{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T16:53:00Z","timestamp":1790009580374,"version":"4.0.1"},"reference-count":28,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"CAMS Innovation Fund for Medical Sciences (CIFMS) from Chinese Academy of Medical Sciences","award":["2021-I2M-1-062"],"award-info":[{"award-number":["2021-I2M-1-062"]}]},{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["2023ZD0506505"],"award-info":[{"award-number":["2023ZD0506505"]}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2022YFC2304601"],"award-info":[{"award-number":["2022YFC2304601"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Clin Appl Thromb Hemost"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>This study aimed to investigate the causal relationship between complement system overactivation and coagulopathy in sepsis using a two-sample Mendelian Randomization (MR) approach.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted genome-wide association studies (GWAS) using UK Biobank data to identify genetic variants associated with high complement levels in sepsis patients (exposure) and with coagulopathy (outcome). Single nucleotide polymorphisms (SNPs) robustly associated with the exposure were used as instrumental variables in a bidirectional MR analysis to assess causality. The primary analysis utilized the inverse variance weighted (IVW) method, supplemented by extensive sensitivity analyses to test for pleiotropy. Multivariable MR (MVMR) was performed to adjust for the potential confounding effects of C-reactive protein (CRP), a key inflammatory marker.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The GWAS identified distinct and shared genetic loci for high-complement sepsis and coagulopathy, including in key complement (CFH, C3) and coagulation (F5) genes. The primary MR analysis revealed a significant positive causal effect of genetically predicted high C3 levels on the risk of developing coagulopathy (\u03b2\u2009=\u20090.62,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009=\u2009.0008). This finding was robust across all sensitivity analyses, with no evidence of significant horizontal pleiotropy. Conversely, the reverse MR analysis showed no causal effect of coagulopathy on complement activation, establishing a unidirectional relationship. The MVMR analysis demonstrated that the causal effect of C3 on coagulopathy remained significant after adjusting for CRP, suggesting that complement can drive coagulopathy through pathways partially independent of systemic inflammation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study provides strong genetic evidence that complement system overactivation is a unidirectional, causal driver of coagulopathy in sepsis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/10760296251396143","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T16:58:46Z","timestamp":1762880326000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":2,"title":["Complement Overactivation as a Causal Driver of Sepsis-Associated Coagulopathy: A Mendelian Randomization Study from the UK Biobank"],"prefix":"10.1177","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7595-4234","authenticated-orcid":false,"given":"Rong","family":"Liufu","sequence":"first","affiliation":[{"name":"Peking Union Medical College & Chinese Academy of Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mao-Mao","family":"Cao","sequence":"additional","affiliation":[{"name":"Peking Union Medical College & Chinese Academy of Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Chen","sequence":"additional","affiliation":[{"name":"Peking Union Medical College & Chinese Academy of Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang-Yan-Qiu","family":"Wang","sequence":"additional","affiliation":[{"name":"Peking Union Medical College & Chinese Academy of Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Wu","sequence":"additional","affiliation":[{"name":"Peking Union Medical College & Chinese Academy of Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Peking Union Medical College & Chinese Academy of Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Min","family":"Peng","sequence":"additional","affiliation":[{"name":"Peking Union Medical College & Chinese Academy of Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Du","sequence":"additional","affiliation":[{"name":"Peking Union Medical College & Chinese Academy of Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Weng","sequence":"additional","affiliation":[{"name":"Peking Union Medical College & Chinese Academy of Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,11,11]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1208623"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-023-04385-x"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2023.05.010"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-11-680744"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.1996.5101050.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199908193410807"},{"issue":"1","key":"e_1_3_2_8_2","article-title":"Crosstalk between the coagulation and complement systems in sepsis [J]","volume":"133","author":"Lupu F","year":"2014","unstructured":"Lupu F, Keshari RS, Lambris JD, et al. Crosstalk between the coagulation and complement systems in sepsis [J]. Thromb Res. 2014;133(Suppl 1(0 1)):S28\u2013S31.","journal-title":"Thromb Res"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.306853"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.42671"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-02-269746"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-018-5203-z"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.18236"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1500960"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000001504"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2402"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000001031"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38383-y"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2012.04810.x"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq061"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2015.251314"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.034600"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtha.2024.01.006"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20020077"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102118"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2006.02033.x"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12786"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e3181faa0f2"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2019.188331"}],"container-title":["Clinical and Applied Thrombosis\/Hemostasis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/10760296251396143","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/10760296251396143","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/10760296251396143","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T14:05:28Z","timestamp":1777385128000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/10760296251396143"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8]]},"references-count":28,"alternative-id":["10.1177\/10760296251396143"],"URL":"https:\/\/doi.org\/10.1177\/10760296251396143","relation":{},"ISSN":["1076-0296","1938-2723"],"issn-type":[{"value":"1076-0296","type":"print"},{"value":"1938-2723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8]]},"article-number":"10760296251396143"}}