{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T18:32:44Z","timestamp":1785522764699,"version":"3.56.0"},"reference-count":35,"publisher":"Georg Thieme Verlag KG","issue":"04","license":[{"start":{"date-parts":[[2022,9,16]],"date-time":"2022-09-16T00:00:00Z","timestamp":1663286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["TH Open"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Heparin has already been found in a variety of animal tissues but only few of them became effective sources for production of pharmaceutical preparations. Here, we correlate physical-chemical features and anticoagulant activities of structurally similar heparins employed in the past (from bovine lung, HBL), in the present (from porcine intestine, HPI) and in development for future use (from ovine intestine, HOI). Although they indeed have similar composition, our physical-chemical analyses with different chromatography and spectrometric techniques show that both HOI and HBL have molecular size notably lower than HPI and that the proportions of some of their minor saccharide components can vary substantially. Measurements of anticoagulant activities with anti-FIIa and anti-FXa assays confirmed that HPI and HOI have potency similar each other but significantly higher than HBL. Such a lower activity of HBL has been attributed to its reduced molecular size. Considering that HOI also has reduced molecular size, we find that its increased anticoagulant potency might result from an improved affinity to antithrombin (three times higher than HBL) promoted by the high content of N,3,6-trisulfated glucosamine units, which in turn are directly involved in the heparin-antithrombin binding. Therefore, the anticoagulant activity of different heparins is driven by a balance between different physical-chemical components, especially molecular size and fine-tuning composition. Although such minor but relevant chemical differences reinforce the concept that heparins from different animal sources should indeed be considered as distinct drugs, HOI could be approved for interchangeable use with the gold standard HPI and as a suitable start material for producing new LMWHs.<\/jats:p>","DOI":"10.1055\/a-1946-0325","type":"journal-article","created":{"date-parts":[[2022,9,16]],"date-time":"2022-09-16T22:57:46Z","timestamp":1663369066000},"page":"e309-e322","source":"Crossref","is-referenced-by-count":13,"title":["Anticoagulant Activity of Heparins from Different Animal Sources are Driven by a Synergistic Combination of Physical-chemical Factors"],"prefix":"10.1055","volume":"06","author":[{"given":"Stephan N.M.C.G.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Tecido Conjuntivo, Hospital Universit\u00e1rio Clementino Fraga Filho and Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana M.F.","family":"Tovar","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Tecido Conjuntivo, Hospital Universit\u00e1rio Clementino Fraga Filho and Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco F.","family":"Bezerra","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Tecido Conjuntivo, Hospital Universit\u00e1rio Clementino Fraga Filho and Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana A.","family":"Piquet","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Tecido Conjuntivo, Hospital Universit\u00e1rio Clementino Fraga Filho and Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina V.","family":"Capill\u00e9","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Tecido Conjuntivo, Hospital Universit\u00e1rio Clementino Fraga Filho and Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paloma S.","family":"Santos","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Tecido Conjuntivo, Hospital Universit\u00e1rio Clementino Fraga Filho and Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Vilanova","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Tecido Conjuntivo, Hospital Universit\u00e1rio Clementino Fraga Filho and Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulo A.S.","family":"Mour\u00e3o","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Tecido Conjuntivo, Hospital Universit\u00e1rio Clementino Fraga Filho and Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2022,10,11]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1016\/S0167-5273(16)12001-7","article-title":"Heparin centenary - an ever-young life-saving drug","volume":"212","author":"G Torri","year":"2016","journal-title":"Int J Cardiol"},{"issue":"03","key":"ref2","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1208\/s12248-017-0047-y","article-title":"A Heparin Purification Process Removes Spiked Transmissible Spongiform Encephalopathy Agent","volume":"19","author":"C Bett","year":"2017","journal-title":"AAPS J"},{"issue":"06","key":"ref3","doi-asserted-by":"crossref","first-page":"E1025","DOI":"10.3390\/molecules22061025","article-title":"From Farm to Pharma: An Overview of Industrial Heparin Manufacturing Methods","volume":"22","author":"J Y van der Meer","year":"2017","journal-title":"Molecules"},{"key":"ref4","first-page":"28","article-title":"Diversifying the global heparin supply chain. Reintroduction of bovine heparin in the United States?","volume":"39","author":"D Keire","year":"2015","journal-title":"Pharm Technol"},{"issue":"02","key":"ref5","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1111\/jth.14372","article-title":"Imminent risk of a global shortage of heparin caused by the African Swine Fever afflicting the Chinese pig herd","volume":"17","author":"E Vilanova","year":"2019","journal-title":"J Thromb Haemost"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"1076029619889406","DOI":"10.1177\/1076029619889406","article-title":"Comparative Pharmacological Profiles of Various Bovine, Ovine, and Porcine Heparins","volume":"25","author":"A Kouta","year":"2019","journal-title":"Clin Appl Thromb Hemost"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.carres.2014.06.023","article-title":"Re-visiting the structure of heparin","volume":"403","author":"B Casu","year":"2015","journal-title":"Carbohydr Res"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"35619","DOI":"10.1038\/srep35619","article-title":"Structural and haemostatic features of pharmaceutical heparins from different animal sources: challenges to define thresholds separating distinct drugs","volume":"6","author":"A MF Tovar","year":"2016","journal-title":"Sci Rep"},{"issue":"01","key":"ref9","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1124\/pr.115.011247","article-title":"Pharmacology of heparin and related drugs","volume":"68","author":"B Mulloy","year":"2016","journal-title":"Pharmacol Rev"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"16","DOI":"10.3389\/fmed.2019.00016","article-title":"Heparins Sourced From Bovine and Porcine Mucosa Gain Exclusive Monographs in the Brazilian Pharmacopeia","volume":"6","author":"E Vilanova","year":"2019","journal-title":"Front Med (Lausanne)"},{"issue":"11","key":"ref11","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1016\/j.drudis.2014.07.004","article-title":"Structural and functional analyses of bovine and porcine intestinal heparins confirm they are different drugs","volume":"19","author":"G RC Santos","year":"2014","journal-title":"Drug Discov Today"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1186\/1756-0500-6-230","article-title":"Bovine and porcine heparins: different drugs with similar effects on human haemodialysis","volume":"6","author":"A M Tovar","year":"2013","journal-title":"BMC Res Notes"},{"issue":"04","key":"ref13","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1055\/s-0039-1678663","article-title":"Converting the Distinct Heparins Sourced from Bovine or Porcine Mucosa into a Single Anticoagulant Drug","volume":"119","author":"A MF Tovar","year":"2019","journal-title":"Thromb Haemost"},{"issue":"02","key":"ref14","doi-asserted-by":"crossref","first-page":"e114","DOI":"10.1055\/s-0042-1745743","article-title":"Pharmacokinetic, Hemostatic, and Anticancer Properties of a Low-Anticoagulant Bovine Heparin","volume":"6","author":"R P Santos","year":"2022","journal-title":"TH Open"},{"issue":"07","key":"ref15","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.3390\/molecules22071214","article-title":"Molecular Weights of Bovine and Porcine Heparin Samples: Comparison of Chromatographic Methods and Results of a Collaborative Survey","volume":"22","author":"S Bertini","year":"2017","journal-title":"Molecules"},{"issue":"06","key":"ref16","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1002\/jssc.201500664","article-title":"Ion chromatography for the separation of heparin and structurally related glycoaminoglycans: A review","volume":"39","author":"J M Fasciano","year":"2016","journal-title":"J Sep Sci"},{"key":"ref18","author":"European Pharmacopoeia"},{"key":"ref19","author":"Brazilian Pharmacopoeia"},{"issue":"05","key":"ref20","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1002\/jps.23501","article-title":"Structural characterization of pharmaceutical heparins prepared from different animal tissues","volume":"102","author":"L Fu","year":"2013","journal-title":"J Pharm Sci"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.sbi.2017.10.011","article-title":"Unveiling the structure of sulfated fucose-rich polysaccharides via nuclear magnetic resonance spectroscopy","volume":"50","author":"P A Mour\u00e3o","year":"2018","journal-title":"Curr Opin Struct Biol"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"142","DOI":"10.3389\/fmed.2019.00142","article-title":"1D and 2D-HSQC NMR: Two Methods to Distinguish and Characterize Heparin From Different Animal and Tissue Sources","volume":"6","author":"L Mauri","year":"2019","journal-title":"Front Med (Lausanne)"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.jpba.2016.12.031","article-title":"Qualification of HSQC methods for quantitative composition of heparin and low molecular weight heparins","volume":"136","author":"L Mauri","year":"2017","journal-title":"J Pharm Biomed Anal"},{"issue":"16","key":"ref24","doi-asserted-by":"crossref","first-page":"4718","DOI":"10.1080\/07391102.2019.1688194","article-title":"The mechanism of high affinity pentasaccharide binding to antithrombin, insights from Gaussian accelerated molecular dynamics simulations","volume":"38","author":"G Balogh","year":"2020","journal-title":"J Biomol Struct Dyn"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.jpba.2017.10.020","article-title":"Authentication of animal origin of heparin and low molecular weight heparin including ovine, porcine and bovine species using 1D NMR spectroscopy and chemometric tools","volume":"149","author":"Y B Monakhova","year":"2018","journal-title":"J Pharm Biomed Anal"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.jpba.2018.02.041","article-title":"Improving reliability of chemometric models for authentication of species origin of heparin by switching from 1D to 2D NMR experiments","volume":"153","author":"Y B Monakhova","year":"2018","journal-title":"J Pharm Biomed Anal"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.jpba.2018.10.052","article-title":"Chemometric analysis of porcine, bovine and ovine heparins","volume":"164","author":"Y Ouyang","year":"2019","journal-title":"J Pharm Biomed Anal"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"78","DOI":"10.3389\/fmed.2019.00078","article-title":"SAX-HPLC and HSQC NMR Spectroscopy: Orthogonal Methods for Characterizing Heparin Batches Composition","volume":"6","author":"F Spelta","year":"2019","journal-title":"Front Med (Lausanne)"},{"issue":"11","key":"ref29","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1080\/17474086.2016.1243052","article-title":"Update on Brazilian biosimilar enoxaparins","volume":"9","author":"E Vilanova","year":"2016","journal-title":"Expert Rev Hematol"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.ijbiomac.2017.03.036","article-title":"Heparin depolymerization by immobilized heparinase: A review","volume":"99","author":"I Bhushan","year":"2017","journal-title":"Int J Biol Macromol"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/0076-6879(93)22033-C","article-title":"Kinetic characterization of heparin-catalyzed and uncatalyzed inhibition of blood coagulation proteinases by antithrombin","volume":"222","author":"S T Olson","year":"1993","journal-title":"Methods Enzymol"},{"issue":"01","key":"ref32","doi-asserted-by":"crossref","first-page":"e0116835","DOI":"10.1371\/journal.pone.0116835","article-title":"Monitoring low molecular weight heparins at therapeutic levels: dose-responses of, and correlations and differences between aPTT, anti-factor Xa and thrombin generation assays","volume":"10","author":"O Thomas","year":"2015","journal-title":"PLoS One"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"133","DOI":"10.2147\/DHPS.S28813","article-title":"Update on the safety and bioequivalence of biosimilars - focus on enoxaparin","volume":"5","author":"W Jeske","year":"2013","journal-title":"Drug Healthc Patient Saf"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"1076029619840701","DOI":"10.1177\/1076029619840701","article-title":"Comparison of Low-Molecular-Weight Heparins Prepared From Ovine Heparins With Enoxaparin","volume":"25","author":"J Chen","year":"2019","journal-title":"Clin Appl Thromb Hemost"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"150S","DOI":"10.1177\/1076029618798956","article-title":"Comparative Pharmacokinetic Profile of 3 Batches of Ovine Low-Molecular-Weight Heparin and 1 Batch of Branded Enoxaparin","volume":"24","author":"W Jeske","year":"2018","journal-title":"Clin Appl Thromb Hemost"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.carbpol.2018.05.070","article-title":"Preparation of low molecular weight heparins from bovine and ovine heparins using nitrous acid degradation","volume":"197","author":"S Xie","year":"2018","journal-title":"Carbohydr Polym"}],"container-title":["TH Open"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-1946-0325.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T23:25:51Z","timestamp":1665530751000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-1946-0325"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,16]]},"references-count":35,"journal-issue":{"issue":"04","published-online":{"date-parts":[[2022,10,7]]},"published-print":{"date-parts":[[2022,10]]}},"URL":"https:\/\/doi.org\/10.1055\/a-1946-0325","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["2512-9465"],"issn-type":[{"value":"2512-9465","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,9,16]]},"published":{"date-parts":[[2022,9,16]]}}}