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Cited by 136Hemoglobinopathies and Related DisordersHemoglobin structure and functionBlood groups and transfusion

Fetal hemoglobin in sickle cell anemia

Open access
Steinberg, Martin H.·2020·Blood
DOI 10.1182/blood.2020007645
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Abstract

Abstract Fetal hemoglobin (HbF) can blunt the pathophysiology, temper the clinical course, and offer prospects for curative therapy of sickle cell disease. This review focuses on (1) HbF quantitative trait loci and the geography of β-globin gene haplotypes, especially those found in the Middle East; (2) how HbF might differentially impact the pathophysiology and many subphenotypes of sickle cell disease; (3) clinical implications of person-to-person variation in the distribution of HbF among HbF-containing erythrocytes; and (4) reactivation of HbF gene expression using both pharmacologic and cell-based therapeutic approaches. A confluence of detailed understanding of the molecular basis of HbF gene expression, coupled with the ability to precisely target by genomic editing most areas of the genome, is producing important preliminary therapeutic results that could provide new options for cell-based therapeutics with curative intent.

Integrity signals

Registry

Crossref · 10.1182/blood.2020007645

Cites

139 of 139 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

78 of 141 cited sources checked · 33 supported · 6 flagged · accuracy not yet measured

  • Premisecitation

    An intronic SNP (rs35685045) in ANTXR1 was associated with HbF in 4 cohorts of adult AI haplotype patients.

    “An intronic SNP (rs35685045) in ANTXR1 (TEM8; chr2p13) was associated with HbF in 4 cohorts of adult AI haplotype patients.41,42”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [41] Vathipadiekal, 2016, A candidate transacting modulator of fetal hemoglobin gene expression in the Arab-Indian haplotype of sickle cell anemia, Am J Hematol source

      The Results section identifies rs35685045 as an intronic ANTXR1 SNP associated with HbF, but it does not support association in four AI-haplotype cohorts. The Results report association in the Saudi AI cohorts and explicitly state that it was not found in the Indian AI cohort. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [42] Al-Ali, 2018, ANTXR1 intronic variants are associated with fetal hemoglobin in the Arab-Indian haplotype of sickle cell disease, Acta Haematol source
  • Interpretationcitation

    Even when started early in life, the HbF response to hydroxyurea might wane.

    “Therefore, even when started early in life, the HbF response to hydroxyurea might wane.88”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [88] Hankins, 2014, From infancy to adolescence: fifteen years of continuous treatment with hydroxyurea in sickle cell anemia, Medicine (Baltimore) source

      The Results section reports that HbF levels remained above expected values for untreated individuals after 15 years of hydroxyurea therapy. The Discussion says hematologic effects were sustained and found no apparent tolerance among patients with adequate adherence. Rather than reporting a waning HbF response, this cohort's findings point to a sustained one. (LLM, conf=0.86)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    BCL11A is a repressor of HbF gene expression.

    “BCL11A is a repressor of HbF gene expression.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [4] Akinsheye, 2011, Fetal hemoglobin in sickle cell anemia, Blood source
    • cites [14] Menzel, 2007, A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15, Nat Genet source
    • cites [15] Sedgewick, 2008, BCL11A is a major HbF quantitative trait locus in three different populations with β-hemoglobinopathies, Blood Cells Mol Dis source

      The Results and Discussion section (page unavailable) says BCL11A functions as a transcriptional repressor and that its variants are associated with HbF levels. It also says the mechanism by which BCL11A modulates HbF production was not understood; it does not establish that BCL11A represses HbF gene expression specifically. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
  • Premisecitation

    Inactivation and activation of genes within the b-globin gene cluster holds the keys to reactivating the usually dormant HbF genes for therapeutic gain.

    “Inactivation and activation of genes within the b-globin gene cluster holds the keys to reactivating for therapeutic gain the usually dormant HbF genes.[6][7][8][9][10][11][12]”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [6] Ikawa, 2019, Gene therapy of hemoglobinopathies: progress and future challenges, Hum Mol Genet source
    • cites [7] Vinjamur, 2018, Recent progress in understanding and manipulating haemoglobin switching for the haemoglobinopathies, Br J Haematol source
    • cites [8] Blobel, 2015, An international effort to cure a global health problem: A report on the 19th Hemoglobin Switching Conference, Exp Hematol source
  • Interpretationcitation

    The most efficient means of treating sickle cell disease is interrupting disease pathophysiology by preventing deoxyHbS polymerization.

    “The most efficient means of treatment is interrupting disease pathophysiology by preventing deoxyHbS polymerization.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [5] Eaton, 2017, Treating sickle cell disease by targeting HbS polymerization, Blood source

      The Introduction (page unavailable) identifies HbS polymerization as the root cause of sickle cell pathology and argues for directing more research and trials toward inhibiting it. It does not establish that preventing polymerization is the most efficient treatment; the Conclusion (page unavailable) says polymerization inhibitors still face hurdles before clinical use. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 12
  • May combine two claims. 48
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    When HbF/F-cell is 9 to 12 pg, calculations suggested that deoxyHbS polymerization should be prevented at physiologic venous and capillary O2 saturations of 40% to 70%, affording the sickle erythrocyte nearly total protection from HbS polymer-induced damage, although recent studies call this observation into question.

    “When HbF/F-cell is 9 to 12 pg, calculations suggested that deoxyHbS polymerization should be prevented at physiologic venous and capillary O 2 saturations of 40% to 70%, affording the sickle erythrocyte nearly total protection from HbS polymerinduced damage, although recent studies call into question this observation.3,48,49”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [3] Henry, 2020, Allosteric control of hemoglobin S fiber formation by oxygen and its relation to the pathophysiology of sickle cell disease, Proc Natl Acad Sci USA source

      Split into 2 atoms — 1 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [48] Maier-Redelsperger, 1994, Variation in fetal hemoglobin parameters and predicted hemoglobin S polymerization in sickle cell children in the first two years of life: Parisian Prospective Study on Sickle Cell Disease, Blood source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [49] Horiuchi, 1995, Estimation of fetal hemoglobin levels in individual red cells via fluorescence image cytometry, Cytometry source

  • May combine two claims.

    Interpretationcitation

    As HbF falls and fewer F-cells are protected from HbS polymer damage, the propensity for vascular occlusion and intravascular hemolysis increases with the release of heme products into the circulation that scavenge nitric oxide causing endothelial damage and vasculopathy.

    “As HbF falls and fewer F-cells are protected from HbS polymer damage, the propensity for vascular occlusion and intravascular hemolysis increases with the release of heme products into the circulation that scavenge nitric oxide causing endothelial damage and vasculopathy.[57][58][59]”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [57] Kato, 2007, Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes, Blood Rev source
    • cites [58] Kato, 2017, Intravascular hemolysis and the pathophysiology of sickle cell disease, J Clin Invest source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [59] Reiter, 2002, Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease, Nat Med source

  • May combine two claims.

    Premisecitation

    Several approaches to reducing the expression of HbF suppressors in CD34+ cells have entered clinical trials, including the first use of CRISPR-Cas9 in humans.

    “Several approaches to reducing the expression of HbF suppressors in CD34 1 cells have entered clinical trials, including the first use of CRISPR-Cas9 in humans (Figure 2).123-125”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [123] Porteus, 2017, Genome Editing for the β-Hemoglobinopathies, Adv Exp Med Biol source
    • cites [124] Hoban, 2016, Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease, Blood source

      The 'Current SCD gene therapy clinical trials' section describes trials using globin gene-addition vectors, including one treatment with an antisickling β-globin vector. The paper discusses BCL11A suppression and CRISPR-based editing as novel approaches, not as approaches that had entered clinical trials; it does not report a first use of CRISPR-Cas9 in humans. Page numbers were not available in our copy. (LLM, conf=0.87)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [125] Corbacioglu, 2020, Initial safety and efficacy results with a single dose of autologous crispr-cas9 modified CD34+ hematopoietic stem and progenitor cells in transfusion-dependent β-thalassemia and sickle cell disease, Eur Soc Haematol

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    HbF prolongs the time needed for HbS polymerization, allowing sickle erythrocytes to escape the microcirculation into larger veins and the lungs, where HbS polymer melts on reoxygenation.

    “HbF prolongs the time needed for HbS polymerization (delay time), allowing the escape of sickle erythrocytes from the microcirculation into larger veins and hence the lungs, where on reoxygenation, HbS polymer melts.3”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [3] Henry, 2020, Allosteric control of hemoglobin S fiber formation by oxygen and its relation to the pathophysiology of sickle cell disease, Proc Natl Acad Sci USA source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    BCL11A expression is controlled by transcriptional and/or translational mechanisms.

    “BCL11A expression is controlled by transcriptional and/or translational mechanisms.[22][23][24]”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [22] Basak, 2020, Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation, Nat Genet source
    • cites [23] Lessard, 2018, 14q32 and let-7 microRNAs regulate transcriptional networks in fetal and adult human erythroblasts, Hum Mol Genet source
    • cites [24] Huang, 2017, Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element, Genes Dev source

      The Abstract describes BCL11A as a repressor of γ-globin transcription, and the Results examine what happens when BCL11A is knocked out. Neither passage addresses whether BCL11A’s own expression is controlled transcriptionally or translationally; searches for those mechanisms found no supporting passage in our copy. (LLM, conf=0.77)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    ZBTB7A is not polymorphic and does not account for HbF variation in patients with sickle cell anemia.

    “ZBTB7A is not polymorphic and does not account for HbF variation in patients with sickle cell anemia.26”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [26] Shaikho, 2016, Variants of ZBTB7A (LRF) and its β-globin gene cluster binding motifs in sickle cell anemia, Blood Cells Mol Dis source

      In the paper’s discussion of ZBTB7A variants (page unavailable), the authors conclude that common variants in ZBTB7A or its nearby regulatory regions are unlikely to account for HbF variation in sickle cell anemia. But they report a CGC insertion polymorphism in two patients, so the claim that ZBTB7A is not polymorphic is incorrect. The claim also states the HbF conclusion more definitively than the paper does. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Inactivation of ZBTB7A in HUDEP-2 cells led to approximately 50% HbF, and BCL11A plus ZBTB7A knockout caused more than 90% HbF.

    “Its inactivation in HUDEP-2 cells led to ;50% HbF; BCL11A plus ZBTB7A knockout caused .90% HbF. 25”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Masuda, 2016, Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin, Science source

      The HUDEP-2 results report HbF above 60% in all three ZBTB7A-knockout clones, not approximately 50%. The double-knockout results report HbF at 91–94% of total hemoglobin, supporting the second figure. (LLM, conf=0.91)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    BCL11A binds TGACCA motifs in the HBB gene cluster, preferentially binding to position -115 in the HBG2 and HBG1 promoters.

    “BCL11A binds TGACCA motifs in the HBB gene cluster, preferentially binding to position 2115 in the HBG2 and HBG1 promoters.20,21”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [20] Liu, 2018, Direct promoter repression by BCL11A controls the fetal to adult hemoglobin switch, Cell source
    • cites [21] Martyn, 2018, Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding, Nat Genet source

  • May combine two claims.

    Premisecitation

    KLF1 binds to the promoter of ZBTB7A increasing its expression, and KLF1 also activates the expression of BCL11A.

    “Kr üppel-like factor 1 (KLF1) binds to the promoter of ZBTB7A increasing its expression; KLF1 also activates the expression of BCL11A.28,29”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [28] Norton, 2017, KLF1 directly activates expression of the novel fetal globin repressor ZBTB7A/LRF in erythroid cells, Blood Adv source
    • cites [29] Bieker, 2010, Putting a finger on the switch, Nat Genet source

      The Common ties section reports that KLF1 binds the BCL11A gene and that BCL11A levels rise with KLF1 levels, supporting the BCL11A part of the claim. Our copy does not mention ZBTB7A or say that KLF1 binds its promoter or increases its expression. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The HbS gene had a single origin in West Central Africa or in the Sahara during the Holocene Wet Phase between 3400 and 11,100 years ago or in agriculturists approximately 22,000 years ago, and was introduced into rainforest dwellers within the last 6000 years.

    “The HbS gene had a single origin in West Central Africa or in the Sahara during the Holocene Wet Phase between 3400 and 11 100 years ago or in agriculturists ;22 000 years ago, which was introduced into rainforest dwellers within the last 6000 years.32,33”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [32] Shriner, 2018, Whole-genome-sequence-based haplotypes reveal single origin of the sickle allele during the Holocene wet phase, Am J Hum Genet source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [33] Laval, 2019, Recent adaptive acquisition by African rainforest hunter-gatherers of the late Pleistocene sickle-cell mutation suggests past differences in malaria exposure, Am J Hum Genet source

  • May combine two claims.

    Premisecitation

    The ANTXR1 variant explained approximately 10% of HbF variability compared with approximately 8% for BCL11A.

    “This variant explained ;10% of HbF variability compared with ;8% for BCL11A.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [41] Vathipadiekal, 2016, A candidate transacting modulator of fetal hemoglobin gene expression in the Arab-Indian haplotype of sickle cell anemia, Am J Hematol source
    • cites [42] Al-Ali, 2018, ANTXR1 intronic variants are associated with fetal hemoglobin in the Arab-Indian haplotype of sickle cell disease, Acta Haematol source

  • May combine two claims.

    Premisecitation

    The AI haplotype in Saudi patients is associated with a unique pattern of SNPs in putative cis-acting globin regulatory elements and is linked to a novel variant in ANTXR1.

    “The AI haplotype in Saudi patients is associated with a unique pattern of SNPs in putative cis-acting globin regulatory elements and is linked to a novel variant in ANTXR1.40,41”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [40] Vathipadiekal, 2016, Homozygosity for a haplotype in the HBG2-OR51B4 region is exclusive to Arab-Indian haplotype sickle cell anemia, Am J Hematol source

      The Results (“A unique AI haplotype”) and Discussion describe a distinctive SNP haplotype in Saudi AI patients that may involve cis-acting globin regulatory elements. The paper does not report a link to a novel ANTXR1 variant; a search for ANTXR1 found no matching passage in our copy. Page numbers were not provided. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [41] Vathipadiekal, 2016, A candidate transacting modulator of fetal hemoglobin gene expression in the Arab-Indian haplotype of sickle cell anemia, Am J Hematol source

      The Introduction (page unavailable) describes a unique cis-acting sub-haplotype containing putative functional elements in the AI haplotype, but does not establish the claimed pattern of SNPs in Saudi patients. The Results (page unavailable) identify ANTXR1 SNPs associated with fetal hemoglobin specifically in Saudi AI-haplotype patients; they do not show that the AI haplotype itself is linked to a novel ANTXR1 variant. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The earlier origin of the HbS gene in agriculturists might have resulted from destruction of the rain forest canopy that created conditions favorable for malaria.

    “The earlier origin in agriculturists might have resulted from destruction of the rain forest canopy that created conditions favorable for malaria.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [32] Shriner, 2018, Whole-genome-sequence-based haplotypes reveal single origin of the sickle allele during the Holocene wet phase, Am J Hum Genet source

      The Discussion (page unavailable) estimates that the sickle allele arose about 7,300 years ago and mentions the equatorial rainforest as a possible place of origin. It does not address an earlier origin in agriculturists or propose that destruction of the rainforest canopy created conditions favorable for malaria. Searches for agriculturists and forest clearing found no supporting passage. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [33] Laval, 2019, Recent adaptive acquisition by African rainforest hunter-gatherers of the late Pleistocene sickle-cell mutation suggests past differences in malaria exposure, Am J Hum Genet source

  • May combine two claims.

    Premisecitation

    As HbF levels decline, AI haplotype adults have more numerous symptoms, and their disease begins to resemble that of African patients, but with a lower incidence of stroke, no leg ulcers, and more than 70% prevalence of splenomegaly.

    “As HbF levels decline, AI haplotype adults have more numerous symptoms, and their disease begins to resemble that of African patients, but with a lower incidence of stroke, no leg ulcers, and .70%prevalence of splenomegaly.37,38”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [37] Perrine, 1972, Benign sickle-cell anaemia, Lancet source
    • cites [38] Alsultan, 2014, Sickle cell disease in Saudi Arabia: the phenotype in adults with the Arab-Indian haplotype is not benign, Br J Haematol source

      The Discussion (page not provided) says the adult Arab–Indian haplotype phenotype is broadly similar to that of African-haplotype patients, except for fewer overt strokes, no leg ulcers, and more persistent splenomegaly. It proposes declining HbF as an explanation for the change from the milder childhood phenotype, but the Results report only that a majority had a palpable spleen; the copy does not establish prevalence above 70%. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Individuals with HbS-HPFH do not have hemolytic anemia and are usually asymptomatic.

    “Individuals with this genotype do not have hemolytic anemia and are usually asymptomatic.50”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [50] Ngo, 2012, Fetal haemoglobin levels and haematological characteristics of compound heterozygotes for haemoglobin S and deletional hereditary persistence of fetal haemoglobin, Br J Haematol source

  • May combine two claims.

    Findingcitation

    When HbF is near 30%, disease can be relatively benign and 70% of cells can be protected.

    “When HbF is near 30%, disease can be relatively benign and 70% of cells can be protected.[52][53][54]”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [52] Steinberg, 2014, Fetal hemoglobin in sickle cell anemia: a glass half full?, Blood source
    • cites [53] Perrine, 1978, Natural history of sickle cell anemia in Saudi Arabs. A study of 270 subjects, Ann Intern Med source
    • cites [54] Perrine, 1981, Sickle cell disease in Saudi Arabs in early childhood, Arch Dis Child source

      The Results report a mean HbF level of 29% in one group of Saudi Arab infants with HbSS, and the introductory passage says the unusually high HbF is believed to account for their relatively mild clinical course. The paper does not report that 70% of cells were protected; the Subjects and methods passage describes HbF distribution as heterocellular without giving a protected-cell percentage. Page numbers were not available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    High HbF is strongly associated with a reduced rate of acute painful episodes, fewer leg ulcers, and longevity.

    “High HbF is strongly associated with a reduced rate of acute painful episodes, fewer leg ulcers, and longevity.55”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [55] Steinberg, 2012, Genetic modifiers of sickle cell disease, Am J Hematol source

  • May combine two claims.

    Premisecitation

    Of 375 children with sickle cell anemia or HbS-β0 thalassemia followed in a longitudinal prospective study, 59 had cerebrovascular disease or a stroke at a mean age of 4.4 years, and HbF was protective (HR: 0.68; 95% CI: 0.48-0.96).

    “Of 375 children with sickle cell anemia or Figure 1.HbF distribution in sickle erythrocytes from 3 patients with 20% HbF.An example of 3 possible distributions of HbF/F-cell in 1000 cells from 3 individuals with mean HbF levels of 20%.The y axis represents numbers of cells, and the x axis represents HbF concentration in 5-pg increments.In red are cells likely to be least protected from HbS polymer”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [69] Sommet, 2016, Clinical and haematological risk factors for cerebral macrovasculopathy in a sickle cell disease newborn cohort: a prospective study, Br J Haematol source

      The cohort table lists 375 children, and the Cerebral vasculopathy and stroke section reports 59 with cerebral vasculopathy, including seven who had a stroke. The paper gives 4.4 years as the median age at cerebral vasculopathy diagnosis, not the mean. Its risk-factor table reports HbF as protective against cerebral vasculopathy (HR 0.68, 95% CI 0.48–0.96, per 5% increase). (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisereasoning

    Acute painful episodes and acute chest syndrome are a result of sickle vasoocclusion, and HbF has the most noticeable beneficial effect on these subphenotypes.

    “Acute painful episodes and acute chest syndrome are a result of sickle vasoocclusion; HbF has the most noticeable beneficial effect on these subphenotypes.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [57] Kato, 2007, Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes, Blood Rev source
    • cites [58] Kato, 2017, Intravascular hemolysis and the pathophysiology of sickle cell disease, J Clin Invest source

  • May combine two claims.

    Premisecitation

    Priapism, nephropathy, and sickle vasculopathy are associated with hemolysis.

    “Priapism, nephropathy, and sickle vasculopathy are associated with hemolysis.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [57] Kato, 2007, Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes, Blood Rev source
    • cites [58] Kato, 2017, Intravascular hemolysis and the pathophysiology of sickle cell disease, J Clin Invest source
    • cites [59] Reiter, 2002, Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease, Nat Med source

  • May combine two claims.

    Premisecitation

    In 57 infants studied at 4.4±1 months of age and followed for approximately 19 months, HbF fell from 42% to 21% and was the strongest prognostic factor for disease complications.

    “To identify prognostic factors for clinical complications, 57 infants were studied at 4.4 6 1 months of age and followed for ;19 months.HbF, which fell from 42% to 21% during the observation period, was the strongest prognostic factor for disease complications.64”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [64] Brousse, 2018, Prognostic factors of disease severity in infants with sickle cell anemia: A comprehensive longitudinal cohort study, Am J Hematol source

  • May combine two claims.

    Premisecitation

    Of 230 children treated with hydroxyurea with 510 patient-years of follow-up, patients with HbF less than 20% had twice the risk of hospitalization for pain and acute chest syndrome and 2 times the risk of fever as patients with greater than 20% HbF.

    “Of 230 children treated with hydroxyurea with 510 patient-years of follow-up, patients with HbF less than 20% had twice the risk of hospitalization for pain and acute chest syndrome and 2 times the risk of fever as patients with .20%HbF.65”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [65] Estepp, 2017, A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy, Am J Hematol source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CRISPR-Cas dominates the genome editing field because of the ease of using guide RNAs directing the CRISPR complex to specific DNA sequences and the increasing ability to target most sites in the genome.

    “CRISPR-Cas dominates the field because of the ease of using guide RNAs directing the CRISPR complex to specific DNA sequences and the increasing ability to target most sites in the genome.121,122”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [121] Doudna, 2020, The promise and challenge of therapeutic genome editing, Nature source

      The GENOME EDITING STRATEGIES section (page unavailable) says CRISPR-Cas9 was widely adopted because its DNA-binding and editing capabilities are easy to program, and explains how guide RNA directs it to a complementary DNA sequence. It also describes an expanding collection of enzymes, but does not establish that most genomic sites can be targeted; the section notes a PAM requirement for Cas9 binding. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [122] Walton, 2020, Unconstrained genome targeting with near-PAMless engineered CRISPR-Cas9 variants, Science source

      The Discussion (page not provided) says that SpRY makes the vast majority of the genome targetable, supporting the claim about increasing targeting range. The passages do not say that CRISPR-Cas dominates genome editing because guide RNAs make it easy to direct the complex to specific sequences. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Preclinical testing in sickle CD34+ cells transduced with a lentiviral shRNA miR targeting BCL11A achieved a vector copy number greater than 5 and gene marking greater than 80%, resulting in a three- to fivefold induction of HbF, with growth, differentiation, and engraftment of gene-modified cells unaffected in vitro or in vivo.

    “Preclinical testing in sickle CD34 1 cells transduced with this shRNA miR achieved a vector copy .5 and gene marking of .80%, resulting in a three-to fivefold induction of HbF.Growth, differentiation, and engraftment of gene-modified cells in vitro or in vivo were unaffected.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [119] Brendel, 2020, Preclinical evaluation of a novel lentiviral vector driving lineage-specific BCL11A knockdown for sickle cell gene therapy, Mol Ther Methods Clin Dev source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Hydroxyurea started at approximately 11 months at a dose of approximately 27 mg/kg was associated with HbF levels of 33.3±9.1%; 33% of patients had HbF greater than 40% with a hemoglobin concentration of 10.1±1.3 g/dL; acute events were markedly reduced; and toxicity was minimal.

    “Hydroxyurea started at ;11 months at a dose of ;27 mg/kg was associated with HbF levels of 33.3 6 9.1%; 33% of patients had HbF .40% with a hemoglobin concentration of 10.1 6 1.3 g/dL; acute events were markedly reduced; and toxicity was minimal.89”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [89] McGann, 2019, Robust clinical and laboratory response to hydroxyurea using pharmacokinetically guided dosing for young children with sickle cell anemia, Am J Hematol source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    These approaches include disrupting the erythroid enhancer of BCL11A or the binding sites for BCL11A in the gamma-globin gene promoters.

    “They include disrupting the erythroid enhancer of BCL11A or the binding sites for BCL11A in the g-globin gene promoters.126”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [126] Métais, 2019, Genome editing of HBG1 and HBG2 to induce fetal hemoglobin, Blood Adv source

  • May combine two claims.

    Premisecitation

    In a patient with sickle cell anemia treated with the HbA T87Q-lentiviral approach, about 1 copy of the vector was present per cell; after 15 months, total hemoglobin was 11 to 12 g/dL, HbA T87Q formed about half of total hemoglobin, and the patient was asymptomatic.

    “This same approach was used in a patient with sickle cell anemia.About 1 copy of this vector was present in each cell.After 15 months, total hemoglobin level was 11 to 12 g/dL; HbA T87Q formed about half of the total hemoglobin; and the patient was asymptomatic.117”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [117] Ribeil, 2017, Gene therapy in a patient with sickle cell disease, N Engl J Med source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Gene therapy will have to compete with the improving prospects for haploidentical allogeneic transplantation that could extend the proven effectiveness of allogeneic transplantation.

    “Gene therapy will also have to compete with the improving prospects for haploidentical allogeneic transplantation that could extend the proven effectiveness of allogeneic transplantation.128”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [128] Leonard, 2020, Curative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy?, Br J Haematol source

  • May combine two claims.

    Findingcitation

    It is nearly impossible to have a clinically important number of fully protected F-cells when HbF is 5%, and no more than 15% of cells can be protected when HbF is 10%.

    “It is nearly impossible to have a clinically important number of fully protected F-cells when HbF is 5%; no more than 15% of cells can be protected when HbF is 10%.52”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Steinberg, 2014, Fetal hemoglobin in sickle cell anemia: a glass half full?, Blood source

  • May combine two claims.

    Premisecitation

    Reduction of let-7 or overexpression of its regulator LIN28B is associated with increased HBG expression.

    “Reduction of let-7 or overexpression of its regulator LIN28B is associated with increased HBG expression. 13”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Lee, 2013, LIN28B-mediated expression of fetal hemoglobin and production of fetal-like erythrocytes from adult human erythroblasts ex vivo, Blood source

  • May combine two claims.

    Premisecitation

    Sickle cell disease is caused by homozygosity for the sickle hemoglobin gene or compound heterozygosity of the HbS gene and other HBB disorders.

    “Sickle cell disease is caused by homozygosity for the sickle hemoglobin (HbS) gene (b 7glu-val , GAG-GTG) or compound heterozygosity of the HbS gene and other HBB disorders.1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Piel, 2017, Sickle cell disease, N Engl J Med source

  • May combine two claims.

    Premisenone given

    Fetal hemoglobin can blunt the pathophysiology, temper the clinical course, and offer prospects for curative therapy of sickle cell disease.

    “Fetal hemoglobin (HbF) can blunt the pathophysiology, temper the clinical course, and offer prospects for curative therapy of sickle cell disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Only HBG2 expression is affected by the -158 polymorphism, whereas both HbF genes are affected by BCL11A polymorphisms.

    “Only HBG2 expression is affected by the 2158 polymorphism; both HbF genes are affected by BCL11A polymorphisms.30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Shaikho, 2018, Cis- and trans-acting expression quantitative trait loci differentially regulate gamma-globin gene expression, bioRxiv source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    From the primordial haplotype the HbS gene subsequently became associated with 5 common HBB haplotypes: Bantu, Cameroon, Arab-Indian, Senegal, and Benin.

    “From the primordial haplotype the HbS gene subsequently became associated with 5 common HBB haplotypes: Bantu (CAR or Central African Republic), Cameroon, Arab-Indian (AI), Senegal, and Benin.34”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Nagel RL , SteinbergMH. Genetics of the βs gene: origins, genetic epidemiology, and epistasis in sickle cell anemia. In: SteinbergM, ForgetBG, HiggsDR, NagelRL, eds.Disorders of Hemoglobin: Genetics, Pathophysiology, Clinical Management, Cambridge, United Kingdom: Cambridge University Press; 2001:711-755.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Benin haplotype patients of African descent have HbF of approximately 6%, and Saudi Arab patients with the Benin haplotype have HbF of approximately 11%.

    “Benin haplotype patients of African descent have HbF of ;6%; Saudi Arab patients with the Benin haplotype have HbF of ;11%.36”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Alsultan, 2011, Fetal hemoglobin in sickle cell anemia: Saudi patients from the Southwestern province have similar HBB haplotypes but higher HbF levels than African Americans, Am J Hematol source

  • The quote only partly states this claim.

    Interpretationreasoning

    Targeting the HBG2 site had a smaller effect on HbF than targeting BCL11A and ZBTB7A binding sites.

    “making it unsurprising that targeting the HBG2 site had a smaller effect on HbF.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Each HbS haplotype is associated with a distinctive mean HbF level, albeit with wide dispersion, making ascertainment of haplotype in individuals of little prognostic value.

    “Each haplotype is associated with a distinctive mean HbF level, albeit with wide dispersion, making ascertainment of haplotype in individuals of little prognostic value.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Adult HbS homozygotes with the AI haplotype have a mean baseline HbF of 17%, and Senegal haplotype patients have HbF of approximately 10%.

    “Adult HbS homozygotes with the AI haplotype have a mean baseline HbF of 17% 35 ; Senegal haplotype patients have HbF of ;10%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Al-Ali, 2020, Prevalence and diversity of haplotypes of sickle cell disease in the Eastern Province of Saudi Arabia, Hemoglobin source

  • May combine two claims.

    Premisenone given

    The protection provided by HbF can be nearly absolute or only partial.

    “This protection provided by HbF can be nearly absolute or only partial.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    HbF is distributed nearly evenly, or pancellularly, in HbS-HPFH erythrocytes, endowing each cell with approximately 10 pg HbF, and HbS polymer is not present in these erythrocytes.

    “HbF is distributed nearly evenly, or pancellularly, in HbS-HPFH erythrocytes, endowing each cell with ;10 pg HbF; HbS polymer is not present in these erythrocytes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Treatment with hydroxyurea increases the number of F-cells and the concentration of HbF/F-cell.

    “Treatment with hydroxyurea increases the number of F-cells and the concentration of HbF/F-cell.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In sickle cell anemia, HbS polymer is present at 70% O2 saturation, and the polymer fraction rises steeply as O2 saturation falls.

    “In sickle cell anemia, HbS polymer is present at 70% O 2 saturation, and the polymer fraction rises steeply as O 2 saturation falls.51”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Brittenham, 1985, Hemoglobin S polymerization: primary determinant of the hemolytic and clinical severity of the sickling syndromes, Blood source

  • May combine two claims.

    Premisenone given

    Patients with untreated sickle cell anemia, sickle cell anemia treated with hydroxyurea, or HbS-β thalassemia, who can have total HbF levels similar to those found in HbS-HPFH, are usually symptomatic and all have hemolytic anemia.

    “Patients with untreated sickle cell anemia, sickle cell anemia treated with hydroxyurea or HbS-db thalassemia, who can have total HbF levels similar to those found in HbS-HPFH, are usually symptomatic; all have hemolytic anemia.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Each erythrocyte contains approximately 30 pg hemoglobin.

    “Each erythrocyte contains ;30 pg hemoglobin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Patients with sickle cell anemia have 2% to 80% F-cells, which survive longer than non-HbF cells.

    “Patients with sickle cell anemia have 2% to 80% F-cells, which survive longer than non-HbF cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    In priapism, nephropathy, and sickle vasculopathy, HbF has a less obvious beneficial effect, perhaps because only a small number of lysed sickle erythrocytes are needed to trigger these subphenotypes.

    “In these complications HbF has a less obvious beneficial effect, perhaps because only a small number of lysed sickle erythrocytes are needed to trigger these subphenotypes.59”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Reiter, 2002, Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease, Nat Med source

  • May combine two claims.

    Premisecitation

    Pre-hydroxyurea era studies of patients with a mean age of 14.1±12.7 years suggested that neither stroke nor silent cerebrovascular disease was associated with HbF.

    “Pre-hydroxyurea era studies of patients with a mean age of 14.1 6 12.7 years suggested that neither stroke nor silent cerebrovascular disease was associated with HbF.66,67”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [66] Ohene-Frempong, 1998, Cerebrovascular accidents in sickle cell disease: rates and risk factors, Blood

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [67] Kinney, 1999, Silent cerebral infarcts in sickle cell anemia: a risk factor analysis, Pediatrics source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Correcting the HbS mutation itself requires a slightly different approach relying on homology-directed repair, which as currently used is a less efficient reparative pathway.

    “Correcting the HbS mutation itself requires a slightly different approach relying on homology-directed repair, which as currently used, is a less efficient reparative pathway.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Cell-mediated therapy either adds a b-globin gene with a HbF-like substitution or reverses the silencing of the HbF genes by curbing HbF repressors or disrupting their binding motifs in g-globin gene promoters.

    “Cell-mediated therapy either adds a b-globin gene with a HbF-like substitution or reverses the silencing of the HbF genes by curbing HbF repressors or disrupting their binding motifs in g-globin gene promoters.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Cure by inducing enough HbF has not yet been achieved with drug therapy but might be possible with cell-based therapeutics.

    “This has not yet been achieved with drug therapy but might be possible with cell-based therapeutics.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Using a modified manufacturing process, 13 patients had plerixafor mobilized CD34+ cells transfected with the HbA T87Q-containing vector and were followed for 3 to 15 months; vector copy number was 3.8, HbA T87Q was nearly 50% of total hemoglobin, hemoglobin levels were 10.2 to 15 g/dL, and patients became asymptomatic.

    “Using a modified manufacturing process, 13 patients had plerixafor mobilized CD34 1 cells transfected with the HbA T87Q -containing vector and were followed for 3 to 15 months.The vector copy number was 3.8, HbA T87Q was nearly 50% of total hemoglobin, and hemoglobin levels were 10.2 to 15 g/dL; patients became asymptomatic.118”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] Kanter, 2019, Resolution of sickle cell disease manifestations in patients treated with lentiglobin gene therapy: updates results from the phase 1/2 HGB-206 group C study, Blood source

  • May combine two claims.

    Premisenone given

    Other drugs that act epigenetically or with novel mechanisms of action have increased HbF levels in preclinical and early-phase clinical trials, and none are approved for treatment.

    “Other drugs that act epigenetically or with novel mechanisms of action have increased HbF levels in preclinical and early-phase clinical trials; none are approved for treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the patient, baseline HbF of 9.1% increased to 25.9% after 2 months and appeared to stabilize between 46% and 48% when tested at 4 through 9 months.

    “The baseline HbF of 9.1% increased to 25.9% after 2 months and appeared to stabilize between 46% and 48% when tested at 4 through 9 months”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Corbacioglu, 2020, Initial safety and efficacy results with a single dose of autologous crispr-cas9 modified CD34+ hematopoietic stem and progenitor cells in transfusion-dependent β-thalassemia and sickle cell disease, Eur Soc Haematol

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisereasoning

    Many of these studies had follow-up of more than 1 year, with near normalization of the hematologic findings.

    “Many of these studies had follow-up of more than 1 year, with near normalization of the hematologic findings.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationnone given

    Cell-based therapeutics are developing rapidly.

    “Cell-based therapeutics are developing rapidly.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Genomic editing and shRNA-mediated knockdown of BCL11A should erase lingering doubts that the clinical and hematologic phenotypes of sickle cell anemia can be reversed by high HbF levels in most sickle erythrocytes.

    “Genomic editing and shRNA-mediated knockdown of BCL11A should erase lingering doubts that the clinical and hematologic phenotypes of sickle cell anemia can be reversed by high HbF levels in most sickle erythrocytes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: BCL11A is one of two major repressors of HbF gene expression.
    • Rests on an assumption: BCL11A expression is controlled by an erythroid-specific enhancer.
    • Rests on an assumption: BCL11A binds to a TGACCA motif centered at position 2115 in the promoters of both HBG2 and HBG1.
    • Rests on an assumption: CRISPR-Cas9 editing of either the BCL11A erythroid-specific enhancer or its binding sites in the HbF gene promoters reverses the repression of these genes increasing HbF.

  • May combine two claims.

    Premisecitation

    Two patients with beta thalassemia treated similarly achieved HbF .97% of the hemolysate with a hemoglobin concentration at 15 months of 14 g/dL.

    “Two patients with b thalassemia treated similarly achieved HbF .97% of the hemolysate with a hemoglobin concentration at 15 months of 14 g/dL.125”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Corbacioglu, 2020, Initial safety and efficacy results with a single dose of autologous crispr-cas9 modified CD34+ hematopoietic stem and progenitor cells in transfusion-dependent β-thalassemia and sickle cell disease, Eur Soc Haematol

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

57 of 57

  • The paper relies on this without support.

    Gene therapy does not require immunosuppression.

    “Gene therapy does not require the immunosuppression.”

  • The paper relies on this without support.

    Experience with allogeneic transplantation is far greater than with gene therapy.

    “Nevertheless, experience with allogeneic transplantation is far greater”

  • The paper relies on this without support.

    Myeloablative conditioning is required for all cell-based therapeutics.

    “Myeloablative conditioning is required for all cell-based therapeutics”

  • The paper relies on this without support.

    Genomic editing does not use lentiviral transduction.

    “Genomic editing does not use lentiviral transduction.”

  • The paper relies on this without support.

    BCL11A is one of two major repressors of HbF gene expression.

    “The expression of BCL11A, 1 of 2 major repressors of HbF gene expression, is controlled by an erythroid-specific enhancer.”

  • The paper relies on this without support.

    BCL11A expression is controlled by an erythroid-specific enhancer.

    “The expression of BCL11A, 1 of 2 major repressors of HbF gene expression, is controlled by an erythroid-specific enhancer.”

  • The paper relies on this without support.

    BCL11A binds to a TGACCA motif centered at position 2115 in the promoters of both HBG2 and HBG1.

    “BCL11A binds to a TGACCA motif centered at position 2115 in the promoters of both HBG2 and HBG1.”

  • The paper relies on this without support.

    CRISPR-Cas9 editing of either the BCL11A erythroid-specific enhancer or its binding sites in the HbF gene promoters reverses the repression of these genes increasing HbF.

    “CRISPR-Cas9 editing of either the BCL11A erythroid-specific enhancer, shown as a double-strand break, or its binding sites in the HbF gene promoters, shown before editing, reverses the repression of these genes increasing HbF.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Co-inheritance of hereditary persistence of fetal hemoglobin results in little or no disease in TDT or SCD.

    “Patients with TDT or SCD who co-inherit hereditary persistence of fetal hemoglobin, in which fetal expression continues into adulthood, have little or no disease.25”

    From CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia (2021) · cites this paper as [25]

    The “F-cells: heterogeneity of HbF concentrations” section reports that people with HbS-HPFH usually have no symptoms or hemolytic anemia, supporting the SCD part of the claim. It does not establish the same outcome for patients with transfusion-dependent thalassemia (TDT), so the claim extends beyond the source. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Nagel RL , SteinbergMH. Genetics of the βs gene: origins, genetic epidemiology, and epistasis in sickle cell anemia. In: SteinbergM, ForgetBG, HiggsDR, NagelRL, eds.Disorders of Hemoglobin: Genetics, Pathophysiology, Clinical Management, Cambridge, United Kingdom: Cambridge University Press; 2001:711-755.

Cited by

Sorted by citations

Related

Authors
Steinberg, M. H.
Affiliations
Boston University (US)
Corresponding author
Steinberg, Martin H.
ORCID
Steinberg, Martin H.
Venue
Blood
Publisher
American Society of Hematology
Published
2020-11-19
Volume
136
Issue
21
Pages
2392-2400
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.2020007645
OpenAlex
W4211089719
Cited by
136
References
135
Citations by year
2026: 27 · 2025: 28 · 2024: 35 · 2023: 11 · 2022: 21 · 2021: 11 · 2020: 2 · 2016: 1
FWCI
1.65
Type
journal article
Language
en
Open access
Locations
Blood (publishedVersion)
Funders
  • University of Dammam (SP 11/2011)
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL133350, R01HL068970)
Topics
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
  • Health Sciences › Medicine › Hematology › Blood groups and transfusion
Keywords
fetal hemoglobin, sickle cell disease, quantitative trait loci, beta-globin gene haplotypes, cell therapy, genome editing, curative treatment, Middle Eastern populations

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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