{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T06:40:35Z","timestamp":1792478435542,"version":"4.5.0"},"reference-count":35,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["RG231458"],"award-info":[{"award-number":["RG231458"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Anaesthesiol Scand"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Sepsis\u2010induced coagulopathy is characterised by consumptive coagulation abnormalities and resistance to fibrinolysis, which is increasingly recognised as a driver of microvascular thrombosis, organ dysfunction and mortality. The molecular determinants of the fibrinolysis\u2010resistant phenotype remain incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To present a pre\u2010specified statistical analysis plan for a plasma proteomic investigation of fibrinolysis resistance in 89 samples collected serially from 32 critically ill patients with sepsis, using the Olink Explore HT platform (approximately 5400 proteins). The plan is designed to characterise protein associations with a validated bedside measure of fibrinolysis resistance, the ratio of tissue plasminogen activator\u2010induced lysis time to fibrin clot amplitude (TPA\u2010LT\/FIBA10). The associations will be examined across the fibrinolysis resistance severity continuum and between three ordinal severity grades, and over time within individual patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The analytic framework combines five complementary approaches: (i) limit\u2010of\u2010detection\u2010based data filtering, (ii) continuous\u2010variable modelling of protein abundance against TPA\u2010LT\/FIBA10 using limma\u2010trend regression, (iii) categorical comparison across severity grades using empirical Bayes moderated statistics, (iv) linear mixed\u2010effects modelling of longitudinal intra\u2010patient trajectories and (v) pathway\u2010level enrichment analysis to translate statistical associations into mechanistic hypotheses. A semi\u2010supervised pathway clustering analysis will describe how proteins change by fibrinolysis resistance in eight a priori defined domains.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This multi\u2010model design is intended to define genuine biological signals in a high\u2010dimensional dataset while remaining transparent about the exploratory nature of several components. The statistical reasoning behind each method is discussed alongside anticipated limitations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                      : NCT06680180\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/aas.70358","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T05:20:31Z","timestamp":1792128031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigating Fibrinolysis Resistance in Sepsis Using High\u2010Multiplex Plasma Proteomics: A Statistical Analysis 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