{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T12:15:13Z","timestamp":1792757713998,"version":"4.5.0"},"reference-count":29,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,12,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The pathophysiology of venous thromboembolism (VTE) is complex. While perturbations in the coagulation system have generally been considered the primary driver of VTE risk, there is increasing recognition that additional whole-blood components also play a crucial role in clot formation. The erythrocyte is a particularly important\u2014and often overlooked\u2014contributor to venous thrombi (\u201cred clots\u201d). Sickle cell trait (SCT), the most common hemoglobin variant worldwide, has been consistently shown to confer a modestly increased risk of VTE, and pathophysiologic studies indicate that subclinical erythrocyte changes in SCT interact both with the coagulation system and with clot composition. In this review, we characterize SCT (\u201cHbAS\u201d or \u201cheterozygous HbS\u201d) as a low-risk inherited thrombophilia and compare it to the most well-known thrombophilias: heterozygous factor V Leiden and prothrombin 20210A mutation.<\/jats:p>","DOI":"10.1182\/hematology.2025000717","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T14:08:24Z","timestamp":1764943704000},"page":"291-294","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":2,"title":["When sickle cell trait is not just trait: risk of VTE"],"prefix":"10.1182","volume":"2025","author":[{"given":"Rakhi P.","family":"Naik","sequence":"first","affiliation":[{"name":"1 Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafal","family":"Pawlinski","sequence":"additional","affiliation":[{"name":"2 UNC Blood Research Center and Division of Hematology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel S.","family":"Key","sequence":"additional","affiliation":[{"name":"2 UNC Blood Research Center and Division of Hematology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"issue":"21","key":"2025120616331117200_hem2025000717C1","doi-asserted-by":"crossref","first-page":"5710","DOI":"10.1182\/bloodadvances.2024014252","article-title":"Ancestry-independent risk of venous thromboembolism in individuals with sickle cell trait vs factor V Leiden","volume":"8","author":"Lin","year":"2024","journal-title":"Blood Adv"},{"issue":"8","key":"2025120616331117200_hem2025000717C2","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1007\/s10654-013-9825-8","article-title":"Risk of venous thromboembolism associated with single and combined effects of factor V Leiden, prothrombin 20210A and methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls","volume":"28","author":"Simone","year":"2013","journal-title":"Eur J Epidemiol"},{"issue":"1-2","key":"2025120616331117200_hem2025000717C3","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ymgme.2005.04.002","article-title":"Factor V Leiden, prothrombin 20210A, methylenetetrahydrofolate reductase 677T, and population genetics","volume":"86","author":"Bauduer","year":"2005","journal-title":"Mol Genet Metab"},{"issue":"6","key":"2025120616331117200_hem2025000717C4","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/S1473-3099(12)70055-5","article-title":"Haemoglobinopathies and the clinical epidemiology of malaria: a systematic review and meta-analysis","volume":"12","author":"Taylor","year":"2012","journal-title":"Lancet Infect Dis"},{"issue":"3","key":"2025120616331117200_hem2025000717C5","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1182\/blood-2006-11-057604","article-title":"Sickle cell trait and the risk of venous thromboembolism among blacks","volume":"110","author":"Austin","year":"2007","journal-title":"Blood"},{"key":"2025120616331117200_hem2025000717C6","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1097\/GIM.0b013e3181fbe46f","article-title":"Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden (R506Q) and prothrombin (20210G&gt;A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members","volume":"13","author":"Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group","year":"2011","journal-title":"Genet Med"},{"issue":"4","key":"2025120616331117200_hem2025000717C7","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.ajhg.2018.02.003","article-title":"Whole-genome-sequence-based haplotypes reveal single origin of the sickle allele during the Holocene wet phase","volume":"102","author":"Shriner","year":"2018","journal-title":"Am J Hum Genet"},{"issue":"1","key":"2025120616331117200_hem2025000717C8","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.amjmed.2004.01.018","article-title":"Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology","volume":"117","author":"Cushman","year":"2004","journal-title":"Am J Med"},{"issue":"1","key":"2025120616331117200_hem2025000717C9","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1111\/j.1538-7836.2006.02291.x","article-title":"Type and location of venous thromboembolism in patients with factor V Leiden or prothrombin G20210A and in those with no thrombophilia","volume":"5","author":"Martinelli","year":"2007","journal-title":"J Thromb Haemost"},{"issue":"1","key":"2025120616331117200_hem2025000717C10","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/jth.12787","article-title":"Prospective study of sickle cell trait and venous thromboembolism incidence","volume":"13","author":"Folsom","year":"2015","journal-title":"J Thromb Haemost"},{"issue":"4","key":"2025120616331117200_hem2025000717C11","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1111\/bjh.13641","article-title":"Coagulation activation in sickle cell trait: an exploratory study","volume":"171","author":"Amin","year":"2015","journal-title":"Br J Haematol"},{"issue":"2","key":"2025120616331117200_hem2025000717C12","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1046\/j.1365-2141.1997.4173226.x","article-title":"Sickle cell disease: relation between procoagulant activity of red blood cells from different phenotypes and in vivo blood coagulation activation","volume":"99","author":"Helley","year":"1997","journal-title":"Br J Haematol"},{"issue":"10","key":"2025120616331117200_hem2025000717C13","doi-asserted-by":"crossref","first-page":"2368","DOI":"10.3324\/haematol.2019.239350","article-title":"The molecular basis for the prothrombotic state in sickle cell disease","volume":"105","author":"Shet","year":"2020","journal-title":"Haematologica"},{"issue":"5","key":"2025120616331117200_hem2025000717C14","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.thromres.2013.01.023","article-title":"The role of the red cell membrane in thrombin generation","volume":"131","author":"Whelihan","year":"2013","journal-title":"Thromb Res"},{"issue":"2","key":"2025120616331117200_hem2025000717C15","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1097\/00062752-199903000-00004","article-title":"Role of red blood cells in thrombosis","volume":"6","author":"Andrews","year":"1999","journal-title":"Curr Opin Hematol"},{"issue":"18","key":"2025120616331117200_hem2025000717C16","doi-asserted-by":"crossref","first-page":"3837","DOI":"10.1182\/blood-2012-05-427856","article-title":"Prothrombin activation in blood coagulation: the erythrocyte contribution to thrombin generation","volume":"120","author":"Whelihan","year":"2012","journal-title":"Blood"},{"issue":"2","key":"2025120616331117200_hem2025000717C17","article-title":"PIEZO1 and Gardos channels regulate membrane phosphatidylserine exposure in sickle red blood cells","volume":"9","author":"Moonla","year":"2025","journal-title":"Res Pract Thromb Haemost"},{"issue":"7","key":"2025120616331117200_hem2025000717C18","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1111\/jth.13717","article-title":"Prothrombotic aspects of sickle cell disease","volume":"15","author":"Sparkenbaugh","year":"2017","journal-title":"J Thromb Haemost"},{"issue":"1","key":"2025120616331117200_hem2025000717C19","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1172\/JCI111672","article-title":"Uncoupling of the membrane skeleton from the lipid bilayer. The cause of accelerated phospholipid flip-flop leading to an enhanced procoagulant activity of sickled cells","volume":"75","author":"Franck","year":"1985","journal-title":"J Clin Invest"},{"issue":"1","key":"2025120616331117200_hem2025000717C20","doi-asserted-by":"crossref","first-page":"5112","DOI":"10.1038\/s41598-020-59526-x","article-title":"The distinctive structure and composition of arterial and venous thrombi and pulmonary emboli","volume":"10","author":"Chernysh","year":"2020","journal-title":"Sci Rep"},{"issue":"5","key":"2025120616331117200_hem2025000717C21","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1002\/ajh.23958","article-title":"The delay time in sickle cell disease after 40 years: a paradigm assessed","volume":"90","author":"Ferrone","year":"2015","journal-title":"Am J Hematol"},{"issue":"23","key":"2025120616331117200_hem2025000717C22","doi-asserted-by":"crossref","first-page":"2529","DOI":"10.1182\/blood.2019000424","article-title":"Red blood cells modulate structure and dynamics of venous clot formation in sickle cell disease","volume":"133","author":"Faes","year":"2019","journal-title":"Blood"},{"issue":"4","key":"2025120616331117200_hem2025000717C23","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1111\/bjh.19669","article-title":"Hypertonicity and\/or acidosis induce marked rheological changes under hypoxic conditions in sickle trait red blood cells","volume":"205","author":"Ellsworth","year":"2024","journal-title":"Br J Haematol"},{"issue":"24","key":"2025120616331117200_hem2025000717C24","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1056\/NEJM197706162962406","article-title":"Pelvic phleboliths; epidemiology and postulated etiology","volume":"296","author":"Burkitt","year":"1977","journal-title":"N Engl J Med"},{"issue":"3","key":"2025120616331117200_hem2025000717C25","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1002\/bjs.1800680308","article-title":"The PO2 in venous valve pockets: its possible bearing on thrombogenesis","volume":"68","author":"Hamer","year":"1981","journal-title":"Br J Surg"},{"issue":"1","key":"2025120616331117200_hem2025000717C26","doi-asserted-by":"crossref","first-page":"e104","DOI":"10.1055\/s-0038-1635572","article-title":"Reduced contraction of blood clots in venous thromboembolism is a potential thrombogenic and embologenic mechanism","volume":"2","author":"Peshkova","year":"2018","journal-title":"TH Open"},{"issue":"1","key":"2025120616331117200_hem2025000717C27","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1182\/asheducation-2015.1.160","article-title":"Sickle cell trait diagnosis: clinical and social implications","volume":"2015","author":"Naik","year":"2015","journal-title":"Hematology Am Soc Hematol Educ Program"},{"key":"2025120616331117200_hem2025000717C28","article-title":"How a genetic trait in black people can give the police cover","volume-title":"New York Times","author":"LaForgia","year":"2021"},{"issue":"6","key":"2025120616331117200_hem2025000717C29","doi-asserted-by":"crossref","first-page":"e545","DOI":"10.1016\/j.chest.2021.07.055","article-title":"Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report","volume":"160","author":"Stevens","year":"2021","journal-title":"Chest"}],"container-title":["Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2025\/1\/291\/2470171\/291naik.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2025\/1\/291\/2470171\/291naik.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T21:33:21Z","timestamp":1765056801000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/hematology\/article\/2025\/1\/291\/556874\/When-sickle-cell-trait-is-not-just-trait-risk-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,5]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12,5]]},"published-print":{"date-parts":[[2025,12,5]]}},"URL":"https:\/\/doi.org\/10.1182\/hematology.2025000717","relation":{},"ISSN":["1520-4391","1520-4383"],"issn-type":[{"value":"1520-4391","type":"print"},{"value":"1520-4383","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,12,5]]},"published":{"date-parts":[[2025,12,5]]}}}