{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T19:58:30Z","timestamp":1780862310105,"version":"3.54.1"},"posted":{"date-parts":[[2026,6,4]]},"group-title":"Hematology","reference-count":29,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Fetal hemoglobin (HbF) prevents the polymerization of sickle hemoglobin (HbS). HbF, measured usually as a percent of total hemoglobin (%HbF), is inversely associated with the severity of sickle cell disease (SCD) but fails to capture the distribution of HbF concentrations within red blood cells (RBCs). The relative proportion of HbF and HbS within a RBC is reflected by the HbF:HbS ratio whereas HbF\/F-cell quantifies the absolute amount of HbF\/RBC. While correlated, HbF:HbS ratio and HbF\/F-cell are not interchangeable. In the context of mean corpuscular hemoglobin (MCH), HbF\/F-cell approximates whether sufficient HbF is present to inhibit HbS polymerization. We examined the association of mean HbF\/F-cell with sub-phenotypes of sickle cell disease in three independent cohorts. Both %HbF and HbF\/F-cell were significantly associated with multiple clinical and laboratory features of SCD; however, HbF\/F-cell demonstrated stronger associations with clinical severity measures across cohorts. Higher HbF\/F-cell was associated with fewer clinical events, reduced hemolysis, and mortality. Changes in HbF\/F-cell after hydroxyurea treatment were associated with ~11-13% reduction in acute events in patients with &lt;1 pg increase and &gt;60% reduction with a &gt;5 pg increase in HbF\/F-cell. For each pg increase in HbF\/F-cell there was ~6% reduction in the rate of acute events. As a surrogate for the distribution of HbF concentrations among F-cells, HbF\/F-cell adds physiologically relevant insights that could guide prognosis and treatment.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Key points<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>HbF\/F-cell reflects protective intracellular HbF:HbS stoichiometry.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Higher HbF\/F-cell demonstrated stronger associations with clinical severity than %HbF and predicts VOEs and ACS, reduced hemolysis, and mortality.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Regardless of %HbF, as MCH decreases, the HbF:HbS ratio increases<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>HbF\/F-cell is a surrogate for the distribution of HbF concentrations among F-cells and could guide prognosis and treatment.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.02.26354737","type":"posted-content","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:20:16Z","timestamp":1780618816000},"source":"Crossref","is-referenced-by-count":0,"title":["HbF\/F-cell and the Phenotype of Sickle Cell Disease"],"prefix":"10.64898","author":[{"given":"J.","family":"Lofters","sequence":"first","affiliation":[{"name":"Division of Hematology & Medical Oncology, Boston University Chobanian & Avedisian School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6607-4340","authenticated-orcid":false,"given":"A.","family":"Wilks","sequence":"additional","affiliation":[{"name":"Division of Hematology & Medical Oncology, Boston University Chobanian & Avedisian School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Boston University School of Public Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. N.","family":"Hicks","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Boston University School of Public Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. S.","family":"Klings","sequence":"additional","affiliation":[{"name":"The Pulmonary Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. H","family":"Steinberg","sequence":"additional","affiliation":[{"name":"Division of Hematology & Medical Oncology, Boston University Chobanian & Avedisian School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026060712150581000_2026.06.02.26354737v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(79)90402-9"},{"key":"2026060712150581000_2026.06.02.26354737v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-3233(08)60287-9"},{"key":"2026060712150581000_2026.06.02.26354737v1.3","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-03-325258"},{"key":"2026060712150581000_2026.06.02.26354737v1.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199406093302303"},{"key":"2026060712150581000_2026.06.02.26354737v1.5","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2016.153791"},{"key":"2026060712150581000_2026.06.02.26354737v1.6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0141706"},{"issue":"2","key":"2026060712150581000_2026.06.02.26354737v1.7","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s11136-018-2031-0","article-title":"Hemoglobin F as a predictor of health related quality of life in children with sickle cell anemia","volume":"28","year":"2019","journal-title":"Qual Life Res"},{"key":"2026060712150581000_2026.06.02.26354737v1.8","first-page":"E32","article-title":"Fetal hemoglobin per erythrocyte (HbF\/F-cell) after gene therapy for sickle cell anemia","volume":"98","year":"2023","journal-title":"Am J Hematol"},{"key":"2026060712150581000_2026.06.02.26354737v1.9","doi-asserted-by":"publisher","DOI":"10.1126\/science.804182"},{"key":"2026060712150581000_2026.06.02.26354737v1.10","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V89.3.1078"},{"key":"2026060712150581000_2026.06.02.26354737v1.11","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2011.08916.x"},{"key":"2026060712150581000_2026.06.02.26354737v1.12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2309676"},{"key":"2026060712150581000_2026.06.02.26354737v1.13","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2504835"},{"key":"2026060712150581000_2026.06.02.26354737v1.14","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1056\/NEJMoa2415550","article-title":"CRISPR-Cas12a gene editing of HBG1 and HBG2 promoters to treat sickle cell disease","volume":"394","year":"2026","journal-title":"N Engl J Med"},{"key":"2026060712150581000_2026.06.02.26354737v1.15","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-199611000-00002"},{"key":"2026060712150581000_2026.06.02.26354737v1.16","doi-asserted-by":"publisher","DOI":"10.1001\/jama.289.13.1645"},{"key":"2026060712150581000_2026.06.02.26354737v1.17","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1002\/ajh.27729","article-title":"Mean corpuscular hemoglobin modulates HbF\/F- Cell and clinical response to gene therapy and hydroxyurea in sickle cell disease","volume":"100","year":"2025","journal-title":"Am J Hematol"},{"key":"2026060712150581000_2026.06.02.26354737v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/0197-2456(87)90016-X"},{"key":"2026060712150581000_2026.06.02.26354737v1.19","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V89.3.1078"},{"key":"2026060712150581000_2026.06.02.26354737v1.20","first-page":"288","article-title":"Cerebrovascular accidents in sickle cell disease: rates and risk factors","volume":"91","year":"1998","journal-title":"Blood"},{"key":"2026060712150581000_2026.06.02.26354737v1.21","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200006223422502"},{"key":"2026060712150581000_2026.06.02.26354737v1.22","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-553X.2011.01367.x"},{"key":"2026060712150581000_2026.06.02.26354737v1.23","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-04-218040"},{"key":"2026060712150581000_2026.06.02.26354737v1.24","unstructured":"Habibi A , De Pierrefeu V , Bencheikh L , et al. 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