{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T06:01:00Z","timestamp":1762063260758,"version":"build-2065373602"},"reference-count":31,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T00:00:00Z","timestamp":1661299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004606","name":"Chang Gung Research Program","doi-asserted-by":"publisher","award":["CMRPG8L0391","104-2314-B-182A-005-MY3","107-2314-B-182A-040","108-2314-B-182A-076-MY3"],"award-info":[{"award-number":["CMRPG8L0391","104-2314-B-182A-005-MY3","107-2314-B-182A-040","108-2314-B-182A-076-MY3"]}],"id":[{"id":"10.13039\/501100004606","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Science Council","award":["CMRPG8L0391","104-2314-B-182A-005-MY3","107-2314-B-182A-040","108-2314-B-182A-076-MY3"],"award-info":[{"award-number":["CMRPG8L0391","104-2314-B-182A-005-MY3","107-2314-B-182A-040","108-2314-B-182A-076-MY3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Genetic polymorphism of nitric oxide synthase (NOS) can cause reduction of nitric oxide (NO) levels and may be associated with osteonecrosis of the femoral head (ONFH). However, the association of coagulopathy and NOS polymorphism in ONFH patients has not been confirmed. Between November 2005 and October 2013, 155 patients with ONFH were recruited in the study of serum coagulation profiles and NOS polymorphism. Another 43 patients who had dysplasia, osteoarthritis, or trauma of hip joints were included as controls. PCR genotyping for the analysis of NOS 27-bp polymorphism in intron 4 was performed. The analysis of coagulation profiles included fibrinogen, fibrinogen degradation product (FDP), protein S, protein C, and anti-thrombin III. The results showed that 27-bp repeat polymorphism was significantly associated with ONFH (OR 4.32). ONFH patients had significantly higher fibrinogen, FDP, protein S, and anti-thrombin III levels than that of the controls. The incidence of coagulopathy was significantly higher in ONFH patients (73.2%), and the odds ratio increased from 2.38 to 7.33 when they had 27-bp repeat polymorphism. Patients with hyperfibrinogenemia, elevated FDP levels, and with the risk factor of alcohol or steroid use had significantly higher risks of bilateral hip involvement. This study demonstrated the presence of NOS polymorphism, and a resultant reduction in NO production was associated with coagulopathy, which in turn might contribute to higher risks of bilateral ONFH. Our data suggests that checking NOS polymorphism and coagulopathy may provide a new avenue in managing ONFH.<\/jats:p>","DOI":"10.3390\/jcm11174963","type":"journal-article","created":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T23:48:58Z","timestamp":1661384938000},"page":"4963","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Association of Nitric Oxide Synthase Polymorphism and Coagulopathy in Patients with Osteonecrosis of the Femoral Head"],"prefix":"10.3390","volume":"11","author":[{"given":"Cheng-Ta","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rio L. C.","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei-Hsun","family":"Sung","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5205-8333","authenticated-orcid":false,"given":"Feng-Chih","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6305-5717","authenticated-orcid":false,"given":"Hon-Kan","family":"Yip","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mel S.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"},{"name":"Department of Othopaedic Surgery, Pao-Chien Hospital, Pingyung 90064, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,24]]},"reference":[{"key":"ref_1","first-page":"337","article-title":"Osteonecrosis of the hip: Management in the 21st century","volume":"52","author":"Lieberman","year":"2003","journal-title":"Instr. Course Lect."},{"key":"ref_2","first-page":"1117","article-title":"Nontraumatic osteonecrosis of the femoral head: Ten years later","volume":"88","author":"Mont","year":"2006","journal-title":"J. Bone Jt. Surg."},{"key":"ref_3","first-page":"351","article-title":"Non-traumatic osteonecrosis of the femoral head\u2014From clinical to bench","volume":"33","author":"Lee","year":"2010","journal-title":"Chang Gung Med. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1055\/s-0038-1651633","article-title":"Familial high plasminogen activator inhibitor with hypofibrinolysis, a new pathophysiologic cause of osteonecrosis?","volume":"69","author":"Glueck","year":"1993","journal-title":"Thromb. Haemost."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1097\/00003086-199909000-00017","article-title":"The plasminogen activator inhibitor-1 gene, hypofibrinolysis, and osteonecrosis","volume":"366","author":"Glueck","year":"1999","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1097\/00003086-200105000-00004","article-title":"Hypofibrinolysis, thrombophilia, osteonecrosis","volume":"386","author":"Glueck","year":"2001","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1097\/00003086-199701000-00007","article-title":"Thrombophilia and hypofibrinolysis: Pathophysiologies of osteonecrosis","volume":"334","author":"Glueck","year":"1997","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1002\/ajh.2830440405","article-title":"Decreased fibrinolytic potential in patients with idiopathic avascular necrosis and transient osteoporosis of the hip","volume":"44","author":"Neff","year":"1993","journal-title":"Am. J. Hematol."},{"key":"ref_9","first-page":"783","article-title":"Procoagulants and osteonecrosis","volume":"30","author":"Jones","year":"2003","journal-title":"J. Rheumatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1097\/01.blo.0000127921.13253.e3","article-title":"Genetic background of osteonecrosis: Associated with thrombophilic mutations?","volume":"422","author":"Zalavras","year":"2004","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1097\/01.blo.0000092972.12414.a5","article-title":"Role of thrombotic and fibrinolytic disorders in osteonecrosis of the femoral head","volume":"417","author":"Lee","year":"2003","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1007\/s11999-008-0147-1","article-title":"Genetic background of nontraumatic osteonecrosis of the femoral head in the Korean population","volume":"466","author":"Chang","year":"2008","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1007\/s10059-010-0054-7","article-title":"Lack of association of MTHFR gene polymorphisms with the risk of osteonecrosis of the femoral head in a Korean population","volume":"29","author":"Kim","year":"2010","journal-title":"Mol. Cells"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Peng, K.T., Huang, K.C., Huang, T.W., Lee, Y.S., Hsu, W.H., Hsu, R.W., Ueng, S.W., and Lee, M.S. (2014). Single nucleotide polymorphisms other than factor V Leiden are associated with coagulopathy and osteonecrosis of the femoral head in Chinese patients. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0104461"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1055\/s-0036-1597968","article-title":"Risks of Factor V rs6020 or Methylenetetrahydrofolate Reductase rs12121543 Polymorphism with Hyperhomocysteinemia in the Development of Osteonecrosis of the Femoral Head","volume":"1","author":"Lu","year":"2017","journal-title":"J. Hip Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"134","DOI":"10.3109\/17453674.2014.960997","article-title":"iNOS expression and osteocyte apoptosis in idiopathic, non-traumatic osteonecrosis","volume":"86","author":"Wang","year":"2015","journal-title":"Acta Orthop."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1002\/jor.20164","article-title":"Endothelial nitric oxide synthase gene polymorphisms in patients with nontraumatic femoral head osteonecrosis","volume":"24","author":"Koo","year":"2006","journal-title":"J. Orthop. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2460","DOI":"10.2106\/00004623-200711000-00018","article-title":"Association between the T-786C eNOS polymorphism and idiopathic osteonecrosis of the head of the femur","volume":"89","author":"Glueck","year":"2007","journal-title":"J. Bone Jt. Surg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2220","DOI":"10.2106\/JBJS.G.00616","article-title":"Thrombophilia, hypofibrinolysis, the eNOS T-786C polymorphism, and multifocal osteonecrosis","volume":"90","author":"Glueck","year":"2008","journal-title":"J. Bone Jt. Surg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3096","DOI":"10.1161\/01.CIR.99.24.3096","article-title":"G894T polymorphism in the endothelial nitric oxide synthase gene is associated with an enhanced vascular responsiveness to phenylephrine","volume":"99","author":"Philip","year":"1999","journal-title":"Circulation"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/path.1250","article-title":"Protective role of endothelial nitric oxide synthase","volume":"199","author":"Albrecht","year":"2003","journal-title":"J. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1161\/hh0801.089861","article-title":"Nitric oxide insufficiency, platelet activation, and arterial thrombosis","volume":"88","author":"Loscalzo","year":"2001","journal-title":"Circ. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1210\/en.2002-220597","article-title":"Inducible nitric oxide synthase mediates bone loss in ovariectomized mice","volume":"144","author":"Cuzzocrea","year":"2003","journal-title":"Endocrinology"},{"key":"ref_24","first-page":"79","article-title":"ARCO (Association Research Circulation Osseous) international classification of osteonecrosis. ARCO Committee on Terminology and Staging. Report on the committee meeting at Santiago de Compostella","volume":"5","author":"Gardeniers","year":"1993","journal-title":"ARCO Newsl."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1097\/00003086-199204000-00006","article-title":"Intravascular coagulation and osteonecrosis","volume":"277","author":"Jones","year":"1992","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1182\/blood.V95.6.1935","article-title":"Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S","volume":"95","author":"Makris","year":"2000","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1055\/s-0038-1657602","article-title":"The Leiden Thrombophilia Study (LETS)","volume":"78","author":"Koster","year":"1997","journal-title":"Thromb. Haemost."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1093\/aje\/kwr203","article-title":"Free protein S level as a risk factor for coronary heart disease and stroke in a prospective cohort study of healthy United Kingdom men","volume":"174","author":"Cooper","year":"2011","journal-title":"Am. J. Epidemiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1007\/s11999.0000000000000161","article-title":"Cardiovascular and Cerebrovascular Events Are Associated With Nontraumatic Osteonecrosis of the Femoral Head","volume":"476","author":"Sung","year":"2018","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1007\/s00264-018-3866-2","article-title":"Nationwide study on the risk of unprovoked venous thromboembolism in non-traumatic osteonecrosis of femoral head","volume":"42","author":"Sung","year":"2018","journal-title":"Int. Orthop."},{"key":"ref_31","first-page":"44","article-title":"Genetic hypofibrinolysis in complicated pregnancies","volume":"97","author":"Glueck","year":"2001","journal-title":"Obstet. Gynecol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/17\/4963\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:14:33Z","timestamp":1760141673000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/17\/4963"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,24]]},"references-count":31,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["jcm11174963"],"URL":"https:\/\/doi.org\/10.3390\/jcm11174963","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2022,8,24]]}}}