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Cited by 469Erythrocyte Function and PathophysiologyBlood properties and coagulationHemoglobin structure and function

Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia

Open access
Kuhn, Viktoria, Diederich, Lukas, Keller, T.C. Stevenson, Kramer, Christian M., Lückstädt, Wiebke, Panknin, Christina, Suvorava, Tatsiana, Isakson, Brant E. +2 more·2017·Antioxidants & Redox Signaling
DOI 10.1089/ars.2016.6954PMC PMC5421513
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Abstract

SIGNIFICANCE: Recent clinical evidence identified anemia to be correlated with severe complications of cardiovascular disease (CVD) such as bleeding, thromboembolic events, stroke, hypertension, arrhythmias, and inflammation, particularly in elderly patients. The underlying mechanisms of these complications are largely unidentified. Recent Advances: Previously, red blood cells (RBCs) were considered exclusively as transporters of oxygen and nutrients to the tissues. More recent experimental evidence indicates that RBCs are important interorgan communication systems with additional functions, including participation in control of systemic nitric oxide metabolism, redox regulation, blood rheology, and viscosity. In this article, we aim to revise and discuss the potential impact of these noncanonical functions of RBCs and their dysfunction in the cardiovascular system and in anemia. CRITICAL ISSUES: The mechanistic links between changes of RBC functional properties and cardiovascular complications related to anemia have not been untangled so far. FUTURE DIRECTIONS: To allow a better understanding of the complications associated with anemia in CVD, basic and translational science studies should be focused on identifying the role of noncanonical functions of RBCs in the cardiovascular system and on defining intrinsic and/or systemic dysfunction of RBCs in anemia and its relationship to CVD both in animal models and clinical settings. Antioxid. Redox Signal. 26, 718-742.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that red blood cells (RBCs) have noncanonical roles in redox regulation, nitric oxide (NO) metabolism, blood rheology, and erythrocrine signaling, and that RBC dysfunction may contribute mechanistically to anemia-associated cardiovascular complications. It synthesizes basic, translational, and clinical evidence and calls for studies distinguishing intrinsic RBC dysfunction from reduced RBC number in anemia.

Key findings

  • RBCs are highly exposed to oxidants: about 3% of hemoglobin undergoes autoxidation every 24 h, yet only about 1% of Hb is present as methemoglobin; RBCs contain 10 mM heme and maintain 90%–95% of glutathione in the reduced GSH form.
  • RBCs were traditionally viewed as NO scavengers, but intact RBCs consume NO with a 1000-fold discrepancy compared with free Hb; proposed RBC-mediated NO pathways include deoxyhemoglobin-catalyzed nitrite reduction, with one study proposing only 25% of nitrite is directly reduced to NO, plus RBC eNOS and ATP release.
  • Anemia is defined as Hb <12 g/dL in females and <13 g/dL in males; 20%–30% of patients with cardiovascular disease (CVD) have concomitant anemia, and elderly patients aged 65+ have a 10% higher risk of anemia, rising to 20% in those aged 85+.
  • In β-thalassemic mice, heme degradation products were increased 3.5-fold; mouse models in Table 1 cover disorders of erythropoiesis, increased hemolysis/RBC depletion, blood loss, and RBC distribution.

Methods

  • Design: narrative review, not a primary experimental study; it synthesizes mechanistic, animal-model, and clinical literature.
  • Data/sample: cited basic science studies, transgenic and knockout mouse models (Table 1), and clinical/epidemiological evidence on anemia and CVD.
  • Main analysis: conceptual synthesis of RBC redox regulation, NO metabolism, mechanical/rheological properties, anemia pathophysiology, and therapeutic approaches including transfusion and erythropoiesis-stimulating agents (ESAs).

Limitations

  • The paper states that mechanistic links between changes in RBC functional properties and cardiovascular complications related to anemia have not been untangled, and that many aspects of RBC-mediated NO metabolism and ATP release remain speculative or not universally accepted.
  • The paper notes that interpretation of large cohort/epidemiological studies is complex and requires recognition of many interacting disease and physiological features.
  • Evident from the text: as a narrative review, it presents no new experimental data and does not describe a systematic search strategy or formal quality appraisal.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1089/ars.2016.6954

Cites

198 of 198 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Findingcitation

    The effects of NO donors on RBC deformability ex vivo were not confirmed by others.

    “However, recently, the effects of NO donors on RBCs deformability ex vivo were not confirmed by others (15).”
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  • Premisecitation

    In healthy human RBCs, 90%-95% of glutathione is present in the reduced form GSH.

    “In healthy human RBCs, 90%–95% of glutathione is present in the reduced form GSH (200) that can be utilized for the reduction of ascorbate, oxidized proteins, and oxidized lipids (184).”
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  • Premisecitation

    GSH can be utilized for the reduction of ascorbate, oxidized proteins, and oxidized lipids.

    “In healthy human RBCs, 90%–95% of glutathione is present in the reduced form GSH (200) that can be utilized for the reduction of ascorbate, oxidized proteins, and oxidized lipids (184).”
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  • Premisecitation

    The reaction between H2O2 and both ferrous and ferric hemoglobin results in heme degradation and release of free iron.

    “Another important oxidative pathway is the reaction between H2O2 and both ferrous and ferric Hb, resulting in heme degradation and release of free iron (3), as described in detail in an older comprehensive review by Reeder (150).”
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  • Premisecitation

    Lack of riboflavins can impair antioxidant defense in fasting.

    “In addition, the lack of riboflavins—components of the cosubstrate flavin adenine dinucleotide (FAD) important for glutathione reductase functionality—can impair antioxidant defense in fasting (10).”
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    Findingreasoning

    A single erythrocyte traverses the circulatory system in approximately 1 min, and during its average lifetime of 120 days undergoes on the order of 10^5 cycles of high flow conditions in the aorta followed by squeezing through capillaries.

    “one can calculate that a single erythrocyte traverses the circulatory system in ∼1 min; therefore, during its average lifetime of 120 days (42), one RBC undergoes on the order of 105 cycles of high flow conditions in the aorta, followed by squeezing through the capillaries.”
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    • cites [42] David Shemin DR., 1946, J Biol Chem source

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    Interpretationcitation

    PMRS in RBCs may act as a compensatory mechanism against increased ROS/oxidative stress and represents a potential mechanism of how RBCs contribute to redox regulation throughout the whole body.

    “Thus, PMRS in RBCs may act as a compensatory mechanism against increased ROS/oxidative stress and represents a potential mechanism of how RBCs contribute to redox regulation throughout the whole body (173).”
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    Premisecitation

    These reactions lead to generation of the potent oxidizing ferrylHb species as well as secondary radicals from the reaction between H2O2 and either oxyHb or metHb.

    “These reactions lead to generation of the potent oxidizing ferrylHb species as well as secondary radicals from the reaction between H2O2 and either oxyHb or metHb.”
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    Premisecitation

    Ascorbate is involved in several antioxidant mechanisms such as reduction of diffusible oxidants and methemoglobin, as well as maintenance of the plasma membrane redox system.

    “It is involved in several antioxidant mechanisms such as reduction of diffusible oxidants and metHb, as well as maintenance of plasma membrane redox system (PMRS) (51).”
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    Premisecitation

    Increased PMRS activity in erythrocytes during aging may be a protective mechanism for efficient extracellular dehydroascorbate reduction and ascorbate recycling under conditions of increased oxidative stress.

    “The physiological significance of the PMRS is not completely understood, but it was reported that the increased PMRS activity in erythrocytes during aging may be a protective mechanism of the system for efficient extracellular dehydroascorbate reduction and ascorbate recycling under conditions of increased oxidative stress (173).”
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    Premisecitation

    α-Tocopherol accumulates in RBC membranes and plays a central role in preventing lipid peroxidation, probably by limiting the amplification of peroxidation chain reactions within the plasma membrane.

    “Due to its lipophilicity, α-tocopherol accumulates in RBC membranes and plays a central role in preventing lipid peroxidation, probably by limiting the amplification of peroxidation chain reactions within the plasma membrane (24).”
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    • cites [24] Brownlee NR, 1977, J Lipid Res source

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    Premisecitation

    The enzyme responsible for GSH recycling is glutathione reductase, which reduces glutathione disulfide back to reduced GSH via consumption of NADPH.

    “The enzyme responsible for GSH recycling is glutathione reductase, which reduces glutathione disulfide (GSSG) back to the reduced GSH via consumption of NADPH (197).”
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    Premisecitation

    Ascorbate is an essential hydrophilic vitamin and an important reducing equivalent in RBCs, which is (re)synthesized from dehydroascorbic acid at the expense of GSH in a reaction catalyzed by glutaredoxins.

    “Ascorbate is an essential hydrophilic vitamin and an important reducing equivalent in RBCs, which is (re)synthesized from dehydroascorbic acid at the expense of GSH in a reaction catalyzed by a variety of enzymes, especially GRxs (190), which are small cytoplasmic enzymes also catalyzing deglutathionylation, reduction of protein disulfides, or Fe-S linkage formation.”
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    • cites [190] Wells WW, 1990, J Biol Chem source

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    Premisecitation

    The consequence of hemolysis is particularly evident in hemolytic anemia, where fragility of RBCs is mainly due to redox dysbalance or hemoglobinopathies, for example, sickle cell disease, and observed in transfusion of older blood.

    “The consequence of hemolysis is particularly evident in hemolytic anemia, where fragility of RBCs is mainly due to redox dysbalance or hemoglobinopathies, for example, sickle cell disease (SCD) (see the section “RBC Dysfunction and Anemia” for more details), and observed in transfusion of older blood (71).”
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    Interpretationreasoning

    RBC antioxidant pathways and their ability to reduce extracellular antioxidants via the transmembrane electron transport system, along with RBC mobility through the circulation, make them an ideal ROS buffering component, which may contribute to overall systemic homeostasis of redox balance.

    “Beyond this, RBC antioxidant pathways and their ability to reduce extracellular antioxidants via the transmembrane electron transport system, along with RBC mobility through the circulation, make them an ideal ROS buffering component, which may contribute to overall systemic homeostasis of redox balance.”
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    Premisecitation

    GSSG is recycled by GSH reductase, which consumes NADPH.

    “GSSG is recycled by GSH reductase, which consumes NAPDH (38).”
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    Premisecitation

    Deoxyhemoglobin may be the only nitrite reductase of physiological relevance under hypoxic conditions, as inactivation of deoxyhemoglobin by treatment with carbon monoxide completely blocked NO release from RBCs as assessed by electron paramagnetic resonance.

    “However, it was shown recently that deoxyhemoglobin may be the only nitrite reductase of physiological relevance under hypoxic conditions (Eq. 17) as inactivation of deoxyhemoglobin by treatment with carbon monoxide completely blocked NO release from RBCs as assessed by electron paramagnetic resonance (107).”
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    Interpretationreasoning

    RBCs induce NO synthesis in the vessel wall and thereby participate indirectly in maintenance of NO bioavailability.

    “Thus, RBCs induce NO synthesis in the vessel wall and thereby participate indirectly in maintenance of NO bioavailability.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Chimera mice lacking eNOS in blood present a hypertensive phenotype along with decreased circulating nitrite and nitrate levels.

    “these chimera mice present a hypertensive phenotype along with decreased circulating nitrite and nitrate levels (196)”
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    Premisecitation

    Other proposed nitrite reductases catalyzing NO formation from nitrite under hypoxic conditions are carbonic anhydrase, xanthine oxidase, or eNOS, which are all present in RBCs.

    “Other proposed nitrite reductases catalyzing NO formation from nitrite under hypoxic conditions are carbonic anhydrase (1), xanthine oxidase (68), or eNOS (189), which are all present in RBCs.”
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    Premisecitation

    NO can easily diffuse through plasma membranes, but its diffusion into RBCs is limited by transmembrane and intracellular resistances, as well as by the presence of an unstirred layer of solvent around the RBC.

    “Thanks to its small size and lack of charge, NO can easily diffuse through plasma membranes, but its diffusion into the RBCs is limited by transmembrane and intracellular resistances (185), as well as by the presence of an unstirred layer of solvent around the RBC (extracellular resistance) (46).”
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    Interpretationnone given

    RBCs are particularly well equipped with potent nonenzymatic and enzymatic antioxidant systems, which are important to maintain hemoglobin in a reduced oxygen binding form, to limit oxidative modifications of membrane lipids, structural proteins, channels, and metabolic enzymes, and therefore to keep the cell alive and functional for its average 120-day life.

    “To summarize, RBCs are particularly well equipped with potent nonenzymatic and enzymatic antioxidant systems, which are important to maintain Hb in a reduced oxygen binding form, to limit oxidative modifications of membrane lipids, structural proteins, channels, and metabolic enzymes, and therefore to keep the cell alive and functional for its (average) 120-day life.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Loss of hemoglobin compartmentalization may lead to systemic NO scavenging and may affect endothelial function.

    “Loss of Hb compartmentalization may lead to systemic NO scavenging and may affect endothelial function (72, 153).”
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    Premisecitation

    High concentrations of polyunsaturated fatty acids in RBC membrane make them susceptible to peroxidation leading to loss of RBC membrane integrity and decreased activity of membrane enzymes.

    “High concentrations of polyunsaturated fatty acids in RBC membrane make them susceptible to peroxidation leading to the loss of RBC membrane integrity and decreased activity of membrane enzymes [e.g., ATPase (198) and acetylcholinesterase (183)].”
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    Premisecitation

    Hemoglobin may react with H2O2, promote ferrylHb formation, and induce lipid peroxidation.

    “According to Eqs. 4–7, Hb may also react with H2O2 (e.g., generated during inflammatory conditions), promote ferrylHb formation, and induce lipid peroxidation (3).”
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    Premisecitation

    NOS in RBCs is a catalytically active eNOS (NOS3 type 1) identical to endothelial eNOS.

    “Recently, the NOS in RBCs was identified as a catalytically active eNOS (NOS3 type 1), which is identical to the eNOS expressed in endothelium, as assessed by immunoprecipitation and liquid chromatography mass spectroscopy (40), and confirmed by others through the analysis of conversion of L-15N-arginine into L-15N-citrulline (52).”
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    Premisereasoning

    Disorders of the RBC cytoskeleton lead to abnormal cell shapes such as spherocytosis and elliptocytosis, and the abnormal morphology and decreased surface area-to-volume ratio decrease deformability and ability to move through capillary beds and exchange gases.

    “Disorders of the RBC cytoskeleton lead to changes in overall shape of the cells such as spherocytosis and elliptocytosis. The abnormal cellular morphology and decreased surface area-to-volume ratio in these disorders decrease deformability and the ability of cells to move through capillary beds and exchange gases.”
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    Premisereasoning

    The equilibrium of spectrin-actin interaction with transmembrane and membrane-associated proteins gives functional shape to RBC and allows elasticity.

    “The equilibrium of spectrin–actin interaction along with transmembrane proteins (e.g., ion channels, receptors) and membrane-associated proteins (ankyrin, band 3, etc.) gives a functional shape to the RBC and allows for elasticity (i.e., reversible deformation) of the cell.”
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    Premisereasoning

    Hematocrit is the major determinant of blood viscosity; increased hematocrit increases blood viscosity.

    “While hematocrit values are the major determinant of blood viscosity, as a more packed fluid (increased hematocrit) blood is more resistant to flow (increased viscosity)”
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    Premisenone given

    The average internal volume of an RBC is 94 μm3 at 300 mOsmol/kg.

    “The average internal volume of an RBC is 94 μm3 at 300 mOsmol/kg.”
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    Premisecitation

    Low concentrations of NO donors increase RBC deformability, membrane fluidity, and RBC filterability.

    “while low concentrations of NO donors increase RBC deformability (22), membrane fluidity (181), and RBC filterability (99).”
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    Premisenone given

    Blood behaves as a shear-thinning non-Newtonian fluid during flow, so increased shear stress decreases blood viscosity.

    “Blood instead behaves as a shear-thinning non-Newtonian fluid during flow so that increased shear stress on blood decreases blood viscosity (i.e., thinning of the liquid).”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Normal RBCs have several possible modes of changing shape, including elongation, end-over-end tumbling, periodic swinging, and membrane tanktreading.

    “Normal RBCs have a few possible modes of changing their shape (114, 168, 188).”
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    • cites [168] Simchon S, 1987, Am J Physiol

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    Premisereasoning

    The discoid donut-like shape of RBCs is fundamental for their physiological function because it increases cell flexibility and creates a high surface area-to-volume ratio allowing efficient gas exchange.

    “The discoid donut-like shape of RBCs is fundamental for their physiological function as it increases overall cell flexibility and creates a high cellular surface area-to-volume ratio allowing for efficient gas exchange.”
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    Premisecitation

    Cytoskeletal proteins (mainly spectrin, actin, band 3, and ankyrin) form a pseudohexagonal structure that creates a dynamic scaffold supporting integral membrane proteins and promoting cell integrity under constant stress.

    “In RBCs, cytoskeletal proteins (mainly spectrin, actin, band 3, and ankyrin) form a pseudohexagonal structure. This structure creates a dynamic scaffold that supports integral membrane proteins and promotes integrity of the cells under constant stress (115).”
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    Premisecitation

    A small increase in plasma viscosity increases NO release by endothelium and can lead to decreased blood pressure.

    “It was reported that a small increase in plasma viscosity (whether by increased hematocrit or non-O2-carrying dextran molecules) increases NO release by endothelium and can lead to decreased blood pressure (27, 119, 179).”
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    Interpretationreasoning

    RBCs play a central role in defining biophysics of blood rheology as well as efficiency of tissue perfusion and gas exchange.

    “Being the major cellular component of blood, RBCs play a central role in defining biophysics of blood rheology as well as efficiency of tissue perfusion and gas exchange.”
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    Premisenone given

    Erythropoiesis can be impaired by lack of substrates needed for Hb synthesis (e.g., iron) or cell division (e.g., vitamin B12 or folic acid), lack of EPO, or bone marrow disorders/aplasia.

    “Erythropoiesis can be impaired due to a lack of substrates needed for Hb synthesis (e.g., iron) or for cell division (e.g., vitamin B12 or folic acid), lack of erythropoietin (EPO) to stimulate erythropoiesis, or due to bone marrow disorders/aplasia.”
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    Premisecitation

    RBC membrane flexibility depends on interactions of cytoskeletal proteins spectrin and actin and on intrinsic plasticity of the spectrin molecule.

    “The flexibility of the RBC membrane depends on the interactions of cytoskeletal proteins, spectrin and actin (109), as well as on the intrinsic plasticity of the spectrin molecule which is due to its peculiar macromolecular structure (104).”
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    Premisenone given

    Decreases in circulating RBC numbers can be due to increased hemolysis or RBC depletion.

    “Beyond that decreases in circulating RBC numbers can be due to increased hemolysis or RBC depletion (Fig. 6).”
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    Interpretationreasoning

    Accumulating evidence indicates RBCs play an important role in control of systemic NO metabolism, transport, and release of vasoactive substances, participating in systemic control of cardiovascular function and cardioprotection.

    “Taken together, there is accumulating evidence that RBCs play an important role in control of systemic NO metabolism, transport, and (as discussed in the RBC Mechanical Properties and Blood Rheology section) release of vasoactive substances, participating in systemic control of cardiovascular function and cardioprotection.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Increased hemolysis may be caused by RBC dysfunction correlated with defects of Hb, cytoskeletal proteins, metabolic enzymes, redox dysregulation, antibodies against RBC surface antigens, chronic inflammation, drug/poisoning, other genetic defects, or RBC extrinsic factors.

    “Increased hemolysis may be caused by dysfunction of RBCs correlated with (I) defects of Hb (hemoglobinopathies) (18, 94, 161, 199), including alterations in structure and function of Hb chains; (II) defects of cytoskeletal proteins such as spectrin and ankyrin, which are essential for maintaining cell shape and integrity (19, 134, 149, 169); (III) defects in metabolic enzymes catalyzing the pentos”
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    Premisecitation

    A major source of ROS in sickle RBCs is autoxidation of sickle cell Hb and increase in NADPH oxidase activity.

    “A major source of ROS in sickle RBCs is autoxidation of sickle cell Hb (80) and increase in NADPH oxidase activity (66).”
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    Premisenone given

    Genetic deficiency of G6PDH is one of the most common enzyme defects in humans leading to hemolytic anemia.

    “One of the most common enzyme defects in humans is the deficiency of G6PDH.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Thalassemic patients show altered deformability and increased rigidity and instability of RBCs.

    “As in SCD, thalassemic patients show altered deformability as well as increased rigidity and instability of RBCs (166).”
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    Premisenone given

    Ankyrin connects the spectrin cytoskeleton to the RBC membrane, specifically to band 3.

    “Ankyrin connects the spectrin cytoskeleton to the RBC membrane, specifically to band 3, a transmembrane anion exchanger channel.”
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    Premisenone given

    The SCD mutation (Val6→Glu) causes the Hb tetramer to have different properties; the abnormal tetramer Hb S has decreased solubility in deoxygenated conditions and aggregates into long chains.

    “This mutation (Val6→Glu) causes the Hb tetramer to have different properties. The abnormal tetramer (called Hb S) is characterized by decreased solubility in deoxygenated conditions, and aggregates form into long chains.”
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    Premisecitation

    Most G6PDH-deficient patients are asymptomatic throughout their lifetime.

    “Most G6PDH-deficient patients are asymptomatic throughout their lifetime and acute hemolytic anemia only occurs when triggered with certain drugs (antimalarial drugs such as primaquine), infections (hepatitis A virus), or pro-oxidative ingredients in food [e.g., fava beans, as already observed by the antiques (30)].”
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    Premisereasoning

    Deficiency of G6PDH induces a lack of reducing equivalents in RBCs and decreases activity of GSH reductase, which reduces GSSG to GSH.

    “Deficiency of G6PDH induces a lack of reducing equivalents in RBCs and therefore decreases activity of GSH reductase, which reduces GSSG to GSH.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Accumulation of long Hb S chains in an RBC causes sickling, decreased deformability, and increased blood viscosity, resulting in peripheral vasoocclusion.

    “Accumulation of the long Hb S chains in an RBC causes a change in the shape (sickling) of RBCs, decreased deformability, and increased blood viscosity (34), resulting in peripheral vasoocclusion, a painful symptom.”
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    • cites [34] Chien S, 1970, Am J Physiol source

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    Premisenone given

    G6PDH is the enzyme that reduces NADP+ to NADPH as a branch of the glycolytic pathway.

    “As described in the section “RBCs and Redox Regulation”, G6PDH is the enzyme that reduces NADP+ to NADPH as a branch of the glycolytic pathway.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    A consequence of sickling is increased RBC hemolysis, which releases Hb and other cytoplasmic proteins into the bloodstream, affecting plasma viscosity and colloid properties and increasing systemic NO scavenging.

    “A further consequence of sickling of cells is increased RBC hemolysis. Hemolysis affects not only the number of circulating RBCs but also release of Hb (and other cytoplasmic proteins) within the blood stream, thus profoundly affecting the viscosity and colloid properties of plasma and increasing systemic NO scavenging (71, 152).”
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A disorder of cell distribution, for example because of hypersplenism, may lead to anemia.

    “Moreover, a disorder of cell distribution (for example, because of hypersplenism) may lead to anemia (Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Table 1

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oxidized, heme-depleted Hb forms precipitates (Heinz bodies), which accumulate within the cells, resulting in membrane rigidity and decreased RBC deformability.

    “Oxidized, heme-depleted Hb forms precipitates (Heinz bodies), which accumulate within the cells, resulting in membrane rigidity and decreased RBC deformability (151).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [151] Reinhart WH, 1986, Blood source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SOD2 KO mice show severe RBC dysfunction and anemic phenotype characterized by decreased RBC deformability, increased heme degradation, and a reduced lifetime of RBCs.

    “Although SOD2 is a mitochondrial enzyme and therefore existent in the RBC precursor cells only (118), SOD2 KO mice show severe RBC dysfunction and anemic phenotype characterized by decreased RBC deformability, increased heme degradation, and a reduced lifetime of RBCs (128).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] source

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  • May combine two claims.

    Premisecitation

    Deficiency of ankyrin in RBCs results in disruption of cytoskeletal formation, spherocytosis, and markedly increased mortality.

    “Deficiency of ankyrin in RBCs results in disruption of cytoskeletal formation, spherocytosis, and markedly increased mortality (149).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] source

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  • May combine two claims.

    Premisecitation

    Redox dysregulation in RBCs leads to membrane protein thiol oxidation and membrane damage, as well as oxidative damage of proteins, including Hb and cytoskeletal proteins in the spectrin-actin network.

    “Redox dysregulation in RBCs leads to membrane protein thiol oxidation and membrane damage, as well as oxidative damage of proteins, including Hb and cytoskeletal proteins in the spectrin–actin network (90).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Johnson RM, 1994, Blood source

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

    Premisenone given

    Thalassemia is an autosomal recessive group of genetic diseases resulting from defects in synthesis/structural properties of Hb subunits.

    “Thalassemia is another autosomal recessive group of genetic diseases resulting from defects in synthesis/structural properties of Hb subunits.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SCD is caused by a point mutation in the β Hb subunit chain and shows multiple clinical manifestations and early mortality, particularly if the individual is homozygous for the mutation or untreated.

    “SCD is caused by a point mutation in the β Hb subunit chain and shows multiple clinical manifestations and early mortality, particularly if the individual is homozygous for the mutation or untreated (80).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] source

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  • May combine two claims.

    Premisecitation

    Mice with a deficiency of Prx2 have decreased hematocrit levels and an increased amount of circulating reticulocytes.

    “Mice with a deficiency of Prx2, the more abundant peroxiredoxin in RBCs, have decreased hematocrit levels and an increased amount of circulating reticulocytes (106).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [106] source

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

    Premisecitation

    G6PDH deficiency is one of the most common enzyme defects in humans due to multiple mutations of the G6PDH gene.

    “G6PDH deficiency is one of the most common enzyme defects in humans due to multiple mutations of the G6PDH gene and imparts different phenotypes, from acute hemolytic anemia to chronic hemolysis (30).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] source

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  • May combine two claims.

    Premisecitation

    An excess of one Hb subunit leads to denaturation of the excessive globin chain followed by formation of inclusion bodies.

    “An excess of one subunit leads to denaturation of the excessive globin chain (165), followed by the formation of inclusion bodies (57).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [165] Shinar E, 1990, Semin Hematol

      Not checked in the free run.

    • cites [57] Fessas P., 1963, Blood source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Anemia conditions due to RBC dysfunction induced by genetic defects include hemoglobinopathies such as SCD and thalassemia, defects of cytoskeletal proteins, and redox dysregulation leading to hemolytic anemia.

    “These include (I) hemoglobinopathies, such as SCD, and thalassemia, which are well-described human genetic defects; (II) defects of cytoskeletal proteins, mainly described in transgenic mice; and (III) redox dysregulation related to genetic defects leading to increased production of oxidants and/or decreased antioxidant capacity, which ultimately lead to hemolytic anemia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SOD2 is a mitochondrial enzyme and therefore existent in the RBC precursor cells only.

    “Although SOD2 is a mitochondrial enzyme and therefore existent in the RBC precursor cells only (118), SOD2 KO mice show severe RBC dysfunction and anemic phenotype characterized by decreased RBC deformability, increased heme degradation, and a reduced lifetime of RBCs (128).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of hydroxyurea induces expression of HbF, which interferes with polymerization of HbS.

    “Administration of hydroxyurea has been shown to induce expression of HbF, which interferes with the polymerization of HbS (33).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Erythroid cell-specific knockout mice of band 3 have changes in cell geometry and decreased cellular surface area-to-volume ratio, implying membrane/cytoskeleton interactions play a central role in defining RBC shape and functionality.

    “Erythroid cell-specific knockout (KO) mice of band 3 induce changes in cell geometry, decreasing the cellular surface area-to-volume ratio, implying that the membrane/cytoskeleton interactions play a central role in defining RBC shape and functionality (169).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice lacking the SOD1 gene show increased levels of ROS, decreased life span, increased reticulocyte counts, and increased levels of Heinz bodies, but overall display a comparatively benign anemia and no changes in intracellular GSH levels.

    “Mice lacking the SOD1 gene show increased levels of ROS, decreased life span, increased reticulocyte counts, and increased levels of Heinz bodies, but overall these mice display a comparatively benign anemia and no changes in intracellular GSH levels (76).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] source

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  • May combine two claims.

    Premisecitation

    In β-thalassemic mice, heme degradation products are increased 3.5-fold, suggesting a less efficient antioxidant system within RBCs.

    “Nagababu et al. (137) determined a 3.5-fold increase in heme degradation products in β-thalassemic mice and propose a less efficient antioxidant system within RBCs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RBC dysfunction leading to anemia may be due to defects in cytoskeletal proteins, as demonstrated by transgenic mouse models lacking cytoskeletal proteins.

    “RBC dysfunction leading to anemia may be also due to defects in cytoskeletal proteins (115, 127), as demonstrated by numerous transgenic mouse models lacking cytoskeletal proteins (see Fig. 3 for description of the cytoskeleton) (134).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [115] source

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    • cites [127] source

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    • cites [134] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nrf2 KO mice and Trsp KO mice are not anemic; but hemolytic anemia can be induced by treatment with oxidant drugs.

    “Nrf2 KO mice and Trsp KO mice are not anemic; but hemolytic anemia can be induced by treatment with oxidant drugs (54).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is accumulating evidence that anemia is related to a series of severe complications in CVD such as thromboembolic events, bleeding complications, uncontrolled hypertension, more frequent supraventricular and ventricular arrhythmias, and inflammation characterized by elevated levels of inflammatory cytokines.

    “There is accumulating evidence that anemia is related to a series of severe complications in CVD such as thromboembolic events (e.g., venous thrombosis and stroke), bleeding complications (191), uncontrolled hypertension (117), more frequent supraventricular and ventricular arrhythmias, and inflammation characterized by elevated levels of inflammatory cytokines (170).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [170] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elderly patients aged 65 years and older have a 10% higher risk for the development of anemia, which increases to 20% in those aged 85 years and older.

    “There is compelling evidence that elderly patients—aged 65 years and older—have a 10% higher risk for the development of anemia, which increases to 20% in those aged 85 years and older (77).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    A decrease in blood viscosity may reduce endothelial-derived NO production and decrease NO bioavailability.

    “Effects of blood viscosity on shear stress-induced activation of eNOS in the endothelium were also proposed (119); therefore, a decrease in blood viscosity may also reduce endothelial-derived NO production and decrease NO bioavailability.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Decrease in viscosity of blood reduces systemic vascular resistance and affects cardiovascular hemodynamics.

    “Decrease in viscosity of blood reduces systemic vascular resistance and affects cardiovascular hemodynamics (20).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anemia is a frequent comorbidity in CVD and is associated with higher mortality as well as increased hospitalization after myocardial infarction, even under mild anemic conditions.

    “Anemia is a frequent comorbidity in CVD (48) and is associated with higher mortality as well as increased hospitalization after myocardial infarction (91), even under mild anemic conditions (13, 156).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [48] source

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    • cites [91] source

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    • cites [13] source

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  • May combine two claims.

    Premisecitation

    In anemic conditions where the number of circulating RBCs is decreased without concomitant hemolysis, a decrease of RBC-dependent scavenging of NO may increase systemic NO bioavailability and cause vasodilation, increased flow, and may affect cardiovascular hemodynamics.

    “On the contrary, in anemic conditions where the number of circulating RBCs is decreased without concomitant hemolysis, a decrease of RBC-dependent scavenging of NO may instead increase systemic NO bioavailability and cause vasodilation, increased flow, and may affect cardiovascular hemodynamics (140).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Myelodysplastic syndrome was proposed to be a frequent cause of idiopathic anemia; however, myelodysplastic syndrome is a rare disease, which mostly emerges initially in elderly patients who display alterations in blood cell counts.

    “Moreover, the myelodysplastic syndrome (also defined as aplastic anemia) was proposed to be a frequent cause of idiopathic anemia (77); however, myelodysplastic syndrome is a rare disease, which mostly emerges initially in elderly patients who display alterations in blood cell counts (135).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [77] source

      Not checked in the free run.

    • cites [135] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blood loss in healthy dogs increased heart rate, stroke volume, and cardiac output and decreased mean arterial pressure and systemic vascular resistance.

    “They showed that blood loss in healthy dogs increased heart rate, stroke volume, and cardiac output and decreased mean arterial pressure and systemic vascular resistance.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [62] source

      Not checked in the free run.

    • cites [136] Murray JF, 1969, Am J Physiol source

      Not checked in the free run.

    • cites [138] Neill WA, 1969, Am J Physiol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This persistent increase in cardiac work may induce progressive damage of cardiomyocytes, possibly leading to cardiac remodeling and to impairment of myocardial performance.

    “This persistent increase in cardiac work may induce progressive damage of cardiomyocytes, possibly leading to cardiac remodeling and to impairment of myocardial performance.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Anemia significantly affects tissue perfusion and oxygenation mainly via a decreased O2-carrying capacity of the blood and a change in the apparent viscosity of blood because of a decrease in the RBC number/concentration.

    “According to the classical view, anemia significantly affects tissue perfusion and oxygenation mainly via a decreased O2-carrying capacity of the blood (due to decreased Hb concentrations) and a change in the apparent viscosity of blood because of a decrease in the RBC number/concentration (78).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] GuytonAC and HallJE. Textbook of Medical Physiology. Philadelphia: Elsevier Saunders, 2006, xxxv, p. 1116.

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Idiopathic anemia in these patients may be caused by blood loss due to repetitive blood tests and surgical interventions, as well as occult bleeding during hospitalization.

    “Moreover, a high percentage (almost 30%) of these patients exhibit idiopathic anemia (77) that may be caused by blood loss due to repetitive blood tests and surgical interventions, as well as occult bleeding (mainly in the gastrointestinal tract) during hospitalization.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of Nrf2 decreased production of inflammatory cytokines and decreased the number of irregularly shaped erythrocytes in SCD.

    “Activation of Nrf2 was proposed to be a potential therapeutic target for the treatment of SCD and its activation decreased production of inflammatory cytokines and decreased the number of irregularly shaped erythrocytes (16).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These changes are mainly due to increased preload, decreased afterload, and changes in cardiac geometry so that left ventricular systolic dysfunction may develop over time in patients without CVD.

    “These changes are mainly due to increased preload, decreased afterload, and changes in cardiac geometry so that left ventricular systolic dysfunction may develop over time in patients without CVD.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Increase in NO bioavailability would increase cardiac output and thereby affect cardiovascular hemodynamics.

    “They proposed that increase in NO bioavailability would increase cardiac output and thereby affect cardiovascular hemodynamics.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anemic patients and patients with coronary artery disease exhibit an elevated risk of major bleeding during hospitalization.

    “Increasing evidence exists that anemic patients and patients with coronary artery disease exhibit an elevated risk of major bleeding during hospitalization (48, 132, 174).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [48] source

      Not checked in the free run.

    • cites [132] source

      Not checked in the free run.

    • cites [174] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nrf2/Trsp double-KO mice show a massive increase in ROS and severe anemia.

    “In contrast, Nrf2/Trsp double-KO mice show a massive increase in ROS and severe anemia (95).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stored RBCs release membrane fragments, or microparticles, containing Hb, which are able to scavenge NO and decrease endothelial function.

    “More recently, it was shown that stored RBCs release membrane fragments, or microparticles, containing Hb, which are able to scavenge NO and decrease endothelial function (153).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [153] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PLTs can be activated via pharmacological inhibition of endogenous NO production in humans, leading to hypercoagulability and thrombotic complications.

    “Experimental studies demonstrated that PLTs can be activated via pharmacological inhibition of endogenous NO production in humans (159), leading to hypercoagulability and thrombotic complications (186).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [159] source

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    • cites [186] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The risk of thromboembolism is elevated after transfusion of packed/damaged RBCs, which correlates with impaired outcome and survival of patients.

    “Furthermore, the risk of thromboembolism is elevated after transfusion of packed/damaged RBCs, which correlates with impaired outcome and survival of patients (47).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EPO therapy can only be effective if the EPO responsiveness in the bone marrow is still intact, EPO is not removed from the circulation, or if EPO can reach its receptor on the bone marrow and if the receptors and signaling pathways downstream can be activated.

    “EPO therapy can only be effective if the EPO responsivness in the bone marrow is still intact, EPO is not removed from the circulation (via receptor-mediated endocytosis, followed by degradation in lysosomes) (74), or if EPO can reach its receptor on the bone marrow and if the receptors and signaling pathways downstream can be activated.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with CVD, treated acutely by blood transfusion, have a worsened outcome and show adverse events such as thromboembolism, allergic reactions, and fever, in addition to acute hemodynamic changes.

    “However, there is compelling evidence that patients with CVD, treated acutely by blood transfusion, have a worsened outcome and show adverse events such as thromboembolism, allergic reactions, and fever, in addition to acute hemodynamic changes (such as elevated blood pressure and increased total blood volume and left ventricular work) (158).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158] source

      Not checked in the free run.

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

    Premisenone given

    20%-30% of patients with CVD have concomitant anemia and anemia itself may contribute to clinical complications and death.

    “In particular, one challenge is that 20%–30% of patients with CVD have concomitant anemia and that anemia itself may contribute to clinical complications and death.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Elevated oxidative stress can be found in PLTs when incubated with thalassemic RBCs compared with normal RBCs, leading to increased PLT activation.

    “In particular, experimental studies indicate that elevated oxidative stress can be found in PLTs when incubated with thalassemic RBCs compared with normal RBCs, leading to increased PLT activation (5).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Amer J, 2004, Thromb Haemost source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Transfusion of older blood may profoundly affect cardiovascular hemodynamics and increase mortality by decreasing NO bioavailability.

    “These findings imply that transfusion of older blood may profoundly affect cardiovascular hemodynamics and increase mortality by decreasing NO bioavailability.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Administration of EPO under nonanemic conditions protects cardiomyocytes against ischemic injury in vitro, limits infarct size, and improves myocardial function after I/R injury.

    “However, experimental studies showed that administration of EPO under nonanemic conditions protects cardiomyocytes against ischemic injury in vitro, limits infarct size, and improves myocardial function after I/R injury (145).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Clinical and experimental evidence reveals a complex role for RBCs in homeostasis and thrombosis, implicating RBC-PLT interactions, which involve membrane adhesion molecules, NO metabolism, and redox equilibria.

    “Taken together, clinical and experimental evidence reveals a complex role for RBCs in homeostasis and thrombosis, implicating RBC-PLT interactions, which involve membrane adhesion molecules, NO metabolism, and redox equilibria.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Altered NO metabolism and NO scavenging by transfusion of damaged RBCs was proposed to play a role in cardiovascular effects of older blood, but alteration of other noncanonical functions of RBCs, including redox dysregulation and mechanical properties, may be involved in these effects.

    “Altered NO metabolism and NO scavenging by transfusion of damaged RBCs was proposed to play a role in cardiovascular effects of older blood, but alteration of other noncanonical functions of RBCs, including redox dysregulation and mechanical properties, may be involved in these effects.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Anemia is characterized by multiple etiologies, phenotype of circulating RBCs, and pathophysiological outcome.

    “Despite its simple definition, anemia is characterized by multiple etiologies, phenotype of circulating RBCs, and pathophysiological outcome.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PLTs and RBCs from patients with different types of anemia such as SCD, β-thalassemia, and myelodysplastic syndrome show a dysregulation of redox systems and altered PLT-RBC interactions.

    “There is compelling evidence that PLTs and RBCs from patients with different types of anemia such as SCD, β-thalassemia, and myelodysplastic syndrome show a dysregulation of redox systems (5, 6, 69) and altered PLT-RBC interactions.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] Amer J, 2004, Thromb Haemost source

      Not checked in the free run.

    • cites [6] source

      Not checked in the free run.

    • cites [69] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EPO administration to normovolemic anemic patients increased systemic vascular resistance and arterial blood pressure and decreased cardiac output due to diminished heart rate and venous return.

    “Indeed, it was shown that EPO administration to normovolemic anemic patients increased systemic vascular resistance and arterial blood pressure and decreased cardiac output due to diminished heart rate and venous return (103, 194).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [103] source

      Not checked in the free run.

    • cites [194] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    According to basic science studies, RBCs may control systemic hemodynamics by influencing blood rheological properties and contribute to tissue protection and cardiovascular homeostasis.

    “Additionally, according to basic science studies, RBCs may control systemic hemodynamics by influencing blood rheological properties and contribute to tissue protection and cardiovascular homeostasis (40, 73, 82).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [40] source

      Not checked in the free run.

    • cites [73] source

      Not checked in the free run.

    • cites [82] source

      Not checked in the free run.

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

    Interpretationnone given

    The therapeutic approaches currently applied in clinical practice do not appear to be beneficial for these patients and, in some cases such as in transfusion of stored blood, may increase risk of mortality.

    “The therapeutic approaches currently applied in clinical practice not appear to be beneficial for these patients and, in some cases such as in transfusion of stored blood, may increase risk of mortality.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Storage of RBCs may affect noncanonical function of RBCs, leading to decreased RBC deformability, impaired redox regulation, decrease of NO metabolites and increased membrane fragility, and thus to hemolysis and release of free Hb.

    “In addition, storage of RBCs may affect also noncanonical function of RBCs, leading to decreased RBC deformability, impaired redox regulation, decrease of NO metabolites and increased membrane fragility, and thus to hemolysis and release of free Hb.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A negative correlation between Hb levels and inflammatory markers was found in poor EPO responders, indicating that the severity of anemia correlates with the state of inflammation.

    “Moreover, a negative correlation between Hb levels and inflammatory markers was found in poor EPO responders, indicating that the severity of anemia correlates with the state of inflammation (176).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [176] Taniguchi S, 1997, Blood source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    In case of repeated blood transfusions, additional transfusion-related complications arise, including acute lung injury, electrolyte disorders, and iron overload.

    “In case of repeated blood transfusions, additional transfusion-related complications arise, including acute lung injury, electrolyte disorders (hyperkalemia and hypocalcemia), and iron overload.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    While effects of blood loss may be strictly linked to effects of decreased RBC count and volume, the pathological consequences of hemolytic anemia may be related more closely to massive release of Hb in the circulation and its NO-scavenging properties.

    “For example, while effects of blood loss may be strictly linked to effects of decreased RBC count and volume, the pathological consequences of hemolytic anemia (which is mainly linked to a dysregulation of redox homeostasis or to hemoglobinopathies) may be related more closely to massive release of Hb in the circulation and its NO-scavenging properties.”
    Quote in the paperSubstantial claim
101 of 101

  • The paper relies on this without support.

    Anemia is associated with severe complications of cardiovascular disease such as bleeding, thromboembolic events, stroke, hypertension, arrhythmias, and inflammation, particularly in elderly patients.

    “Recent clinical evidence identified anemia to be correlated with severe complications of cardiovascular disease (CVD) such as bleeding, thromboembolic events, stroke, hypertension, arrhythmias, and inflammation, particularly in elderly patients.”

  • The paper relies on this without support.

    The underlying mechanisms of the cardiovascular complications associated with anemia are largely unidentified.

    “The underlying mechanisms of these complications are largely unidentified.”

  • The paper relies on this without support.

    The mechanistic links between changes of RBC functional properties and cardiovascular complications related to anemia have not been untangled so far.

    “The mechanistic links between changes of RBC functional properties and cardiovascular complications related to anemia have not been untangled so far.”

  • The paper relies on this without support.

    Many aspects of RBC-mediated control of NO metabolism and ATP release are still speculative or not universally accepted.

    “However, many aspects of RBC-mediated control of NO metabolism and ATP release are still speculative or not universally accepted.”

  • The paper relies on this without support.

    RBCs have limited capacity to restore damaged elements due to loss of protein expression during erythropoietic maturation.

    “third, RBCs have limited capacity to restore damaged elements due to loss of protein expression during erythropoietic maturation.”
5 of 5

Claims other papers make about this one

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

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Cytoskeleton discussion points to the NO-metabolism figure

    Minor

    The cytoskeleton discussion directs readers to Fig. 3, but the paper identifies Fig. 3 as its illustration of NO metabolism. Fig. 4 is the figure that describes the RBC cytoskeleton.

  • Figure calls motions deformations that the text says do not change cell shape

    Minor

    The Fig. 4 caption presents four modes, including swinging and tumbling, as ways an RBC can deform. The accompanying text explicitly says those two modes are not changes in shape for an individual RBC.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 8

  1. Alsultan AI, 2010, Eur Rev Med Pharmacol Sci, 14, 527
  2. Chiu D, 1979, J Lab Clin Med, 94, 542
  3. GuytonAC and HallJE. Textbook of Medical Physiology. Philadelphia: Elsevier Saunders, 2006, xxxv, p. 1116.
  4. Pfafferott C, 1985, Effects of internal and external phase viscosity and of in vivo aging. Biophys J, 47, 695
  5. Shinar E, 1990, Semin Hematol, 27, 70
  6. Simchon S, 1987, Am J Physiol, 253, H898
  7. WHO, 2011, Haemoglobin Concentrations for the Diagnosis of Anaemia and Assessment of Severity. Vitamin and Mineral Nutrition Information System
  8. Wintrobe MM., 1934, Arch Int Med, 20, 987

Cited by

Sorted by citations

Authors
Kuhn, V., Diederich, L., Keller, T. C. S., Kramer, C. M., Lückstädt, W., Panknin, C., Suvorava, T., Isakson, B. E., Kelm, M., & Cortese-Krott, M. M.
Affiliations
  • Heinrich Heine University Düsseldorf (DE)
  • University of Virginia (US)
Corresponding author
Cortese-Krott, Miriam M.
ORCID
Venue
Antioxidants & Redox Signaling
Publisher
SAGE Publications
Published
2017-05
Volume
26
Issue
13
Pages
718-742
ISSN
  • 1523-0864 (ISSN-L)
  • 1557-7716
DOI
10.1089/ars.2016.6954
PMC
PMC5421513
OpenAlex
W2558688385
Semantic Scholar
9e37cabe13f5c23e031f935234be9fa2bc6ec2b1
Cited by
469
References
198
Citations by year
2026: 38 · 2025: 54 · 2024: 69 · 2023: 62 · 2022: 70 · 2021: 62 · 2020: 52 · 2019: 36 · 2018: 23 · 2017: 2 · 2014: 1
FWCI
2.38
Type
journal article
Language
en
Open access
Locations
  • Antioxidants and Redox Signaling (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • American Heart Association (16PRE31180040)
  • Deutsche Forschungsgemeinschaft (DFG CO 1305/2-1, CO 1305/2-1)
  • Servier
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL088554)
Topics
  • Health Sciences › Medicine › Physiology › Erythrocyte Function and Pathophysiology
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Blood properties and coagulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
Keywords
red blood cell function, redox regulation, nitric oxide metabolism, anemia, inter-organ communication, hemorheology, blood viscosity, oxidative stress, elderly patients
MeSH terms
Anemia, Animals, Erythrocytes, Humans, Nitric Oxide, Oxidation-Reduction

About these checks

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

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

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

What counts as a claim ›How we measure confidence ›How we check this ›

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