Conntact9608.html |access-date= |
It had at first been accepted that it was Howell who discovered heparin. However in the 1940s, Jay McLean became unhappy that he had not received appropriate recognition for what he saw as his own discovery. Though relatively discreet about his claim and not wanting to upset his former chief, he gave lectures and wrote letters claiming that the discovery was his. This gradually became accepted as fact, and indeed after his death in 1959, his obituary credited him as being the true discoverer of heparin. This was elegantly restated in 1963 in a plaque unveiled in Johns Hopkins to commemorate the major contribution (of McLean) to the discovery of heparin in 1916 in collaboration with Professor William Henry Howell.<ref>{{Cite web |date=2024-03-21 |title=The discovery of heparin - Hektoen International |url=https://hekint.org/2024/03/21/the-discovery-of-heparin/ |access-date=2024-03-30 |website=hekint.org |language=en-US}}</ref> |
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In the 1930s, several researchers were investigating heparin. [[Erik Jorpes]] at [[Karolinska Institutet]] published his research on the structure of heparin in 1935,<ref>{{cite journal | vauthors = Jorpes E | title = The chemistry of heparin | journal = The Biochemical Journal | volume = 29 | issue = 8 | pages = 1817–30 | date = August 1935 | pmid = 16745848 | pmc = 1266692 | doi = 10.1042/bj0291817 }}</ref> which made it possible for the Swedish company [[Vitrum AB]] to launch the first heparin product for [[intravenous]] use in 1936. Between 1933 and 1936, [[Connaught Medical Research Laboratories]], then a part of the University of Toronto, perfected a technique for producing safe, nontoxic heparin that could be administered to patients, in a saline solution. The first human trials of heparin began in May 1935, and, by 1937, it was clear that Connaught's heparin was safe, easily available, and effective as a blood anticoagulant. Prior to 1933, heparin was available in small amounts, was extremely expensive and toxic, and, as a consequence, of no medical value.<ref>{{cite web| vauthors = Rutty CJ |title=Miracle Blood Lubricant: Connaught and the Story of Heparin, 1928–1937 |publisher=Health Heritage Research Services |url=http://www.healthheritageresearch.com/Heparin-Conntact9608.html |access-date=21 May 2007 |url-status=dead |archive-url=https://web.archive.org/web/20070823120920/http://www.healthheritageresearch.com/Heparin-Conntact9608.html |archive-date=23 August 2007}}</ref> |
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Heparin production experienced a break in the 1990s. Until then, heparin was mainly obtained from cattle tissue, which was a by-product of the meat industry, especially in North America. With the rapid spread of [[Bovine spongiform encephalopathy|BSE]], more and more manufacturers abandoned this source of supply. As a result, global heparin production became increasingly concentrated in China, where the substance was now procured from the expanding industry of breeding and slaughtering hog. The dependence of medical care on the meat industry assumed threatening proportions in the wake of the [[COVID-19 pandemic]]. In 2020, several studies demonstrated the efficacy of heparin in mitigating severe disease progression, as its anticoagulant effect counteracted the formation of [[Intravascular immunity#Immunothrombosis|immunothrombosis]]. However, the availability of heparin on the world market was decreased, because concurrently a renewed swine flu epidemic had reduced significant portions of the Chinese hog population. The situation was further exacerbated by the fact that mass slaughterhouses around the world became corona hotspots themselves and were forced to close temporarily. In less affluent countries, the resulting heparin shortage also led to worsened health care beyond the treatment of covid, for example through the cancellation of [[Cardiac surgery|cardiac surgeries]].<ref>{{ |
Heparin production experienced a break in the 1990s. Until then, heparin was mainly obtained from cattle tissue, which was a by-product of the [[meat industry]], especially in North America. With the rapid spread of [[Bovine spongiform encephalopathy|BSE]], more and more manufacturers abandoned this source of supply. As a result, global heparin production became increasingly concentrated in China, where the substance was now procured from the expanding industry of breeding and slaughtering hog. The dependence of medical care on the meat industry assumed threatening proportions in the wake of the [[COVID-19 pandemic]]. In 2020, several studies demonstrated the efficacy of heparin in mitigating severe disease progression, as its anticoagulant effect counteracted the formation of [[Intravascular immunity#Immunothrombosis|immunothrombosis]]. However, the availability of heparin on the world market was decreased, because concurrently a renewed [[swine flu]] epidemic had reduced significant portions of the Chinese hog population. The situation was further exacerbated by the fact that mass slaughterhouses around the world became corona hotspots themselves and were forced to close temporarily. In less affluent countries, the resulting heparin shortage also led to worsened health care beyond the treatment of covid, for example through the cancellation of [[Cardiac surgery|cardiac surgeries]].<ref>{{cite journal | vauthors = Prinz B | title = How blood met plastics, plant and animal extracts: Material encounters between medicine and industry in the twentieth century | journal = Studies in History and Philosophy of Science | volume = 92 | pages = 45–55 | date = April 2022 | pmid = 35131685 | doi = 10.1016/j.shpsa.2022.01.007 | s2cid = 246575794 }}</ref> |
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==Medical use== |
==Medical use== |
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[[File:Heparin Sodium sample.jpg|thumb|A vial of heparin sodium for injection]] |
[[File:Heparin Sodium sample.jpg|thumb|A vial of heparin sodium for injection]] |
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Heparin acts as an anticoagulant, preventing the formation of clots and extension of existing clots within the blood. While heparin itself does not break down clots that have already formed (unlike [[tissue plasminogen activator]]), it allows the body's natural [[Fibrinolysis|clot lysis]] mechanisms to work normally to break down clots that have formed. Heparin is generally used for anticoagulation for the following conditions: |
Heparin acts as an anticoagulant, preventing the formation of clots and extension of existing clots within the blood. While heparin itself does not break down clots that have already formed (unlike [[tissue plasminogen activator]]), it allows the body's natural [[Fibrinolysis|clot lysis]] mechanisms to work normally to break down clots that have formed. Heparin is generally used for anticoagulation for the following conditions:<ref name=":0">{{cite book | vauthors = Warnock LB, Huang D |chapter=Heparin |date=2022 | chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK538247/ | title = StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30855835 |access-date=31 October 2022 }}</ref> |
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* [[Acute coronary syndrome]], e.g., [[NSTEMI]] |
* [[Acute coronary syndrome]], e.g., [[NSTEMI]] |
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* [[Atrial fibrillation]] |
* [[Atrial fibrillation]] |
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* [[Deep-vein thrombosis]] and [[pulmonary embolism]] |
* [[Deep-vein thrombosis]] and [[pulmonary embolism]] (both prevention and treatment) |
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* Other [[Thrombosis|thrombotic states]] and conditions |
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* [[Cardiopulmonary bypass]] for [[heart surgery]] |
* [[Cardiopulmonary bypass]] for [[heart surgery]] |
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* [[ECMO]] circuit for [[extracorporeal life support]] |
* [[ECMO]] circuit for [[extracorporeal life support]] |
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* [[Hemofiltration]] |
* [[Hemofiltration]] |
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* Indwelling central or peripheral venous [[catheters]] |
* Indwelling central or peripheral venous [[catheters]] |
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Heparin and its low-molecular-weight derivatives (e.g., [[enoxaparin]], [[dalteparin]], [[tinzaparin]]) are effective in preventing deep vein thromboses and pulmonary emboli in people at risk,<ref>{{cite journal | vauthors = Agnelli G, Piovella F, Buoncristiani P, Severi P, Pini M, D'Angelo A, Beltrametti C, Damiani M, Andrioli GC, Pugliese R, Iorio A, Brambilla G |
Heparin and its low-molecular-weight derivatives (e.g., [[enoxaparin]], [[dalteparin]], [[tinzaparin]]) are effective in preventing deep vein thromboses and pulmonary emboli in people at risk,<ref>{{cite journal | vauthors = Agnelli G, Piovella F, Buoncristiani P, Severi P, Pini M, D'Angelo A, Beltrametti C, Damiani M, Andrioli GC, Pugliese R, Iorio A, Brambilla G | title = Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery | journal = The New England Journal of Medicine | volume = 339 | issue = 2 | pages = 80–5 | date = July 1998 | pmid = 9654538 | doi = 10.1056/NEJM199807093390204 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bergqvist D, Agnelli G, Cohen AT, Eldor A, Nilsson PE, Le Moigne-Amrani A, Dietrich-Neto F | title = Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer | journal = The New England Journal of Medicine | volume = 346 | issue = 13 | pages = 975–80 | date = March 2002 | pmid = 11919306 | doi = 10.1056/NEJMoa012385 | doi-access = free }}</ref> but no evidence indicates any one is more effective than the other in preventing mortality.<ref>{{cite journal | vauthors = Handoll HH, Farrar MJ, McBirnie J, Tytherleigh-Strong G, Milne AA, Gillespie WJ | title = Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD000305 | year = 2002 | volume = 2021 | pmid = 12519540 | pmc = 7043307 | doi = 10.1002/14651858.CD000305 }}</ref> |
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In angiography, 2 to 5 units/mL of unfractionated heparin saline flush is used to prevent the clotting of blood in guidewires, sheaths, and catheters, thus preventing thrombus from dislodging from these devices into the circulatory system .<ref>{{Cite journal| vauthors = Korzewski M, Madden L, Schomer K, Van Leuven K |date=September 2020|title=Heparin Flush Use in Transfemoral Cerebral Angiography Survey |journal=Journal of Radiology Nursing|language=en|volume=39|issue=3|pages=199–206|doi=10.1016/j.jradnu.2020.06.001|s2cid=225587226}}</ref><ref>{{cite journal | vauthors = Wiersema AM, Watts C, Durran AC, Reijnen MM, van Delden OM, Moll FL, Vos JA |
In [[angiography]], 2 to 5 units/mL of unfractionated heparin saline flush is used as a [[Catheter lock solution|locking solution]] to prevent the clotting of blood in guidewires, sheaths, and catheters, thus preventing thrombus from dislodging from these devices into the circulatory system .<ref>{{Cite journal| vauthors = Korzewski M, Madden L, Schomer K, Van Leuven K |date=September 2020|title=Heparin Flush Use in Transfemoral Cerebral Angiography Survey |journal=Journal of Radiology Nursing|language=en|volume=39|issue=3|pages=199–206|doi=10.1016/j.jradnu.2020.06.001|s2cid=225587226}}</ref><ref>{{cite journal | vauthors = Wiersema AM, Watts C, Durran AC, Reijnen MM, van Delden OM, Moll FL, Vos JA | title = The Use of Heparin during Endovascular Peripheral Arterial Interventions: A Synopsis | journal = Scientifica | volume = 2016 | pages = 1456298 | date = 2016 | pmid = 27190678 | pmc = 4852120 | doi = 10.1155/2016/1456298 | doi-access = free }}</ref> |
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Unfractionated heparin is used in [[hemodialysis]]. Comparing to [[low-molecular-weight heparin]], unfractionated heparin does not have prolonged anticoagulation action after dialysis, and low cost. However, the short duration of action for heparin would require it to maintain continuous infusion to maintain its action. Meanwhile, unfractionated heparin has higher risk of [[heparin-induced thrombocytopenia]].<ref>{{cite journal |vauthors=Cronin RE, Reilly RF |title=Unfractionated heparin for hemodialysis: still the best option |journal=Seminars in Dialysis |volume=23 |issue=5 |pages=510–5 |date=2010 |pmid=21039876 |pmc=3229102 |doi=10.1111/j.1525-139X.2010.00770.x |url=}}</ref> |
Unfractionated heparin is used in [[hemodialysis]]. Comparing to [[low-molecular-weight heparin]], unfractionated heparin does not have prolonged anticoagulation action after dialysis, and low cost. However, the short duration of action for heparin would require it to maintain continuous infusion to maintain its action. Meanwhile, unfractionated heparin has higher risk of [[heparin-induced thrombocytopenia]].<ref>{{cite journal |vauthors=Cronin RE, Reilly RF |title=Unfractionated heparin for hemodialysis: still the best option |journal=Seminars in Dialysis |volume=23 |issue=5 |pages=510–5 |date=2010 |pmid=21039876 |pmc=3229102 |doi=10.1111/j.1525-139X.2010.00770.x |url=}}</ref> |
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==Adverse effects== |
==Adverse effects== |
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A serious side-effect of heparin is [[heparin-induced thrombocytopenia]] (HIT), caused by an immunological reaction that makes [[platelet]]s 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. |
A serious side-effect of heparin is [[heparin-induced thrombocytopenia]] (HIT), caused by an immunological reaction that makes [[platelet]]s a target of immunological response, resulting in the degradation of platelets, which causes thrombocytopenia.<ref>{{cite journal | vauthors = Ahmed I, Majeed A, Powell R | title = Heparin induced thrombocytopenia: diagnosis and management update | journal = Postgraduate Medical Journal | volume = 83 | issue = 983 | pages = 575–582 | date = September 2007 | pmid = 17823223 | pmc = 2600013 | doi = 10.1136/pgmj.2007.059188 }}</ref> This condition is usually reversed on discontinuation, and in general can be avoided with the use of synthetic heparins. Not all patients with heparin antibodies will develop thrombocytopenia. Also, a benign form of thrombocytopenia is associated with early heparin use, which resolves without stopping heparin. Approximately one-third of patients with diagnosed heparin-induced thrombocytopenia will ultimately develop thrombotic complications.<ref>{{cite journal | vauthors = Nand S, Wong W, Yuen B, Yetter A, Schmulbach E, Gross Fisher S | title = Heparin-induced thrombocytopenia with thrombosis: incidence, analysis of risk factors, and clinical outcomes in 108 consecutive patients treated at a single institution | journal = American Journal of Hematology | volume = 56 | issue = 1 | pages = 12–16 | date = September 1997 | pmid = 9298861 | doi = 10.1002/(sici)1096-8652(199709)56:1<12::aid-ajh3>3.0.co;2-5 | s2cid = 22963756 }}</ref> |
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Two non-hemorrhagic 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. |
Two non-hemorrhagic 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.<ref name=":0" /> |
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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.<ref>{{cite news| vauthors = Kusmer K |publisher=Fox News |agency=Associated Press |title=3rd Ind. preemie infant dies of overdose |url=http://www.foxnews.com/story/0,2933,214729,00.html |date=20 September 2006 |access-date=2007 |
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.<ref>{{cite news| vauthors = Kusmer K |publisher=Fox News |agency=Associated Press |title=3rd Ind. preemie infant dies of overdose |url=http://www.foxnews.com/story/0,2933,214729,00.html |date=20 September 2006 |access-date=8 January 2007 |url-status=dead |archive-url=https://web.archive.org/web/20071018064124/http://www.foxnews.com/story/0,2933,214729,00.html |archive-date=18 October 2007}}</ref> |
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===Contraindications=== |
===Contraindications=== |
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{{more citations needed section|date=April 2017}} |
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Heparin is contraindicated in those with risk of bleeding (especially in people with uncontrolled blood pressure, liver disease, and stroke), severe liver disease, or severe hypertension.<ref>{{cite book | title = Australian Medicines Handbook | edition = 2019 (online) | location = Adelaide | publisher = Australian Medicines Handbook Pty Ltd | date = January 2019 | url = https://amhonline.amh.net.au/ }}</ref> |
Heparin is contraindicated in those with risk of bleeding (especially in people with uncontrolled blood pressure, liver disease, and stroke), severe liver disease, or severe hypertension.<ref>{{cite book | title = Australian Medicines Handbook | edition = 2019 (online) | location = Adelaide | publisher = Australian Medicines Handbook Pty Ltd | date = January 2019 | url = https://amhonline.amh.net.au/ }}</ref> |
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==Physiological function== |
==Physiological function== |
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Heparin's normal role in the body is unclear. Heparin is usually stored within the secretory granules of [[mast cell]]s and released only into the [[vasculature]] at sites of tissue injury. It has been proposed that, rather than anticoagulation, the main purpose of heparin is defense at such sites against invading bacteria and other foreign materials.<ref>{{cite journal | vauthors = Nader HB, Chavante SF, dos-Santos EA, Oliveira TW, de-Paiva JF, Jerônimo SM, Medeiros GF, de-Abreu LR, Leite EL, de-Sousa-Filho JF, Castro RA, Toma L, Tersariol IL, Porcionatto MA, Dietrich CP |
Heparin's normal role in the body is unclear. Heparin is usually stored within the secretory granules of [[mast cell]]s and released only into the [[vasculature]] at sites of tissue injury. It has been proposed that, rather than anticoagulation, the main purpose of heparin is defense at such sites against invading bacteria and other foreign materials.<ref>{{cite journal | vauthors = Nader HB, Chavante SF, dos-Santos EA, Oliveira TW, de-Paiva JF, Jerônimo SM, Medeiros GF, de-Abreu LR, Leite EL, de-Sousa-Filho JF, Castro RA, Toma L, Tersariol IL, Porcionatto MA, Dietrich CP | title = Heparan sulfates and heparins: similar compounds performing the same functions in vertebrates and invertebrates? | journal = Brazilian Journal of Medical and Biological Research = Revista Brasileira de Pesquisas Medicas e Biologicas | volume = 32 | issue = 5 | pages = 529–38 | date = May 1999 | pmid = 10412563 | doi = 10.1590/S0100-879X1999000500005 | doi-access = free }}</ref> In addition, it is observed across a number of widely different species, including some invertebrates that do not have a similar blood coagulation system. It is a highly sulfated glycosaminoglycan. It has the highest negative [[charge density]] of any known [[biomolecule|biological molecule]].<ref name=cox>{{cite book| vauthors = Cox M, Nelson D |title=Lehninger, Principles of Biochemistry |issue=4 |publisher=Freeman |year=2004 |page=[https://archive.org/details/lehningerprincip00lehn_0/page/254 254] |isbn=978-0-7167-4339-2 |url-access=registration |url=https://archive.org/details/lehningerprincip00lehn_0/page/254}}</ref> |
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===Evolutionary conservation=== |
===Evolutionary conservation=== |
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# [[Domestic turkey|Turkey]]<ref>{{cite journal | vauthors = Warda M, Mao W, Toida T, Linhardt RJ | title = Turkey intestine as a commercial source of heparin? Comparative structural studies of intestinal avian and mammalian glycosaminoglycans | journal = Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology | volume = 134 | issue = 1 | pages = 189–97 | date = January 2003 | pmid = 12524047 | doi = 10.1016/S1096-4959(02)00250-6 }}</ref> |
# [[Domestic turkey|Turkey]]<ref>{{cite journal | vauthors = Warda M, Mao W, Toida T, Linhardt RJ | title = Turkey intestine as a commercial source of heparin? Comparative structural studies of intestinal avian and mammalian glycosaminoglycans | journal = Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology | volume = 134 | issue = 1 | pages = 189–97 | date = January 2003 | pmid = 12524047 | doi = 10.1016/S1096-4959(02)00250-6 }}</ref> |
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# [[Whale]]<ref>{{cite journal | vauthors = Ototani N, Kikuchi M, Yosizawa Z | title = Comparative studies on the structures of highly active and relatively inactive forms of whale heparin | journal = Journal of Biochemistry | volume = 90 | issue = 1 | pages = 241–6 | date = July 1981 | pmid = 7287679 | doi = 10.1093/oxfordjournals.jbchem.a133456 }}</ref> |
# [[Whale]]<ref>{{cite journal | vauthors = Ototani N, Kikuchi M, Yosizawa Z | title = Comparative studies on the structures of highly active and relatively inactive forms of whale heparin | journal = Journal of Biochemistry | volume = 90 | issue = 1 | pages = 241–6 | date = July 1981 | pmid = 7287679 | doi = 10.1093/oxfordjournals.jbchem.a133456 }}</ref> |
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# [[Dromedary camel]]<ref>{{cite journal | vauthors = Warda M, Gouda EM, Toida T, Chi L, Linhardt RJ |
# [[Dromedary camel]]<ref>{{cite journal | vauthors = Warda M, Gouda EM, Toida T, Chi L, Linhardt RJ | title = Isolation and characterization of raw heparin from dromedary intestine: evaluation of a new source of pharmaceutical heparin | journal = Comparative Biochemistry and Physiology. Toxicology & Pharmacology | volume = 136 | issue = 4 | pages = 357–65 | date = December 2003 | pmid = 15012907 | doi = 10.1016/j.cca.2003.10.009 }}</ref> |
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# [[Mouse]]<ref>{{cite journal | vauthors = Bland CE, Ginsburg H, Silbert JE, Metcalfe DD | title = Mouse heparin proteoglycan. Synthesis by mast cell-fibroblast monolayers during lymphocyte-dependent mast cell proliferation | journal = The Journal of Biological Chemistry | volume = 257 | issue = 15 | pages = 8661–6 | date = August 1982 | pmid = 6807978 | doi = 10.1016/S0021-9258(18)34179-6 | doi-access = free }}</ref> |
# [[Mouse]]<ref>{{cite journal | vauthors = Bland CE, Ginsburg H, Silbert JE, Metcalfe DD | title = Mouse heparin proteoglycan. Synthesis by mast cell-fibroblast monolayers during lymphocyte-dependent mast cell proliferation | journal = The Journal of Biological Chemistry | volume = 257 | issue = 15 | pages = 8661–6 | date = August 1982 | pmid = 6807978 | doi = 10.1016/S0021-9258(18)34179-6 | doi-access = free }}</ref> |
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# [[Humans]]<ref>{{cite journal | vauthors = Linhardt RJ, Ampofo SA, Fareed J, Hoppensteadt D, Mulliken JB, Folkman J |
# [[Humans]]<ref>{{cite journal | vauthors = Linhardt RJ, Ampofo SA, Fareed J, Hoppensteadt D, Mulliken JB, Folkman J | title = Isolation and characterization of human heparin | journal = Biochemistry | volume = 31 | issue = 49 | pages = 12441–5 | date = December 1992 | pmid = 1463730 | doi = 10.1021/bi00164a020 }}</ref> |
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# [[Homarus americanus|Lobster]]<ref>{{cite journal | vauthors = Hovingh P, Linker A | title = An unusual heparan sulfate isolated from lobsters (Homarus americanus) | journal = The Journal of Biological Chemistry | volume = 257 | issue = 16 | pages = 9840–4 | date = August 1982 | pmid = 6213614 | doi = 10.1016/S0021-9258(18)34147-4 | doi-access = free }}</ref> |
# [[Homarus americanus|Lobster]]<ref>{{cite journal | vauthors = Hovingh P, Linker A | title = An unusual heparan sulfate isolated from lobsters (Homarus americanus) | journal = The Journal of Biological Chemistry | volume = 257 | issue = 16 | pages = 9840–4 | date = August 1982 | pmid = 6213614 | doi = 10.1016/S0021-9258(18)34147-4 | doi-access = free }}</ref> |
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# [[Anodonta californiensis|Fresh water mussel]]<ref>{{cite journal | vauthors = Hovingh P, Linker A | title = Glycosaminoglycans in Anodonta californiensis, a Freshwater Mussel | journal = The Biological Bulletin | volume = 185 | issue = 2 | pages = 263–276 | date = October 1993 | pmid = 27768418 | doi = 10.2307/1542006 | url = http://www.biolbull.org/cgi/content/abstract/185/2/263 | url-status = dead | access-date = |
# [[Anodonta californiensis|Fresh water mussel]]<ref>{{cite journal | vauthors = Hovingh P, Linker A | title = Glycosaminoglycans in Anodonta californiensis, a Freshwater Mussel | journal = The Biological Bulletin | volume = 185 | issue = 2 | pages = 263–276 | date = October 1993 | pmid = 27768418 | doi = 10.2307/1542006 | url = http://www.biolbull.org/cgi/content/abstract/185/2/263 | url-status = dead | access-date = 22 March 2007 | jstor = 1542006 | s2cid = 42108805 | archive-date = 27 September 2007 | archive-url = https://web.archive.org/web/20070927200255/http://www.biolbull.org/cgi/content/abstract/185/2/263 }}</ref> |
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# [[Clam]]<ref>{{cite journal | vauthors = Pejler G, Danielsson A, Björk I, Lindahl U, Nader HB, Dietrich CP |
# [[Clam]]<ref>{{cite journal | vauthors = Pejler G, Danielsson A, Björk I, Lindahl U, Nader HB, Dietrich CP | title = Structure and antithrombin-binding properties of heparin isolated from the clams Anomalocardia brasiliana and Tivela mactroides | journal = The Journal of Biological Chemistry | volume = 262 | issue = 24 | pages = 11413–21 | date = August 1987 | pmid = 3624220 | doi = 10.1016/S0021-9258(18)60822-1 | doi-access = free }}</ref> |
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# [[Shrimp]]<ref>{{cite journal | vauthors = Dietrich CP, Paiva JF, Castro RA, Chavante SF, Jeske W, Fareed J, Gorin PA, Mendes A, Nader HB |
# [[Shrimp]]<ref>{{cite journal | vauthors = Dietrich CP, Paiva JF, Castro RA, Chavante SF, Jeske W, Fareed J, Gorin PA, Mendes A, Nader HB | title = Structural features and anticoagulant activities of a novel natural low molecular weight heparin from the shrimp Penaeus brasiliensis | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1428 | issue = 2–3 | pages = 273–83 | date = August 1999 | pmid = 10434045 | doi = 10.1016/S0304-4165(99)00087-2 }}</ref> |
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# [[Mangrove crab]]<ref name=medeiros>{{cite journal | vauthors = Medeiros GF, Mendes A, Castro RA, Baú EC, Nader HB, Dietrich CP |
# [[Mangrove crab]]<ref name=medeiros>{{cite journal | vauthors = Medeiros GF, Mendes A, Castro RA, Baú EC, Nader HB, Dietrich CP | title = Distribution of sulfated glycosaminoglycans in the animal kingdom: widespread occurrence of heparin-like compounds in invertebrates | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1475 | issue = 3 | pages = 287–94 | date = July 2000 | pmid = 10913828 | doi = 10.1016/S0304-4165(00)00079-9 }}</ref> |
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# [[Sand dollar]]<ref name=medeiros/> |
# [[Sand dollar]]<ref name=medeiros/> |
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# [[Atlantic salmon]]<ref>{{cite journal | vauthors = Flengsrud R, Larsen ML, Ødegaard OR | title = Purification, characterization and in vivo studies of salmon heparin | journal = Thrombosis Research | volume = 126 | issue = 6 | pages = e409-17 | date = December 2010 | pmid = 20937523 | doi = 10.1016/j.thromres.2010.07.004 }}</ref><ref>{{cite journal | vauthors = Flengsrud R | title = Disaccharide analysis of chondroitin and heparin from farmed Atlantic salmon | journal = Glycoconjugate Journal | volume = 33 | issue = 2 | pages = 121–3 | date = April 2016 | pmid = 26993287 | doi = 10.1007/s10719-016-9652-8 | hdl-access = free | s2cid = 671954 | hdl = 11250/2388232 }}</ref> |
# [[Atlantic salmon]]<ref>{{cite journal | vauthors = Flengsrud R, Larsen ML, Ødegaard OR | title = Purification, characterization and in vivo studies of salmon heparin | journal = Thrombosis Research | volume = 126 | issue = 6 | pages = e409-17 | date = December 2010 | pmid = 20937523 | doi = 10.1016/j.thromres.2010.07.004 }}</ref><ref>{{cite journal | vauthors = Flengsrud R | title = Disaccharide analysis of chondroitin and heparin from farmed Atlantic salmon | journal = Glycoconjugate Journal | volume = 33 | issue = 2 | pages = 121–3 | date = April 2016 | pmid = 26993287 | doi = 10.1007/s10719-016-9652-8 | hdl-access = free | s2cid = 671954 | hdl = 11250/2388232 }}</ref> |
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# [[Zebra fish]]<ref>{{cite journal | vauthors = Zhang F, Zhang Z, Thistle R, McKeen L, Hosoyama S, Toida T, Linhardt RJ, Page-McCaw P |
# [[Zebra fish]]<ref>{{cite journal | vauthors = Zhang F, Zhang Z, Thistle R, McKeen L, Hosoyama S, Toida T, Linhardt RJ, Page-McCaw P | title = Structural characterization of glycosaminoglycans from zebrafish in different ages | journal = Glycoconjugate Journal | volume = 26 | issue = 2 | pages = 211–8 | date = February 2009 | pmid = 18777207 | pmc = 2643322 | doi = 10.1007/s10719-008-9177-x }}</ref> |
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{{div col end}} |
{{div col end}} |
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The biological activity of heparin within species 6–11 is unclear and further supports the idea that the main physiological role of heparin is not anticoagulation. These species do not possess any blood coagulation system similar to that present within the species listed 1–5. The above list also demonstrates how heparin has been highly [[conserved sequence|evolutionarily conserved]], with molecules of a similar structure being produced by a broad range of organisms belonging to many different [[phylum|phyla]].{{citation needed|date=November 2016}} |
The biological activity of heparin within species 6–11 is unclear and further supports the idea that the main physiological role of heparin is not anticoagulation. These species do not possess any blood coagulation system similar to that present within the species listed 1–5. The above list also demonstrates how heparin has been highly [[conserved sequence|evolutionarily conserved]], with molecules of a similar structure being produced by a broad range of organisms belonging to many different [[phylum|phyla]].{{citation needed|date=November 2016}} |
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: GlcNAc/NS(6S)-GlcA-GlcNS(3S,6S)-IdoA(2S)-GlcNS(6S) |
: GlcNAc/NS(6S)-GlcA-GlcNS(3S,6S)-IdoA(2S)-GlcNS(6S) |
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The conformational change in AT on heparin-binding mediates its inhibition of factor Xa. For thrombin inhibition, however, thrombin must also bind to the heparin polymer at a site proximal to the pentasaccharide. The highly negative charge density of heparin contributes to its very strong [[electrostatic]] interaction with [[thrombin]].<ref name=cox/> The formation of a [[ternary complex]] between AT, thrombin, and heparin results in the inactivation of thrombin. For this reason, heparin's activity against thrombin is size-dependent, with the ternary complex requiring at least 18 saccharide units for efficient formation.<ref>{{cite journal | vauthors = Petitou M, Hérault JP, Bernat A, Driguez PA, Duchaussoy P, Lormeau JC, Herbert JM |
The conformational change in AT on heparin-binding mediates its inhibition of factor Xa. For thrombin inhibition, however, thrombin must also bind to the heparin polymer at a site proximal to the pentasaccharide. The highly negative charge density of heparin contributes to its very strong [[electrostatic]] interaction with [[thrombin]].<ref name=cox/> The formation of a [[ternary complex]] between AT, thrombin, and heparin results in the inactivation of thrombin. For this reason, heparin's activity against thrombin is size-dependent, with the ternary complex requiring at least 18 saccharide units for efficient formation.<ref>{{cite journal | vauthors = Petitou M, Hérault JP, Bernat A, Driguez PA, Duchaussoy P, Lormeau JC, Herbert JM | title = Synthesis of thrombin-inhibiting heparin mimetics without side effects | journal = Nature | volume = 398 | issue = 6726 | pages = 417–22 | date = April 1999 | pmid = 10201371 | doi = 10.1038/18877 | s2cid = 4339441 | bibcode = 1999Natur.398..417P }}</ref> In contrast, antifactor Xa activity via AT requires only the pentasaccharide-binding site. |
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This size difference has led to the development of [[low-molecular-weight heparin]]s (LMWHs) and [[fondaparinux]] as anticoagulants. Fondaparinux targets anti-factor Xa activity rather than inhibiting thrombin activity, with the aim of facilitating a more subtle regulation of coagulation and an improved therapeutic index. It is a synthetic pentasaccharide, whose chemical structure is almost identical to the AT binding pentasaccharide sequence that can be found within polymeric heparin and [[heparan sulfate]]. |
This size difference has led to the development of [[low-molecular-weight heparin]]s (LMWHs) and [[fondaparinux]] as anticoagulants. Fondaparinux targets anti-factor Xa activity rather than inhibiting thrombin activity, with the aim of facilitating a more subtle regulation of coagulation and an improved therapeutic index. It is a synthetic pentasaccharide, whose chemical structure is almost identical to the AT binding pentasaccharide sequence that can be found within polymeric heparin and [[heparan sulfate]]. |
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With LMWH and fondaparinux, the risk of [[osteoporosis]] and [[heparin-induced thrombocytopenia]] (HIT) is reduced. Monitoring of the [[APTT|activated partial thromboplastin time]] is also not required and does not reflect the anticoagulant effect, as APTT is insensitive to alterations in factor Xa. |
With LMWH and fondaparinux, the risk of [[osteoporosis]] and [[heparin-induced thrombocytopenia]] (HIT) is reduced. Monitoring of the [[APTT|activated partial thromboplastin time]] is also not required and does not reflect the anticoagulant effect, as APTT is insensitive to alterations in factor Xa. |
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[[Danaparoid]], a mixture of heparan sulfate, [[dermatan sulfate]], and [[chondroitin sulfate]] can be used as an anticoagulant in patients having developed HIT. Because danaparoid does not contain heparin or heparin fragments, cross-reactivity of danaparoid with heparin-induced antibodies is reported as less than 10%.<ref>Shalansky, Karen. [http://www.vhpharmsci.com/Newsletters/1990s-NEWS/article6.htm DANAPAROID (Orgaran) for Heparin-Induced Thrombocytopenia.] {{webarchive|url=https://web.archive.org/web/20070928130132/http://www.vhpharmsci.com/Newsletters/1990s-NEWS/article6.htm |date= |
[[Danaparoid]], a mixture of heparan sulfate, [[dermatan sulfate]], and [[chondroitin sulfate]] can be used as an anticoagulant in patients having developed HIT. Because danaparoid does not contain heparin or heparin fragments, cross-reactivity of danaparoid with heparin-induced antibodies is reported as less than 10%.<ref>Shalansky, Karen. [http://www.vhpharmsci.com/Newsletters/1990s-NEWS/article6.htm DANAPAROID (Orgaran) for Heparin-Induced Thrombocytopenia.] {{webarchive|url=https://web.archive.org/web/20070928130132/http://www.vhpharmsci.com/Newsletters/1990s-NEWS/article6.htm |date=28 September 2007}} Vancouver Hospital & Health Sciences Centre, February 1998 ''Drug & Therapeutics Newsletter''. Retrieved on 8 January 2007.</ref> |
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The effects of heparin are measured in the lab by the partial thromboplastin time ([[aPTT]]), one of the measures of the time it takes the [[blood plasma]] to clot. Partial thromboplastin time should not be confused with [[prothrombin time]], or PT, which measures blood clotting time through a different pathway of the [[coagulation cascade]]. |
The effects of heparin are measured in the lab by the partial thromboplastin time ([[aPTT]]), one of the measures of the time it takes the [[blood plasma]] to clot. Partial thromboplastin time should not be confused with [[prothrombin time]], or PT, which measures blood clotting time through a different pathway of the [[coagulation cascade]]. |
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===Administration=== |
===Administration=== |
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[[File:Heparin 1.jpg|thumb|right|Heparin vial for subcutaneous injection]] |
[[File:Heparin 1.jpg|thumb|right|Heparin vial for subcutaneous injection]] |
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Heparin is given [[parenteral]]ly because it is not absorbed from the gut, due to its high negative charge and large size. It can be injected intravenously or subcutaneously (under the skin); intramuscular injections (into muscle) are avoided because of the potential for forming [[hematoma]]s. Because of its short biologic [[half-life]] of about one hour, heparin must be given frequently or as a continuous [[infusion]]. [[fractionation|Unfractionated]] heparin has a half-life of about one to two hours after infusion,<ref name="pmid12358583">{{cite journal | vauthors = Eikelboom JW, Hankey GJ | title = Low molecular weight heparins and heparinoids | journal = The Medical Journal of Australia | volume = 177 | issue = 7 | pages = 379–83 | date = October 2002 | pmid = 12358583 | doi = 10.5694/j.1326-5377.2002.tb04807.x | url = http://www.mja.com.au/public/issues/177_07_071002/eik10205_fm.html | url-status = live | s2cid = 25553190 | archive-url = https://web.archive.org/web/20110909061753/http://www.mja.com.au/public/issues/177_07_071002/eik10205_fm.html | archive-date = 2011 |
Heparin is given [[parenteral]]ly because it is not absorbed from the gut, due to its high negative charge and large size. It can be injected intravenously or subcutaneously (under the skin); intramuscular injections (into muscle) are avoided because of the potential for forming [[hematoma]]s. Because of its short biologic [[half-life]] of about one hour, heparin must be given frequently or as a continuous [[infusion]]. [[fractionation|Unfractionated]] heparin has a half-life of about one to two hours after infusion,<ref name="pmid12358583">{{cite journal | vauthors = Eikelboom JW, Hankey GJ | title = Low molecular weight heparins and heparinoids | journal = The Medical Journal of Australia | volume = 177 | issue = 7 | pages = 379–83 | date = October 2002 | pmid = 12358583 | doi = 10.5694/j.1326-5377.2002.tb04807.x | url = http://www.mja.com.au/public/issues/177_07_071002/eik10205_fm.html | url-status = live | s2cid = 25553190 | archive-url = https://web.archive.org/web/20110909061753/http://www.mja.com.au/public/issues/177_07_071002/eik10205_fm.html | archive-date = 9 September 2011 }}</ref> whereas LMWH has a half-life of four to five hours.<ref>{{cite journal | vauthors = Weitz JI | title = New anticoagulants for treatment of venous thromboembolism | journal = Circulation | volume = 110 | issue = 9 Suppl 1 | pages = I19-26 | date = August 2004 | pmid = 15339877 | doi = 10.1161/01.CIR.0000140901.04538.ae | doi-access = free }}</ref> The use of LMWH has allowed once-daily dosing, thus not requiring a continuous infusion of the drug. If long-term anticoagulation is required, heparin is often used only to commence anticoagulation therapy until an oral anticoagulant e.g. [[warfarin]] takes effect. |
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The [[American College of Chest Physicians]] publishes [[Medical guideline|clinical guidelines]] on heparin dosing.<ref>{{cite journal | vauthors = Hirsh J, Raschke R | title = Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy | journal = Chest | volume = 126 | issue = 3 Suppl | pages = 188S–203S | date = September 2004 | pmid = 15383472 | doi = 10.1378/chest.126.3_suppl.188S }}</ref> |
The [[American College of Chest Physicians]] publishes [[Medical guideline|clinical guidelines]] on heparin dosing.<ref>{{cite journal | vauthors = Hirsh J, Raschke R | title = Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy | journal = Chest | volume = 126 | issue = 3 Suppl | pages = 188S–203S | date = September 2004 | pmid = 15383472 | doi = 10.1378/chest.126.3_suppl.188S }}</ref> |
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=== Heparin structure === |
=== Heparin structure === |
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[[File:Heparin ball-and-stick.png|thumb|right|270px|[[Ball-and-stick model]] of heparin]] |
[[File:Heparin ball-and-stick.png|thumb|right|270px|[[Ball-and-stick model]] of heparin]] |
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Native heparin is a polymer with a [[molecular weight]] ranging from 3 to 30 [[atomic mass unit|kDa]], although the average molecular weight of most commercial heparin preparations is in the range of 12 to 15 kDa.<ref>{{cite book |vauthors=Francis CW, Kaplan KL |chapter=Chapter 21. Principles of Antithrombotic Therapy |veditors=Lichtman MA, Beutler E, Kipps TJ |title=Williams Hematology |edition=7th |year=2006 |chapter-url=http://www.accessmedicine.com/content.aspx?aID=2138678 |isbn=978-0-07-143591-8 |display-editors=etal |url-status=dead |archive-url=https://web.archive.org/web/20110707080715/http://www.accessmedicine.com/content.aspx?aID=2138678 |archive-date=2011 |
Native heparin is a polymer with a [[molecular weight]] ranging from 3 to 30 [[atomic mass unit|kDa]], although the average molecular weight of most commercial heparin preparations is in the range of 12 to 15 kDa.<ref>{{cite book |vauthors=Francis CW, Kaplan KL |chapter=Chapter 21. Principles of Antithrombotic Therapy |veditors=Lichtman MA, Beutler E, Kipps TJ |title=Williams Hematology |edition=7th |year=2006 |publisher=McGraw-Hill Companies,Incorporated |chapter-url=http://www.accessmedicine.com/content.aspx?aID=2138678 |isbn=978-0-07-143591-8 |display-editors=etal |url-status=dead |archive-url=https://web.archive.org/web/20110707080715/http://www.accessmedicine.com/content.aspx?aID=2138678 |archive-date=7 July 2011}}</ref> 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.<ref>{{cite journal | vauthors = Bentolila A, Vlodavsky I, Haloun C, Domb AJ |title=Synthesis and heparin-like biological activity of amino acid-based polymers |doi=10.1002/1099-1581(200008/12)11:8/12<377::AID-PAT985>3.0.CO;2-D |volume=11 |issue=8–12 |journal=Polymers for Advanced Technologies |pages=377–387 |year=2000}}</ref> |
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The main disaccharide units that occur in heparin are shown below. The most common disaccharide unit<sup>*</sup> (see below) is composed of a 2-O-sulfated [[iduronic acid]] and 6-O-sulfated, N-sulfated glucosamine, IdoA(2S)-GlcNS(6S). For example, this makes up 85% of heparins from beef lung and about 75% of those from porcine intestinal mucosa.<ref>{{cite journal| vauthors = Gatti G, Casu B, Hamer GK, Perlin AS |title=Studies on the Conformation of Heparin by1H and13C NMR Spectroscopy|journal=Macromolecules|volume=12|issue=5|year=1979|pages=1001–1007|issn=0024-9297|doi=10.1021/ma60071a044|bibcode=1979MaMol..12.1001G}}</ref> |
The main disaccharide units that occur in heparin are shown below. The most common disaccharide unit<sup>*</sup> (see below) is composed of a 2-O-sulfated [[iduronic acid]] and 6-O-sulfated, N-sulfated glucosamine, IdoA(2S)-GlcNS(6S). For example, this makes up 85% of heparins from beef lung and about 75% of those from porcine intestinal mucosa.<ref>{{cite journal| vauthors = Gatti G, Casu B, Hamer GK, Perlin AS |title=Studies on the Conformation of Heparin by1H and13C NMR Spectroscopy|journal=Macromolecules|volume=12|issue=5|year=1979|pages=1001–1007|issn=0024-9297|doi=10.1021/ma60071a044|bibcode=1979MaMol..12.1001G}}</ref> |
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GlcA = β-{{small|D}}-[[glucuronic acid]], IdoA = α-{{small|L}}-[[iduronic acid]], IdoA(2S) = 2-''O''-sulfo-α-{{small|L}}-iduronic acid, GlcNAc = 2-deoxy-2-acetamido-α-{{small|D}}-glucopyranosyl, GlcNS = 2-deoxy-2-sulfamido-α-{{small|D}}-glucopyranosyl, GlcNS(6S) = 2-deoxy-2-sulfamido-α-{{small|D}}-glucopyranosyl-6-''O''-sulfate |
GlcA = β-{{small|D}}-[[glucuronic acid]], IdoA = α-{{small|L}}-[[iduronic acid]], IdoA(2S) = 2-''O''-sulfo-α-{{small|L}}-iduronic acid, GlcNAc = 2-deoxy-2-acetamido-α-{{small|D}}-glucopyranosyl, GlcNS = 2-deoxy-2-sulfamido-α-{{small|D}}-glucopyranosyl, GlcNS(6S) = 2-deoxy-2-sulfamido-α-{{small|D}}-glucopyranosyl-6-''O''-sulfate |
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One unit of heparin (the "[[William Henry Howell|Howell]] unit") is an amount approximately equivalent to 0.002 mg of pure heparin, which is the quantity required to keep 1 ml of cat's blood fluid for 24 hours at 0 °C.<ref>{{cite web|url=http://cancerweb.ncl.ac.uk/cgi-bin/omd?Howell+unit|archive-url=https://archive. |
One unit of heparin (the "[[William Henry Howell|Howell]] unit") is an amount approximately equivalent to 0.002 mg of pure heparin, which is the quantity required to keep 1 ml of cat's blood fluid for 24 hours at 0 °C.<ref>{{cite web|url=http://cancerweb.ncl.ac.uk/cgi-bin/omd?Howell+unit|archive-url=https://archive.today/20070813174048/http://cancerweb.ncl.ac.uk/cgi-bin/omd?Howell+unit|url-status=dead|archive-date=13 August 2007|title=Online Medical Dictionary|access-date=11 July 2008|publisher=Centre for Cancer Education|year=2000}}</ref> |
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====Three-dimensional structure==== |
====Three-dimensional structure==== |
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The three-dimensional structure of heparin is complicated because [[iduronic acid]] may be present in either of two low-energy conformations when internally positioned within an oligosaccharide. The conformational equilibrium is influenced by sulfation state of adjacent glucosamine sugars.<ref>{{cite journal | vauthors = Ferro DR, Provasoli A, Ragazzi M, Casu B, Torri G, Bossennec V, Perly B, Sinaÿ P, Petitou M, Choay J |
The three-dimensional structure of heparin is complicated because [[iduronic acid]] may be present in either of two low-energy conformations when internally positioned within an oligosaccharide. The conformational equilibrium is influenced by sulfation state of adjacent glucosamine sugars.<ref>{{cite journal | vauthors = Ferro DR, Provasoli A, Ragazzi M, Casu B, Torri G, Bossennec V, Perly B, Sinaÿ P, Petitou M, Choay J | title = Conformer populations of L-iduronic acid residues in glycosaminoglycan sequences | journal = Carbohydrate Research | volume = 195 | issue = 2 | pages = 157–67 | date = January 1990 | pmid = 2331699 | doi = 10.1016/0008-6215(90)84164-P }}</ref> Nevertheless, the solution structure of a heparin dodecasaccharide composed solely of six GlcNS(6S)-IdoA(2S) repeat units has been determined using a combination of NMR spectroscopy and molecular modeling techniques.<ref>{{cite journal | vauthors = Mulloy B, Forster MJ, Jones C, Davies DB | title = N.m.r. and molecular-modelling studies of the solution conformation of heparin | journal = The Biochemical Journal | volume = 293 | issue = Pt 3 | pages = 849–58 | date = August 1993 | pmid = 8352752 | pmc = 1134446 | doi = 10.1042/bj2930849 }}</ref> Two models were constructed, one in which all IdoA(2S) were in the <sup>2</sup>S<sub>0</sub> conformation ('''A''' and '''B''' below), and one in which they are in the <sup>1</sup>C<sub>4</sub> conformation ('''C''' and '''D''' below). However, no evidence suggests that changes between these conformations occur in a concerted fashion. These models correspond to the protein data bank code 1HPN.<ref>{{cite web |url=http://www.rcsb.org/pdb/files/1hpn.pdb |vauthors=Mulloy B, Forster MJ |title=N.M.R. and molecular-modeling studies of the solution conformation of heparin |access-date=17 July 2006 |archive-date=11 October 2008 |archive-url=https://web.archive.org/web/20081011120801/http://www.rcsb.org/pdb/files/1hpn.pdb |url-status=live }}</ref> |
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{{wide image|Heparin-3D-structures.png|600px|Two different structures of heparin}} |
{{wide image|Heparin-3D-structures.png|600px|Two different structures of heparin}} |
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====Enzymatic==== |
====Enzymatic==== |
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The enzymes traditionally used to digest heparin or HS are naturally produced by the soil bacterium ''Pedobacter heparinus'' (formerly named ''Flavobacterium heparinum'').<ref>{{cite journal | vauthors = Shaya D, Tocilj A, Li Y, Myette J, Venkataraman G, Sasisekharan R, Cygler M |
The enzymes traditionally used to digest heparin or HS are naturally produced by the soil bacterium ''Pedobacter heparinus'' (formerly named ''Flavobacterium heparinum'').<ref>{{cite journal | vauthors = Shaya D, Tocilj A, Li Y, Myette J, Venkataraman G, Sasisekharan R, Cygler M | title = Crystal structure of heparinase II from Pedobacter heparinus and its complex with a disaccharide product | journal = The Journal of Biological Chemistry | volume = 281 | issue = 22 | pages = 15525–35 | date = June 2006 | pmid = 16565082 | doi = 10.1074/jbc.M512055200 | doi-access = free}}</ref> This bacterium is capable of using either heparin or HS as its sole carbon and nitrogen source. To do so, it produces a range of enzymes such as [[lyase]]s, [[Glucuronidation|glucuronidases]], [[sulfoesterase]]s, and [[sulfamidase]]s.<ref>{{cite journal | vauthors = Galliher PM, Cooney CL, Langer R, Linhardt RJ | title = Heparinase production by Flavobacterium heparinum | journal = Applied and Environmental Microbiology | volume = 41 | issue = 2 | pages = 360–5 | date = February 1981 | pmid = 7235692 | pmc = 243699 | doi = 10.1128/AEM.41.2.360-365.1981 | bibcode = 1981ApEnM..41..360G }}</ref> The lyases have mainly been used in heparin/HS studies. The bacterium produces three lyases, heparinases I ({{EC number|4.2.2.7}}), II (no [[Enzyme Commission number|EC number]] assigned) and III ({{EC number|4.2.2.8}}) and each has distinct substrate specificities as detailed below.<ref>{{cite journal | vauthors = Linhardt RJ, Turnbull JE, Wang HM, Loganathan D, Gallagher JT | title = Examination of the substrate specificity of heparin and heparan sulfate lyases | journal = Biochemistry | volume = 29 | issue = 10 | pages = 2611–7 | date = March 1990 | pmid = 2334685 | doi = 10.1021/bi00462a026 }}</ref><ref>{{cite journal | vauthors = Desai UR, Wang HM, Linhardt RJ | title = Specificity studies on the heparin lyases from Flavobacterium heparinum | journal = Biochemistry | volume = 32 | issue = 32 | pages = 8140–5 | date = August 1993 | pmid = 8347612 | doi = 10.1021/bi00083a012 }}</ref> |
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[[File:UA(2S)-GlcNS(6S).svg|thumb|300px|right|UA(2S)-GlcNS(6S)]] |
[[File:UA(2S)-GlcNS(6S).svg|thumb|300px|right|UA(2S)-GlcNS(6S)]] |
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The lyases cleave heparin/HS by a [[beta elimination]] mechanism. This action generates an unsaturated double bond between C4 and C5 of the uronate residue.<ref>{{cite journal | vauthors = Linker A, Hovingh P | title = Isolation and characterization of oligosaccharides obtained from heparin by the action of heparinase | journal = Biochemistry | volume = 11 | issue = 4 | pages = 563–8 | date = February 1972 | pmid = 5062409 | doi = 10.1021/bi00754a013 }}</ref><ref>{{cite journal | vauthors = Linhardt RJ, Rice KG, Kim YS, Lohse DL, Wang HM, Loganathan D |
The lyases cleave heparin/HS by a [[beta elimination]] mechanism. This action generates an unsaturated double bond between C4 and C5 of the uronate residue.<ref>{{cite journal | vauthors = Linker A, Hovingh P | title = Isolation and characterization of oligosaccharides obtained from heparin by the action of heparinase | journal = Biochemistry | volume = 11 | issue = 4 | pages = 563–8 | date = February 1972 | pmid = 5062409 | doi = 10.1021/bi00754a013 }}</ref><ref>{{cite journal | vauthors = Linhardt RJ, Rice KG, Kim YS, Lohse DL, Wang HM, Loganathan D | title = Mapping and quantification of the major oligosaccharide components of heparin | journal = The Biochemical Journal | volume = 254 | issue = 3 | pages = 781–7 | date = September 1988 | pmid = 3196292 | pmc = 1135151 | doi = 10.1042/bj2540781 }}</ref> The C4-C5 unsaturated uronate is termed ΔUA or UA. It is a sensitive UV [[chromophore]] (max absorption at 232 nm) and allows the rate of an enzyme digest to be followed, as well as providing a convenient method for detecting the fragments produced by enzyme digestion. |
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====Chemical==== |
====Chemical==== |
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[[Nitrous acid]] can be used to chemically depolymerize heparin/HS. Nitrous acid can be used at pH 1.5 or at a higher pH of 4. Under both conditions, nitrous acid effects deaminative cleavage of the chain.<ref>{{cite journal | vauthors = Shively JE, Conrad HE | title = Formation of anhydrosugars in the chemical depolymerization of heparin | journal = Biochemistry | volume = 15 | issue = 18 | pages = 3932–42 | date = September 1976 | pmid = 9127 | doi = 10.1021/bi00663a005 }}</ref> [[File:Reduction fig.png|thumb|right|IdoA(2S)-aMan: The anhydromannose can be reduced to an anhydromannitol]] At both 'high' (4) and 'low' (1.5) pH, deaminative cleavage occurs between GlcNS-GlcA and GlcNS-IdoA, albeit at a slower rate at the higher pH. The deamination reaction, and therefore chain cleavage, is regardless of O-sulfation carried by either monosaccharide unit. |
[[Nitrous acid]] can be used to chemically depolymerize heparin/HS. Nitrous acid can be used at pH 1.5 or at a higher pH of 4. Under both conditions, nitrous acid effects deaminative cleavage of the chain.<ref>{{cite journal | vauthors = Shively JE, Conrad HE | title = Formation of anhydrosugars in the chemical depolymerization of heparin | journal = Biochemistry | volume = 15 | issue = 18 | pages = 3932–42 | date = September 1976 | pmid = 9127 | doi = 10.1021/bi00663a005 }}</ref> [[File:Reduction fig.png|thumb|right|IdoA(2S)-aMan: The anhydromannose can be reduced to an anhydromannitol]] At both 'high' (4) and 'low' (1.5) pH, deaminative cleavage occurs between GlcNS-GlcA and GlcNS-IdoA, albeit at a slower rate at the higher pH. The deamination reaction, and therefore chain cleavage, is regardless of O-sulfation carried by either monosaccharide unit. |
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At low pH, deaminative cleavage results in the release of inorganic SO<sub>4</sub>, and the conversion of GlcNS into [[anhydromannose]] (aMan). Low-pH nitrous acid treatment is an excellent method to distinguish N-sulfated polysaccharides such as heparin and HS from non N-sulfated |
At low pH, deaminative cleavage results in the release of inorganic SO<sub>4</sub>, and the conversion of GlcNS into [[anhydromannose]] (aMan). Low-pH nitrous acid treatment is an excellent method to distinguish N-sulfated polysaccharides such as heparin and HS from non N-sulfated polysaccharides such as [[chondroitin sulfate]] and [[dermatan sulfate]], chondroitin sulfate and dermatan sulfate not being susceptible to nitrous acid cleavage. |
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===Detection in body fluids=== |
===Detection in body fluids=== |
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Current clinical laboratory assays for heparin rely on an indirect measurement of the effect of the drug, rather than on a direct measure of its chemical presence. These include [[activated partial thromboplastin time]] (APTT) and antifactor Xa activity. The specimen of choice is usually fresh, nonhemolyzed plasma from blood that has been anticoagulated with citrate, fluoride, or oxalate.<ref>{{cite journal | vauthors = Hansen R, Koster A, Kukucka M, Mertzlufft F, Kuppe H |
Current clinical laboratory assays for heparin rely on an indirect measurement of the effect of the drug, rather than on a direct measure of its chemical presence. These include [[activated partial thromboplastin time]] (APTT) and antifactor Xa activity. The specimen of choice is usually fresh, nonhemolyzed plasma from blood that has been anticoagulated with citrate, fluoride, or oxalate.<ref>{{cite journal | vauthors = Hansen R, Koster A, Kukucka M, Mertzlufft F, Kuppe H | title = A quick anti-Xa-activity-based whole blood coagulation assay for monitoring unfractionated heparin during cardiopulmonary bypass: a pilot investigation | journal = Anesthesia and Analgesia | volume = 91 | issue = 3 | pages = 533–8 | date = September 2000 | pmid = 10960371 | doi = 10.1213/00000539-200009000-00006 | s2cid = 44678237 | doi-access = free }}</ref><ref>{{cite book|author=R. Baselt |title=Disposition of Toxic Drugs and Chemicals in Man |edition=8 |publisher=Biomedical Publications |location=Foster City, CA |year=2008 |pages=728–729 |isbn=978-0-9626523-7-0}}</ref> |
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==Other functions==<!--bit of a dustbin title, and can't we organise this better than a random list?--> |
==Other functions==<!--bit of a dustbin title, and can't we organise this better than a random list?--> |
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* |
* Blood specimen test tubes, [[vacutainer]]s, and [[capillary]] tubes that use the [[lithium]] salt of heparin (lithium heparin) as an anticoagulant are usually marked with green stickers and green tops. Heparin has the advantage over [[EDTA]] of not affecting levels of most [[ion]]s. However, the concentration of ionized calcium may be decreased if the concentration of heparin in the blood specimen is too high.<ref>{{cite journal | vauthors = Higgins C | title = The use of heparin in preparing samples for blood-gas analysis | journal = Medical Laboratory Observer| volume = 39 | issue = 10 | pages = 16–8, 20; quiz 22–3 | date = October 2007 | pmid = 18018679 | url = http://www.mlo-online.com/articles/200710/1007cover_story.pdf | access-date = 18 April 2016 | url-status = dead | archive-url = https://web.archive.org/web/20160910124849/http://www.mlo-online.com/articles/200710/1007cover_story.pdf | archive-date = 10 September 2016 }}</ref> Heparin can interfere with some [[immunoassay]]s, however. As lithium heparin is usually used, a person's lithium levels cannot be obtained from these tubes; for this purpose, royal-blue-topped (and dark green-topped) vacutainers containing [[sodium]] heparin are used. |
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* [[Heparin-coated blood oxygenator]]s are available for use in heart-lung machines. Among other things, these specialized oxygenators are thought to improve overall [[biocompatibility]] and host homeostasis by providing characteristics similar to those of native endothelium. |
* [[Heparin-coated blood oxygenator]]s are available for use in heart-lung machines. Among other things, these specialized oxygenators are thought to improve overall [[biocompatibility]] and host homeostasis by providing characteristics similar to those of native endothelium. |
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* The DNA binding sites on [[RNA polymerase]] can be occupied by heparin, preventing the polymerase from binding to promoter DNA. This property is exploited in a range of molecular biological assays. |
* The DNA binding sites on [[RNA polymerase]] can be occupied by heparin, preventing the polymerase from binding to promoter DNA. This property is exploited in a range of molecular biological assays. |
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* Common diagnostic procedures require [[PCR]] amplification of a patient's DNA, which is easily extracted from white blood cells treated with heparin. This poses a potential problem, since heparin may be extracted along with the DNA, and it has been found to interfere with the PCR reaction at levels as low as 0.002 U in a 50 μL reaction mixture.<ref>{{cite journal | vauthors = Yokota M, Tatsumi N, Nathalang O, Yamada T, Tsuda I |
* Common diagnostic procedures require [[Polymerase chain reaction|PCR]] amplification of a patient's DNA, which is easily extracted from white blood cells treated with heparin. This poses a potential problem, since heparin may be extracted along with the DNA, and it has been found to interfere with the PCR reaction at levels as low as 0.002 U in a 50 μL reaction mixture.<ref>{{cite journal | vauthors = Yokota M, Tatsumi N, Nathalang O, Yamada T, Tsuda I | title = Effects of heparin on polymerase chain reaction for blood white cells | journal = Journal of Clinical Laboratory Analysis | volume = 13 | issue = 3 | pages = 133–40 | year = 1999 | pmid = 10323479 | pmc = 6807949 | doi = 10.1002/(SICI)1098-2825(1999)13:3<133::AID-JCLA8>3.0.CO;2-0 }}</ref> |
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* Heparin has been used as a [[chromatography]] resin, acting as both an [[affinity chromatography|affinity ligand]] and an [[ion-exchange resin|ion exchanger]].<ref>{{cite book| vauthors=Xiong S, Zhang L, He QY| title=2D PAGE: Sample Preparation and Fractionation| chapter=Fractionation of proteins by heparin chromatography| volume=424| pages=[https://archive.org/details/2dpagesampleprep00anto/page/213 213–21]| year=2008| doi=10.1007/978-1-60327-064-9_18| pmid=18369865| series=Methods in Molecular Biology | isbn=978-1-58829-722-8| chapter-url=https://archive.org/details/2dpagesampleprep00anto/page/213}}</ref><ref>{{cite web| website=Sigma-Aldrich| title=Affinity Chromatography| url=http://www.sigmaaldrich.com/life-science/proteomics/protein-chromatography/affinity-chromatography.html#heparin| url-status=live| archive-url=https://web.archive.org/web/20160507193750/http://www.sigmaaldrich.com/life-science/proteomics/protein-chromatography/affinity-chromatography.html#heparin| archive-date=2016 |
* Heparin has been used as a [[chromatography]] resin, acting as both an [[affinity chromatography|affinity ligand]] and an [[ion-exchange resin|ion exchanger]].<ref>{{cite book| vauthors=Xiong S, Zhang L, He QY| title=2D PAGE: Sample Preparation and Fractionation| chapter=Fractionation of proteins by heparin chromatography| volume=424| pages=[https://archive.org/details/2dpagesampleprep00anto/page/213 213–21]| year=2008| doi=10.1007/978-1-60327-064-9_18| pmid=18369865| series=Methods in Molecular Biology | isbn=978-1-58829-722-8| chapter-url=https://archive.org/details/2dpagesampleprep00anto/page/213}}</ref><ref>{{cite web| website=Sigma-Aldrich| title=Affinity Chromatography| url=http://www.sigmaaldrich.com/life-science/proteomics/protein-chromatography/affinity-chromatography.html#heparin| url-status=live| archive-url=https://web.archive.org/web/20160507193750/http://www.sigmaaldrich.com/life-science/proteomics/protein-chromatography/affinity-chromatography.html#heparin| archive-date=7 May 2016}}</ref><ref>{{cite web| website=GE Healthcare Life Sciences| title=HiTrap Heparin HP| url=http://www.gelifesciences.com/webapp/wcs/stores/servlet/ProductDisplay?categoryId=11426&catalogId=10101&productId=21154&storeId=11786&langId=-1| url-status=live| archive-url=https://web.archive.org/web/20170801195351/http://www.gelifesciences.com/webapp/wcs/stores/servlet/ProductDisplay?categoryId=11426&catalogId=10101&productId=21154&storeId=11786&langId=-1| archive-date=1 August 2017}}</ref> Its polyanionic structure can mimic nucleic acids like DNA and RNA, making it useful for purification of nucleic acid-binding proteins including [[DNA polymerase|DNA]] and [[RNA polymerase]]s and [[transcription factor]]s.<ref>{{Cite web|url=https://www.sigmaaldrich.com/technical-documents/protocols/biology/affinity-chromatography/separating-dna-binding-proteins-with-heparin.html|title=Performing a Separation of DNA binding proteins with GE Healthcare Products Based on Heparin|website=Sigma-Aldrich|access-date=16 April 2019|archive-date=16 April 2019|archive-url=https://web.archive.org/web/20190416120906/https://www.sigmaaldrich.com/technical-documents/protocols/biology/affinity-chromatography/separating-dna-binding-proteins-with-heparin.html|url-status=live}}</ref> Heparin's specific affinity for [[Vesicular stomatitis virus|VSV-G]],<ref>{{cite journal | vauthors = Guibinga GH, Miyanohara A, Esko JD, Friedmann T | title = Cell surface heparan sulfate is a receptor for attachment of envelope protein-free retrovirus-like particles and VSV-G pseudotyped MLV-derived retrovirus vectors to target cells | journal = Molecular Therapy | volume = 5 | issue = 5 Pt 1 | pages = 538–46 | date = May 2002 | pmid = 11991744 | doi = 10.1006/mthe.2002.0578 | doi-access = free }}</ref> a [[viral envelope]] [[glycoprotein]] often used to [[pseudotype]] [[retrovirus|retroviral]] and [[lentivirus|lentiviral]] [[Viral vector|vectors]] for [[gene therapy]], allows it to be used for downstream purification of viral vectors.<ref>{{cite book| chapter=Purification of retrovirus particles using heparin affinity chromatography| vauthors=Segura MM, Kamen A, Garnier A| series=Methods in Molecular Biology| volume=434| year=2008| issue=434| pages=1–11| doi=10.1007/978-1-60327-248-3_1| pmid=18470635| isbn=978-1-60327-247-6| title=Gene Therapy Protocols}}</ref><ref>{{cite journal | vauthors = Segura MM, Kamen A, Trudel P, Garnier A | title = A novel purification strategy for retrovirus gene therapy vectors using heparin affinity chromatography | journal = Biotechnology and Bioengineering | volume = 90 | issue = 4 | pages = 391–404 | date = May 2005 | pmid = 15812800 | doi = 10.1002/bit.20301 }}</ref> |
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* Heparin is being trialed in a nasal spray form as prophylaxis against [[COVID-19]] infection.<ref>{{cite news| |
* Heparin is being trialed in a nasal spray form as prophylaxis against [[COVID-19]] infection.<ref>{{cite news|vauthors=Rollason B|newspaper=ABC News|title=Melbourne researchers trial use of common blood-thinning drug heparin to combat COVID-19|date=21 December 2021|url=https://www.abc.net.au/news/2021-12-22/melbourne-researchers-trial-use-of-common-drug-to-combat-covid/100717224|access-date=22 December 2021|archive-date=22 December 2021|archive-url=https://web.archive.org/web/20211222090726/https://www.abc.net.au/news/2021-12-22/melbourne-researchers-trial-use-of-common-drug-to-combat-covid/100717224|url-status=live}}</ref> Furthermore, its reported from trials that due to anti-viral, anti-inflammatory and its anti-clotting effects its inhalation could improve at a 70% rate on patients that were actively struck by a COVID-19 infection.<ref>{{Cite web | vauthors=Margo J | url=https://www.afr.com/policy/health-and-education/a-70-year-old-drug-may-be-the-answer-to-treating-covid-19-20220119-p59pjt | title=A 70-year-old drug may be the answer to treating COVID-19 | publisher=The Australian Financial Review | date=19 January 2022 | url-access=subscription | access-date=22 January 2022 | archive-date=22 January 2022 | archive-url=https://web.archive.org/web/20220122081032/https://www.afr.com/policy/health-and-education/a-70-year-old-drug-may-be-the-answer-to-treating-covid-19-20220119-p59pjt | url-status=live }}</ref> |
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==Society and culture== |
==Society and culture== |
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Considering the animal source of pharmaceutical heparin, the numbers of potential impurities are relatively large compared with a wholly synthetic therapeutic agent. The range of possible biological contaminants includes viruses, bacterial endotoxins, transmissible spongiform encephalopathy (TSE) agents, lipids, proteins, and DNA. During the preparation of pharmaceutical-grade heparin from animal tissues, impurities such as solvents, heavy metals, and extraneous cations can be introduced. However, the methods employed to minimize the occurrence and to identify and/or eliminate these contaminants are well established and listed in guidelines and pharmacopoeias. The major challenge in the analysis of heparin impurities is the detection and identification of structurally related impurities. The most prevalent impurity in heparin is dermatan sulfate (DS), also known as chondroitin sulfate B. The building-block of DS is a disaccharide composed of 1,3-linked N-acetyl galactosamine (GalN) and a uronic acid residue, connected via 1,4 linkages to form the polymer. DS is composed of three possible uronic acid (GlcA, IdoA or IdoA2S) and four possible hexosamine (GalNAc, Gal- NAc4S, GalNAc6S, or GalNAc4S6S) building-blocks. The presence of iduronic acid in DS distinguishes it from chrondroitin sulfate A and C and likens it to heparin and HS. DS has a lower negative charge density overall compared to heparin. A common natural contaminant, DS is present at levels of 1–7% in heparin API, but has no proven biological activity that influences the anticoagulation effect of heparin.<ref>{{cite journal | vauthors = Beni S, Limtiaco JF, Larive CK | title = Analysis and characterization of heparin impurities | journal = Analytical and Bioanalytical Chemistry | volume = 399 | issue = 2 | pages = 527–39 | date = January 2011 | pmid = 20814668 | pmc = 3015169 | doi = 10.1007/s00216-010-4121-x }}</ref> |
Considering the animal source of pharmaceutical heparin, the numbers of potential impurities are relatively large compared with a wholly synthetic therapeutic agent. The range of possible biological contaminants includes viruses, bacterial endotoxins, transmissible spongiform encephalopathy (TSE) agents, lipids, proteins, and DNA. During the preparation of pharmaceutical-grade heparin from animal tissues, impurities such as solvents, heavy metals, and extraneous cations can be introduced. However, the methods employed to minimize the occurrence and to identify and/or eliminate these contaminants are well established and listed in guidelines and pharmacopoeias. The major challenge in the analysis of heparin impurities is the detection and identification of structurally related impurities. The most prevalent impurity in heparin is dermatan sulfate (DS), also known as chondroitin sulfate B. The building-block of DS is a disaccharide composed of 1,3-linked N-acetyl galactosamine (GalN) and a uronic acid residue, connected via 1,4 linkages to form the polymer. DS is composed of three possible uronic acid (GlcA, IdoA or IdoA2S) and four possible hexosamine (GalNAc, Gal- NAc4S, GalNAc6S, or GalNAc4S6S) building-blocks. The presence of iduronic acid in DS distinguishes it from chrondroitin sulfate A and C and likens it to heparin and HS. DS has a lower negative charge density overall compared to heparin. A common natural contaminant, DS is present at levels of 1–7% in heparin API, but has no proven biological activity that influences the anticoagulation effect of heparin.<ref>{{cite journal | vauthors = Beni S, Limtiaco JF, Larive CK | title = Analysis and characterization of heparin impurities | journal = Analytical and Bioanalytical Chemistry | volume = 399 | issue = 2 | pages = 527–39 | date = January 2011 | pmid = 20814668 | pmc = 3015169 | doi = 10.1007/s00216-010-4121-x }}</ref> |
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In December 2007, the [[Food and Drug Administration (United States)|US Food and Drug Administration]] (FDA) recalled a shipment of heparin because of bacterial growth (''[[Serratia marcescens]]'') in several unopened syringes of this product. ''S. marcescens'' can lead to life-threatening injuries and/or death.<ref>{{cite press release| title= AM2 PAT, Inc. Issues Nationwide Recall of Pre-Filled Heparin Lock Flush Solution USP (5 mL in 12 mL Syringes)| url= https://www.fda.gov/oc/po/firmrecalls/am2pat12_07.html| agency= US FDA| date= |
In December 2007, the [[Food and Drug Administration (United States)|US Food and Drug Administration]] (FDA) recalled a shipment of heparin because of bacterial growth (''[[Serratia marcescens]]'') in several unopened syringes of this product. ''S. marcescens'' can lead to life-threatening injuries and/or death.<ref>{{cite press release| title= AM2 PAT, Inc. Issues Nationwide Recall of Pre-Filled Heparin Lock Flush Solution USP (5 mL in 12 mL Syringes)| url= https://www.fda.gov/oc/po/firmrecalls/am2pat12_07.html| agency= US FDA| date= 20 December 2007| archive-url = https://web.archive.org/web/20071223165114/https://www.fda.gov/oc/po/firmrecalls/am2pat12_07.html| archive-date = 23 December 2007}}</ref> |
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====2008 recall due to adulteration in drug from China==== |
====2008 recall due to adulteration in drug from China==== |
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{{Main|2008 Chinese heparin adulteration}} |
{{Main|2008 Chinese heparin adulteration}} |
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In March 2008, major [[Product recall|recalls]] of heparin were announced by the FDA due to contamination of the raw heparin stock imported from China.<ref>{{cite news |author=CBS News|url=http://www.cbsnews.com/stories/2008/03/01/eveningnews/main3896578.shtml |title=Blood-thinning drug under suspicion|archive-url=https://web.archive.org/web/20121023013930/http://www.cbsnews.com/stories/2008/03/01/eveningnews/main3896578.shtml |archive-date= |
In March 2008, major [[Product recall|recalls]] of heparin were announced by the FDA due to contamination of the raw heparin stock imported from China.<ref>{{cite news |author=CBS News|url=http://www.cbsnews.com/stories/2008/03/01/eveningnews/main3896578.shtml |title=Blood-thinning drug under suspicion|archive-url=https://web.archive.org/web/20121023013930/http://www.cbsnews.com/stories/2008/03/01/eveningnews/main3896578.shtml |archive-date=23 October 2012}}</ref><ref>{{cite press release| title = Information on Heparin| url= https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM112597| agency= US FDA| archive-url = https://web.archive.org/web/20120415102511/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM112597| archive-date = 15 April 2012}}</ref> According to the FDA, the adulterated heparin killed nearly 80 people in the United States.<ref>{{Cite news|url=https://www.drugdiscoveryonline.com/doc/the-past-and-future-of-managing-raw-material-and-process-risks-in-biomanufacturing-0001|title=The Past And Future Of Managing Raw Material And Process Risks In Biomanufacturing|vauthors=Darby N|date=18 September 2018|work=Drug Discovery Online|access-date=1 November 2018|publisher=VertMarkets|at=A Supply Chain Under Scrutiny|archive-date=1 November 2018|archive-url=https://web.archive.org/web/20181101140243/https://www.drugdiscoveryonline.com/doc/the-past-and-future-of-managing-raw-material-and-process-risks-in-biomanufacturing-0001|url-status=live}}</ref> The adulterant was identified as an "over-sulphated" derivative of [[chondroitin sulfate]], a popular shellfish-derived supplement often used for [[arthritis]], which was intended to substitute for actual heparin in potency tests.<ref>{{cite web|url=https://www.fda.gov/downloads/NewsEvents/Newsroom/MediaTranscripts/UCM169342.pdf|title=FDA Media Briefing on Heparin|publisher=[[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] | vauthors = Zawisza J |date=29 March 2008|access-date=23 April 2008|url-status=live|archive-url=https://web.archive.org/web/20100306183003/https://www.fda.gov/downloads/NewsEvents/Newsroom/MediaTranscripts/UCM169342.pdf|archive-date=6 March 2010}}</ref> |
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According to the ''New York Times'': "Problems with heparin reported to the agency include difficulty breathing, nausea, vomiting, excessive sweating and rapidly falling blood pressure that in some cases led to life-threatening shock". |
According to the ''New York Times'': "Problems with heparin reported to the agency include difficulty breathing, nausea, vomiting, excessive sweating and rapidly falling blood pressure that in some cases led to life-threatening shock". |
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===Use in homicide=== |
===Use in homicide=== |
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In 2006, [[Petr Zelenka (serial killer)|Petr Zelenka]], a nurse in the [[Czech Republic]], deliberately administered large doses to patients, killing seven, and attempting to kill ten others.<ref>{{cite news| |
In 2006, [[Petr Zelenka (serial killer)|Petr Zelenka]], a nurse in the [[Czech Republic]], deliberately administered large doses to patients, killing seven, and attempting to kill ten others.<ref>{{cite news| vauthors = Velinger J |url=http://www.radio.cz/en/article/85964|title=Nurse committed murders to "test" doctors|publisher=Radio Praha|date=12 May 2006|archive-url=https://web.archive.org/web/20090924090006/http://www.radio.cz/en/article/85964 |archive-date=24 September 2009}}</ref> |
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===Overdose issues=== |
===Overdose issues=== |
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In 2007, a nurse at [[Cedars-Sinai Medical Center]] mistakenly gave the 12-day-old twins of actor [[Dennis Quaid]] a dose of heparin that was 1,000 times the recommended dose for infants.<ref>{{cite web | vauthors = Ornstein C, Gorman A | date = 21 November 2007 | work = [[Los Angeles Times]] | url = http://www.cnn.com/2007/SHOWBIZ/Movies/11/21/quaid.newborns.ap/index.html | title = Report: Dennis Quaid's twins get accidental overdose | archive-url = https://web.archive.org/web/20080307193136/http://www.cnn.com/2007/SHOWBIZ/Movies/11/21/quaid.newborns.ap/index.html | archive-date=March |
In 2007, a nurse at [[Cedars-Sinai Medical Center]] mistakenly gave the 12-day-old twins of actor [[Dennis Quaid]] a dose of heparin that was 1,000 times the recommended dose for infants.<ref>{{cite web | vauthors = Ornstein C, Gorman A | date = 21 November 2007 | work = [[Los Angeles Times]] | url = http://www.cnn.com/2007/SHOWBIZ/Movies/11/21/quaid.newborns.ap/index.html | title = Report: Dennis Quaid's twins get accidental overdose | archive-url = https://web.archive.org/web/20080307193136/http://www.cnn.com/2007/SHOWBIZ/Movies/11/21/quaid.newborns.ap/index.html | archive-date=7 March 2008}}</ref> The overdose allegedly arose because the labeling and design of the adult and infant versions of the product were similar. The Quaid family subsequently sued the manufacturer, [[Baxter Healthcare Corp.]],<ref>{{cite web | vauthors = Jablon R | url = https://www.usatoday.com/life/people/2007-12-04-quaid-lawsuit_N.htm | title = Dennis Quaid and wife sue drug maker | archive-url = https://web.archive.org/web/20100628031940/http://www.usatoday.com/life/people/2007-12-04-quaid-lawsuit_N.htm | archive-date= 28 June 2010| work = USA Today | date = 4 December 2007 }}</ref><ref>{{cite news| vauthors = Ornstein C |url=http://www.latimes.com/features/health/la-me-quaid5dec05,1,1883436.story|title=Dennis Quaid files suit over drug mishap|archive-url=https://web.archive.org/web/20080704134949/http://www.latimes.com/features/health/la-me-quaid5dec05,1,1883436.story |archive-date=4 July 2008|work=Los Angeles Times|date=5 December 2007}}</ref> and settled with the hospital for $750,000.<ref>{{cite news|url=http://www.sfgate.com/cgi-bin/blogs/dailydish/detail?blogid=7&entry_id=33678|title=Quaid Awarded $750,000 Over Hospital Negligence|archive-url=https://web.archive.org/web/20090415140001/http://www.sfgate.com/cgi-bin/blogs/dailydish/detail?blogid=7&entry_id=33678|archive-date=15 April 2009|publisher= SFGate.com|date=16 December 2008}}</ref> Prior to the Quaid accident, six newborn babies at Methodist Hospital in Indianapolis, Indiana, were given an overdose. Three of the babies died after the mistake.<ref>{{cite news| vauthors = Sanz A |url=http://www.wthr.com/Global/story.asp?s=5418800 |title=Coroner's office investigates infant deaths |archive-url= https://web.archive.org/web/20110629131727/http://www.wthr.com/Global/story.asp?s=5418800 |archive-date=29 June 2011|publisher=WTHR NBC News}}</ref> |
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In July 2008, another set of twins born at Christus Spohn Hospital South, in [[Corpus Christi, Texas]], died after an accidentally administered overdose of the drug. The overdose was due to a mixing error at the hospital pharmacy and was unrelated to the product's packaging or labeling.<ref>[http://christusspohn.netreturns.biz/NewsReleases/Article_Detail.aspx?id=b8250e15-c437-48f3-8345-edc85a47565a Statement by Dr. Richard Davis, Chief Medical Officer, CHRISTUS Spohn Health System]{{dead link|date=September 2017 |bot=Level C |fix-attempted=yes}}, July |
In July 2008, another set of twins born at Christus Spohn Hospital South, in [[Corpus Christi, Texas]], died after an accidentally administered overdose of the drug. The overdose was due to a mixing error at the hospital pharmacy and was unrelated to the product's packaging or labeling.<ref>[http://christusspohn.netreturns.biz/NewsReleases/Article_Detail.aspx?id=b8250e15-c437-48f3-8345-edc85a47565a Statement by Dr. Richard Davis, Chief Medical Officer, CHRISTUS Spohn Health System]{{dead link|date=September 2017 |bot=Level C |fix-attempted=yes}}, 10 July 2008</ref> {{As of|2008|7}}, the exact cause of the twins' death was under investigation.<ref>{{cite news|url=http://www.dallasnews.com/sharedcontent/dws/news/texassouthwest/stories/DN-bloodthinner_11tex.ART.State.Edition1.4d4aa44.html |title=At a Glance Heparin Overdose at Hospital|archive-url=https://web.archive.org/web/20081025104636/http://www.dallasnews.com/sharedcontent/dws/news/texassouthwest/stories/DN-bloodthinner_11tex.ART.State.Edition1.4d4aa44.html |archive-date=25 October 2008 |publisher=Dallas Morning News |date=11 July 2008}}</ref><ref>{{cite news| vauthors = Vonfremd M, Ibanga I |url= https://abcnews.go.com/GMA/Parenting/story?id=5346509&page=1 |title=Officials Investigate Infants' Heparin OD at Texas Hospital |archive-url=https://web.archive.org/web/20080711162058/https://abcnews.go.com/GMA/Parenting/story?id=5346509&page=1 |archive-date=11 July 2008 |publisher=ABC News |date=11 July 2008 |access-date=24 July 2008}}</ref> |
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In March 2010, a two-year-old transplant patient from Texas was given a lethal dose of heparin at the University of Nebraska Medical Center. The exact circumstances surrounding her death are still under investigation.<ref>{{cite news|url=http://www.ketv.com/news/23020944/detail.html |title=Nebraska Med. Center Investigates Staff After Girl's Death |archive-url=https://web.archive.org/web/20120320093130/http://www.ketv.com/news/23020944/detail.html |archive-date= |
In March 2010, a two-year-old transplant patient from Texas was given a lethal dose of heparin at the [[University of Nebraska Medical Center]]. The exact circumstances surrounding her death are still under investigation.<ref>{{cite news|url=http://www.ketv.com/news/23020944/detail.html |title=Nebraska Med. Center Investigates Staff After Girl's Death |archive-url=https://web.archive.org/web/20120320093130/http://www.ketv.com/news/23020944/detail.html |archive-date=20 March 2012 |publisher=KETV Omaha |date=31 March 2010}}</ref> |
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===Production=== |
===Production=== |
||
Pharmaceutical-grade heparin is derived from [[mucosal]] tissues of [[slaughterhouse|slaughtered]] meat animals such as [[porcine]] (pig) intestines or [[bovine]] (cattle) lungs.<ref>{{cite journal | vauthors = Linhardt RJ, Gunay NS | title = Production and chemical processing of low molecular weight heparins | journal = Seminars in Thrombosis and Hemostasis | volume = 25 | issue = Suppl 3 | pages = 5–16 | year = 1999 | pmid = 10549711 }}</ref> Advances to produce heparin synthetically have been made in 2003 and 2008.<ref>{{cite web| vauthors = Bhattacharya A |title=Flask synthesis promises untainted heparin|url=http://www.rsc.org/chemistryworld/News/2008/August/19080803.asp|work=Chemistry World|publisher=Royal Society of Chemistry|access-date=6 February 2011|date=August 2008|url-status=live|archive-url=https://web.archive.org/web/20121021055549/http://www.rsc.org/chemistryworld/News/2008/August/19080803.asp|archive-date=21 October 2012}}</ref> In 2011, a chemoenzymatic process of synthesizing low molecular weight heparins from simple disaccharides was reported.<ref>{{cite journal | vauthors = Xu Y, Masuko S, Takieddin M, Xu H, Liu R, Jing J, Mousa SA, Linhardt RJ, Liu J |
Pharmaceutical-grade heparin is derived from [[mucosal]] tissues of [[slaughterhouse|slaughtered]] meat animals such as [[porcine]] (pig) intestines or [[bovine]] (cattle) lungs.<ref>{{cite journal | vauthors = Linhardt RJ, Gunay NS | title = Production and chemical processing of low molecular weight heparins | journal = Seminars in Thrombosis and Hemostasis | volume = 25 | issue = Suppl 3 | pages = 5–16 | year = 1999 | pmid = 10549711 }}</ref> Advances to produce heparin synthetically have been made in 2003 and 2008.<ref>{{cite web| vauthors = Bhattacharya A |title=Flask synthesis promises untainted heparin|url=http://www.rsc.org/chemistryworld/News/2008/August/19080803.asp|work=Chemistry World|publisher=Royal Society of Chemistry|access-date=6 February 2011|date=August 2008|url-status=live|archive-url=https://web.archive.org/web/20121021055549/http://www.rsc.org/chemistryworld/News/2008/August/19080803.asp|archive-date=21 October 2012}}</ref> In 2011, a chemoenzymatic process of synthesizing low molecular weight heparins from simple disaccharides was reported.<ref>{{cite journal | vauthors = Xu Y, Masuko S, Takieddin M, Xu H, Liu R, Jing J, Mousa SA, Linhardt RJ, Liu J | title = Chemoenzymatic synthesis of homogeneous ultralow molecular weight heparins | journal = Science | volume = 334 | issue = 6055 | pages = 498–501 | date = October 2011 | pmid = 22034431 | pmc = 3425363 | doi = 10.1126/science.1207478 | bibcode = 2011Sci...334..498X }}</ref> |
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===Research=== |
===Research=== |
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| |'''Disease states sensitive to heparin'''||'''Heparin's effect in experimental models''' || '''Clinical status''' |
| |'''Disease states sensitive to heparin'''||'''Heparin's effect in experimental models''' || '''Clinical status''' |
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|| [[Acquired immunodeficiency syndrome]] || Reduces the ability of [[human immunodeficiency virus]] types 1 and 2 to adsorb to cultured T4 cells.<ref>{{cite journal | vauthors = Baba M, Pauwels R, Balzarini J, Arnout J, Desmyter J, De Clercq E |
|| [[Acquired immunodeficiency syndrome]] || Reduces the ability of [[human immunodeficiency virus]] types 1 and 2 to adsorb to cultured T4 cells.<ref>{{cite journal | vauthors = Baba M, Pauwels R, Balzarini J, Arnout J, Desmyter J, De Clercq E | title = Mechanism of inhibitory effect of dextran sulfate and heparin on replication of human immunodeficiency virus in vitro | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 85 | issue = 16 | pages = 6132–6 | date = August 1988 | pmid = 2457906 | pmc = 281919 | doi = 10.1073/pnas.85.16.6132 | bibcode = 1988PNAS...85.6132B | doi-access = free }}</ref> || – |
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|| [[Adult respiratory distress syndrome]] || Reduces cell activation and accumulation in airways, neutralizes mediators and cytotoxic cell products, and improves lung function in animal models || Controlled [[clinical trial]]s |
|| [[Adult respiratory distress syndrome]] || Reduces cell activation and accumulation in airways, neutralizes mediators and cytotoxic cell products, and improves lung function in animal models || Controlled [[clinical trial]]s |
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== External links == |
== External links == |
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{{commons category|Heparins}} |
{{commons category|Heparins}} |
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* {{cite web|url=https://druginfo.nlm.nih.gov/drugportal/name/heparin |publisher=U.S. National Library of Medicine |work=Drug Information Portal |title=Heparin}} |
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* [https://web.archive.org/web/20070823120920/http://www.healthheritageresearch.com/Heparin-Conntact9608.html History of heparin] |
* [https://web.archive.org/web/20070823120920/http://www.healthheritageresearch.com/Heparin-Conntact9608.html History of heparin] |
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{{Glycosaminoglycans}} |
{{Glycosaminoglycans}} |
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{{Portal bar | Medicine}} |
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[[Category:Wikipedia medicine articles ready to translate]] |
[[Category:Wikipedia medicine articles ready to translate]] |
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[[Category:Aldols]] |
[[Category:Aldols]] |
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[[Category:Ophthalmology drugs]] |
Revision as of 13:49, 17 July 2024
![]() | |
Clinical data | |
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Pronunciation | /ˈhɛpərɪn/ HEP-ər-in |
AHFS/Drugs.com | Monograph |
License data | |
Pregnancy category |
|
Routes of administration | Intravenous therapy, subcutaneous injection |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | Erratic |
Metabolism | Liver |
Elimination half-life | 1.5 hours |
Excretion | Urine[2] |
Identifiers | |
CAS Number | |
PubChem CID | |
IUPHAR/BPS | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEMBL | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.029.698 |
Chemical and physical data | |
Formula | C12H19NO20S3 |
Molar mass | 593.45 g·mol−1 |
| |
![]() ![]() |
Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan.[3][4] Heparin is a blood anticoagulant that increases the activity of antithrombin.[5] It is used in the treatment of heart attacks and unstable angina.[3] It can be given intravenously or by injection under the skin.[3] Its anticoagulant properties make it useful to prevent blood clotting in blood specimen test tubes and kidney dialysis machines.[4][6]
Common side effects include bleeding, pain at the injection site, and low blood platelets.[3] Serious side effects include heparin-induced thrombocytopenia.[3] Greater care is needed in those with poor kidney function.[3]
Heparin is contraindicated for suspected cases of vaccine-induced pro-thrombotic immune thrombocytopenia (VIPIT) secondary to SARS-CoV-2 vaccination, as heparin may further increase the risk of bleeding in an anti-PF4/heparin complex autoimmune manner, in favor of alternative anticoagulant medications (such as argatroban or danaparoid).[7][8][9]
Heparin appears to be relatively safe for use during pregnancy and breastfeeding.[10] Heparin is produced by basophils and mast cells in all mammals.[11]
The discovery of heparin was announced in 1916.[12] It is on the World Health Organization's List of Essential Medicines.[13] A fractionated version of heparin, known as low molecular weight heparin, is also available.[14]
History
Heparin was discovered by Jay McLean and William Henry Howell in 1916, although it did not enter clinical trials until 1935.[15] It was originally isolated from dog liver cells, hence its name (ἧπαρ hēpar is Greek for 'liver'; hepar + -in).
McLean was a second-year medical student at Johns Hopkins University, and was working under the guidance of Howell investigating pro-coagulant preparations, when he isolated a fat-soluble phosphatide anticoagulant in canine liver tissue.[16] In 1918, Howell coined the term 'heparin' for this type of fat-soluble anticoagulant. In the early 1920s, Howell isolated a water-soluble polysaccharide anticoagulant, which he also termed 'heparin', although it was different from the previously discovered phosphatide preparations.[17][18] McLean's work as a surgeon probably changed the focus of the Howell group to look for anticoagulants, which eventually led to the polysaccharide discovery.
It had at first been accepted that it was Howell who discovered heparin. However in the 1940s, Jay McLean became unhappy that he had not received appropriate recognition for what he saw as his own discovery. Though relatively discreet about his claim and not wanting to upset his former chief, he gave lectures and wrote letters claiming that the discovery was his. This gradually became accepted as fact, and indeed after his death in 1959, his obituary credited him as being the true discoverer of heparin. This was elegantly restated in 1963 in a plaque unveiled in Johns Hopkins to commemorate the major contribution (of McLean) to the discovery of heparin in 1916 in collaboration with Professor William Henry Howell.[19]
In the 1930s, several researchers were investigating heparin. Erik Jorpes at Karolinska Institutet published his research on the structure of heparin in 1935,[20] which made it possible for the Swedish company Vitrum AB to launch the first heparin product for intravenous use in 1936. Between 1933 and 1936, Connaught Medical Research Laboratories, then a part of the University of Toronto, perfected a technique for producing safe, nontoxic heparin that could be administered to patients, in a saline solution. The first human trials of heparin began in May 1935, and, by 1937, it was clear that Connaught's heparin was safe, easily available, and effective as a blood anticoagulant. Prior to 1933, heparin was available in small amounts, was extremely expensive and toxic, and, as a consequence, of no medical value.[21]
Heparin production experienced a break in the 1990s. Until then, heparin was mainly obtained from cattle tissue, which was a by-product of the meat industry, especially in North America. With the rapid spread of BSE, more and more manufacturers abandoned this source of supply. As a result, global heparin production became increasingly concentrated in China, where the substance was now procured from the expanding industry of breeding and slaughtering hog. The dependence of medical care on the meat industry assumed threatening proportions in the wake of the COVID-19 pandemic. In 2020, several studies demonstrated the efficacy of heparin in mitigating severe disease progression, as its anticoagulant effect counteracted the formation of immunothrombosis. However, the availability of heparin on the world market was decreased, because concurrently a renewed swine flu epidemic had reduced significant portions of the Chinese hog population. The situation was further exacerbated by the fact that mass slaughterhouses around the world became corona hotspots themselves and were forced to close temporarily. In less affluent countries, the resulting heparin shortage also led to worsened health care beyond the treatment of covid, for example through the cancellation of cardiac surgeries.[22]
Medical use
![](http://upload.wikimedia.org/wikipedia/commons/thumb/d/d0/Heparin_Sodium_sample.jpg/220px-Heparin_Sodium_sample.jpg)
Heparin acts as an anticoagulant, preventing the formation of clots and extension of existing clots within the blood. While heparin itself does not break down clots that have already formed (unlike tissue plasminogen activator), it allows the body's natural clot lysis mechanisms to work normally to break down clots that have formed. Heparin is generally used for anticoagulation for the following conditions:[23]
- Acute coronary syndrome, e.g., NSTEMI
- Atrial fibrillation
- Deep-vein thrombosis and pulmonary embolism (both prevention and treatment)
- Other thrombotic states and conditions
- Cardiopulmonary bypass for heart surgery
- ECMO circuit for extracorporeal life support
- Hemofiltration
- Indwelling central or peripheral venous catheters
Heparin and its low-molecular-weight derivatives (e.g., enoxaparin, dalteparin, tinzaparin) are effective in preventing deep vein thromboses and pulmonary emboli in people at risk,[24][25] but no evidence indicates any one is more effective than the other in preventing mortality.[26]
In angiography, 2 to 5 units/mL of unfractionated heparin saline flush is used as a locking solution to prevent the clotting of blood in guidewires, sheaths, and catheters, thus preventing thrombus from dislodging from these devices into the circulatory system .[27][28]
Unfractionated heparin is used in hemodialysis. Comparing to low-molecular-weight heparin, unfractionated heparin does not have prolonged anticoagulation action after dialysis, and low cost. However, the short duration of action for heparin would require it to maintain continuous infusion to maintain its action. Meanwhile, unfractionated heparin has higher risk of heparin-induced thrombocytopenia.[29]
Adverse effects
A serious side-effect of heparin is heparin-induced thrombocytopenia (HIT), caused by an immunological reaction that makes platelets a target of immunological response, resulting in the degradation of platelets, which causes thrombocytopenia.[30] This condition is usually reversed on discontinuation, and in general can be avoided with the use of synthetic heparins. Not all patients with heparin antibodies will develop thrombocytopenia. Also, a benign form of thrombocytopenia is associated with early heparin use, which resolves without stopping heparin. Approximately one-third of patients with diagnosed heparin-induced thrombocytopenia will ultimately develop thrombotic complications.[31]
Two non-hemorrhagic 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.[23]
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.[32]
Contraindications
Heparin is contraindicated in those with risk of bleeding (especially in people with uncontrolled blood pressure, liver disease, and stroke), severe liver disease, or severe hypertension.[33]
Antidote to heparin
Protamine sulfate has been given to counteract the anticoagulant effect of heparin (1 mg per 100 units of heparin that had been given over the past 6 hours).[34] It may be used in those who overdose on heparin or to reverse heparin's effect when it is no longer needed.[35]
Physiological function
Heparin's normal role in the body is unclear. Heparin is usually stored within the secretory granules of mast cells and released only into the vasculature at sites of tissue injury. It has been proposed that, rather than anticoagulation, the main purpose of heparin is defense at such sites against invading bacteria and other foreign materials.[36] In addition, it is observed across a number of widely different species, including some invertebrates that do not have a similar blood coagulation system. It is a highly sulfated glycosaminoglycan. It has the highest negative charge density of any known biological molecule.[37]
Evolutionary conservation
In addition to the bovine and porcine tissue from which pharmaceutical-grade heparin is commonly extracted, it has also been extracted and characterized from:
The biological activity of heparin within species 6–11 is unclear and further supports the idea that the main physiological role of heparin is not anticoagulation. These species do not possess any blood coagulation system similar to that present within the species listed 1–5. The above list also demonstrates how heparin has been highly evolutionarily conserved, with molecules of a similar structure being produced by a broad range of organisms belonging to many different phyla.[citation needed]
Pharmacology
In nature, heparin is a polymer of varying chain size. Unfractionated heparin (UFH) as a pharmaceutical is heparin that has not been fractionated to sequester the fraction of molecules with low molecular weight. In contrast, low-molecular-weight heparin (LMWH) has undergone fractionation for the purpose of making its pharmacodynamics more predictable. Often either UFH or LMWH can be used; in some situations one or the other is preferable.[51]
Mechanism of action
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.[52] The activated AT then inactivates thrombin, factor Xa and other proteases. The rate of inactivation of these proteases by AT can increase by up to 1000-fold due to the binding of heparin.[53] Heparin binds to AT via a specific pentasaccharide sulfation sequence contained within the heparin polymer:
- GlcNAc/NS(6S)-GlcA-GlcNS(3S,6S)-IdoA(2S)-GlcNS(6S)
The conformational change in AT on heparin-binding mediates its inhibition of factor Xa. For thrombin inhibition, however, thrombin must also bind to the heparin polymer at a site proximal to the pentasaccharide. The highly negative charge density of heparin contributes to its very strong electrostatic interaction with thrombin.[37] The formation of a ternary complex between AT, thrombin, and heparin results in the inactivation of thrombin. For this reason, heparin's activity against thrombin is size-dependent, with the ternary complex requiring at least 18 saccharide units for efficient formation.[54] In contrast, antifactor Xa activity via AT requires only the pentasaccharide-binding site.
This size difference has led to the development of low-molecular-weight heparins (LMWHs) and fondaparinux as anticoagulants. Fondaparinux targets anti-factor Xa activity rather than inhibiting thrombin activity, with the aim of facilitating a more subtle regulation of coagulation and an improved therapeutic index. It is a synthetic pentasaccharide, whose chemical structure is almost identical to the AT binding pentasaccharide sequence that can be found within polymeric heparin and heparan sulfate.
With LMWH and fondaparinux, the risk of osteoporosis and heparin-induced thrombocytopenia (HIT) is reduced. Monitoring of the activated partial thromboplastin time is also not required and does not reflect the anticoagulant effect, as APTT is insensitive to alterations in factor Xa.
Danaparoid, a mixture of heparan sulfate, dermatan sulfate, and chondroitin sulfate can be used as an anticoagulant in patients having developed HIT. Because danaparoid does not contain heparin or heparin fragments, cross-reactivity of danaparoid with heparin-induced antibodies is reported as less than 10%.[55]
The effects of heparin are measured in the lab by the partial thromboplastin time (aPTT), one of the measures of the time it takes the blood plasma to clot. Partial thromboplastin time should not be confused with prothrombin time, or PT, which measures blood clotting time through a different pathway of the coagulation cascade.
Administration
![](http://upload.wikimedia.org/wikipedia/commons/thumb/4/4f/Heparin_1.jpg/220px-Heparin_1.jpg)
Heparin is given parenterally because it is not absorbed from the gut, due to its high negative charge and large size. It can be injected intravenously or subcutaneously (under the skin); intramuscular injections (into muscle) are avoided because of the potential for forming hematomas. Because of its short biologic half-life of about one hour, heparin must be given frequently or as a continuous infusion. Unfractionated heparin has a half-life of about one to two hours after infusion,[56] whereas LMWH has a half-life of four to five hours.[57] The use of LMWH has allowed once-daily dosing, thus not requiring a continuous infusion of the drug. If long-term anticoagulation is required, heparin is often used only to commence anticoagulation therapy until an oral anticoagulant e.g. warfarin takes effect.
The American College of Chest Physicians publishes clinical guidelines on heparin dosing.[58]
Natural degradation or clearance
Unfractionated heparin has a half-life of about one to two hours after infusion,[56] whereas low-molecular-weight heparin's half-life is about four times longer. Lower doses of heparin have a much shorter half-life than larger ones. Heparin binding to macrophage cells is internalized and depolymerized by the macrophages. It also rapidly binds to endothelial cells, which precludes the binding to antithrombin that results in anticoagulant action. For higher doses of heparin, endothelial cell binding will be saturated, such that clearance of heparin from the bloodstream by the kidneys will be a slower process.[59]
Chemistry
Heparin structure
![](http://upload.wikimedia.org/wikipedia/commons/thumb/7/78/Heparin_ball-and-stick.png/270px-Heparin_ball-and-stick.png)
Native heparin is a polymer with a molecular weight ranging from 3 to 30 kDa, although the average molecular weight of most commercial heparin preparations is in the range of 12 to 15 kDa.[60] 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.[61] The main disaccharide units that occur in heparin are shown below. The most common disaccharide unit* (see below) is composed of a 2-O-sulfated iduronic acid and 6-O-sulfated, N-sulfated glucosamine, IdoA(2S)-GlcNS(6S). For example, this makes up 85% of heparins from beef lung and about 75% of those from porcine intestinal mucosa.[62]
Not shown below are the rare disaccharides containing a 3-O-sulfated glucosamine (GlcNS(3S,6S)) or a free amine group (GlcNH3+). Under physiological conditions, the ester and amide sulfate groups are deprotonated and attract positively charged counterions to form a heparin salt. Heparin is usually administered in this form as an anticoagulant.
-
IdoA(2S)-GlcNS(6S)*
-
IdoA(2S)-GlcNS
-
IdoA-GlcNS(6S)
-
GlcA-GlcNAc
-
GlcA-GlcNS
-
IdoA-GlcNS
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
One unit of heparin (the "Howell unit") is an amount approximately equivalent to 0.002 mg of pure heparin, which is the quantity required to keep 1 ml of cat's blood fluid for 24 hours at 0 °C.[63]
Three-dimensional structure
The three-dimensional structure of heparin is complicated because iduronic acid may be present in either of two low-energy conformations when internally positioned within an oligosaccharide. The conformational equilibrium is influenced by sulfation state of adjacent glucosamine sugars.[64] Nevertheless, the solution structure of a heparin dodecasaccharide composed solely of six GlcNS(6S)-IdoA(2S) repeat units has been determined using a combination of NMR spectroscopy and molecular modeling techniques.[65] Two models were constructed, one in which all IdoA(2S) were in the 2S0 conformation (A and B below), and one in which they are in the 1C4 conformation (C and D below). However, no evidence suggests that changes between these conformations occur in a concerted fashion. These models correspond to the protein data bank code 1HPN.[66]
In the image above:
- A = 1HPN (all IdoA(2S) residues in 2S0 conformation) Jmol viewer
- B = van der Waals radius space filling model of A
- C = 1HPN (all IdoA(2S) residues in 1C4 conformation) Jmol viewer
- D = van der Waals radius space filling model of C
In these models, heparin adopts a helical conformation, the rotation of which places clusters of sulfate groups at regular intervals of about 17 angstroms (1.7 nm) on either side of the helical axis.
Depolymerization techniques
Either chemical or enzymatic depolymerization 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).
Enzymatic
The enzymes traditionally used to digest heparin or HS are naturally produced by the soil bacterium Pedobacter heparinus (formerly named Flavobacterium heparinum).[67] This bacterium is capable of using either heparin or HS as its sole carbon and nitrogen source. To do so, it produces a range of enzymes such as lyases, glucuronidases, sulfoesterases, and sulfamidases.[68] The lyases have mainly been used in heparin/HS studies. The bacterium produces three lyases, heparinases I (EC 4.2.2.7), II (no EC number assigned) and III (EC 4.2.2.8) and each has distinct substrate specificities as detailed below.[69][70]
Heparinase enzyme | Substrate specificity |
Heparinase I | GlcNS(±6S)-IdoA(2S) |
Heparinase II | GlcNS/Ac(±6S)-IdoA(±2S) GlcNS/Ac(±6S)-GlcA |
Heparinase III | GlcNS/Ac(±6S)-GlcA/IdoA (with a preference for GlcA) |
![](http://upload.wikimedia.org/wikipedia/commons/thumb/7/7d/UA%282S%29-GlcNS%286S%29.svg/300px-UA%282S%29-GlcNS%286S%29.svg.png)
The lyases cleave heparin/HS by a beta elimination mechanism. This action generates an unsaturated double bond between C4 and C5 of the uronate residue.[71][72] The C4-C5 unsaturated uronate is termed ΔUA or UA. It is a sensitive UV chromophore (max absorption at 232 nm) and allows the rate of an enzyme digest to be followed, as well as providing a convenient method for detecting the fragments produced by enzyme digestion.
Chemical
Nitrous acid can be used to chemically depolymerize heparin/HS. Nitrous acid can be used at pH 1.5 or at a higher pH of 4. Under both conditions, nitrous acid effects deaminative cleavage of the chain.[73]
![](http://upload.wikimedia.org/wikipedia/commons/thumb/a/a9/Reduction_fig.png/220px-Reduction_fig.png)
At both 'high' (4) and 'low' (1.5) pH, deaminative cleavage occurs between GlcNS-GlcA and GlcNS-IdoA, albeit at a slower rate at the higher pH. The deamination reaction, and therefore chain cleavage, is regardless of O-sulfation carried by either monosaccharide unit.
At low pH, deaminative cleavage results in the release of inorganic SO4, and the conversion of GlcNS into anhydromannose (aMan). Low-pH nitrous acid treatment is an excellent method to distinguish N-sulfated polysaccharides such as heparin and HS from non N-sulfated polysaccharides such as chondroitin sulfate and dermatan sulfate, chondroitin sulfate and dermatan sulfate not being susceptible to nitrous acid cleavage.
Detection in body fluids
Current clinical laboratory assays for heparin rely on an indirect measurement of the effect of the drug, rather than on a direct measure of its chemical presence. These include activated partial thromboplastin time (APTT) and antifactor Xa activity. The specimen of choice is usually fresh, nonhemolyzed plasma from blood that has been anticoagulated with citrate, fluoride, or oxalate.[74][75]
Other functions
- Blood specimen test tubes, vacutainers, and capillary tubes that use the lithium salt of heparin (lithium heparin) as an anticoagulant are usually marked with green stickers and green tops. Heparin has the advantage over EDTA of not affecting levels of most ions. However, the concentration of ionized calcium may be decreased if the concentration of heparin in the blood specimen is too high.[76] Heparin can interfere with some immunoassays, however. As lithium heparin is usually used, a person's lithium levels cannot be obtained from these tubes; for this purpose, royal-blue-topped (and dark green-topped) vacutainers containing sodium heparin are used.
- Heparin-coated blood oxygenators are available for use in heart-lung machines. Among other things, these specialized oxygenators are thought to improve overall biocompatibility and host homeostasis by providing characteristics similar to those of native endothelium.
- The DNA binding sites on RNA polymerase can be occupied by heparin, preventing the polymerase from binding to promoter DNA. This property is exploited in a range of molecular biological assays.
- Common diagnostic procedures require PCR amplification of a patient's DNA, which is easily extracted from white blood cells treated with heparin. This poses a potential problem, since heparin may be extracted along with the DNA, and it has been found to interfere with the PCR reaction at levels as low as 0.002 U in a 50 μL reaction mixture.[77]
- Heparin has been used as a chromatography resin, acting as both an affinity ligand and an ion exchanger.[78][79][80] Its polyanionic structure can mimic nucleic acids like DNA and RNA, making it useful for purification of nucleic acid-binding proteins including DNA and RNA polymerases and transcription factors.[81] Heparin's specific affinity for VSV-G,[82] a viral envelope glycoprotein often used to pseudotype retroviral and lentiviral vectors for gene therapy, allows it to be used for downstream purification of viral vectors.[83][84]
- Heparin is being trialed in a nasal spray form as prophylaxis against COVID-19 infection.[85] Furthermore, its reported from trials that due to anti-viral, anti-inflammatory and its anti-clotting effects its inhalation could improve at a 70% rate on patients that were actively struck by a COVID-19 infection.[86]
Society and culture
Contamination recalls
Considering the animal source of pharmaceutical heparin, the numbers of potential impurities are relatively large compared with a wholly synthetic therapeutic agent. The range of possible biological contaminants includes viruses, bacterial endotoxins, transmissible spongiform encephalopathy (TSE) agents, lipids, proteins, and DNA. During the preparation of pharmaceutical-grade heparin from animal tissues, impurities such as solvents, heavy metals, and extraneous cations can be introduced. However, the methods employed to minimize the occurrence and to identify and/or eliminate these contaminants are well established and listed in guidelines and pharmacopoeias. The major challenge in the analysis of heparin impurities is the detection and identification of structurally related impurities. The most prevalent impurity in heparin is dermatan sulfate (DS), also known as chondroitin sulfate B. The building-block of DS is a disaccharide composed of 1,3-linked N-acetyl galactosamine (GalN) and a uronic acid residue, connected via 1,4 linkages to form the polymer. DS is composed of three possible uronic acid (GlcA, IdoA or IdoA2S) and four possible hexosamine (GalNAc, Gal- NAc4S, GalNAc6S, or GalNAc4S6S) building-blocks. The presence of iduronic acid in DS distinguishes it from chrondroitin sulfate A and C and likens it to heparin and HS. DS has a lower negative charge density overall compared to heparin. A common natural contaminant, DS is present at levels of 1–7% in heparin API, but has no proven biological activity that influences the anticoagulation effect of heparin.[87]
In December 2007, the US Food and Drug Administration (FDA) recalled a shipment of heparin because of bacterial growth (Serratia marcescens) in several unopened syringes of this product. S. marcescens can lead to life-threatening injuries and/or death.[88]
2008 recall due to adulteration in drug from China
In March 2008, major recalls of heparin were announced by the FDA due to contamination of the raw heparin stock imported from China.[89][90] According to the FDA, the adulterated heparin killed nearly 80 people in the United States.[91] The adulterant was identified as an "over-sulphated" derivative of chondroitin sulfate, a popular shellfish-derived supplement often used for arthritis, which was intended to substitute for actual heparin in potency tests.[92]
According to the New York Times: "Problems with heparin reported to the agency include difficulty breathing, nausea, vomiting, excessive sweating and rapidly falling blood pressure that in some cases led to life-threatening shock".
Use in homicide
In 2006, Petr Zelenka, a nurse in the Czech Republic, deliberately administered large doses to patients, killing seven, and attempting to kill ten others.[93]
Overdose issues
In 2007, a nurse at Cedars-Sinai Medical Center mistakenly gave the 12-day-old twins of actor Dennis Quaid a dose of heparin that was 1,000 times the recommended dose for infants.[94] The overdose allegedly arose because the labeling and design of the adult and infant versions of the product were similar. The Quaid family subsequently sued the manufacturer, Baxter Healthcare Corp.,[95][96] and settled with the hospital for $750,000.[97] Prior to the Quaid accident, six newborn babies at Methodist Hospital in Indianapolis, Indiana, were given an overdose. Three of the babies died after the mistake.[98]
In July 2008, another set of twins born at Christus Spohn Hospital South, in Corpus Christi, Texas, died after an accidentally administered overdose of the drug. The overdose was due to a mixing error at the hospital pharmacy and was unrelated to the product's packaging or labeling.[99] As of July 2008[update], the exact cause of the twins' death was under investigation.[100][101]
In March 2010, a two-year-old transplant patient from Texas was given a lethal dose of heparin at the University of Nebraska Medical Center. The exact circumstances surrounding her death are still under investigation.[102]
Production
Pharmaceutical-grade heparin is derived from mucosal tissues of slaughtered meat animals such as porcine (pig) intestines or bovine (cattle) lungs.[103] Advances to produce heparin synthetically have been made in 2003 and 2008.[104] In 2011, a chemoenzymatic process of synthesizing low molecular weight heparins from simple disaccharides was reported.[105]
Research
As detailed in the table below, the potential is great for the development of heparin-like structures as drugs to treat a wide range of diseases, in addition to their current use as anticoagulants.[106][107]
Disease states sensitive to heparin | Heparin's effect in experimental models | Clinical status |
Acquired immunodeficiency syndrome | Reduces the ability of human immunodeficiency virus types 1 and 2 to adsorb to cultured T4 cells.[108] | – |
Adult respiratory distress syndrome | Reduces cell activation and accumulation in airways, neutralizes mediators and cytotoxic cell products, and improves lung function in animal models | Controlled clinical trials |
Allergic encephalomyelitis | Effective in animal models | – |
Allergic rhinitis | Effects as for adult respiratory distress syndrome, although no specific nasal model has been tested | Controlled clinical trial |
Arthritis | Inhibits cell accumulation, collagen destruction and angiogenesis | Anecdotal report |
Asthma | As for adult respiratory distress syndrome, however, it has also been shown to improve lung function in experimental models | Controlled clinical trials |
Cancer | Inhibits tumour growth, metastasis and angiogenesis, and increases survival time in animal models | Several anecdotal reports |
Delayed-type hypersensitivity reactions | Effective in animal models | – |
Inflammatory bowel disease | Inhibits inflammatory cell transport in general, no specific model tested | Controlled clinical trials |
Interstitial cystitis | Effective in a human experimental model of interstitial cystitis | Related molecule now used clinically |
Transplant rejection | Prolongs allograft survival in animal models | – |
- – indicates that no information is 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.[106]
Drug molecule | Effect of new drug compared to heparin | Biological activities |
Heparin tetrasaccharide | Nonanticoagulant, nonimmunogenic, orally active | Antiallergic |
Pentosan polysulfate | Plant derived, little anticoagulant activity, anti-inflammatory, orally active | Anti-inflammatory, antiadhesive, antimetastatic |
Phosphomannopentanose sulfate | Potent inhibitor of heparanase activity | Antimetastatic, antiangiogenic, anti-inflammatory |
Selectively chemically O-desulphated heparin | Lacks anticoagulant activity | Anti-inflammatory, antiallergic, antiadhesive |
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Further reading
- Marcum JA (January 2000). "The origin of the dispute over the discovery of heparin". Journal of the History of Medicine and Allied Sciences. 55 (1): 37–66. doi:10.1093/jhmas/55.1.37. PMID 10734720. S2CID 30050513.
- Mulloy B, Hogwood J, Gray E, Lever R, Page CP (January 2016). "Pharmacology of Heparin and Related Drugs". Pharmacological Reviews. 68 (1): 76–141. doi:10.1124/pr.115.011247. PMID 26672027.
External links
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