The DOI matches its Crossref record; 237 of the 239 references it cites were found in a registry or an index; 80 of the 157 sources its claims cite were checked for support.
Pathophysiology of Sickle Cell Disease
Open accessAbstract
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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Claims the paper makes
39 Partly supported · 32 No full text of the sources · 16 Own interpretation · 15 Supported · 12 No basis given · 9 Supported so far · 5 Not checked yet · 1 Mixed support · 1 Sources not found · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > VASO-OCCLUSION
What the sources say
- Partly supportedcites [14] sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > VASO-OCCLUSION
What the sources say
- Not checked — no full text of the sourcecites [7] source
- Not checked — no full text of the sourcecites [9] source
- Partly supportedcites [15] sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Large-Vessel Vasculopathy in the Central Nervous System
What the sources say
- Partly supportedcites [152] sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“the oxygen extraction fraction is also increased at baseline (139, 140).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Large-Vessel Vasculopathy in the Central Nervous System
What the sources say
- Supportedcites [139] source
The SCD results report significantly higher whole-brain oxygen extraction fraction in children with sickle cell disease than in healthy controls. Table 2 gives 42.7 versus 28.8 (p < 0.001). No page number is provided in our copy. (LLM, conf=0.94)
- Supportedcites [140] source
The Results report significantly higher oxygen extraction fraction in adults with sickle cell anaemia than in controls in this observational study (adjusted P = 0.0012 for participants not receiving transfusions). This supports the claim about baseline oxygen extraction fraction in the adults studied. (LLM, conf=0.92)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“a worrisome finding that suggests accelerated brain aging in SCD (145).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Large-Vessel Vasculopathy in the Central Nervous System
What the sources say
- Partly supportedcites [145] sourceExperimental — accuracy not yet measured
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)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“There is recent evidence that cortical atrophy progresses in children with SCD at a rate similar to that of adults without SCD but with small-vessel disease (0.6–1% per year)—a worrisome finding that suggests accelerated brain aging in SCD (145).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Large-Vessel Vasculopathy in the Central Nervous System
What the sources say
- Partly supportedcites [145] sourceExperimental — accuracy not yet measured
The reported results (labelled Abstract in our copy) give annual brain-volume losses of 0.62% and 0.96%, and the summary says cerebral atrophy was comparable to that in adults with small-vessel disease. The study measured global brain-volume change, not specifically cortical atrophy, and its children with sickle cell disease all had existing silent cerebral infarction. (LLM, conf=0.87)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“degeneration of the internal elastic lamina”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Large-Vessel Vasculopathy in the Central Nervous System
What the sources say
- Not checked — no full text of the sourcecites [134] source
- Supportedcites [135] source
The Neuropathologic Findings describe focal splitting of the internal elastic lamina in the cerebral arteries of a child with sickle cell anemia and strokes. The Discussion identifies splitting as a sign of degeneration of that lamina. (LLM, conf=0.93)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Young sickle mice do not commonly develop large-vessel vasculopathy and stroke (153, 154)”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Large-Vessel Vasculopathy in the Central Nervous System
What the sources say
- Supportedcites [153] source
The Discussion reports no large-vessel vasculopathy, thrombotic or embolic infarcts, or hemorrhagic strokes in the relatively young Berkeley sickle mice studied. The paper identifies these mice as 1 to 6 months old (Histopathology; page numbers not supplied). (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [154] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“the cerebral autoregulatory capacity, i.e., the capacity to adjust vessel volume in response to carbon monoxide challenge or systemic blood pressure changes, is impaired in SCD (137, 138).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Large-Vessel Vasculopathy in the Central Nervous System
What the sources say
- Supportedcites [137] source
The Discussion reports impaired dynamic cerebral autoregulation in patients with sickle cell disease. It specifically describes a reduced capacity to buffer blood-pressure surges, supporting the claim about autoregulatory capacity. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [138] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“These studies have shown that the large and medium-sized branches of the internal carotid artery are affected.”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Large-Vessel Vasculopathy in the Central Nervous System
What the sources say
- Not checked — no full text of the sourcecites [134] source
- Supportedcites [135] source
The Abstract describes a child with sickle cell anemia who died of strokes and had severe occlusive disease at the major bifurcations of both internal carotid arteries. The figure descriptions also identify thrombi in the anterior and middle cerebral arteries, supporting the paraphrase that larger carotid branches were affected. (LLM, conf=0.88)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 45
- Borderline: one of the tests for a substantial claim is unclear. 1
- Probably not a substantial claim. 5
- The quote only partly states this claim. 1
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Development of Pulmonary Hypertension and Left Ventricular Diastolic Heart Dysfunction in Adults with Sickle Cell Disease
What the sources say
- Disputedcites [66] sourceExperimental — accuracy not yet measured
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.
- Supportedcites [194] source
The Results state that 531 patients were screened by echocardiography and that median follow-up since enrollment was 4.4 years. The Comment also describes this as, to the authors’ knowledge, the largest cohort of its kind. (LLM, conf=0.94)
plainn = 531- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Disputed
Every source the paper cites for this claim was checked and supports it.
In the paper
“Recently (96), cell-free heme was shown to promote NLRP3 inflammasome activation in LPS-primed macrophages, leading to IL-1β release.”
§ Pathophysiology of Sickle Cell Disease > STERILE INFLAMMATION
What the sources say
- Supportedcites [96] source
The Results passage beginning “To examine the ability of heme to act as a second signal” reports that LPS-pretreated bone-marrow–derived macrophages secreted processed IL-1β after heme stimulation. The Results passage headed “Heme Causes Activation of NLRP3 Inflammasome” shows that NLRP3-deficient macrophages could not process or secrete IL-1β in response to heme. (LLM, conf=0.94)
direct- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Borderline substantial claim. It is unclear whether the paper’s conclusions depend on it.
- 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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites [1] source
- Partly supportedcites [3] sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [5] source
- Not checked — no full text of the sourcecites [6] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > VASO-OCCLUSION
What the sources say
- Not checked — no full text of the sourcecites [19] source
- Not checked — no full text of the sourcecites [20] source
- Not checked — no full text of the sourcecites [21] Westwick J, 1983, J. Med.
- Partly supportedcites [22] sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [23] source
- Partly supportedcites [24] sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [25] sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [26] source
- Not checked — no full text of the sourcecites [27] source
- Not checked — no full text of the sourcecites [28] source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Pathophysiology of Sickle Cell Disease > CURRENT AND FUTURE THERAPIES TARGETING SICKLE CELL DISEASE PATHOBIOLOGY
What the sources say
- Partly supportedcites [130] sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [131] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > STERILE INFLAMMATION
What the sources say
- Partly supportedcites [14] sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [17] sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- 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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > STERILE INFLAMMATION
What the sources say
- Partly supportedcites [14] sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [17] sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [18] sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- 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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Large-Vessel Vasculopathy in the Central Nervous System
What the sources say
- Partly supportedcites [149] sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [150] source
- Not checked — no full text of the sourcecites [151] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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.”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Large-Vessel Vasculopathy in the Central Nervous System
What the sources say
- Not checked — no full text of the sourcecites [134] source
- Not checked — no full text of the sourcecites [141] source
- Supportedcites [142] source
The Results section reports infarcts in the deep white-matter internal borderzone and cortical borderzone regions in children with sickle cell disease. The Discussion describes the borderzone as highly vulnerable to ischemia and says restricted blood flow may lead to acute ischemic events. Page numbers were not provided in our copy. (LLM, conf=0.87)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > ENDOTHELIAL DYSFUNCTION
What the sources say
- Partly supportedcites [62] sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [64] source
- Partly supportedcites [65] sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [70] sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [79] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Development of Pulmonary Hypertension and Left Ventricular Diastolic Heart Dysfunction in Adults with Sickle Cell Disease
What the sources say
- Not checked — no full text of the sourcecites [193] source
- Partly supportedcites [62] sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Development of Pulmonary Hypertension and Left Ventricular Diastolic Heart Dysfunction in Adults with Sickle Cell Disease
What the sources say
- Partly supportedcites [183] sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Small-Vessel Vasculopathy in the Central Nervous System
What the sources say
- Supportedcites [172] source
The Methods define the primary endpoint as stroke or a new or enlarged silent cerebral infarct. The Abstract Results report fewer new or enlarged silent infarcts with transfusion (5 versus 7), but the reported effect estimate and significance test are for the combined endpoint, not silent infarcts alone. The trial enrolled children with sickle cell anemia who already had a silent cerebral infarct. (LLM, conf=0.88)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Development of Pulmonary Hypertension and Left Ventricular Diastolic Heart Dysfunction in Adults with Sickle Cell Disease
What the sources say
- Partly supportedcites [66] sourceExperimental — accuracy not yet measured
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)
- Could not verifycites [194] sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Development of Pulmonary Hypertension and Left Ventricular Diastolic Heart Dysfunction in Adults with Sickle Cell Disease
What the sources say
- Supportedcites [191] source
The Results (page unavailable) report that sickle cell disease patients with elevated estimated pulmonary artery systolic pressure walked 30.4 (6.9–53.9) metres less and had a pooled mortality hazard ratio of 4.9 (2.4–9.7). The Abstract (page unavailable) states that elevated pressure was defined by tricuspid regurgitant velocity in most studies. (LLM, conf=0.94)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Development of Pulmonary Hypertension and Left Ventricular Diastolic Heart Dysfunction in Adults with Sickle Cell Disease
What the sources say
- Supportedcites [66] source
The Methods state that 84 of 529 screened adults with sickle cell disease underwent right heart catheterization because of elevated echocardiographic readings and clinical suspicion of pulmonary hypertension. Hemodynamic Parameters reports that 55 of the 529 (10.4%) were diagnosed with pulmonary hypertension; the paper defines it as mean pulmonary artery pressure >25 mm Hg. (LLM, conf=0.94)
- Partly supportedcites [194] sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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%).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Small-Vessel Vasculopathy in the Central Nervous System
What the sources say
- Partly supportedcites [178] sourceExperimental — accuracy not yet measured
Split into 3 atoms — 2 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Development of Pulmonary Hypertension and Left Ventricular Diastolic Heart Dysfunction in Adults with Sickle Cell Disease
What the sources say
- Partly supportedcites [77] sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [82] sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > CONVERGENCE OF MULTIPLE PATHOGENIC PATHWAYS: ACUTE CHEST SYNDROME
What the sources say
- Partly supportedcites [206] sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Development of Pulmonary Hypertension and Left Ventricular Diastolic Heart Dysfunction in Adults with Sickle Cell Disease
What the sources say
- Not checked — no full text of the sourcecites [197] source
- Partly supportedcites [198] sourceExperimental — accuracy not yet measured
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)
- Supportedcites [199] source
The Introduction reports that diastolic dysfunction in sickle cell anemia mice was associated with microscopic myocardial fibrosis. The Abstract and Discussion report diffuse myocardial fibrosis in patients, assessed using cardiac MRI measurements of extracellular volume, and its association with diastolic dysfunction. (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > CONVERGENCE OF MULTIPLE PATHOGENIC PATHWAYS: ACUTE CHEST SYNDROME
What the sources say
- Not checked — no full text of the sourcecites [209] source
- Partly supportedcites [210] sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [211] sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“it is more common in children and, if untreated, has a high mortality [9% in adults (111)].”
§ Pathophysiology of Sickle Cell Disease > CONVERGENCE OF MULTIPLE PATHOGENIC PATHWAYS: ACUTE CHEST SYNDROME
What the sources say
- Partly supportedcites [111] sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“high levels of hemopexin, the enzyme that scavenges heme, can rescue acute lung injury (89), while HO-1 deficiency potentiates it (57).”
§ Pathophysiology of Sickle Cell Disease > CONVERGENCE OF MULTIPLE PATHOGENIC PATHWAYS: ACUTE CHEST SYNDROME
What the sources say
- Supportedcites [89] source
The Results section reports that sickle mice treated with recombinant human hemopexin after a hemin challenge did not develop respiratory symptoms and all survived. The HO-1-deficiency statement has a separate citation in the citing sentence, so it is not assessed against this source. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [57] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Infection is the most common ACS trigger in children; common isolates include atypical microorganisms and Streptococcus pneumoniae (208).”
§ Pathophysiology of Sickle Cell Disease > CONVERGENCE OF MULTIPLE PATHOGENIC PATHWAYS: ACUTE CHEST SYNDROME
What the sources say
- Partly supportedcites [208] sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In its most extreme manifestation (207), acute lung injury presents with or evolves into acute respiratory distress syndrome.”
§ Pathophysiology of Sickle Cell Disease > CONVERGENCE OF MULTIPLE PATHOGENIC PATHWAYS: ACUTE CHEST SYNDROME
What the sources say
- Supportedcites [207] source
The Definitions section (p. 1) defines ARDS using a more severe hypoxemia threshold than acute lung injury, supporting the description of ARDS as its more extreme manifestation. Figure 1 (p. 2) also describes early lung injury progressing to respiratory failure. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Pathophysiology of Sickle Cell Disease > HEMOGLOBIN S POLYMERIZATION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > HEMOGLOBIN S POLYMERIZATION
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“stroke affected up to 10% of children prior to the implementation of screening programs (81, 133).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Large-Vessel Vasculopathy in the Central Nervous System
What the sources say
- Not matchedcites [81] Ohene-Frempong K, 1998, Blood
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites [133] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Pathophysiology of Sickle Cell Disease > ENDOTHELIAL DYSFUNCTION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Stenosis of the large branches of the internal carotid artery predisposes children to devastating strokes.”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Large-Vessel Vasculopathy in the Central Nervous System
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
In the paper
“red blood cell transfusion rapidly improves stroke symptoms and cerebral tissue oxygen saturation in children (147)”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Large-Vessel Vasculopathy in the Central Nervous System
What the sources say
- Not checked — no full text of the sourcecites [147] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS
What the sources say
- Not checked — no full text of the sourcecites [132] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > ENDOTHELIAL DYSFUNCTION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > CURRENT AND FUTURE THERAPIES TARGETING SICKLE CELL DISEASE PATHOBIOLOGY
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Large-Vessel Vasculopathy in the Central Nervous System
What the sources say
- Not checked — no full text of the sourcecites [155] source
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [157] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Aneurysms are typically saccular and <5 mm in size and may coexist with vasculopathy and a Moyamoya pattern of cerebral vascularization (182).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Vasculopathy as a Risk Factor for Intracerebral Hemorrhage
What the sources say
- Not checked — no full text of the sourcecites [182] source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Small-Vessel Vasculopathy in the Central Nervous System
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Development of Pulmonary Hypertension and Left Ventricular Diastolic Heart Dysfunction in Adults with Sickle Cell Disease
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Intracerebral hemorrhage preferentially affects young adults with SCD and is particularly common in those suffering from aneurysms and Moyamoya syndrome (180).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Vasculopathy as a Risk Factor for Intracerebral Hemorrhage
What the sources say
- Not checked — no full text of the sourcecites [180] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Small-Vessel Vasculopathy in the Central Nervous System
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Development of Pulmonary Hypertension and Left Ventricular Diastolic Heart Dysfunction in Adults with Sickle Cell Disease
What the sources say
- Not checked — no full text of the sourcecites [192] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Pathophysiology of Sickle Cell Disease > CONCLUSION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Development of Pulmonary Hypertension and Left Ventricular Diastolic Heart Dysfunction in Adults with Sickle Cell Disease
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > CONVERGENCE OF MULTIPLE PATHOGENIC PATHWAYS: ACUTE CHEST SYNDROME
What the sources say
- Not checked — no full text of the sourcecites [110] source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > CONVERGENCE OF MULTIPLE PATHOGENIC PATHWAYS: ACUTE CHEST SYNDROME
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“Proposed mechanisms for SCD nephropathy include hemoglobinuria, ischemia-reperfusion injury, hyperfiltration, and hypertension (203).”
§ Pathophysiology of Sickle Cell Disease > THE PERFUSION PARADOX OF SICKLE CELL DISEASE: PATHOLOGY IN THE CENTRAL NERVOUS AND CARDIOPULMONARY SYSTEMS > Development of Pulmonary Hypertension and Left Ventricular Diastolic Heart Dysfunction in Adults with Sickle Cell Disease
What the sources say
- Not checked — no full text of the sourcecites [203] source
plainconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The five mechanisms described above may coexist or independently cause ACS”
§ Pathophysiology of Sickle Cell Disease > CONVERGENCE OF MULTIPLE PATHOGENIC PATHWAYS: ACUTE CHEST SYNDROME
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Fat embolism is suspected when abundant lipid-laden macrophages are detected in the bronchoalveolar lavage, a sensitive but nonspecific test (214).”
§ Pathophysiology of Sickle Cell Disease > CONVERGENCE OF MULTIPLE PATHOGENIC PATHWAYS: ACUTE CHEST SYNDROME
What the sources say
- Not checked — no full text of the sourcecites [214] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pathophysiology of Sickle Cell Disease > CONCLUSION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > CONVERGENCE OF MULTIPLE PATHOGENIC PATHWAYS: ACUTE CHEST SYNDROME
What the sources say
- Not checked — no full text of the sourcecites [224] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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).”
§ Pathophysiology of Sickle Cell Disease > CONVERGENCE OF MULTIPLE PATHOGENIC PATHWAYS: ACUTE CHEST SYNDROME
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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).”
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“sRBCs exhibit increased adherence to other blood cells or to the endothelium, and are prone to undergo premature clearance or hemolysis (Sundd et al., 2019).”
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“Sickle cell disease (SCD) is a group of inherited hemolytic anemias arising from mutation in b-globin gene resulting in an abnormal hemoglobin tetramer HbS.(293,294) The most frequent cause of hospitalization in SCD are vaso-occlusive crises (VOCs),(295) which result from a complex interplay of red cells, endothelial…”
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“Hemolysis promotes an inflammatory milieu in SCD by releasing erythrocytederived damage-associated molecular pattern molecules (DAMPs), such as Hb and heme (8), that scavenge nitric oxide, generate reactive oxygen species (ROS) and “prime” TLR4 (toll-like receptor 4)dependent innate immune signaling in vascular cells…”
BackgroundSelf-citationEmerging disease-modifying therapies for sickle cell disease
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“Children with sickle cell anemia (SCA), for example, are at extreme risk of stroke and brain small-vessel vasculopathy, especially those with high cerebral blood flow (CBF) as measured by transcranial Doppler (58).”
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“SCD is caused by a single mutation resulting in valine-glutamic acid residue substitution at position 6 of b globin (HbS), which induces polymerization of deoxygenated hemoglobin tetramers and induces the typical sickle-shaped erythrocyte formation, causing hemolytic anemia and stroke.(78)”
BackgroundDeterminants of severity in sickle cell disease
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“Sickle cell disease (SCD) is a widespread inherited disorder with a mutation in the hemoglobin (Hb) gene (HbS), affecting over 6 million people worldwide.(1) The altered characteristics of the sickle red blood cells (RBCs) leading to hemolysis, adhesion and abnormal hemorheological properties are responsible for vaso-…”
BackgroundThe molecular basis for the prothrombotic state in sickle cell disease
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BackgroundEtavopivat, a Pyruvate Kinase Activator in Red Blood Cells, for the Treatment of Sickle Cell Disease
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IL-18 mediates sickle cell cardiomyopathy and ventricular arrhythmias
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“, cell-free hemoglobin, high-mobility group box 1 (HMGB1) and extracellular purine nucleotides) play a fundamental role in VTE pathophysiology [77–79] and also seem to drive SCD pathophysiology [26,61,80,81].”
BackgroundHaploidentical Bone Marrow Transplantation for Sickle Cell Disease
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“It is now known that the products of hemolysis promote acute and chronic vasculopathy through a combination of different mechanisms [4,5].”
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Silva-Junior, A. L., Garcia, N. P., Cardoso, E. C., Dias, S., Tarragô, A. M., Fraiji, N. A., Gomes, M. S., do Amaral, L. R., Teixeira‐Carvalho, A., Martins‐Filho, O. A., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.559925 · Cited by 45
“In addition, the findings regarding chemokines support the statement that these circulating cells show a higher capacity to adhere to endothelial cells and form cell-to-cell and cell-endothelium aggregates in VOC, which contributes to endothelial injury, inflammatory marker production, immune cell recruitment, vaso-oc…”
BackgroundInfluentialHsp90 in Human Diseases: Molecular Mechanisms to Therapeutic Approaches
Sumi, M. P., & Ghosh, A. (2022) · Cells · doi:10.3390/cells11060976 · Cited by 42
Cell and Gene Therapy for Anemia: Hematopoietic Stem Cells and Gene Editing
Anurogo, D., Budi, N. Y. P., Ngo, M.-H. T., Huang, Y., & Pawitan, J. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126275 · Cited by 43
Hematopoietic Stem Cell-Targeted Gene-Addition and Gene-Editing Strategies for β-hemoglobinopathies
Drysdale, C. M., Nassehi, T., Gamer, J., Yapundich, M., Tisdale, J. F., & Uchida, N. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.01.001 · Cited by 39
The Current Role of Hydroxyurea in the Treatment of Sickle Cell Anemia
Rubio, M. L., & Marina, M. A. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13216404 · Cited by 44
“…to the formation of HbS instead of HbA, which in sufficient proportions and under conditions of deoxygenation polymerizes and leads to the deformation of red blood cells, which affects their flexibility and adherence to the vascular endothelium [1,2], causing both acute and chronic complications.”
BackgroundRevolutionising healing: Gene Editing's breakthrough against sickle cell disease
Dimitrievska, M., Bansal, D., Vitale, M., Strouboulis, J., Miccio, A., Nicolaides, K. H., Hoss, S. E., Shangaris, P., & Jackow, J. (2024) · Blood Reviews · doi:10.1016/j.blre.2024.101185 · Cited by 41
Fisher, A. L., Srole, D. N., Palaskas, N. J., Meriwether, D., Reddy, S. T., Ganz, T., & Nemeth, E. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101156 · Cited by 37
“Vasculopathy and endothelial dysfunction is one of the hallmarks of sickle cell disease pathophysiology (56) and is increasingly recognized in thalassemia as a contributor to disease-related complications (57, 58).”
BackgroundGoreke, U., Bode, A., Yaman, S., Gurkan, U. A., & Durmus, N. G. (2022) · Lab on a Chip · doi:10.1039/d1lc00686j · Cited by 35
Migotsky, M., Beestrum, M., & Badawy, S. M. (2022) · Pharmacy · doi:10.3390/pharmacy10050123 · Cited by 33
“Due to a single amino acid substitution in the beta-globin chain, sickle cells are more prone to polymerization, vaso-occlusion, and hemolytic anemia in the setting of hemoglobin deoxygenation [3].”
BackgroundDiverse Approaches to Gene Therapy of Sickle Cell Disease
White, S. L., Hart, K. L., & Kohn, D. B. (2022) · Annual Review of Medicine · doi:10.1146/annurev-med-042921-021707 · Cited by 33
Cost-effectiveness of a hypothetical cell or gene therapy cure for sickle cell disease
Salcedo, J. D., Bulovic, J., & Young, C. M. (2021) · Scientific Reports · doi:10.1038/s41598-021-90405-1 · Cited by 31
P-selectin–deficient mice to study pathophysiology of sickle cell disease
Bennewitz, M. F., Tütüncüoğlu, E., Gudapati, S., Brzóska, T., Watkins, S. C., Monga, S. P., Pradhan‐Sundd, T., & Sundd, P. (2020) · Blood Advances · doi:10.1182/bloodadvances.2019000603 · Cited by 32
“Interestingly, P-selectin is constitutively expressed on SCD mice and patient platelets,33,34 and it is expressed on the vascular endothelium in the skin, lung, brain, liver, and kidney of SCD mice.20 Recently,35,36 P-selectin inhibition was also shown to prevent hypoxia-induced pulmonary hypertension in WT mice, sugg…”
BackgroundInfluentialSelf-citationInsights into Sickle Cell Disease through the Retinal Microvasculature
Pinhas, A., Migacz, J. V., Zhou, D. B., et al. (2022) · Ophthalmology Science · doi:10.1016/j.xops.2022.100196 · Cited by 31
“These events cause ischemiaereperfusion injury and complete infarctions, leading to painful crises, progressive organ damage, and significant morbidity and mortality in relatively young patients.(44) The traditional concept of sickled RBCs blocking microvascular blood flow is now understood to represent only a fractio…”
BackgroundSiciliano, A., Malpeli, G., Platt, O., Lebœuf, C., Janin, A., Scarpa, A., Olivieri, O., Amato, E., Corrocher, R., Beuzard, Y., et al. (2010) · Haematologica · doi:10.3324/haematol.2010.028506 · Cited by 31
Rao, P. P., Raj, E. A., Natesan, S. K. A., & Gudi, N. (2024) · Clinical Epidemiology and Global Health · doi:10.1016/j.cegh.2024.101678 · Cited by 34
Nyffenegger, N., Zennadi, R., Kalleda, N., Flace, A., Ingoglia, G., Buzzi, R. M., Doucerain, C., Buehler, P. W., Schaer, D. J., Dürrenberger, F., et al. (2022) · Blood · doi:10.1182/blood.2021014716 · Cited by 30
Red blood cells undergo lytic programmed cell death involving NLRP3
Chen, Y., Chen, S., Liu, Z., Wang, Y., An, N., Chen, Y., Peng, Y., Liu, Z., Liu, Q., & Hu, X. (2025) · Cell · doi:10.1016/j.cell.2025.03.039 · Cited by 32
Hadjesfandiari, N., Khorshidfar, M., & Devine, D. V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22083943 · Cited by 29
Udeze, C., Evans, K. A., Yang, Y., et al. (2023) · Advances in Therapy · doi:10.1007/s12325-023-02545-7 · Cited by 28
“This mutation leads to the production of abnormal or sickled hemoglobin, which polymerizes in its deoxygenated form to promote a cycle of cellular adhesion, vaso-occlusion, endothelial dysfunction, and inflammation [4, 5].”
The relationship between anemia and obesity
Saad, R. A., & Qutob, H. M. H. (2022) · Expert Review of Hematology · doi:10.1080/17474086.2022.2131521 · Cited by 33
“blood vessels, cause severe pain, and leave residual organ damage [41].”
BackgroundSzafraniec, H. M., Valdez, J. M., Iffrig, E., Lam, W. A., Higgins, J. M., Pearce, P., & Wood, D. K. (2022) · Lab on a Chip · doi:10.1039/d1lc01133b · Cited by 28
How Severe Anaemia Might Influence the Risk of Invasive Bacterial Infections in African Children
Abuga, K. M., Muriuki, J. M., Williams, T. N., & Atkinson, S. H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186976 · Cited by 32
“Sickle cell disease may also induce iron deficiency anaemia through increased iron utilization to replace damaged red blood cells or urinary iron loss [16].”
BackgroundSickle Cell Trait and Risk for Common Diseases: Evidence from the UK Biobank
Hulsizer, J., Resurreccion, W. K., Shi, Z., et al. (2022) · The American Journal of Medicine · doi:10.1016/j.amjmed.2022.03.024 · Cited by 27
Sharma, A., Leonard, A. K., West, K. A., Gossett, J. M., Uchida, N., Panch, S. R., Stroncek, D. F., Poston, L., Akel, S. M., Hankins, J. S., et al. (2022) · British Journal of Haematology · doi:10.1111/bjh.18311 · Cited by 26
Stroke and stroke prevention in sickle cell anemia in developed and selected developing countries
Bhattacharya, P., Sarmah, D., Dave, K. R., Goswami, A., Watanabe, M., Wang, X., Kalia, K., Plesnila, N., Yavagal, D. R., & Alvarez, O. A. (2021) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2021.117510 · Cited by 26
Hemoglobinopathy and pediatrics in the time of COVID-19
Vilela, T. D. S., Braga, J. A. P., & Loggetto, S. R. (2020) · Hematology Transfusion and Cell Therapy · doi:10.1016/j.htct.2020.11.002 · Cited by 25
Redox signaling in sickle cell disease
Nolfi‐Donegan, D., Pradhan‐Sundd, T., Pritchard, K. A., & Hillery, C. A. (2019) · Current Opinion in Physiology · doi:10.1016/j.cophys.2019.04.022 · Cited by 26
“microvascular stasis (“vaso-occlusion”), tissue ischemia and cumulative organ damage (2).”
BackgroundCritical Role of Hemopexin Mediated Cytoprotection in the Pathophysiology of Sickle Cell Disease
Ashouri, R., Fangman, M., Burris, A. O., Ezenwa, M. O., Wilkie, D. J., & Doré, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126408 · Cited by 27
Zheng, Y., Gossett, J. M., Chen, P., Barton, M., Ryan, M., Yu, J., Kang, G., Hankins, J. S., & Chou, S. T. (2023) · Blood Advances · doi:10.1182/bloodadvances.2022008647 · Cited by 26
GTP cyclohydroxylase1 (GCH1): Role in neurodegenerative diseases
Gupta, P., & Kumar, R. (2023) · Gene · doi:10.1016/j.gene.2023.147749 · Cited by 25
Neuroprotective Effects of Phenolic Antioxidant Tert-butylhydroquinone (tBHQ) in Brain Diseases
Liu, X., Yang, L., Zhang, G., & Ling, J. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03370-3 · Cited by 25
“Complex cytokine networks and immune cells are created by pro- and anti-inflammatory cytokines, and their dynamic equilibrium influences the course of inflammation and its outcome [19, 20].”
BackgroundFerraresi, M., Panzieri, D. L., Leoni, S., Cappellini, M. D., Kattamis, A., & Motta, I. (2023) · European Journal of Pediatrics · doi:10.1007/s00431-023-04900-w · Cited by 31
“Current and future therapies target different pathophysiological mechanisms of SCD: (a) modulation of Hb polymerization, erythrocyte dehydration, and Hb oxygen affinity; (b) prevention of vaso-occlusion by inhibiting cells interactions; (c) prevention of endothelial dysfunction; and (d) modulation of inflammation [46].”
BackgroundThe NLRP3 inflammasome fires up heme-induced inflammation in hemolytic conditions
Salgar, S., Bolívar, B. E., Flanagan, J. M., Anum, S. J., & Bouchier‐Hayes, L. (2022) · Translational research · doi:10.1016/j.trsl.2022.08.011 · Cited by 28
Severity and burden of sickle cell disease in France: a nationwide real-world study
Brousse, V. A. M., Bernaudin, F., Melaine, A., Goguillot, M., Gallagher, M. E., Bénard, S., & Habibi, A. (2023) · Haematologica · doi:10.3324/haematol.2022.282098 · Cited by 25
L-glutamine for sickle cell disease: more than reducing redox
Jafri, F. M., Seong, G., Jang, T., Cimpeanu, E., Poplawska, M., Dutta, D., & Lim, S. H. (2022) · Annals of Hematology · doi:10.1007/s00277-022-04867-y · Cited by 29
“Toll-like receptor 4 (TLR4) activation, neutrophil extracellular trap (NET) generation, and release of tissue or cell-derived DAMPs contribute to a sterile inflammation that further promotes vaso-occlusion by activating neutrophils, platelets, and endothelial cells [1].”
BackgroundInfluentialHeeney, M. M., Abboud, M. R., Githanga, J. N., Inusa, B. P. D., Kanter, J., Michelson, A. D., Nduba, V., Musiime, V., Apte, M., Inati, A. C., et al. (2022) · Blood · doi:10.1182/blood.2021014095 · Cited by 26
Allogeneic hematopoietic stem cell transplantation to cure sickle cell disease: A review
Bhalla, N., Bhargav, A., Yadav, S. K., & Singh, A. K. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1036939 · Cited by 30
“Over the 12 decades, four major pathological processes, namely HbS polymerization, vaso-occlusion, hemolysis-mediated endothelial dysfunction, and sterile inflammation, have emerged and are characterized (34).”
BackgroundXanthine Oxidase Drives Hemolysis and Vascular Malfunction in Sickle Cell Disease
Schmidt, H. M., Wood, K. C., Lewis, S. E., Hahn, S. A., Williams, X. M., McMahon, B., Baust, J., Yuan, S. S., Bachman, T. N., Wang, Y., et al. (2020) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.120.315081 · Cited by 24
Circulating Extracellular Vesicles and Endothelial Damage in Sickle Cell Disease
Lapping‐Carr, G., Gemel, J., Mao, Y. V., & Beyer, E. C. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.01063 · Cited by 24
Global burden of transfusion in sickle cell disease
Inusa, B. P. D., Atoyebi, W., Andemariam, B., Hourani, J., & Omert, L. (2023) · Transfusion and Apheresis Science · doi:10.1016/j.transci.2023.103764 · Cited by 26
Manifestations of HbSE sickle cell disease: a systematic review
Khamees, I., Ata, F., Choudry, H. A., Soliman, A. T., Sanctis, V. D., & Yassin, M. A. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-021-02931-1 · Cited by 24
The oxygen dissociation curve of blood in COVID-19–An update
Boning, D. G., Kuebler, W. M., Vogel, D. J., & Bloch, W. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1098547 · Cited by 22
Kilonzi, M., Mwakawanga, D. L., Felician, F. F., Mlyuka, H. J., Chirande, L., Myemba, D. T., Sambayi, G., Mutagonda, R. F., Mikomangwa, W. P., Ndunguru, J., et al. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph19116871 · Cited by 22
“Sickle cell disease (SCD) is a devastating hematologic disorder caused by a single nucleotide mutation that leads to formation of abnormal hemoglobin S which has the tendency to polymerize and cause sickling of erythrocytes [1].”
BackgroundMohiuddin, M., Pivetta, B., Gilron, I., & Khan, J. S. (2021) · Pain Medicine · doi:10.1093/pm/pnab042 · Cited by 26
van Veelen, S., Vuong, C., Gerritsma, J. J., Eckhardt, C. L., Verbeek, S. E. M., Peters, M., & Fijnvandraat, K. (2023) · Pediatric Blood & Cancer · doi:10.1002/pbc.30315 · Cited by 27
P-selectin deficiency promotes liver senescence in sickle cell disease mice
Vats, R., Kaminski, T. W., Ju, E.-M., Brozska, T., Tütüncüoğlu, E., Tejero, J., Novelli, E. M., Sundd, P., & Pradhan‐Sundd, T. (2021) · Blood · doi:10.1182/blood.2020009779 · Cited by 25
Self-citationVenkatesan, V., Srinivasan, S., Babu, P., & Thangavel, S. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00253-20 · Cited by 22
Sickle cell nephropathy: insights into the pediatric population
Adebayo, O. C., van den Heuvel, L. P., Olowu, W. A., Levtchenko, E. N., & Labarque, V. (2021) · Pediatric Nephrology · doi:10.1007/s00467-021-05126-4 · Cited by 21
“Although studies have shown potential roles of TLR4 pathway activation in the endothelial cells as one of the relevant mechanisms for vaso-occlusion [30] and acute chest syndrome in SCD [31], there is no study that we are currently aware of pointing to the direct potential role of free heme in SCN. Clinical manifestat…”
BackgroundKamal, S. M., Naghib, M. M., Alzahrani, J. M., Hassan, H., Moawado, K. A. A., & Arrahman, O. (2020) · Mediterranean Journal of Hematology and Infectious Diseases · doi:10.4084/mjhid.2021.007 · Cited by 23
The Cardiopulmonary Complications of Sickle Cell Disease
Desai, A. A., Machado, R. F., & Cohen, R. T. (2022) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2022.07.014 · Cited by 24
Zhang, P., Nguyen, J., Abdulla, F. A., Nelson, A. T., Beckman, J. D., Vercellotti, G. M., & Belcher, J. D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.632709 · Cited by 20
“org 7 SCD patients more susceptible to pulmonary infections and acute chest syndrome, especially in response to enhanced hemolysis (9, 61).”
BackgroundOng, S. S. Y., Ahmed, I., & Scott, A. W. (2021) · Ophthalmology Retina · doi:10.1016/j.oret.2021.01.003 · Cited by 20
Analysis of the temporal trend of mortality from sickle cell anemia in Brazil
Mota, F. M., Júnior, M. A. F., Cardoso, A. I. D. Q., Pompeo, C. M., Frota, O. P., Tsuha, D. H., & de Souza, A. S. (2022) · Revista Brasileira de Enfermagem · doi:10.1590/0034-7167-2021-0640 · Cited by 19
“2022;75(4): e20210640 8 of Analysis of the temporal trend of mortality from sickle cell anemia in Brazil”
BackgroundImpaired Bile Secretion Promotes Hepatobiliary Injury in Sickle Cell Disease
Vats, R., Liu, S., Zhu, J., Mukhi, D., Tütüncüoğlu, E., Cárdenes, N., Singh, S., Brzóska, T., Kosar, K., Bamne, M. N., et al. (2020) · Hepatology · doi:10.1002/hep.31239 · Cited by 20
“(1) Sickle cell anemia, the most common form of SCD, is caused by a homozygous mutation in the β-globin gene, leading to hemoglobin polymerization, erythrocyte rigidity, dehydration, vaso-occlusion (tissue ischemia), and premature hemolysis.(2,3) Vaso-occlusion and hemolysis are the predominant pathophysiological even…”
BackgroundSelf-citationNeutrophils as drivers of vascular injury in sickle cell disease
Torres, L. S., & Hidalgo, A. (2022) · Immunological Reviews · doi:10.1111/imr.13146 · Cited by 22
A Small Key for a Heavy Door: Genetic Therapies for the Treatment of Hemoglobinopathies
Zittersteijn, H. A., Harteveld, C. L., Klaver-Flores, S., Lankester, A. C., Hoeben, R. C., Staal, F. J. T., & Gonçalves, M. A. F. V. (2021) · Frontiers in Genome Editing · doi:10.3389/fgeed.2020.617780 · Cited by 21
“Due to this cell sickling (S) mutation, HbS tetramers carrying the abnormal βS globin chains polymerize through hydrophobic valine interactions that form large HbS polymers (Sundd et al., 2019).”
BackgroundNitric oxide: A potential etiological agent for vaso-occlusive crises in sickle cell disease
Gupta, P., & Kumar, R. (2024) · Nitric Oxide · doi:10.1016/j.niox.2024.01.008 · Cited by 21
Metadata
- Authors
- Sundd, P., Gladwin, M. T., & Novelli, E. M.
- Affiliations
- University of Pittsburgh (US)
- 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
- 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
- FWCI
- 5.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- 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 (clinical) › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Health Sciences › Medicine › Hematology › 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
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