{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T19:21:59Z","timestamp":1791400919482,"version":"4.3.3"},"reference-count":24,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T00:00:00Z","timestamp":1626739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Cantabria","award":["06.3653.64001"],"award-info":[{"award-number":["06.3653.64001"]}]},{"name":"FIISS","award":["00\/0015"],"award-info":[{"award-number":["00\/0015"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>The possible association of common polymorphic variants related to thrombophilia (the rs6025(A) allele encoding the Leiden mutation, rs1799963(A), i.e., the G20210A mutation of the prothrombin F2 gene, the rs1801133(T) variant of the methylenetetrahydrofolate reductase (MTHFR) gene that encodes an enzyme involved in folate metabolism, and rs5918(C), i.e., the \u2018A2\u2019 allele of the platelet-specific alloantigen system that increases platelet aggregation induced by agonists), with the risk of Legg\u2013Calv\u00e9\u2013Perthes disease (LCPD) and the degree of hip involvement (Catterall stages I to IV) was analyzed in a cohort study, including 41 children of ages 2 to 10.9 (mean 5.4, SD 2.2), on the basis of clinical and radiological criteria of LCPD. In 10 of the cases, hip involvement was bilateral; thus, a total of 51 hips were followed-up for a mean of 75.5 months. The distribution of genotypes among patients and 118 controls showed no significant differences, with a slightly increased risk for LCPD in rs6025(A) carriers (OR: 2.9, CI: 0.2\u201347.8). Regarding the severity of LCPD based on Catterall classification, the rs1801133(T) variant of the MTHFR gene and the rs5918(C) variant of the platelet glycoprotein IIb\/IIIa were associated with more severe forms of Perthes disease (Catterall III\u2013IV) (p &lt; 0.05). The four children homozygous for mutated MTHFR had a severe form of the disease (Stage IV of Catterall) and a higher risk of non-favorable outcome (Stulberg IV\u2013V).<\/jats:p>","DOI":"10.3390\/children8070614","type":"journal-article","created":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T11:26:10Z","timestamp":1626780370000},"page":"614","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["PlA2 Polymorphism of Platelet Glycoprotein IIb\/IIIa and C677T Polymorphism of Methylenetetrahydrofolate Reductase (MTHFR), but Not Factor V Leiden and Prothrombin G20210A Polymorphisms, Are Associated with More Severe Forms of Legg\u2013Calv\u00e9\u2013Perthes Disease"],"prefix":"10.3390","volume":"8","author":[{"given":"Mar\u00eda Dolores","family":"Garc\u00eda-Alfaro","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, Hospital Universitario Marqu\u00e9s de Valdecilla, Avda Valdecilla s\/n, 39008 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Isabel","family":"P\u00e9rez-Nu\u00f1ez","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Hospital Universitario Marqu\u00e9s de Valdecilla, Avda Valdecilla s\/n, 39008 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Teresa","family":"Amigo","sequence":"additional","affiliation":[{"name":"Laboratorio de Pediatr\u00eda, Departamento de Ciencias M\u00e9dicas y Quir\u00fargicas, Universidad de Cantabria, Cardenal Herrera Oria s\/n, 39011 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmelo","family":"Arbona","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Hospital Universitario Marqu\u00e9s de Valdecilla, Avda Valdecilla s\/n, 39008 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4032-9973","authenticated-orcid":false,"given":"Mar\u00eda \u00c1ngeles","family":"Ballesteros","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Hospital Marqu\u00e9s de Valdecilla-IDIVAL, Avda Valdecilla s\/n, 39008 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7578-241X","authenticated-orcid":false,"given":"Domingo","family":"Gonz\u00e1lez-Lamu\u00f1o","sequence":"additional","affiliation":[{"name":"Laboratorio de Pediatr\u00eda, Departamento de Ciencias M\u00e9dicas y Quir\u00fargicas, Universidad de Cantabria, Cardenal Herrera Oria s\/n, 39011 Santander, Spain"},{"name":"Division of Pediatrics, Hospital Universitario Marqu\u00e9s de Valdecilla-IDIVAL, Avda Valdecilla s\/n, 39008 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.2106\/00004623-198163070-00006","article-title":"The natural history of Legg-Calve-Perthes disease","volume":"63","author":"Stulberg","year":"1981","journal-title":"J. Bone Jt. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1097\/00003086-198007000-00019","article-title":"Methods of measuring in Legg-Calv\u00e9-Perthes disease with special regard to the prognosis","volume":"150","author":"Mose","year":"1980","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1302\/0301-620X.53B1.37","article-title":"The natural history of Perthes\u2019 disease","volume":"53","author":"Catterall","year":"1971","journal-title":"J. Bone Jt. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.2106\/00004623-200410000-00001","article-title":"Legg-Calv\u00e9-Perthes disease. Part I: Classification of radiographs with use of the modified lateral pillar and Stulberg classifications","volume":"86","author":"Herring","year":"2004","journal-title":"J. Bone Jt. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2903","DOI":"10.2106\/JBJS.H.01464","article-title":"Femoral head deformation and repair following induction of ischemic necrosis: A histologic and magnetic resonance imaging study in the piglet","volume":"91","author":"Shapiro","year":"2009","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"335","DOI":"10.2106\/00004623-197355020-00009","article-title":"The experimental simulation of Perthes disease by consecutive interruptions of the blood supply to the capital femoral epiphysis in the puppy","volume":"55","author":"Sanchis","year":"1973","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.2106\/00004623-200412000-00009","article-title":"Legg-Calve-Perthes disease and thrombophilia","volume":"86","author":"Balasa","year":"2004","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jor.22473","article-title":"Meta-analysis of hypercoagulability genetic polymorphisms in Perthes disease","volume":"32","author":"Woratanarat","year":"2014","journal-title":"J. Orthop. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s00439-007-0354-y","article-title":"A recurrent mutation in type II collagen gene causes Legg-Calv\u00e9-Perthes disease in a Japanese family","volume":"121","author":"Miyamoto","year":"2007","journal-title":"Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1056\/NEJMoa042480","article-title":"Type II collagen gene variants and inherited osteonecrosis of the femoral head","volume":"352","author":"Liu","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1302\/0301-620X.62B4.7430217","article-title":"Catterall grouping of Perthes\u2019 disease. An assessment of observer error and prognosis using the Catterall classification","volume":"62","author":"Hardcastle","year":"1980","journal-title":"J. Bone Jt. Surg. Br."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1302\/0301-620X.90B10.20649","article-title":"Prognostic factors and outcome of treatment in Perthes\u2019 disease","volume":"90","author":"Wiig","year":"2008","journal-title":"J. Bone Jt. Surg."},{"key":"ref_13","first-page":"1","article-title":"Rapid, efficient DNA extraction for PCR from cells or blood","volume":"2","author":"Higuchi","year":"1989","journal-title":"Amplifications"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1056\/NEJM199604253341703","article-title":"A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis","volume":"334","author":"Weiss","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/ng0595-111","article-title":"A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase","volume":"10","author":"Frosst","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1093\/clinchem\/43.9.1678","article-title":"Leiden and other coagulation factor mutations affecting thrombotic risk","volume":"43","author":"Bertina","year":"1997","journal-title":"Clin. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3698","DOI":"10.1182\/blood.V88.10.3698.bloodjournal88103698","article-title":"A common genetic variant in the 3\u2032-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and a increased in venous thrombosis","volume":"88","author":"Poort","year":"1996","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1111\/ejh.12738","article-title":"Thrombophilic risk of individuals with rare compound factor V Leiden and prothrombin G20210A polymorphisms: An international case series of 100 individuals","volume":"97","author":"Lim","year":"2016","journal-title":"Eur. J. Haematol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1302\/0301-620X.64B3.6807991","article-title":"A review of the morphology of Perthes\u2019 disease","volume":"64","author":"Catterall","year":"1982","journal-title":"J. Bone Jt. Surg. Br."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1160\/THS10-11-0720","article-title":"Platelets, inflammation and tissue regeneration","volume":"105","author":"Nurden","year":"2011","journal-title":"Thromb. Haemost."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1055\/s-0037-1615028","article-title":"Polymorphism of the platelet glycoprotein IIIa gene in patients with coronary stenosis","volume":"79","author":"Colman","year":"1998","journal-title":"Thromb. Haemost."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1161\/01.CIR.101.9.1013","article-title":"Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists","volume":"101","author":"Michelson","year":"2000","journal-title":"Circulation"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1177\/1076029616687847","article-title":"PlA2 Polymorphism in Glycoprotein IIb\/IIIa Modulates the Morphology and Nanomechanics of Platelets","volume":"23","author":"Todinova","year":"2017","journal-title":"Clin. Appl. Thromb. Hemost."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1302\/0301-620X.86B3.13442","article-title":"The most severe forms of Perthes\u2019 disease associated with the homozygous Factor V Leiden mutation","volume":"86","author":"Szepesi","year":"2004","journal-title":"J. Bone Jt. Surg. Br."}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/8\/7\/614\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:32:24Z","timestamp":1760164344000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/8\/7\/614"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,20]]},"references-count":24,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["children8070614"],"URL":"https:\/\/doi.org\/10.3390\/children8070614","relation":{},"ISSN":["2227-9067"],"issn-type":[{"value":"2227-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,20]]}}}