{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T17:05:37Z","timestamp":1773075937058,"version":"3.50.1"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2005,1,11]],"date-time":"2005-01-11T00:00:00Z","timestamp":1105401600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2005,1,11]],"date-time":"2005-01-11T00:00:00Z","timestamp":1105401600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Thrombin is a key factor in the stimulation of fibrin deposition, angiogenesis, proinflammatory processes, and proliferation of fibroblast-like cells. Abnormalities in these processes are primary features of rheumatoid arthritis (RA) in synovial tissues. Tissue destruction in joints causes the accumulation of large quantities of free hyaluronic acid (HA) in RA synovial fluid. The present study was conducted to investigate the effects of HA and several other glycosaminoglycans on antithrombin, a plasma inhibitor of thrombin. Various glycosaminoglycans, including HA, chondroitin sulfate, keratan sulfate, heparin, and heparan, were incubated with human antithrombin III <jats:italic>in vitro<\/jats:italic>. The residual activity of antithrombin was determined using a thrombin-specific chromogenic assay. HA concentrations ranging from 250 to 1000 \u03bcg\/ml significantly blocked the ability of antithrombin to inhibit thrombin in the presence of Ca<jats:sup>2+<\/jats:sup> or Fe<jats:sup>3+<\/jats:sup>, and chondroitin A, B and C also reduced this ability under the same conditions but to a lesser extent. Our study suggests that the high concentration of free HA in RA synovium may block antithrombin locally, thereby deregulating thrombin activity to drive the pathogenic process of RA under physiological conditions. The study also helps to explain why RA occurs and develops in joint tissue, because the inflamed RA synovium is uniquely rich in free HA along with extracellular matrix degeneration. Our findings are consistent with those of others regarding increased coagulation activity in RA synovium.<\/jats:p>","DOI":"10.1186\/ar1487","type":"journal-article","created":{"date-parts":[[2005,1,12]],"date-time":"2005-01-12T13:55:34Z","timestamp":1105538134000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Inhibition of antithrombin by hyaluronic acid may be involved in the pathogenesis of rheumatoid arthritis"],"prefix":"10.1186","volume":"7","author":[{"given":"Xiaotian","family":"Chang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiko","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2005,1,11]]},"reference":[{"key":"1368_CR1","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1055\/s-2007-999049","volume":"22","author":"F Carmassi","year":"1996","unstructured":"Carmassi F, de Negri F, Morale M, Song KY, Chung SI: Fibrin degradation in the synovial fluid of rheumatoid arthritis patients: a model for extravascular fibrinolysis. Semin Thromb Hemost. 1996, 22: 489-496.","journal-title":"Semin Thromb Hemost"},{"key":"1368_CR2","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1136\/ard.58.1.55","volume":"58","author":"H Shin","year":"1999","unstructured":"Shin H, Kitajima I, Nakajima T, Shao Q, Tokioka T, Takasaki I, Hanyu N, Kubo T, Maruyama I: Thrombin receptor mediated signals induce expressions of interleukin 6 and granulocyte colony stimulating factor via NF-kappa B activation in synovial fibroblasts. Ann Rheum Dis. 1999, 58: 55-60.","journal-title":"Ann Rheum Dis"},{"key":"1368_CR3","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1006\/clin.1995.1120","volume":"76","author":"H Shin","year":"1995","unstructured":"Shin H, Nakajima T, Kitajima I, Shigeta K, Abeyama K, Imamura T, Okano T, Kawahara K, Nakamura T, Maruyama I: Thrombin receptor-mediated synovial proliferation in patients with rheumatoid arthritis. Clin Immunol Immunopathol. 1995, 76: 225-233. 10.1006\/clin.1995.1120.","journal-title":"Clin Immunol Immunopathol"},{"key":"1368_CR4","doi-asserted-by":"publisher","first-page":"23969","DOI":"10.1074\/jbc.274.34.23969","volume":"274","author":"NE Tsopanoglou","year":"1999","unstructured":"Tsopanoglou NE, Maragoudakis MEJ: On the mechanism of thrombin-induced angiogenesis. Potentiation of vascular endothelial growth factor activity on endothelial cells by up-regulation of its receptors. J Biol Chem. 1999, 274: 23969-23976. 10.1074\/jbc.274.34.23969.","journal-title":"J Biol Chem"},{"key":"1368_CR5","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1042\/bst0300173","volume":"30","author":"ME Maragoudakis","year":"2002","unstructured":"Maragoudakis ME, Tsopanoglou NE, Andriopoulou P: Mechanism of Thrombin-induced angiogenesis. Biochem Soc Trans. 2002, 30: 173-177. 10.1042\/0300-5127:0300173.","journal-title":"Biochem Soc Trans"},{"key":"1368_CR6","first-page":"275","volume":"29","author":"S Narayanan","year":"1999","unstructured":"Narayanan S: Multifunctional roles of thrombin. Ann Clin Lab Sci. 1999, 29: 275-280.","journal-title":"Ann Clin Lab Sci"},{"key":"1368_CR7","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1136\/ard.53.1.72","volume":"53","author":"R Morris","year":"1994","unstructured":"Morris R, Winyard PG, Brass LF, Blake DR, Morris CJ: Thrombin in inflammation and healing' relevance to rheumatoid arthritis. Ann Rheum Dis. 1994, 53: 72-79.","journal-title":"Ann Rheum Dis"},{"key":"1368_CR8","doi-asserted-by":"publisher","first-page":"35767","DOI":"10.1074\/jbc.M304803200","volume":"278","author":"EM Wiebe","year":"2003","unstructured":"Wiebe EM, Stafford AR, Fredenburgh JC, Weitz JI: Mechanism of catalysis of inhibition of factor IXa by antithrombin in the presence of heparin or pentasaccharide. J Biol Chem. 2003, 278: 35767-35774. 10.1074\/jbc.M304803200.","journal-title":"J Biol Chem"},{"key":"1368_CR9","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1146\/annurev.biochem.67.1.609","volume":"67","author":"RV Lozzo","year":"1998","unstructured":"Lozzo RV: Matrix proteoglycans: from molecular design to cellular function. Annu Rev Biochem. 1998, 67: 609-652. 10.1146\/annurev.biochem.67.1.609.","journal-title":"Annu Rev Biochem"},{"key":"1368_CR10","doi-asserted-by":"publisher","first-page":"14362","DOI":"10.1073\/pnas.222536599","volume":"99","author":"JY Wang","year":"2002","unstructured":"Wang JY, Roehrl MH: Glycosaminoglycans are a potential cause of rheumatoid arthritis. Proc Natl Acad Sci USA. 2002, 99: 14362-14367. 10.1073\/pnas.222536599.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1368_CR11","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1136\/ard.57.3.162","volume":"57","author":"HW Jones","year":"1998","unstructured":"Jones HW, Bailey R, Zhang Z, Dunne KA, Blake DR, Cox NL, Morris CJ, Winyard PG: Inactivation of antithrombin III in synovial fluid from patients with rheumatoid arthritis. Ann Rheum Dis. 1998, 57: 162-165.","journal-title":"Ann Rheum Dis"},{"key":"1368_CR12","first-page":"1505","volume":"23","author":"T Ohba","year":"1996","unstructured":"Ohba T, Takase Y, Ohhara M, Kasukawa R: Thrombin in synovial fluid of paients with rheumatoid arthritis mediates proliferation of synovial fibroblast-like cells by induction of plate derived growth factor. J Rheumatol. 1996, 23: 1505-1511.","journal-title":"J Rheumatol"},{"key":"1368_CR13","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1002\/1529-0131(200108)44:8<1754::AID-ART310>3.0.CO;2-8","volume":"44","author":"A Jain","year":"2001","unstructured":"Jain A, Nanchahal J, Troeberg L, Green P, Brennan F: Production of cytokines, vascular endothelial growth factor, matrix metalloproteinases, and tissue inhibitor of metalloproteinases 1 by tenosynovium demonstrates its potential for tendon destruction in rheumatoid arthritis. Arthritis Rheum. 2001, 44: 1754-1760. 10.1002\/1529-0131(200108)44:8<1754::AID-ART310>3.0.CO;2-8.","journal-title":"Arthritis Rheum"},{"key":"1368_CR14","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1093\/rheumatology\/33.1.5","volume":"33","author":"AA Pitsillides","year":"1994","unstructured":"Pitsillides AA, Worrall JG, Wilkinson LS, Bayliss MT, Edwards JC: Hyaluronan concentration in non-inflamed and rheumatoid synovium. Br J Rheumatol. 1994, 33: 5-10.","journal-title":"Br J Rheumatol"},{"key":"1368_CR15","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1272\/jnms.67.92","volume":"67","author":"Y Nakayama","year":"2000","unstructured":"Nakayama Y, Shirai Y, Yoshihara K, Uesaka S: Evaluation of glycosaminoglycans levels in normal joint fluid of the knee. J Nippon Med Sch. 2000, 67: 92-95. 10.1272\/jnms.67.92.","journal-title":"J Nippon Med Sch"},{"key":"1368_CR16","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1081\/IAS-120002276","volume":"23","author":"YG Takei","year":"2002","unstructured":"Takei YG, Honma T, Ito A: Quantitation of hyaluronic acid in serum with automated microparticle photometric agglutination assay. J Immunoassay Immunochem. 2002, 23: 85-94. 10.1081\/IAS-120002276.","journal-title":"J Immunoassay Immunochem"},{"key":"1368_CR17","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1136\/adc.86.3.190","volume":"86","author":"HA Wyatt","year":"2002","unstructured":"Wyatt HA, Dhawan A, Cheeseman P, Mieli-Vergani G, Price JF: Serum hyaluronic acid concentrations are increased in cystic fibrosis patients with liver disease. Arch Dis Child. 2002, 86: 190-193. 10.1136\/adc.86.3.190.","journal-title":"Arch Dis Child"},{"key":"1368_CR18","first-page":"381","volume":"14","author":"G Partsch","year":"1996","unstructured":"Partsch G, Leeb B, Stancikova M, Raffayova H, Eberl G, Hitzelhammer H, Smolen JS: Low serum hyaluronan in psoriatic arthritis patients in comparison to rheumatoid arthritis patients. Clin Exp Rheumatol. 1996, 14: 381-386.","journal-title":"Clin Exp Rheumatol"},{"key":"1368_CR19","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1006\/jmbi.1996.0798","volume":"266","author":"R Skinner","year":"1997","unstructured":"Skinner R, Abrahams JP, Whisstock JC, Lesk AM, Carrell RW, Wardell MR: The 2.6 A structure of antithrombin indicates a conformational change at the heparin binding site. J Mol Biol. 1997, 266: 601-609. 10.1006\/jmbi.1996.0798.","journal-title":"J Mol Biol"},{"key":"1368_CR20","doi-asserted-by":"publisher","first-page":"14683","DOI":"10.1073\/pnas.94.26.14683","volume":"94","author":"L Jin","year":"1997","unstructured":"Jin L, Abrahams JP, Skinner R, Petitou M, Pike RN, Carrell RW: The anticoagulant activation of antithrombin by heparin. Proc Natl Acad Sci USA. 1997, 94: 14683-14688. 10.1073\/pnas.94.26.14683.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1368_CR21","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1016\/j.joca.2004.03.005","volume":"12","author":"K Kobayashi","year":"2004","unstructured":"Kobayashi K, Matsuzaka S, Yoshida Y, Miyauchi S, Wada Y, Moriya H: The effects of intraarticularly injected sodium hyaluronate on levels of intact aggrecan and nitric oxide in the joint fluid of patients with knee osteoarthritis. Osteoarthritis Cartilage. 2004, 12: 536-542. 10.1016\/j.joca.2004.03.005.","journal-title":"Osteoarthritis Cartilage"},{"key":"1368_CR22","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/ar623","volume":"5","author":"LW Moreland","year":"2003","unstructured":"Moreland LW: Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: mechanisms of action. Arthritis Res Ther. 2003, 5: 54-67. 10.1186\/ar623.","journal-title":"Arthritis Res Ther"},{"key":"1368_CR23","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1136\/ard.58.3.186","volume":"58","author":"H Nagaya","year":"1999","unstructured":"Nagaya H, Yamagata T, Yamagata S, Iyoda K, Ito H, Hasegawa Y, Iwata H: Examination of synovial fluid and serum hyaluronidase activity as a joint marker in rheumatoid arthritis and osteoarthritis patients (by zymography). Ann Rheum Dis. 1999, 58: 186-188.","journal-title":"Ann Rheum Dis"},{"key":"1368_CR24","first-page":"307","volume":"22","author":"E Maneiro","year":"2004","unstructured":"Maneiro E, de Andres MC, Fernandez-Sueiro JL, Galdo F, Blanco FJ: The biological action of hyaluronan on human osteoartritic articular chondrocytes: the importance of molecular weight. Clin Exp Rheumatol. 2004, 22: 307-312.","journal-title":"Clin Exp Rheumatol"},{"key":"1368_CR25","doi-asserted-by":"publisher","first-page":"16824","DOI":"10.1074\/jbc.273.27.16824","volume":"273","author":"AR Rezaie","year":"1998","unstructured":"Rezaie AR: Calcium enhances heparin catalysis of the antithrombin-factor Xa reaction by a template mechanism. Evidence that calcium alleviates Gla domain antagonism of heparin binding to factor Xa. J Biol Chem. 1998, 273: 16824-16827. 10.1074\/jbc.273.27.16824.","journal-title":"J Biol Chem"},{"key":"1368_CR26","doi-asserted-by":"publisher","first-page":"8143","DOI":"10.1021\/bi034363y","volume":"42","author":"T Bedsted","year":"2003","unstructured":"Bedsted T, Swanson R, Chuang YJ, Bock PE, Bjork I, Olson ST: Heparin and calcium ions dramatically enhance antithrombin reactivity with factor IXa by generating new interaction exosites. Biochemistry. 2003, 42: 8143-8152. 10.1021\/bi034363y.","journal-title":"Biochemistry"},{"key":"1368_CR27","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1002\/art.1780270503","volume":"27","author":"DR Blake","year":"1984","unstructured":"Blake DR, Gallagher PJ, Potter AR, Bell MJ, Bacon PA: The effect of synovial iron on the progression of rheumatoid disease. A histologic assessment of patients with early rheumatoid synovitis. Arthritis Rheum. 1984, 27: 495-501.","journal-title":"Arthritis Rheum"},{"key":"1368_CR28","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1007\/BF02030347","volume":"8","author":"N Ahmadzadeh","year":"1989","unstructured":"Ahmadzadeh N, Shingu M, Nobunaga M: Iron-binding proteins and free iron in synovial fluids of rheumatoid arthritis patients. Clin Rheumatol. 1989, 8: 345-351.","journal-title":"Clin Rheumatol"},{"key":"1368_CR29","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1136\/ard.45.1.21","volume":"45","author":"CJ Morris","year":"1986","unstructured":"Morris CJ, Blake DR, Wainwright AC, Steven MM: Relationship between iron deposits and tissue damage in the synovium: an ultrastructural study. Ann Rheum Dis. 1986, 45: 21-26.","journal-title":"Ann Rheum Dis"},{"key":"1368_CR30","first-page":"BR91","volume":"10","author":"JF Telfer","year":"2004","unstructured":"Telfer JF, Brock JH: Proinflammatory cytokines increase iron uptake into human monocytes and synovial fibroblasts from patients with rheumatoid arthritis. Med Sci Monit. 2004, 10: BR91-BR95.","journal-title":"Med Sci Monit"},{"key":"1368_CR31","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1136\/ard.53.7.446","volume":"53","author":"EV Davies","year":"1994","unstructured":"Davies EV, Williams BD, Whiston RJ, Cooper AM, Campbell AK, Hallett : Altered Ca2+ signalling in human neutrophils from inflammatory sites. Ann Rheum Dis. 1994, 53: 446-449.","journal-title":"Ann Rheum Dis"},{"key":"1368_CR32","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1002\/1529-0131(200006)43:6<1257::AID-ANR8>3.0.CO;2-Q","volume":"43","author":"DM Carruthers","year":"2000","unstructured":"Carruthers DM, Arrol HP, Bacon PA, Young SP: Dysregulated intracellular Ca2+ stores and Ca2+ signaling in synovial fluid T lymphocytes from patients with chronic inflammatory arthritis. Arthritis Rheum. 2000, 43: 1257-1265. 10.1002\/1529-0131(200006)43:6<1257::AID-ANR8>3.0.CO;2-Q.","journal-title":"Arthritis Rheum"},{"key":"1368_CR33","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1038\/ng1206","volume":"34","author":"A Suzuki","year":"2003","unstructured":"Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-Hamada M, Kawaida R, Ono M, et al: Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet. 2003, 34: 395-402. 10.1038\/ng1206.","journal-title":"Nat Genet"},{"key":"1368_CR34","volume-title":"Rheumatology (Oxford)","author":"X Chang","year":"2004","unstructured":"Chang X, Yamada R, Sawada T, Suzuki A, Yamamoto K: The inhibition of antithrombin by peptidylarginine deiminase 4 may contribute to pathogenesis of rheumatoid arthritis. Rheumatology (Oxford). 2004,"},{"key":"1368_CR35","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1136\/ard.2003.012211","volume":"63","author":"ER Vossenaar","year":"2004","unstructured":"Vossenaar ER, Radstake TR, Van Der Heijden A, Van Mansum MA, Dieteren C, De Rooij DJ, Barrera P, Zendman AJ, Van Venrooij WJ: Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. Ann Rheum Dis. 2004, 63: 373-381. 10.1136\/ard.2003.012211.","journal-title":"Ann Rheum Dis"},{"key":"1368_CR36","volume-title":"Rheumatology (Oxford)","author":"X Chang","year":"2004","unstructured":"Chang X, Yamada R, Suzuki A, Sawada T, Yoshino S, Tokuhiro S, Yamamoto K: Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis. Rheumatology (Oxford). 2004,"},{"key":"1368_CR37","first-page":"188","volume":"34","author":"HH van Boven","year":"1997","unstructured":"van Boven HH, Lane DA: Antithrombin and its inherited deficiency states. Semin Hematol. 1997, 34: 188-204.","journal-title":"Semin Hematol"},{"key":"1368_CR38","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1172\/JCI10489","volume":"106","author":"K Ishiguro","year":"2000","unstructured":"Ishiguro K, Kojima T, Kadomatsu K, Nakayama Y, Takagi A, Suzuki M, Takeda N, Ito M, Yamamoto K, Matsushita T, et al: Complete antithrombin deficiency in mice results in embryonic lethality. J Clin Invest. 2000, 106: 873-878.","journal-title":"J Clin Invest"}],"container-title":["Arthritis Res Ther"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/ar1487.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/ar1487\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/ar1487.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T10:24:15Z","timestamp":1728383055000},"score":1,"resource":{"primary":{"URL":"https:\/\/arthritis-research.biomedcentral.com\/articles\/10.1186\/ar1487"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,1,11]]},"references-count":38,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2005,12]]}},"alternative-id":["1368"],"URL":"https:\/\/doi.org\/10.1186\/ar1487","relation":{},"ISSN":["1478-6354"],"issn-type":[{"value":"1478-6354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,1,11]]},"assertion":[{"value":"10 July 2004","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 October 2004","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 November 2004","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 January 2005","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"R268"}}