{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T07:03:56Z","timestamp":1789715036743,"version":"4.0.1"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2026,5,19]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">COVID\u201019 and other respiratory viral infections can cause cardiovascular complications. SARS\u2010CoV\u20102 virions are found in the blood, and circulating viral RNA levels are associated with death. We hypothesized that viremia can induce thrombotic endotheliopathy that contributes to death and studied this relationship in patients hospitalized for COVID\u201019 and enrolled in the ACTIV\u20104a (Accelerating COVID\u201019 Therapeutic Interventions and Vaccines) randomized trial of antithrombotic therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">We quantified SARS\u2010CoV\u20102 nucleocapsid RNA and protein in plasma and measured their associations with clinical outcomes and biomarkers of thromboinflammation and endotheliopathy. We used Cox regression and Fine\u2013Gray competing risk models to analyze survival and thrombosis. We conducted causal mediation analysis to explore whether thrombotic endotheliopathy mediates the relationship between viral RNA and death.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      In 93 patients, SARS\u2010CoV\u20102 RNA and N\u2010antigen were higher in nonsurvivors. Baseline viral RNA levels were associated with increased 90\u2010day death (hazard ratio [HR], 1.31 [95% CI, 1.17\u20131.46]) and thrombosis (HR, 1.35 [95% CI, 1.24\u20131.47]). Viral RNA more effectively predicted survivorship than N\u2010antigen levels. Soluble thrombomodulin, a biomarker of thrombotic endotheliopathy, positively correlated with viral RNA levels. Mediation analysis revealed that soluble thrombomodulin accounts for 12.2% (95% CI, 0.1%\u201332.3%;\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      =0.048) after adjustment for age and sex of the relationship between viral RNA and the 90\u2010day mortality rate.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Elevated plasma SARS\u2010CoV\u20102 RNA levels are associated with death in ACTIV\u20104a, which is causally mediated in part by soluble thrombomodulin. We propose that lung\u2013blood viral dissemination is a potential mechanism for cardiovascular complications of respiratory viruses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Registration<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      URL:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n                      ; Unique Identifier: NCT04505774.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.125.047693","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T09:06:38Z","timestamp":1778058398000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Soluble Thrombomodulin Links Viremia and Mortality During COVID\u201019: Results From the ACTIV\u20104a Trial"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0747-292X","authenticated-orcid":false,"given":"Benjamin E.","family":"Zuchelkowski","sequence":"first","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6212-0662","authenticated-orcid":false,"given":"Kyle W.","family":"Inman","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7465-0581","authenticated-orcid":false,"given":"S. Mehdi","family":"Nouraie","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeharika","family":"Beru","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7911-6409","authenticated-orcid":false,"given":"Asma","family":"Naqvi","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shulin","family":"Qin","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calvin H.","family":"Yeh","sequence":"additional","affiliation":[{"name":"Thrombosis and Atherosclerosis Research Institute and McMaster University","place":["Hamilton, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6947-2901","authenticated-orcid":false,"given":"Yingze","family":"Zhang","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2847-7738","authenticated-orcid":false,"given":"Faraaz A.","family":"Shah","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]},{"name":"Veterans Affairs Pittsburgh Healthcare System","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3040-9029","authenticated-orcid":false,"given":"Lokesh","family":"Sharma","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles S.","family":"Dela Cruz","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]},{"name":"Veterans Affairs Pittsburgh Healthcare System","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3037-9173","authenticated-orcid":false,"given":"Lianghui","family":"Zhang","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1175-4874","authenticated-orcid":false,"given":"Bryan J.","family":"McVerry","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9958-0318","authenticated-orcid":false,"given":"Alison","family":"Morris","sequence":"additional","affiliation":[{"name":"Rutgers, Robert Wood Johnson Medical School","place":["New Brunswick, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8931-6236","authenticated-orcid":false,"given":"Matthew D.","family":"Neal","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6850-7495","authenticated-orcid":false,"given":"Jansen","family":"Seheult","sequence":"additional","affiliation":[{"name":"Mayo Clinic","place":["Rochester, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1018-948X","authenticated-orcid":false,"given":"Georgios D.","family":"Kitsios","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3737-9742","authenticated-orcid":false,"given":"John W.","family":"Mellors","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3126-1935","authenticated-orcid":false,"given":"Daniel A.","family":"Lawrence","sequence":"additional","affiliation":[{"name":"University of Michigan Medical School","place":["Ann Arbor, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0504-3064","authenticated-orcid":false,"given":"Paul Y.","family":"Kim","sequence":"additional","affiliation":[{"name":"Thrombosis and Atherosclerosis Research Institute and McMaster University","place":["Hamilton, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0322-585X","authenticated-orcid":false,"given":"Jana L.","family":"Jacobs","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8506-0552","authenticated-orcid":false,"given":"William G.","family":"Bain","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine","place":["Pittsburgh, USA"]},{"name":"Veterans Affairs Pittsburgh Healthcare System","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1702090"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.13372"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/rth2.12496"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2015432"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciab686"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa1285"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa1338"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa1196"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa1085"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI148635"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19057-5"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-23494-1"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-020-03398-0"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiac15"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2022.11.013"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.7326\/M20-2003"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30434-5"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-023-00336-5"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2020.3551"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30937-5"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2103417"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2105911"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2022-0155"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.15327"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-80010-z"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1097\/cce.0000000000000518"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000004018"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.202008-1026OC"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2023-0429OC"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1080\/01621459.1999.10474144"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v059.i05"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00096.2013"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(20)30216-7"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03570-8"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-65489-0"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofad346"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiae198"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.3390\/v13061143"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-020-09730-0"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202107-1774OC"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.14956"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.125.047693","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:37:17Z","timestamp":1789713437000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.125.047693"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,19]]},"references-count":41,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,5,19]]}},"alternative-id":["10.1161\/JAHA.125.047693"],"URL":"https:\/\/doi.org\/10.1161\/jaha.125.047693","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,19]]},"assertion":[{"value":"2025-11-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e047693"}}