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Cited by 813Hemoglobinopathies and Related DisordersHemoglobin structure and functionBlood properties and coagulation

Pathophysiology of Sickle Cell Disease

Open access
Sundd, Prithu, Gladwin, Mark T., Novelli, Enrico M.·2019·Annual Review of Pathology Mechanisms of Disease
DOI 10.1146/annurev-pathmechdis-012418-012838PMC PMC7053558
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Abstract

Since the discovery of sickle cell disease (SCD) in 1910, enormous strides have been made in the elucidation of the pathogenesis of its protean complications, which has inspired recent advances in targeted molecular therapies. In SCD, a single amino acid substitution in the β-globin chain leads to polymerization of mutant hemoglobin S, impairing erythrocyte rheology and survival. Clinically, erythrocyte abnormalities in SCD manifest in hemolytic anemia and cycles of microvascular vaso-occlusion leading to end-organ ischemia-reperfusion injury and infarction. Vaso-occlusive events and intravascular hemolysis promote inflammation and redox instability that lead to progressive small- and large-vessel vasculopathy. Based on current evidence, the pathobiology of SCD is considered to be a vicious cycle of four major processes, all the subject of active study and novel therapeutic targeting: ( a) hemoglobin S polymerization, ( b) impaired biorheology and increased adhesion-mediated vaso-occlusion, ( c) hemolysis-mediated endothelial dysfunction, and ( d) concerted activation of sterile inflammation (Toll-like receptor 4- and inflammasome-dependent innate immune pathways). These molecular, cellular, and biophysical processes synergize to promote acute and chronic pain and end-organ injury and failure in SCD. This review provides an exhaustive overview of the current understanding of the molecular pathophysiology of SCD, how this pathophysiology contributes to complications of the central nervous and cardiopulmonary systems, and how this knowledge is being harnessed to develop current and potential therapies.

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Crossref · 10.1146/annurev-pathmechdis-012418-012838

Cites

237 of 237 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

80 of 157 cited sources checked · 29 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Vaso-occlusion is understood as an interplay of impaired blood rheology, increased adhesion of erythrocytes to inflammatory cells and endothelium, and hemostatic activation.

    “Intravital imaging studies done in transgenic humanized SCD mice and in vitro flow chamber studies done with SCD human blood over the past decade have contributed to the current understanding of vaso-occlusion as the interplay among impaired blood rheology, increased adhesiveness of erythrocytes with inflammatory cells and vascular endothelium, and hemostatic activation (14).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] source

      The Introduction (page unavailable) describes sickle red cells adhering to neutrophils, endothelial activation, and a cycle of obstructed blood flow and further sickling. It also describes a hypercoagulable state, but explicitly says direct evidence that coagulation contributes to vaso-occlusion is lacking. The claimed role of hemostatic activation in vaso-occlusion is therefore stronger than the source supports; impaired blood rheology is not explicitly identified as a component of that model. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from transgenic SCD mice, non-SCD mice with adoptively transferred sickle erythrocytes, and in vitro flow chamber systems are representative of human SCD pathophysiology.
  • Premisecitation

    Sickling-dependent erythrocyte membrane damage exposes adhesion molecules and binding motifs not normally present on erythrocytes, including phosphatidyl serine, B-CAM-1/Lu, IAP, and ICAM-4.

    “Importantly, sickling-dependent damage of erythrocyte membranes also promotes exposure of adhesion molecules and binding motifs not normally expressed on erythrocytes, such as phosphatidyl serine (PS), basal cell adhesion molecule-1/Lutheran (B-CAM-1/Lu), integrin-associated protein (IAP), and intercellular-adhesion-molecule-4 (ICAM-4) (7, 9, 15).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [7] source
    • cites [9] source
    • cites [15] source

      The ADHESION MOLECULES section (page not supplied) identifies exposed PS and lists B-CAM-1/Lu, IAP, and ICAM-4 as molecules involved in sickle red-cell adhesion. It says the latter three require activation via signal transduction, not that sickling-dependent membrane damage exposes them. It also describes ICAM-4 as expressed on erythroid cells, so the claim that these molecules are not normally expressed on erythrocytes is not supported. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
  • Premisecitation

    Hydroxyurea is effective in the primary prevention of stroke in sickle cell disease.

    “therapy with hydroxyurea, which induces HbF and reduces white blood cell count, reticulocyte count, and hemolysis, is effective in the primary prevention of stroke (152).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [152] source

      The Interpretation (page not provided) says hydroxyurea can replace chronic transfusions to maintain TCD velocities and help prevent primary stroke in selected high-risk children with sickle cell anaemia, after years of transfusions and without severe vasculopathy. The claim omits those limits and states stroke-prevention effectiveness more broadly than this trial established; its primary finding concerned TCD velocities, and no strokes occurred in either arm. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    The oxygen extraction fraction is increased at baseline in sickle cell disease.

    “the oxygen extraction fraction is also increased at baseline (139, 140).”
    Quote in the paperSubstantial claim2 of 2 sources checked
  • Interpretationcitation

    The rate of cortical atrophy in children with sickle cell disease suggests accelerated brain aging.

    “a worrisome finding that suggests accelerated brain aging in SCD (145).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [145] source

      The paper’s Abstract reports that brain atrophy in children with sickle cell anaemia and silent cerebral infarction was greater than reported in healthy children and adults, and comparable to that seen in adults with small-vessel disease. This supports the suggestion of accelerated brain aging, but the measured rate was for whole-brain volume change, not cortical atrophy specifically; the study population was also narrower than children with sickle cell disease generally. Page numbers were not supplied in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • May combine two claims. 45
  • Borderline: one of the tests for a substantial claim is unclear. 1
  • Classified as probably not a substantial claim. 5
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    The NIH-PH cohort study screened 531 patients and followed them for a median of 4.4 years.

    “The largest study with the longest follow-up is the NIH-PH cohort study, which screened 531 patients and followed them for a median of 4.4 years (66, 194).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [66] source

      The Methods report 529 subjects screened, not 531. Survival and Risk Factors for Mortality reports a median follow-up of 4.7 years, not 4.4 years. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [194] source

  • Borderline on S3 (load-bearing): unclear from the text.

    Premisecitation

    Cell-free heme promotes NLRP3 inflammasome activation in LPS-primed macrophages, leading to IL-1β release.

    “Recently (96), cell-free heme was shown to promote NLRP3 inflammasome activation in LPS-primed macrophages, leading to IL-1β release.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • Rests on an assumption: Findings from transgenic SCD mice, non-SCD mice with adoptively transferred sickle erythrocytes, and in vitro flow chamber systems are representative of human SCD pathophysiology.

  • May combine two claims.

    Premisecitation

    Sickle cell anemia results from homozygosity for the βS allele, a single nucleotide polymorphism in the β-globin gene that substitutes valine for glutamic acid and produces hemoglobin S.

    “Sickle cell anemia is caused by homozygosity of the beta-S (βS) allele (located on chromosome 11p15.5), which differs from the wild-type β-allele by a single nucleotide polymorphism dbSNP Rs334(T;T) in which GTG is substituted for GAG in the sixth codon of the β-globin gene (1, 3, 5, 6).”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [1] source
    • cites [3] source

      The paper’s Abstract (page not provided) states that HbS has a β-globin Glu→Val substitution at position 6 and that a child inheriting HbS from both parents suffers from sickle cell anaemia. Our copy does not specify the single-nucleotide change, rs334 identifier, GTG/GAG codons, or chromosome location given in the citing sentence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [5] source
    • cites [6] source

  • May combine two claims.

    Premisecitation

    SCD patients have elevated baseline neutrophils, monocytes, and platelets, and elevated circulating neutrophil-platelet and monocyte-platelet aggregates correlate with disease severity.

    “Indeed, SCD patients are known to have elevated levels of neutrophils, monocytes and platelets at baseline, and elevated levels of circulating neutrophil-platelet and monocyte-platelet aggregates in SCD human blood correlate with disease severity (19–28).”
    Quote in the paperSubstantial claim3 of 10 sources checked
    • cites [19] source
    • cites [20] source
    • cites [21] Westwick J, 1983, J. Med.
    • cites [22] source

      The Discussion (page unavailable) reports higher steady-state white blood cell and platelet counts among adults with sickle cell anemia who used the emergency department more frequently. The Methods (page unavailable) list total white blood cell and platelet counts, but not neutrophil or monocyte counts or platelet aggregates. The paper therefore supports the platelet and general white-blood-cell association, not the claim about specific cell types or aggregates correlating with disease severity. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [23] source
    • cites [24] source

      The introduction (p. 1) says high leukocyte counts are often observed in sickle cell anemia and associated with clinical severity; it also describes circulating neutrophil-platelet aggregates as well documented in the condition. It does not establish elevated baseline counts for each named cell type, report monocyte-platelet aggregates, or link either platelet-aggregate type to disease severity. The correlation reported on p. 3 is between platelet counts and neutrophil-reticulocyte aggregates, not disease severity. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [25] source

      The Results section, “Increased platelet-leukocyte aggregation in SCD” (page unavailable), reports higher percentages of both neutrophils and monocytes aggregated with platelets in blood from SCD patients than in controls. It does not establish elevated baseline counts of neutrophils, monocytes, or platelets in patients, or a correlation between aggregate levels and disease severity. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [26] source
    • cites [27] source
    • cites [28] source

  • May combine two claims.

    Premisecitation

    Anakinra, an IL-1RA-blocking antibody, and canakinumab, an IL-1β-blocking antibody, are already FDA approved for rheumatoid arthritis and NLRP3-inflammasome-mediated CAPS, respectively.

    “Interestingly, IL-1RA-blocking Ab (anakinra) and IL-1β-blocking Ab (canakinumab) are already FDA approved as anti-inflammatory biologics for the treatment of rheumatoid arthritis (130) and NLRP3-inflammasome-mediated cryopyrin-associated periodic syndrome (CAPS) (131), respectively.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [130] source

      The Discussion (page unavailable) says anakinra was approved to treat rheumatoid arthritis in adults, supporting the part of the sentence attached to this citation. The paper does not specify FDA approval, and the Conclusion (page unavailable) identifies anakinra as a recombinant IL-1 receptor antagonist, not an antibody. The canakinumab/CAPS statement is attached to a different citation and is not judged here. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [131] source

  • May combine two claims.

    Premisecitation

    IL-1β binding to IL-1R on leukocytes and vascular cells activates neutrophils and platelets and upregulates endothelial E-selectin, P-selectin, VCAM-1, ICAM-1, and IL-8, promoting vaso-occlusion.

    “Once released, IL-1β binds to IL-1 receptor (IL-1R) on leukocytes and vascular cells, promoting a cascade of downstream events that lead to activation of neutrophils and platelets and upregulation of E-selectin, P-selectin, VCAM-1, ICAM-1, and chemokines such as IL-8 in endothelial cells, all of which promote vaso-occlusion (14, 17) (Figure 1).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [14] source

      The Introduction (page not provided) says monocyte-derived IL-1β activates endothelial cells through NF-κB and links endothelial adhesion molecules, including E-selectin, P-selectin, VCAM-1, and ICAM-1, to vaso-occlusive events. It does not establish the specified IL-1R-to-neutrophil-and-platelet activation cascade or IL-1β-induced endothelial IL-8 production. It also says direct evidence that platelets participate in sickle-cell vaso-occlusion is lacking. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [17] source

      The Abstract describes an inflammatory, proadhesive endothelial state that promotes sickle vaso-occlusion, and “Evidence linking cell-free hemoglobin to SCD complications” reports platelet activation. Neither passage attributes those effects to IL-1β binding IL-1R or describes the claimed neutrophil activation and endothelial upregulation of E-selectin, P-selectin, VCAM-1, ICAM-1, and IL-8. Page numbers were not provided in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from transgenic SCD mice, non-SCD mice with adoptively transferred sickle erythrocytes, and in vitro flow chamber systems are representative of human SCD pathophysiology.

  • May combine two claims.

    Premisecitation

    Vaso-occlusion causes ischemia-reperfusion injury, which together with released erythrocyte damage-associated molecular patterns drives progression of sterile inflammation in SCD.

    “Vaso-occlusion contributes to ischemia-reperfusion injury, which, along with release of eDAMPs, promotes the progression of sterile inflammation (Figure 1d) in SCD (14, 17, 18).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [14] source

      The Introduction says that obstructed blood flow produces ischemia and that hemolysis releases hemoglobin and heme, which promote inflammation in SCD. It does not establish the more specific claim that vaso-occlusion causes ischemia-reperfusion injury that, together with erythrocyte damage-associated molecular patterns, drives the progression of sterile inflammation. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [17] source

      The section ‘Evidence linking cell-free hemoglobin to SCD complications’ says eDAMPs promote sterile inflammation and may be central to the inflammation of sickle vaso-occlusion. The cited paper also links vaso-occlusive episodes to enhanced eDAMP release, but the passages do not establish the claimed ischemia-reperfusion injury step; a search for that term found no supporting passage. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [18] source

      The paper’s Abstract (pp. 3689–3690) says that hemolysis releases erythrocyte products that can act as DAMPs and drive sterile inflammation in SCD. It discusses vaso-occlusion, but does not state the claimed link from vaso-occlusion through ischemia-reperfusion injury to sterile inflammation. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from transgenic SCD mice, non-SCD mice with adoptively transferred sickle erythrocytes, and in vitro flow chamber systems are representative of human SCD pathophysiology.

  • May combine two claims.

    Premisecitation

    Reticulocytosis, low HbF levels, leukocytosis, and complications such as acute chest syndrome are associated with increased risk of stroke in sickle cell disease.

    “Observational studies have shown that reticulocytosis (149), low HbF levels, leukocytosis (150, 151), and complications such as ACS (81) are associated with an increased risk of stroke.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [149] source

      The Results and Discussion report that reticulocytosis in early infancy was associated with increased risk of the combined outcome of stroke or death during childhood. They do not establish an increased risk of stroke alone. Citation 149 is attached to reticulocytosis; the other listed factors are not attributed to this source by that citation. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [150] source
    • cites [151] source

  • May combine two claims.

    Premisecitation

    Cortical brain areas and cortical and white matter watershed areas are particularly vulnerable to ischemia and may undergo acute infarction.

    “cortical brain areas and cortical and white matter watershed (border zone) areas (134, 141, 142), which are particularly vulnerable to ischemia, may undergo acute infarction.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [134] source
    • cites [141] source
    • cites [142] source

  • May combine two claims.

    Premisecitation

    SCD patients with higher hemolysis rates have lower steady-state hemoglobin and are more likely to develop vascular injury and organ dysfunction with age, including pulmonary hypertension, diastolic left heart disease, and renal dysfunction.

    “Patients with higher rates of hemolysis have lower steady-state Hb levels and are more likely to develop vascular injury and organ dysfunction as they age, manifesting as pulmonary hypertension, diastolic left heart disease, and renal dysfunction (proteinuria, albuminuria, and chronic kidney dysfunction) (62, 64, 65, 70, 79).”
    Quote in the paperSubstantial claim3 of 5 sources checked
    • cites [62] source

      The Introduction (page unavailable) links hemolysis and anemia to organ injury as patients with sickle cell disease age, and identifies pulmonary vascular disease and renal failure as complications. The copy does not establish that higher hemolysis rates predict lower steady-state hemoglobin or the full specified set of outcomes, particularly left-heart diastolic disease, proteinuria, and albuminuria. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [64] source
    • cites [65] 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
    • cites [70] 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
    • cites [79] source

  • May combine two claims.

    Premisecitation

    NT-proBNP identifies patients at higher risk of having pulmonary hypertension, with lower exercise capacity and increased mortality risk.

    “NT-proBNP, a prepro hormone released from cardiac myocytes of the left and right ventricles in response to pressure overload and wall stress, also identifies patients at higher risk of having pulmonary hypertension, with lower exercise capacity and increased mortality risk.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [193] source
    • cites [62] source

      The Results sections on cohort characteristics and univariate mortality describe NT-proBNP as a marker associated with pulmonary hypertension and report higher mortality among patients with elevated levels. The cohort characteristics report six-minute walk distances separately, but do not link elevated NT-proBNP to lower exercise capacity. These findings concern patients with sickle cell disease, rather than patients generally. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    There is a surprising similarity between the arteriopathy of the central nervous system and pulmonary arterial vasculature in sickle cell disease, and both are epidemiologically and mechanistically related to the severity of hemolytic anemia.

    “There is a surprising similarity between the arteriopathy of the CNS and pulmonary arterial vasculature in SCD, and both are epidemiologically and mechanistically related to the severity of the hemolytic anemia (183).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [183] 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

    In children with sickle cell disease, the SIT trial showed that transfusion may reduce incident silent cerebral infarcts, although SCIs were part of a composite endpoint including stroke, hampering analysis of the effect on SCI alone.

    “In children with SCD, the SIT trial has shown that transfusion may reduce incident SCI, although SCIs were part of a composite endpoint that also included stroke, thus hampering the analysis of the effect of transfusion on SCI alone (172).”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Among the group with pulmonary hypertension, 56.4% had precapillary pulmonary arterial hypertension with a pulmonary artery occlusion pressure ≤15 mm Hg, and the remainder had pulmonary venous hypertension with elevated pulmonary artery occlusion pressures >15 mm Hg.

    “Among the group with pulmonary hypertension, 56.4% had precapillary pulmonary arterial hypertension, with a pulmonary artery occlusion pressure ≤15 mm Hg, and the remainder had pulmonary venous hypertension, with elevated pulmonary artery occlusion pressures >15 mm Hg.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [66] source

      Hemodynamic Parameters reports that 31 of 55 subjects with pulmonary hypertension (56.4%) had precapillary PH and the remaining 24 (43.6%) had postcapillary PH. Methods defines postcapillary PH by PCWP >15 mm Hg, but defines precapillary PH by PCWP <15 mm Hg, not the claimed ≤15 mm Hg; our copy therefore does not support the boundary at exactly 15 mm Hg. The paper uses PCWP (pulmonary capillary wedge pressure) rather than the claim’s term pulmonary artery occlusion pressure. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [194] source

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

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Patients with elevated tricuspid regurgitant jet velocity walked an estimated 30.4 (6.9-53.9) meters less than those without elevated tricuspid regurgitant jet velocity, with an associated hazard ratio for death of 4.9 (2.4-9.7).

    “Patients with elevated tricuspid regurgitant jet velocity walked an estimated 30.4 (6.9–53.9) meters less than those without elevated tricuspid regurgitant jet velocity, with an associated hazard ratio for death of 4.9 (2.4–9.7) (191).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Of these patients, 84 received right heart catheterizations due to suspected pulmonary hypertension, and 55 (10.4%) were diagnosed with pulmonary hypertension based on a mean pulmonary artery pressure >25 mm Hg.

    “Of these patients, 84 received right heart catheterizations due to suspected pulmonary hypertension, and 55 (10.4%) were diagnosed with pulmonary hypertension based on a mean pulmonary artery pressure >25 mm Hg.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [66] source
    • cites [194] source

      The Results report that 84 of 531 patients underwent right heart catheterization and 55 had pulmonary hypertension, representing 10.4% of the total population. The Methods link catheterization to clinical suspicion but define pulmonary hypertension as mean pulmonary artery pressure of 25 mm Hg or greater, not greater than 25 mm Hg. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In the largest study to date of cognitive function in adults with sickle cell disease, 33% of a cohort with homozygous SCD and without severe complications performed 1 standard deviation worse than the population mean in cognitive tests and had a much higher prevalence of lacunar infarcts (13% versus 2%).

    “The largest study to date of cognitive function in adults with SCD has shown that 33% of a cohort of patients with homozygous SCD and without severe complications performed 1 standard deviation worse than the population mean in cognitive tests and had a much higher prevalence of lacunar infarcts (13% versus 2%).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [178] source

      Split into 3 atoms — 2 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

    Development of pulmonary hypertension is related to pulmonary vascular disease in the setting of intravascular hemolysis and thrombotic events, but can also occur secondary to diastolic left heart disease.

    “While the development of pulmonary hypertension is related to pulmonary vascular disease in the setting of intravascular hemolysis and thrombotic events, it can also occur secondary to diastolic left heart disease (77, 82).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [77] source

      The Discussion (page unavailable) reports that confirmed pulmonary hypertension can reflect either increased pulmonary vascular resistance or pulmonary venous hypertension attributed to left ventricular diastolic dysfunction. It also links hemolytic severity to elevated estimated pulmonary pressure. The paper does not link thrombotic events to the development of pulmonary hypertension, so that part of the claim is unsupported. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [82] source

      The introductory passage (page not provided) links pulmonary hypertension in sickle cell disease to vasculopathy arising in the setting of hemolytic anemia and recurrent vaso-occlusion. The Conclusions (page not provided) say diastolic dysfunction directly contributes to elevated pulmonary pressures in a small fraction of patients. The paper does not specifically identify thrombotic events as a cause, and it limits the diastolic contribution rather than presenting it as a general mechanism. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The fundamental lesion of acute chest syndrome is a hyperinflammatory event leading to classic acute lung injury, defined by alveolar-capillary leak and neutrophilic inflammation, most commonly in two or more dependent lobes, which may be radiographically and clinically indistinguishable from multilobar pneumonia.

    “The fundamental lesion of ACS is a hyperinflammatory event leading to classic acute lung injury (Figure 4), defined by alveolar-capillary leak and neutrophilic inflammation, most commonly in two or more dependent lobes, which may be radiographically and clinically indistinguishable from multilobar pneumonia (206).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [206] 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

  • May combine two claims.

    Premisecitation

    Recent studies in sickle cell disease mice highlight the importance of diastolic dysfunction, and myocardial fibrosis is reported to occur both in these mice and in patients (measured by extracellular volume using cardiac MRI).

    “Recent studies in SCD mice further highlight the importance of diastolic dysfunction in SCD, and myocardial fibrosis is reported to occur both in these mice and in patients (the latter measured by extracellular volume using cardiac MRI imaging) (197–199).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [197] source
    • cites [198] source

      The Results section (page unavailable) reports diastolic dysfunction in patients with sickle cell disease, and the Discussion says prior cardiac MRI studies found small degrees of focal myocardial fibrosis in patients. This paper does not report findings in sickle cell disease mice or say that patient fibrosis was measured by MRI-derived extracellular volume; it also notes that MRI studies have been inconsistent about the extent of fibrosis. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [199] source

  • May combine two claims.

    Premisecitation

    Bronchial hyper-reactivity, asthma, and chronic airway inflammation are highly prevalent in children with sickle cell disease and may result in a proinflammatory milieu that amplifies cellular and humoral immunity to airway pathogens, leading to a paroxysmal, detrimental response.

    “Bronchial hyper-reactivity, asthma, and chronic airway inflammation (209) are highly prevalent in children with SCD and may result in a proinflammatory milieu that amplifies cellular and humoral immunity to airway pathogens, thus leading to a paroxysmal, detrimental response (210, 211).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [209] source
    • cites [210] 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 [211] 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

  • May combine two claims.

    Premisecitation

    Acute chest syndrome is more common in children and, if untreated, has a high mortality, including 9% in adults.

    “it is more common in children and, if untreated, has a high mortality [9% in adults (111)].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [111] source

      Table 1 lists more children than adults among the patients studied, and Table 2 reports 9% mortality in patients aged 20 or older. But the Hospital Course and Treatment section says patients received treatment, so the 9% figure is not an untreated mortality rate. The study's age-group counts also do not establish that acute chest syndrome is more common in children in the wider sickle cell population. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    High levels of hemopexin can rescue acute lung injury, while HO-1 deficiency potentiates it.

    “high levels of hemopexin, the enzyme that scavenges heme, can rescue acute lung injury (89), while HO-1 deficiency potentiates it (57).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [89] source
    • cites [57] source

  • May combine two claims.

    Premisecitation

    Infection is the most common acute chest syndrome trigger in children; common isolates include atypical microorganisms and Streptococcus pneumoniae.

    “Infection is the most common ACS trigger in children; common isolates include atypical microorganisms and Streptococcus pneumoniae (208).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [208] source

      The Hospital course section says childhood ACS most likely results from infectious causes, but describes this as an inference rather than a confirmed ranking of triggers. The Results section identifies Streptococcus pneumoniae as a common isolate; it does not identify atypical microorganisms as common isolates. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    In its most extreme manifestation, acute lung injury presents with or evolves into acute respiratory distress syndrome.

    “In its most extreme manifestation (207), acute lung injury presents with or evolves into acute respiratory distress syndrome.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisereasoning

    Deoxygenated HbS tetramers expose hydrophobic motifs, and βS-globin chains from different tetramers bind each other to initiate HbS polymer nucleation.

    “As a result, βS-globin chains on different deoxygenated HbS tetramers bind to each other to hide the hydrophobic motifs, thus initiating the nucleation of an HbS polymer.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The rate of HbS polymerization rises with intraerythrocytic HbS concentration to the 34th power and falls with fetal hemoglobin concentration, since HbF replaces HbS and interferes with polymerization.

    “The rate of polymerization is proportional to the intraerythrocytic concentration of HbS (to the 34th power) and inversely proportional to the concentration of fetal Hb (HbF), which both replaces HbS and interferes with HbS polymerization (7, 10, 11).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] source
    • cites [10] source
    • cites [11] source

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

    Premisecitation

    Before screening programs, stroke affected up to 10% of children aged 2-9 with sickle cell anemia.

    “stroke affected up to 10% of children prior to the implementation of screening programs (81, 133).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [81] Ohene-Frempong K, 1998, Blood

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

    • cites [133] source

  • May combine two claims.

    Premisereasoning

    Oxyhemoglobin reacts rapidly and essentially irreversibly with nitric oxide to form nitrate, so hemoglobin released into plasma during intravascular hemolysis scavenges NO and impairs NO-dependent basal vasodilation.

    “Because oxy-Hb reacts with nitric oxide (NO) in an extremely fast and essentially irreversible reaction to form inert nitrate, the release of intraerythrocytic Hb into plasma during intravascular hemolysis promotes NO scavenging reactions and impairs NO-dependent basal vasodilation.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Interpretationreasoning

    Stenosis of the large branches of the internal carotid artery predisposes children with sickle cell disease to severe strokes.

    “Stenosis of the large branches of the internal carotid artery predisposes children to devastating strokes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Red blood cell transfusion rapidly improves stroke symptoms and cerebral tissue oxygen saturation in children with sickle cell disease.

    “red blood cell transfusion rapidly improves stroke symptoms and cerebral tissue oxygen saturation in children (147)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] source

  • May combine two claims.

    Premisecitation

    In sickle cell disease, microcirculatory hypoperfusion and systemic macrocirculatory hyperperfusion coexist, a phenomenon called the perfusion paradox.

    “both hypoperfusion of the microcirculation (due to microvascular occlusion or altered vasoregulation) and hyperperfusion of the systemic macrocirculation and major organ systems (due to anemia and fixed stenosis) coexist, a phenomenon that has been referred to as the perfusion paradox of SCD (132).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] source

  • May combine two claims.

    Premisereasoning

    Cell-free hemoglobin promotes reactive oxygen species formation, shifting the vascular redox balance from steady-state NO production toward ROS production.

    “Cell-free Hb also promotes ROS formation, critically altering the vascular redox balance of steady-state NO production to ROS production (decreasing NO–ROS balance).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Other proposed or FDA-approved therapies may prevent endothelial dysfunction by scavenging cell-free hemoglobin, promoting NO production, or reducing oxidative stress.

    “Other proposed or FDA-approved therapies may prevent endothelial dysfunction by scavenging cell-free Hb (haptoglobin), promoting NO production (hydroxyurea, oral or IV nitrite, inhaled NO, and oral arginine), or reducing oxidative stress (l-glutamine and antioxidants).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sickle cell disease mouse models exhibit decreased brain oxygen tension, increased cerebral blood flow, decreased blood flow regulation, and microinfarcts.

    “SCD mouse models do, however, exhibit certain specific aspects of the cerebral pathology seen with sickle cell anemia, including decreased brain oxygen tension, increased cerebral blood flow (155), decreased blood flow regulation, and microinfarcts (156, 157).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [155] source
    • cites [156] 156.  Hyacinth HI, Sugihara CL, Spencer TL, Archer DR, Shih AY. 2017. Higher prevalence of spontaneous cerebral vasculopathy and cerebral infarcts in a mouse model of sickle cell disease. J. Cereb. Blood Flow Metab. https://doi.org/10.1177/0271678X17732275 source
    • cites [157] source

  • May combine two claims.

    Premisecitation

    Aneurysms in sickle cell disease are typically saccular and less than 5 mm in size and may coexist with vasculopathy and a Moyamoya pattern of cerebral vascularization.

    “Aneurysms are typically saccular and <5 mm in size and may coexist with vasculopathy and a Moyamoya pattern of cerebral vascularization (182).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [182] source

  • May combine two claims.

    Premisecitation

    Small-vessel lesions are the most common cerebrovascular lesions in sickle cell disease, with prevalence 13% at 14 months of age, rising throughout childhood, and approximately 50% by adulthood.

    “small-vessel lesions are the most common cerebrovascular lesions in SCD, with a prevalence of 13% at 14 months of age (163) that progressively rises throughout childhood (164) such that, by adulthood, it is approximately 50% (165, 166).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [163] source
    • cites [164] source
    • cites [165] source

  • May combine two claims.

    Premisereasoning

    Over time, the right heart begins to fail as afterload increases, leading to progressive dyspnea, reduced exercise capacity, and increased risk of acute cor pulmonale and sudden cardiac death.

    “Over time, the right heart begins to fail as afterload increases, leading to progressive dyspnea, reduced exercise capacity, and increased risk of acute cor pulmonale and sudden cardiac death.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Intracerebral hemorrhage preferentially affects young adults with sickle cell disease and is particularly common in those with aneurysms and Moyamoya syndrome.

    “Intracerebral hemorrhage preferentially affects young adults with SCD and is particularly common in those suffering from aneurysms and Moyamoya syndrome (180).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [180] source

  • May combine two claims.

    Premisecitation

    Anemia plays a role in the development of silent cerebral infarcts, as shown by studies in children without sickle cell disease where an acute severe drop in hemoglobin is associated with new white matter hyperintensities.

    “Anemia clearly also plays a role in the development of SCI, as demonstrated by studies in children without SCD, where an acute, severe drop in hemoglobin has been associated with the development of new white matter hyperintensities.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Another large population screening study confirmed that a tricuspid regurgitant jet velocity ≥2.5 m/s was associated with a hazard ratio of 6.81 in multivariate analysis and rose linearly above this value (50% of death at tricuspid regurgitant jet velocity of 3.2 m/s).

    “Another large population screening study confirmed that a tricuspid regurgitant jet velocity ≥2.5 m/s was associated with a hazard ratio of 6.81 in multivariate analysis and rose linearly above this value (50% of death at tricuspid regurgitant jet velocity of 3.2 m/s) (192).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] source

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

    Premisenone given

    Basic science and clinical studies over the past decade have led to understanding of the cellular, molecular, and biophysical mechanisms that promote these pathophysiological events and inspired the development of several prophylactic therapies that are either FDA approved or currently in clinical trials.

    “Basic science and clinical studies over past decade have led to the understanding of the cellular, molecular, and biophysical mechanisms that promote these pathophysiological events and inspired the development of several prophylactic therapies that are either FDA approved or currently in clinical trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Chronic kidney disease is a risk factor for the development of pulmonary hypertension and appears to occur as a consequence of chronic hemolysis and the injurious effects of filtered cell-free hemoglobin.

    “the development of chronic kidney disease is a risk factor for the development of pulmonary hypertension and appears to occur as a consequence of chronic hemolysis and the injurious effects of filtered cell-free hemoglobin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Any initial lung insult is bound to result in lung ventilation-perfusion mismatch, hypoxemia, and a potentiation of the initial pathogenic triggers, a phenomenon described as the vicious cycle of acute chest syndrome.

    “any initial lung insult is bound to result in lung ventilation–perfusion mismatch, hypoxemia, and a potentiation of the initial pathogenic triggers, a phenomenon that has been described as “the vicious cycle of ACS” (110).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Acute chest syndrome triggers or insults that activate neutrophils and platelets, in the setting of intensifying hemolytic anemia with release of eDAMPs, will propagate sterile inflammatory pathways through TLR4 and inflammasome signaling.

    “It is also likely that ACS triggers or insults that activate neutrophils and platelets, in the setting of intensifying hemolytic anemia with release of eDAMPs, will propagate sterile inflammatory pathways through TLR4 and inflammasome signaling (discussed in Figure 1).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Proposed mechanisms for sickle cell disease nephropathy include hemoglobinuria, ischemia-reperfusion injury, hyperfiltration, and hypertension.

    “Proposed mechanisms for SCD nephropathy include hemoglobinuria, ischemia-reperfusion injury, hyperfiltration, and hypertension (203).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [203] source

  • May combine two claims.

    Interpretationreasoning

    The five mechanisms described may coexist or independently cause acute chest syndrome.

    “The five mechanisms described above may coexist or independently cause ACS”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Fat embolism is suspected when abundant lipid-laden macrophages are detected in the bronchoalveolar lavage, a sensitive but nonspecific test.

    “Fat embolism is suspected when abundant lipid-laden macrophages are detected in the bronchoalveolar lavage, a sensitive but nonspecific test (214).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [214] source

  • May combine two claims.

    Interpretationnone given

    The interplay among genetics, HbS polymerization-dependent hemolysis and sickling, vaso-occlusion-dependent ischemia-reperfusion injury, endothelial dysfunction-dependent vasculopathy, and sterile inflammation contributes to the pathophysiology of sickle cell disease, which promotes acute and chronic complications of the central nervous system, heart, lung, kidney, liver, and other organs.

    “The interplay among genetics, HbS polymerization–dependent hemolysis and sickling, vaso-occlusion-dependent ischemia-reperfusion injury, endothelial dysfunction–dependent vasculopathy, and sterile inflammation contributes to the pathophysiology of SCD, which promotes acute and chronic complications of the CNS, heart, lung, kidney, liver, and other organs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In humans, circulating fibrocytes are present in high numbers; are activated in sickle cell disease, particularly in vaso-occlusive crisis; and are associated with restrictive pulmonary function test patterns.

    “In humans, circulating fibrocytes are present in high numbers; are activated in SCD, particularly in VOC; and are associated with restrictive pulmonary function test patterns (224).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [224] source

  • May combine two claims.

    Premisecitation

    Hypoventilation, as a result of pain with inspiration deriving from rib infarction or oversedation from opiate analgesia, may lead to atelectasis, which is a known risk factor for pneumonia and lung injury.

    “Hypoventilation, as a result of pain with inspiration deriving from rib infarction (220) or oversedation from opiate analgesia, may lead to atelectasis, which is a known risk factor for pneumonia and lung injury (221).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [220] source
    • cites [221] source
51 of 51

  • The paper relies on this without support.

    Findings from transgenic SCD mice, non-SCD mice with adoptively transferred sickle erythrocytes, and in vitro flow chamber systems are representative of human SCD pathophysiology.

    “Intravital imaging studies done in transgenic humanized SCD mice and in vitro flow chamber studies done with SCD human blood over the past decade have contributed to the current understanding of vaso-occlusion as the interplay among impaired blood rheology, increased adhesiveness of erythrocytes with inflammatory cells and vascular endothelium, and hemostatic activation (14).”
1 of 1

Cites

Flagged first, then by citations

2 of the 239 references couldn’t be matched to a known paper.

Research works printed but not linked: 4

  1. Westwick J, 1983, J. Med., 14, 17
  2. Ohene-Frempong K, 1998, Blood, 91, 288
  3. Malik Z, 1983, Cytobios, 38, 33
  4. Koshy M, 1990, J. Assoc. Acad. Minor. Phys., 1, 71

Cited by

Sorted by citations

Related

Authors
Sundd, P., Gladwin, M. T., & Novelli, E. M.
Affiliations
University of Pittsburgh (US)
ORCID
Venue
Annual Review of Pathology Mechanisms of Disease
Publisher
Annual Reviews
Published
2019-01-24
Volume
14
Issue
1
Pages
263-292
ISSN
  • 1553-4006 (ISSN-L)
  • 1553-4014
DOI
10.1146/annurev-pathmechdis-012418-012838
PMC
PMC7053558
OpenAlex
W2898014977
Cited by
813
References
239
Citations by year
2026: 121 · 2025: 155 · 2024: 132 · 2023: 133 · 2022: 114 · 2021: 75 · 2020: 53 · 2019: 22 · 2018: 4 · 2016: 1
FWCI
5.54
Type
journal article
Language
en
Open access
Locations
  • Annual Review of Pathology Mechanisms of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Heart Association (18TPA34170588)
  • National Heart, Lung, and Blood Institute (R01HL127107, K23HL112848, P01HL103455, HL110849, R01HL141080, R01HL128297, R01HL125886, R01HL098032, T32HL110849)
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 › Pulmonary and Respiratory Medicine › Blood properties and coagulation
Keywords
sickle cell disease, hemoglobin S polymerization, erythrocyte rheology, vascular occlusion, hemolysis, endothelial dysfunction, sterile inflammation, TLR4, inflammasome, redox imbalance, vasculopathy, pain, end-organ failure, beta-globin gene mutations, targeted therapy
MeSH terms
Anemia, Sickle Cell, Hemolysis, Humans, Inflammation, Reperfusion Injury, Oxidative Stress, Toll-Like Receptor 4

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 under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

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