{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T20:19:58Z","timestamp":1787170798012,"version":"build-2736575974"},"reference-count":78,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2019,6,15]],"date-time":"2019-06-15T00:00:00Z","timestamp":1560556800000},"content-version":"am","delay-in-days":318,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#am"},{"start":{"date-parts":[[2018,8,16]],"date-time":"2018-08-16T00:00:00Z","timestamp":1534377600000},"content-version":"vor","delay-in-days":15,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000862","name":"Doris Duke Charitable Foundation","doi-asserted-by":"publisher","award":["2013126"],"award-info":[{"award-number":["2013126"]}],"id":[{"id":"10.13039\/100000862","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000862","name":"Doris Duke Charitable Foundation","doi-asserted-by":"publisher","award":["2015191"],"award-info":[{"award-number":["2015191"]}],"id":[{"id":"10.13039\/100000862","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL133574"],"award-info":[{"award-number":["R01HL133574"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["U01HL117659"],"award-info":[{"award-number":["U01HL117659"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["1552782"],"award-info":[{"award-number":["1552782"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2018,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    In sickle cell disease (SCD), \u2018disease severity\u2019 associates with increased RBC adhesion to quiescent endothelium, but the impact on activated endothelium is not known. Increased concentrations of free heme result from intravascular hemolysis in SCD. Heme is essential for aerobic metabolism and plays an important role in numerous biological processes. Excess free heme induces reactive oxygen species generation and endothelial activation, which are associated with cardiovascular disorders including atherosclerosis, hypertension, and thrombosis. Here, we utilized an endothelialized microfluidic platform (Endothelium\u2010on\u2010a\u2010chip) to assess adhesion of sickle hemoglobin\u2010containing red blood cells (HbS RBCs), from adults with homozygous SCD, to heme\u2010activated human endothelial cells (EC)\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Confluent EC monolayers in microchannels were treated with pathophysiologically relevant levels of heme in order to simulate the highly hemolytic intravascular milieu seen in SCD. RBC adhesion to heme\u2010activated ECs varied from subject to subject, and was associated with plasma markers of hemolysis (LDH) and reticulocytosis, thereby linking those RBCs that are most likely to adhere with those that are most likely to hemolyze. These results re\u2010emphasize the critical contribution made by heterogeneous adhesive HbS RBCs to the pathophysiology of SCD. We found that adhesion of HbS RBCs to heme\u2010activated ECs varied amongst individuals in the study population, and associated with biomarkers of hemolysis and inflammation, age, and a recent history of transfusion. Importantly, the microfluidic approach described herein holds promise as a clinically feasible Endothelium\u2010on\u2010a\u2010chip platform with which to study complex heterocellular adhesive interactions in SCD.\n                  <\/jats:p>","DOI":"10.1002\/ajh.25159","type":"journal-article","created":{"date-parts":[[2018,6,15]],"date-time":"2018-06-15T06:52:40Z","timestamp":1529045560000},"page":"1050-1060","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Red blood cell adhesion to heme\u2010activated endothelial cells reflects clinical phenotype in sickle cell disease"],"prefix":"10.1002","volume":"93","author":[{"given":"Erdem","family":"Kucukal","sequence":"first","affiliation":[{"name":"Department of Mechanical and Aerospace Engineering Case Western Reserve University Cleveland Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton","family":"Ilich","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine University of North Carolina Chapel Hill North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel S.","family":"Key","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine University of North Carolina Chapel Hill North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane A.","family":"Little","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology Case Western Reserve University, University Hospitals Seidman Cancer Center Cleveland Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0331-9960","authenticated-orcid":false,"given":"Umut A.","family":"Gurkan","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Aerospace Engineering Case Western Reserve University Cleveland Ohio"},{"name":"Department of Biomedical Engineering Case Western Reserve University Cleveland Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,8,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.293.13.1653"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0950-3536(11)80022-3"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2004-860979"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2005.03.004"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-08-041830"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-07-296483"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4652(199607)168:1<81::AID-JCP10>3.0.CO;2-S"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/mnfr.200500076"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00115"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-216-44197"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-04-495887"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-07-589283"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2008.03177.x"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2014.114728"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1201240109"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0005756"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI58753"},{"key":"e_1_2_8_19_1","article-title":"Do\u2010it\u2010yourself in vitro vasculature that recapitulates in vivo geometries for investigating endothelial\u2010blood cell interactions","volume":"5","author":"Mannino RG","year":"2015","journal-title":"Sci Rep UK."},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198005013021803"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI109646"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V58.5.947.947"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2016.03.008"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/micc.12374"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI110960"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiomech.2016.11.022"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1005426"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep07173"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118355"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1080\/10739680600778456"},{"issue":"2","key":"e_1_2_8_31_1","first-page":"71","article-title":"Dynamic deformability of sickle red blood cells in microphysiological flow","volume":"4","author":"Alapan Y","year":"2016","journal-title":"Technology (Singap World Sci)."},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8IB00004B"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V54.4.872.872"},{"issue":"1","key":"e_1_2_8_35_1","first-page":"163","article-title":"Erythrocyte\/endothelial interactions in the pathogenesis of sickle\u2010cell disease: a \u201creal logical\u201d assessment","volume":"8","author":"Hebbel RP","year":"1982","journal-title":"Blood Cells."},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V88.6.2311.bloodjournal8862311"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V83.2.553.553"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep45036"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2017.018"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-02990-x"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10544-010-9472-8"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2013.08.020"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.124529"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOH.0b013e3283523e1c"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2009.01.004"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/9780470319413.ch2"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2010.07.006"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1974.00320160118010"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)56856-3"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-06-2373"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1202-799"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-08-2760"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V32.5.811.811"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/iub.584"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1177\/1535370216640385"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI89741"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002095"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(81)80529-X"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0123568"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/3982"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.6.3553"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112144"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2007.06894.x"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sjbs.2014.09.005"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2011.07.018"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1152092"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.21952"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-06-649491"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1097\/MPH.0b013e31828e529f"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199406093302303"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1177\/003335491312800206"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.21676"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2016.153791"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1939"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI72305"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2017006742"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-09-618538"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2013.1.362"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.1080\/10739680802279394"}],"container-title":["American Journal of Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fajh.25159","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajh.25159","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajh.25159","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/am-pdf\/10.1002\/ajh.25159","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajh.25159","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T14:57:28Z","timestamp":1692457048000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajh.25159"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8]]},"references-count":78,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2018,8]]}},"alternative-id":["10.1002\/ajh.25159"],"URL":"https:\/\/doi.org\/10.1002\/ajh.25159","archive":["Portico"],"relation":{},"ISSN":["0361-8609","1096-8652"],"issn-type":[{"value":"0361-8609","type":"print"},{"value":"1096-8652","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,8]]},"assertion":[{"value":"2018-05-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-05-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-08-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}