{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T15:29:29Z","timestamp":1778254169609,"version":"3.51.4"},"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T00:00:00Z","timestamp":1666828800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2016\/23\/B\/NZ5\/00573"],"award-info":[{"award-number":["2016\/23\/B\/NZ5\/00573"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2018\/29\/B\/NZ4\/00771"],"award-info":[{"award-number":["2018\/29\/B\/NZ4\/00771"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2019\/33\/B\/NZ4\/01760"],"award-info":[{"award-number":["2019\/33\/B\/NZ4\/01760"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Fibrin clot structure\/function contributes to cardiovascular disease. We examined sulfur-containing metabolites as determinants of fibrin clot lysis time (CLT) and maximum absorbance (Abs<jats:sub>max<\/jats:sub>) in relation to outcomes in coronary artery disease (CAD) patients. Effects of B-vitamin\/folate therapy on CLT and Abs<jats:sub>max<\/jats:sub> were studied. Plasma samples were collected from 1,952 CAD patients randomized in a 2 x 2 factorial design to (<jats:italic>i<\/jats:italic>) folic acid, vitamins B<jats:sub>12<\/jats:sub>, B<jats:sub>6<\/jats:sub>; (<jats:italic>ii<\/jats:italic>) folic acid, vitamin B<jats:sub>12<\/jats:sub>; (<jats:italic>iii<\/jats:italic>) vitamin B<jats:sub>6<\/jats:sub>; (<jats:italic>iv<\/jats:italic>) placebo for 3.8 years in the Western Norway B-Vitamin Intervention Trial. Clot lysis time (CLT) and maximum absorbance (Abs<jats:sub>max<\/jats:sub>) were determined using a validated turbidimetric assay. Acute myocardial infarction (AMI) and mortality were assessed during a 7-year follow-up. Data were analyzed using bivariate and multiple regression. Survival free of events was studied using Kaplan Mayer plots. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Baseline urinary homocysteine (uHcy)-thiolactone and plasma cysteine (Cys) were significantly associated with CLT while plasma total Hcy was significantly associated with Abs<jats:sub>max<\/jats:sub>, independently of fibrinogen, triglycerides, vitamin E, glomerular filtration rate, body mass index, age, sex plasma creatinine, CRP, HDL-C, ApoA1, and previous diseases. B-vitamins\/folate did not affect CLT and Abs<jats:sub>max<\/jats:sub>. Kaplan-Meier analysis showed associations of increased baseline CLT and Abs<jats:sub>max<\/jats:sub> with worse outcomes. In Cox regression analysis, baseline CLT and Abs<jats:sub>max<\/jats:sub> (&gt;cutoff) predicted AMI (CLT: HR 1.58, 95% CI 1.10\u20132.28; <jats:italic>P<\/jats:italic> = 0.013. Abs<jats:sub>max<\/jats:sub>: HR 3.22, CI 1.19\u20138.69; <jats:italic>P<\/jats:italic> = 0.021) and mortality (CLT: HR 2.54, 95% CI 1.40\u20134.63; <jats:italic>P<\/jats:italic> = 0.002. Abs<jats:sub>max<\/jats:sub>: 2.39, 95% CI 1.17\u20134.92; <jats:italic>P<\/jats:italic> = 0.017). After adjustments for other prognostic biomarkers these associations remained significant. Cys and uHcy-thiolactone, but not tHcy, were significant predictors of AMI in Cox regression models that included CLT. <jats:bold>Conclusions<\/jats:bold> uHcy-thiolactone and plasma Cys are novel determinants of CLT, an important predictor of adverse CAD outcomes. CLT and Abs<jats:sub>max<\/jats:sub> were not affected by B-vitamin\/folate therapy, which could account for the lack of efficacy of such therapy in CAD.<\/jats:p>\n<jats:p><jats:bold>Trial registration:<\/jats:bold> URL: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/clinicaltrials.gov\" xlink:type=\"simple\">http:\/\/clinicaltrials.gov<\/jats:ext-link>. Identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00354081\" xlink:type=\"simple\">NCT00354081<\/jats:ext-link>.<\/jats:p>","DOI":"10.1371\/journal.pone.0275956","type":"journal-article","created":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T17:51:33Z","timestamp":1666893093000},"page":"e0275956","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Homocysteine thiolactone contributes to the prognostic value of fibrin clot structure\/function in coronary artery disease"],"prefix":"10.1371","volume":"17","author":[{"given":"Marta","family":"Sikora","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pawe\u0142","family":"Skrzydlewski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanna","family":"Per\u0142a-Kaj\u00e1n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5845-4409","authenticated-orcid":true,"given":"Hieronim","family":"Jakubowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,10,27]]},"reference":[{"key":"pone.0275956.ref001","doi-asserted-by":"crossref","first-page":"e88","DOI":"10.1161\/ATVBAHA.111.230631","article-title":"Fibrin clot structure and function: a role in the pathophysiology of arterial and venous thromboembolic diseases","volume":"31","author":"A Undas","year":"2011","journal-title":"Arteriosclerosis, thrombosis, and vascular biology"},{"key":"pone.0275956.ref002","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1161\/ATVBAHA.107.153221","article-title":"Heritability of clot formation, morphology, and lysis: the EuroCLOT study","volume":"27","author":"AM Carter","year":"2007","journal-title":"Arteriosclerosis, thrombosis, and vascular biology"},{"key":"pone.0275956.ref003","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1161\/01.ATV.20.7.1704","article-title":"Homocysteine and its disulfide derivatives: a suggested consensus terminology","volume":"20","author":"SH Mudd","year":"2000","journal-title":"Arteriosclerosis, thrombosis, and vascular biology"},{"key":"pone.0275956.ref004","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1373\/clinchem.2003.021634","article-title":"Facts and recommendations about total homocysteine determinations: an expert opinion","volume":"50","author":"H Refsum","year":"2004","journal-title":"Clinical chemistry"},{"key":"pone.0275956.ref005","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1152\/physrev.00003.2018","article-title":"Homocysteine Modification in Protein Structure\/Function and Human Disease","volume":"99","author":"H. 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