{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:45:36Z","timestamp":1789469136883,"version":"build-2803163510"},"reference-count":15,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:00:00Z","timestamp":1787961600000},"content-version":"vor","delay-in-days":54,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"the Wenzhou Key Laboratory of Neurogenetics","award":["2024HZSY0010"],"award-info":[{"award-number":["2024HZSY0010"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Ann Hematol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    This study investigates the relationship between hereditary protein S deficiency (PSD) and cerebral venous sinus thrombosis (CVST) through phenotypic and genetic analyses in a proband and family members with compound heterozygous\n                    <jats:italic>PROS1<\/jats:italic>\n                    mutations. A retrospective analysis was conducted on the clinical data of one patient diagnosed with CVST treated in The Second Affiliated Hospital and Yuying Children\u2019s Hospital of Wenzhou Medical University in July 2025. Peripheral venous blood samples were collected from the proband and 14 individuals from three generations, and relevant coagulation parameters and thrombin generation and inhibition assays were performed. Plasma protein S activity (PS: A), total protein S antigen (TPS: Ag), and free protein S antigen (FPS: Ag) were quantified. All exons and flanking regions of PROS1 were amplified by polymerase chain reaction (PCR) and analyzed by Sanger sequencing. Bioinformatics tools were used to evaluate mutation conservation, predict pathogenicity, and analyze structural effects on the protein. Thrombin generation and inhibition assays indicated defective anticoagulant function in the proband. The proband was diagnosed with CVST and type \u2160 PSD (PS: A 39%, TPS: Ag 53 mg\/L, FPS: Ag 42 mg\/L). Genetic analysis identified a heterozygous missense variant c.1544G\u2009&gt;\u2009A (p.Arg515His) and a heterozygous synonymous mutation c.2001 A\u2009&gt;\u2009G (p.Pro667Pro) in the PROS1 gene. Arg515 was highly conserved across nine homologous species. The p.Arg515His mutation was predicted to be pathogenic and associated with reduced protein stability and abnormal folding. Compound heterozygous variants c.1544G\u2009&gt;\u2009A and c.2001 A\u2009&gt;\u2009G in the PROS1 gene may be associated with reduced protein S levels in this pedigree. The occurrence of CVST in the proband with PSD patients may also be related to these compound heterozygous variants.\n                  <\/jats:p>","DOI":"10.1007\/s00277-026-07153-3","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T03:16:35Z","timestamp":1783307795000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pedigree analysis of cerebral venous sinus thrombosis associated with compound heterozygous hereditary protein S deficiency"],"prefix":"10.1007","volume":"105","author":[{"given":"Xuanyu","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beilei","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buyu","family":"Ke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyu","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuyi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"7153_CR1","doi-asserted-by":"publisher","first-page":"e2200","DOI":"10.1212\/WNL.0000000000010598","volume":"95","author":"FO Otite","year":"2020","unstructured":"Otite FO, Patel S, Sharma R et al (2020) Trends in incidence and epidemiologic characteristics of cerebral venous thrombosis in the United States. Neurology 95:e2200\u2013e2213. https:\/\/doi.org\/10.1212\/WNL.0000000000010598","journal-title":"Neurology"},{"key":"7153_CR2","doi-asserted-by":"publisher","first-page":"e77","DOI":"10.1161\/STR.0000000000000456","volume":"55","author":"G Saposnik","year":"2024","unstructured":"Saposnik G, Bushnell C, Coutinho JM et al (2024) Diagnosis and Management of Cerebral Venous Thrombosis: A Scientific Statement From the American Heart Association. Stroke 55:e77\u2013e90. https:\/\/doi.org\/10.1161\/STR.0000000000000456","journal-title":"Stroke"},{"key":"7153_CR3","doi-asserted-by":"publisher","first-page":"2337907","DOI":"10.1080\/09537104.2024.2337907","volume":"35","author":"FS Alshehri","year":"2024","unstructured":"Alshehri FS, Bashmeil AA, Alamar IA et al (2024) The natural anticoagulant protein S; hemostatic functions and deficiency. Platelets 35:2337907. https:\/\/doi.org\/10.1080\/09537104.2024.2337907","journal-title":"Platelets"},{"key":"7153_CR4","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1159\/000508525","volume":"144","author":"D Juhl","year":"2021","unstructured":"Juhl D, Kuta P, Shneyder M et al (2021) Two Novel Variants in the Protein S Gene PROS1 Are Associated with Protein S Deficiency and Thrombophilia. Acta Haematol 144:222\u2013226. https:\/\/doi.org\/10.1159\/000508525","journal-title":"Acta Haematol"},{"key":"7153_CR5","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.3760\/cma.j.cn113694-20240408-00214","volume":"57","author":"LL Hou","year":"2024","unstructured":"Hou LL, Xu F, Xie HX et al (2024) Analysis of cerebral venous sinus thrombosis due to inherited protein S deficiency. Chin J Neurol 57:1248\u20131254. https:\/\/doi.org\/10.3760\/cma.j.cn113694-20240408-00214","journal-title":"Chin J Neurol"},{"key":"7153_CR6","doi-asserted-by":"publisher","first-page":"1358","DOI":"10.1160\/TH17-01-0043","volume":"117","author":"C Chen","year":"2017","unstructured":"Chen C, Yang L, Villoutreix BO et al (2017) Gly74Ser mutation in protein C causes thrombosis due to a defect in protein S-dependent anticoagulant function. Thromb Haemost 117:1358\u20131369. https:\/\/doi.org\/10.1160\/TH17-01-0043","journal-title":"Thromb Haemost"},{"key":"7153_CR7","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1007\/s00277-023-05607-6","volume":"103","author":"F Xu","year":"2024","unstructured":"Xu F, Zhou X, Jin Y et al (2024) Analysis of PROS1 mutations and clinical characteristics in three Chinese families with hereditary protein S deficiency. Ann Hematol 103:653\u2013662. https:\/\/doi.org\/10.1007\/s00277-023-05607-6","journal-title":"Ann Hematol"},{"key":"7153_CR8","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1097\/MOH.0000000000000663","volume":"28","author":"R Majumder","year":"2021","unstructured":"Majumder R, Nguyen T (2021) Protein S: function, regulation, and clinical perspectives. Curr Opin Hematol 28:339\u2013344. https:\/\/doi.org\/10.1097\/MOH.0000000000000663","journal-title":"Curr Opin Hematol"},{"key":"7153_CR9","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/j.thromres.2006.10.014","volume":"120","author":"G Castaman","year":"2007","unstructured":"Castaman G, Biguzzi E, Razzari C et al (2007) Association of protein S p.Pro667Pro dimorphism with plasma protein S levels in normal individuals and patients with inherited protein S deficiency. 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Thromb Res 189:132\u2013139. https:\/\/doi.org\/10.1016\/j.thromres.2020.03.011","journal-title":"Thromb Res"}],"container-title":["Annals of Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00277-026-07153-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00277-026-07153-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00277-026-07153-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:43:04Z","timestamp":1789465384000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00277-026-07153-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,6]]},"references-count":15,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["7153"],"URL":"https:\/\/doi.org\/10.1007\/s00277-026-07153-3","relation":{},"ISSN":["1432-0584"],"issn-type":[{"value":"1432-0584","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,6]]},"assertion":[{"value":"19 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The study received approval from the Ethics Committee of the Second Affiliated Hospital and Yuying Children\u2019s Hospital of Wenzhou Medical University (Approval No. 2024194). All participants provided written informed consent prior to their involvement in the study.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"399"}}