{"doi":"10.1002/ajh.25759","title":"Hemoglobin F mitigation of sickle cell complications decreases with aging","abstract":"To the Editor: Hemoglobin F (HbF) concentration is the major genetic modifier of clinical expression in sickle cell disease (SCD), and high levels improve survival by decreasing intracellular polymerization of hemoglobin S, theoretically affecting downstream vaso-occlusive and hemolytic complications (VOCs).1 However, total HbF level alone is not an accurate predictor of clinical complications as disease manifestations have been observed in individuals with the Arab-Indian haplotype.2 Distribution of HbF (pancellular or heterocellular) and the total amount of HbF/F per cell, as measured in picograms, impacts the ability of HbF to inhibit HbS polymerization. Hereditary persistence of fetal hemoglobin (HPFH) results in inherited HbF levels of ~30% (about 10 pg of HbF/F cell) that are sustained into adulthood. Those with deletional HPFH exhibit decreased or absent β-globin synthesis with pancellular distribution of HbF. Nondeletional HPFH, includes a variety of disorders resulting from mutations within the γ-globin gene, with either pancellular or heterocellular distribution of HbF.3 High levels of HbF are also induced by pharmacological methods, as with hydroxyurea (HU), resulting in heterocellular distribution.4 Individuals with HbS-HPFH have a relatively benign clinical course attributed to pancellular distribution of high HbF. Recent work by Steinberg et al hypothesized that if total HbF levels reach 30% with pancellular distribution, phenotypic cure of SCD should be achieved.5 As survival for patients with SCD has increased dramatically in the past 20 years, we hypothesized that SCD-related complications may increase with age, and progressively affect “high F” individuals. There is a concern that in everyday practice individuals with SCD and “high F,” who typically have few vasocclusive crises in youth, are not further evaluated for the genetic mutation responsible for HPFH. And, they are often classified as “benign,” leading to possible oversight of potential SCD related complications. Here we report the clinical characteristics of adult patients with SCD and inherited high HbF across different ages. Electronic medical records were reviewed for 769 patients with SCD, HbSS/SC/SB0/B+, at Montefiore Medical Center in the Bronx, New York. HbF values using high performance liquid chromatography (BioRad Variant II). Values obtained immediately after a blood transfusion were excluded. A comprehensive chart review for patients with HbF > 14% was completed for VOCs, opioid therapy, acute chest syndrome (ACS), avascular necrosis (AVN), splenomegaly or infarction (including evidence of calcification), pneumonia, retinopathy confirmed by ophthalmology report, stroke, pulmonary hypertension or elevation of tricuspid regurgitant jet velocity (TRV), leg ulcer, myocardial infarction (MI), priapism, chronic kidney disease (CKD with GFR <60), and miscarriage. HbF values were obtained using high performance liquid chromatography (BioRad Variant II). Clinical laboratory values were collected at steady state, or when patient was free of illness. For genetic analysis, all patients had beta globin mutation completed and 12/13 patients had alpha globin mutation completed. Since this cohort of patients sustained high lifetime HbF in the absence of HU, this prompted further analysis with flow cytometry and beta globin dosage analysis for HPFH. In 10/13 subjects, cellular distribution of HbF was analyzed by flow cytometry (CytoFlex, Beckman Coulter, CA) following fixation, permeabilization, and incubation of red blood cells with a monoclonal antibody against HbF, directly conjugated with FITC (Cat # MHFH01, Life Technologies, MD). Beta globin dosage analysis was performed in 7/13 patients using multiplex-polymerase chain reaction (PCR) amplification of fragments specific for portions of the epsilon-, gammaG-, gammaA-, delta-, and beta-globin genes. We identified 150 adults with SCD and HbF ≥ 14%; 137/150 of them, or 91% were taking HU, and were exclu","journal":"American Journal of Hematology","year":2020,"id":107109,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9621,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":515326,"name":"Morayma Reyes‐Gil","orcid":"0000-0002-0337-7941","position":1,"is_corresponding":false},{"id":515327,"name":"Ugochi O. Ogu","orcid":"0000-0002-4662-1414","position":2,"is_corresponding":false},{"id":515906,"name":"Merin Thomas","orcid":null,"position":3,"is_corresponding":false},{"id":366914,"name":"Eric E. Bouhassira","orcid":"0000-0002-1084-2135","position":4,"is_corresponding":false},{"id":366913,"name":"Caterina P. Minniti","orcid":"0000-0002-7059-2959","position":5,"is_corresponding":false},{"id":366906,"name":"Seda S. Tolu","orcid":"0000-0003-2235-4902","position":0,"is_corresponding":true}],"reference_count":7,"raw_metadata":null,"created_at":"2026-07-18T23:12:31.053776Z","pmid":"32072665","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}