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p(HGNC:HBB)

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Entity

Name
HBB
Namespace
hgnc
Namespace Version
20180906
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/hgnc-names.belns

Appears in Networks 1

Heme Curation v0.0.1-dev

Mechanistic knowledge surrounding heme

In-Edges 101

rxn(reactants(a(CHEBI:superoxide), p(HGNC:HBB)), products(a(CHEBI:"hydrogen peroxide"))) hasReactant p(HGNC:HBB) View Subject | View Object

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a(CHEBI:"desferrioxamine B") positiveCorrelation p(HGNC:HBB) View Subject | View Object

We found that hemoglobin contents in hematoma were significantly higher in the DFX treated group compare to the vehicle-treated group (15.9 ± 1.8 vs. 11.8 ± 0.8 mg/g, p<0.05, Fig. 5A). PubMed:27125525

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MeSH
Cerebral Hemorrhage
Text Location
Results

a(CHEBI:"iron trichloride") positiveCorrelation p(HGNC:HBB) View Subject | View Object

Analysis of Hb release from ex vivo vessel chamber experiments revealed a significant (p  0.05; n  4) increase in Hb levels following FeCl3 treatment of isolated aorta in the presence of flowing blood (157  45 g/ml), whereas FeCl3 pretreatment of vessels prior to blood perfusion caused no hemolysis (Fig. 2A). PubMed:19276082

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

a(CHEBI:"iron trichloride") positiveCorrelation p(HGNC:HBB) View Subject | View Object

Analysis of the time course of hemolysis in whole blood revealed a rapid linear increase in Hb levels, peaking 10 min after FeCl3 addition (Fig. 2B), a time course consistent with the rapid hemolysis and vascular injury observed in the ex vivo aortic thrombosis model. PubMed:19276082

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

a(CHEBI:"nitric oxide") negativeCorrelation p(HGNC:HBB) View Subject | View Object

Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24. PubMed:27515135

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Text Location
Introduction

a(CHEBI:lactate) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Children undergoing open heart surgery experience a progressively increasing risk of postoperative infection and thrombosis, increasing need for mechanical ventilation and inotropes, increasing Day 1 through Day 2 peak blood lactate, and decreased nadir mean arterial pressure as the levels of free Hb increase and the levels of haptoglobin decrease. PubMed:29603246

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Annotations
MeSH
Blood
MeSH
Anemia, Sickle Cell
Text Location
Discussion

a(CHEBI:lipopolysaccharide) increases p(HGNC:HBB) View Subject | View Object

In animal experiments, the administration of lipopolysaccharide (LPS) to induce systemic inflammation leads to a significant increase in plasma concentration of cell-free hemoglobin as well [5–8]. PubMed:29956069

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Review

a(HM:"Erythrocytes, lysed") increases p(HGNC:HBB) View Subject | View Object

The results reported here indicate that, once exposed to oxidized plaque material, erythrocytes are lysed, the liberated hemoglobin is oxidized and heme dissociates from the resultant ferrihemoglobin. PubMed:20378845

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Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

a(HM:"oxidative reactions") positiveCorrelation p(HGNC:HBB) View Subject | View Object

The second biochemical process relates to the ability of Hb to facilitate oxidative reactions outside of the reducing environment of the RBC, leading to the accumulation of ferric metHb(Fe3+) in tissue.24 PubMed:29610666

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Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

a(HM:"stored erythrocytes") increases p(HGNC:HBB) View Subject | View Object

In the current observational study in patients undergoing multilevel spinal fusion surgery, we tested the hypothesis that moderate doses of stored RBC transfusions increase intravascular cell-free Hb and decrease NO availability in surgical patients. PubMed:27308950

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MeSH
Endothelium, Vascular
Text Location
Introduction

a(MESH:"Blood Transfusion") positiveCorrelation p(HGNC:HBB) View Subject | View Object

Old blood transfusion resulted in systemic free Hb total exposure (AUC0–∞) of 4600 μmol heme-h/l, which was primarily cleared by the kidney within 24 h. PubMed:26794659

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MeSH
Liver
Text Location
Results

a(MESH:"Blood Transfusion") positiveCorrelation p(HGNC:HBB) View Subject | View Object

In old blood-transfused animals, strong Hb and iron deposition was observed in the tubule lumen and epithelial cells, respectively. PubMed:26794659

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Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney Tubules
Text Location
Results

a(MESH:"Blood Transfusion") positiveCorrelation p(HGNC:HBB) View Subject | View Object

In mice resuscitated with SRBCs, plasma hemoglobin levels were greater than in mice resuscitated with FRBCs or in sham-treated mice at two, four, and 24 hours after transfusion (Figure 1C). PubMed:27515135

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MeSH
Hemorrhage
Text Location
Results

a(MESH:"Blood Transfusion") increases p(HGNC:HBB) View Subject | View Object

There is a clear need for, and medical benefit from, blood transfusions; nonetheless, administration of red blood cells (RBCs) does result in exposure to toxicants specific to hemoglobin (Hb) and its degradation components, hemin and iron. PubMed:30281034

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Review

a(MESH:"Erythrocytes, Abnormal") increases p(HGNC:HBB) View Subject | View Object

When RBCs are damaged by high shear in continuous flow ventricular assist devices, free hemoglobin induces platelet aggregation, contributing to high risk of thrombotic complications [33]. PubMed:28458720

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Annotations
MeSH
Veins
MeSH
Acute Coronary Syndrome
Text Location
Review

a(MESH:"haptoglobin-hemoglobin complex") negativeCorrelation p(HGNC:HBB) View Subject | View Object

Because of its large molecular size, this complex is maintained in the intravascular space, preventing the association of otherwise free Hb with nitric oxide (NO; Reiter et al., 2002) and inhibiting the release of free heme (Melamed-Frank et al., 2001). PubMed:24904418

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Review

a(MESH:"haptoglobin-hemoglobin complex") decreases p(HGNC:HBB) View Subject | View Object

Macrophages and liver cells capture large HP-Hb complexes clearing the plasma from free hemoglobin. PubMed:28088643

Appears in Networks:
Annotations
MeSH
Liver
MeSH
Macrophages
MeSH
Anemia, Sickle Cell
Text Location
Introduction

a(MESH:Fibrin) positiveCorrelation p(HGNC:HBB) View Subject | View Object

During DIC, fibrin strands within the fibrin mesh formed could cut red blood cells, resulting in the formation of schistocytes (strongly deformed red blood cells or fragments of red blood cells) and the release of hemoglobin. PubMed:29956069

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Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Microvessels
MeSH
Disseminated Intravascular Coagulation
Text Location
Review

a(MESH:Kidney) negativeCorrelation p(HGNC:HBB) View Subject | View Object

Old blood transfusion resulted in systemic free Hb total exposure (AUC0–∞) of 4600 μmol heme-h/l, which was primarily cleared by the kidney within 24 h. PubMed:26794659

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Annotations
MeSH
Liver
Text Location
Results

bp(GO:"regulation of glucose-6-phosphatase activity") negativeCorrelation p(HGNC:HBB) View Subject | View Object

Nevertheless, the crosstalk between glucose and heme metabolism in sepsis is bidirectional since an excessive accumulation of cell-free heme following hemolysis influences the glucose metabolism by iron-driven oxidative inhibition of the glucose-6-phosphatase (a liver enzymes being important for endogenous glucose production via gluconeogenesis and glycogenolysis) [14]. PubMed:29956069

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Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Liver
MeSH
Sepsis
Text Location
Review

bp(GO:vasoconstriction) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24. PubMed:27515135

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Text Location
Introduction

bp(MESH:"Blood Transfusion") increases p(HGNC:HBB) View Subject | View Object

An increase in plasma cell-free Hb and vascular dysfunction also has been shown after transfusion of autologous RBCs with long storage duration to healthy human subjects.19,20,37 PubMed:27308950

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Annotations
MeSH
Plasma
Text Location
Discussion

bp(MESH:"Erythrocyte Deformability") positiveCorrelation p(HGNC:HBB) View Subject | View Object

Sickle cell disease (SCD) and malaria are paradigmatic hemolytic disorders, in which alteration in the structure of red blood cells (RBCs) leads to the release of Hb and heme into the circulation. PubMed:26675351

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Annotations
MeSH
Anemia, Sickle Cell
Text Location
Introduction

bp(MESH:"Oxidative Stress") positiveCorrelation p(HGNC:HBB) View Subject | View Object

During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. PubMed:29694434

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Text Location
Introduction

bp(MESH:"Oxidative Stress") positiveCorrelation p(HGNC:HBB) View Subject | View Object

In addition to inflammation, cell-free hemoglobin (Hb) released via hemolysis is a potent inducer of oxidative stress. PubMed:30505280

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Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

bp(MESH:"Platelet Activation") positiveCorrelation p(HGNC:HBB) View Subject | View Object

There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246

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Text Location
Introduction

bp(MESH:Immunomodulation) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Our findings in the complex setting of critically ill pediatric cardiac surgery patients demonstrate that higher levels of free Hb and lower levels of haptoglobin are associated with serious postoperative clinical complications (infection, thrombosis, death), immunomodulation, and inflammation. PubMed:29603246

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Annotations
MeSH
Blood
MeSH
Anemia, Sickle Cell
Text Location
Discussion

bp(MESH:Vasoconstriction) positiveCorrelation p(HGNC:HBB) View Subject | View Object

The first process links the nitric oxide (NO) reactivity of oxyHb to a cascade of cell-free Hb extravasation, hemolysis-associated NO-depletion, and vasoconstriction.21–23 PubMed:29610666

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Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

complex(a(CHEBI:"carbon monoxide"), p(HGNC:HBB)) hasComponent p(HGNC:HBB) View Subject | View Object

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complex(a(CHEBI:"iron(2+)"), a(CHEBI:heme), a(MESH:"Reactive Oxygen Species")) positiveCorrelation deg(p(HGNC:HBB)) View Subject | View Object

Spontaneous decomposition of Hb via auto-oxidation leads to the formation of ROS, free heme groups and free iron, which are highly reactive and have the ability to damage lipids, proteins, and DNA (Olsson et al., 2012). PubMed:30505280

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Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

complex(a(CHEBI:"nitric oxide"), p(HGNC:HBB)) hasComponent p(HGNC:HBB) View Subject | View Object

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complex(a(CHEBI:"nitric oxide"), p(HGNC:HBB)) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Release of hemoglobin (and ultimately heme), and arginase-1 into the plasma results in binding of nitric oxide and also reduction in L-arginine, respectively, causing a relative reduction in vasodilatory effect.[14,29] PubMed:26337933

Appears in Networks:
Annotations
Cell Ontology (CL)
leukocyte
MeSH
Plasma
MeSH
Pulmonary Embolism
Text Location
Discussion

complex(a(HM:"Atheroma lipid"), p(HGNC:HBB)) hasComponent p(HGNC:HBB) View Subject | View Object

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complex(a(MESH:"Blood Transfusion"), p(MGI:Alb)) causesNoChange p(HGNC:HBB) View Subject | View Object

Resuscitation with SRBCs together with albumin did not alter plasma levels of hemoglobin, hemopexin, haptoglobin, or heme as compared to resuscitation with SRBCs alone (Figure 3C–E, I, Supplemental Material and Supplemental Figure II A–B). PubMed:27515135

Appears in Networks:
Annotations
MeSH
Plasma
MeSH
Hemorrhage
Text Location
Results

complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Co-administration of haptoglobin with SRBCs results in a prolonged increase in plasma hemoglobin levels for more than 48 hours after transfusion. PubMed:27515135

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Annotations
MeSH
Plasma
MeSH
Hemorrhage
Text Location
Results

complex(a(MESH:"Reactive Oxygen Species"), p(HGNC:HBB)) hasComponent p(HGNC:HBB) View Subject | View Object

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complex(a(MESH:Lipopolysaccharides), p(HGNC:HBB)) hasComponent p(HGNC:HBB) View Subject | View Object

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complex(p(HGNC:HBB), p(MGI:Hp)) hasComponent p(HGNC:HBB) View Subject | View Object

Appears in Networks:

complex(p(HGNC:HBB), p(MGI:Hpx)) hasComponent p(HGNC:HBB) View Subject | View Object

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p(HGNC:HP) decreases p(HGNC:HBB) View Subject | View Object

Haptoglobin (Hp) is an abundant and conserved plasma glycoprotein, which binds acellular adult hemoglobin (Hb) dimers with high affinity and facilitates their rapid clearance from circulation following hemolysis. PubMed:24486321

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Abstract

p(HGNC:HP) decreases p(HGNC:HBB) View Subject | View Object

Haptoglobin (Hp) is a Hb-scavenging plasma glycoprotein which binds non-covalently to hemoglobin dimers that are generated by dissociation of acellular Hb tetramers after hemolysis [6]. PubMed:24486321

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Introduction

p(HGNC:HP) decreases p(HGNC:HBB) View Subject | View Object

Hp is the first-line scavenger that binds and accelerates the clearance of Hb in the circulation, although the macrophage CD163 receptor has also been the focus of several recent investigations [66– 68]. PubMed:24486321

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Discussion

p(HGNC:HP) decreases p(HGNC:HBB) View Subject | View Object

Based on clinical observations the Hb and heme scavenger proteins haptoglobin (Hp) and hemopexin (Hx) have been characterized as a sequential defense system with Hp as the primary protector and Hx as a backup when all Hp is depleted during more severe intravascular hemolysis. PubMed:26475040

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MeSH
Anemia, Sickle Cell
Text Location
Abstract

p(HGNC:HP) decreases p(HGNC:HBB) View Subject | View Object

Free Hb is bound by the plasma protein haptoglobin, and the large molecular size Hb: Hp complexes are ultimately cleared by spleen and liver macrophages expressing the Hb scavenger receptor CD163.8 PubMed:26794659

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Annotations
MeSH
Liver
Text Location
Introduction

p(HGNC:HP) decreases p(HGNC:HBB) View Subject | View Object

Hp treatment prevented renal Hb exposure. PubMed:26794659

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Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney Tubules
Text Location
Results

p(HGNC:HP) decreases p(HGNC:HBB) View Subject | View Object

The prevention of renal Hb filtration by Hp may be a therapeutic strategy to block renal Hb exposure and to rescue renal function in patients with severe hemoglobinuria. PubMed:26794659

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Annotations
Cell Ontology (CL)
epithelial cell
MeSH
Kidney
MeSH
Hemoglobinuria
Text Location
Discussion

p(HGNC:HP) decreases p(HGNC:HBB) View Subject | View Object

Thus, the interactions of hemoglobin with haptoglobin, and of heme with hemopexin, ensure safe disposal of potentially dangerous molecules [6,7,15–19] PubMed:26875449

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Review

p(HGNC:HP) negativeCorrelation p(HGNC:HBB) View Subject | View Object

However, patients who died had significantly higher plasma cell-free Hb and lower haptoglobin concentrations at all time points, preoperatively and immediately postoperatively and 6 and 12 hours postoperatively (Fig. 1 shows the 12-hr postoperative data). PubMed:29603246

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Annotations
MeSH
Anemia, Sickle Cell
Text Location
Results

p(HGNC:HP) negativeCorrelation p(HGNC:HBB) View Subject | View Object

Children undergoing open heart surgery experience a progressively increasing risk of postoperative infection and thrombosis, increasing need for mechanical ventilation and inotropes, increasing Day 1 through Day 2 peak blood lactate, and decreased nadir mean arterial pressure as the levels of free Hb increase and the levels of haptoglobin decrease. PubMed:29603246

Appears in Networks:
Annotations
MeSH
Blood
MeSH
Anemia, Sickle Cell
Text Location
Discussion

p(HGNC:HP) decreases p(HGNC:HBB) View Subject | View Object

free hemoglobin is rapidly cleared from the circulation by several scavenging mechanisms; however, we found that the plasma-free hemoglobin was high and haptoglobin levels were low in the patients examined (Table 1). PubMed:29929138

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
Cell Ontology (CL)
neutrophil
Cell Ontology (CL)
platelet
MeSH
Hemoglobinuria, Paroxysmal
Text Location
Results

p(HGNC:HP) decreases p(HGNC:HBB) View Subject | View Object

Normally, cellfree hemoglobin will dimerize and rapidly be bound by its hemoglobin scavengers haptoglobin and hemopexin [12]. PubMed:29956069

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Annotations
MeSH
Arteries
MeSH
Sepsis
Text Location
Review

p(HGNC:HP) decreases p(HGNC:HBB) View Subject | View Object

Hp is a plasma glyco-protein that normally circulates in within a concentration range of 0.3–2mg/ml and is the putative scavenger of cell-free Hb with a high affinity (KD¼10–12M) for Hb dimers (Fig. 1 A,B and Fig. 2 C [31]). PubMed:30281034

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Anemia, Sickle Cell
MeSH
beta-Thalassemia
Text Location
Review

p(HGNC:HP) decreases p(HGNC:HBB) View Subject | View Object

On the extracellular level, within the circulation, haptoglobin (Hp) and hemopexin (Hpx) are two of the most prominent scavenger proteins, with antioxidative properties through their capacity to remove cell-free Hb (by Hp) and heme (by Hpx). PubMed:30505280

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MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

p(HGNC:AMBP) positiveCorrelation p(HGNC:HBB) View Subject | View Object

The expression of A1M is up-regulated by elevated levels of free Hb, heme and ROS [23]. PubMed:24489717

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Introduction

p(HGNC:AMBP) positiveCorrelation p(HGNC:HBB) View Subject | View Object

This is consistent with our findings here that both heme and Hb were associated with increased levels of synovial fluid A1M. PubMed:30505280

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MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

p(HGNC:CD59, var("p.Cys89Tyr")) increases p(HGNC:HBB) View Subject | View Object

High free hemoglobin was shown in patients with primary Cys89Tyr mutation in CD59 (Table 1) and it has been suggested in several ways that free hemoglobin may serve as a major mechanism for thrombophilia. PubMed:29929138

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Annotations
Cell Ontology (CL)
erythrocyte
Cell Ontology (CL)
neutrophil
Cell Ontology (CL)
platelet
MeSH
Hemoglobinuria, Paroxysmal
Text Location
Results

p(HGNC:ELANE) increases deg(p(HGNC:HBB)) View Subject | View Object

For instance, earlier studies have demonstrated that neutrophil elastase degrades the hemoglobin liberating free hemin that induces ROS production. PubMed:28716864

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Cell Ontology (CL)
neutrophil
MeSH
Serum
MeSH
Malaria
Text Location
Discussion

p(PFAM:Leukocidin) increases p(HGNC:HBB) View Subject | View Object

The same applies to hemolysin. For one thing, the pore-forming toxin hemolysin is one the pathogens’ tools of causing hemolysis or releasing hemoglobin and poorly available iron [139]; then again it trigger eryptosis, one mechanism of protecting against hemolysis [142]. PubMed:29956069

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Cell Ontology (CL)
erythrocyte
MeSH
Liver
MeSH
Sepsis
Text Location
Review

path(HM:"endothelial lesions") positiveCorrelation p(HGNC:HBB) View Subject | View Object

Endothelial injury may also be related to Free hemoglobin and its breakdown oxidative product heme, and MPs, which mediates direct proinflammatory, proliferative, and pro-oxidant effects on endothelial cells [22–24] both in PNH and congenital CD59 deficiency, but may be more pronounced in congenital CD59 deficiency and perhaps even more in the brain due to loss of CD59 in the endothelium of these patients. PubMed:29929138

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Annotations
Cell Ontology (CL)
platelet
MeSH
Endothelium
MeSH
Hemoglobinuria, Paroxysmal
Text Location
Discussion

path(HM:"vaso-occlusive crisis") positiveCorrelation p(HGNC:HBB) View Subject | View Object

Infusion of exogenous hemoglobin into SS-mice can markedly increase stasis compared to the amount of spontaneous stasis [5]. PubMed:29694434

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Annotations
MeSH
Blood Platelets
MeSH
Anemia, Sickle Cell
Text Location
Results

path(HP:"Elevated mean arterial pressure") negativeCorrelation p(HGNC:HBB) View Subject | View Object

Children undergoing open heart surgery experience a progressively increasing risk of postoperative infection and thrombosis, increasing need for mechanical ventilation and inotropes, increasing Day 1 through Day 2 peak blood lactate, and decreased nadir mean arterial pressure as the levels of free Hb increase and the levels of haptoglobin decrease. PubMed:29603246

Appears in Networks:
Annotations
MeSH
Blood
MeSH
Anemia, Sickle Cell
Text Location
Discussion

path(HP:"Paroxysmal nocturnal hemoglobinuria") increases p(HGNC:HBB) View Subject | View Object

Thus, in severe haemolytic diseases, such as paroxysmal nocturnal haemoglobinuria (PNH) and sickle cell disease (SCD), serum haptoglobin is typically undetectable and plasma haemoglobin is elevated (Tabbara, 1992). PubMed:25307023

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Cell Ontology (CL)
macrophage
Text Location
Review

path(HP:"Paroxysmal nocturnal hemoglobinuria") positiveCorrelation p(HGNC:HBB) View Subject | View Object

In cases of congenital hemoglobinopathies such as sickle cell disease, deficiencies in complement system regulators such as paroxysmal nocturnal hemoglobinuria, and many other disorders, erythrocytes can lyse and liberate large quantities of hemoglobin. PubMed:26875449

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Review

path(MESH:"Anemia, Sickle Cell") increases p(HGNC:HBB) View Subject | View Object

Thus, in severe haemolytic diseases, such as paroxysmal nocturnal haemoglobinuria (PNH) and sickle cell disease (SCD), serum haptoglobin is typically undetectable and plasma haemoglobin is elevated (Tabbara, 1992). PubMed:25307023

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Cell Ontology (CL)
macrophage
Text Location
Review

path(MESH:"Brain Diseases") positiveCorrelation p(HGNC:HBB) View Subject | View Object

Third, exposure to extracellular Hb, in the form of oxygen therapeutics or when Hb is released from old red blood cells, have also been reported to induce oxidative toxicity in kidney and brain tissues [65]. PubMed:24486321

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Discussion

path(MESH:"Kidney Diseases") positiveCorrelation p(HGNC:HBB) View Subject | View Object

Third, exposure to extracellular Hb, in the form of oxygen therapeutics or when Hb is released from old red blood cells, have also been reported to induce oxidative toxicity in kidney and brain tissues [65]. PubMed:24486321

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Discussion

path(MESH:"Knee Injuries") increases p(HGNC:HBB) View Subject | View Object

Altogether, our best interpretation of these data is that increased levels of cell-free Hb and heme in synovial fluid early after injury triggered an increase in the synovial fluid A1M concentration that appeared to be protective of oxidative damage. PubMed:30505280

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Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

path(MESH:"Platelet Aggregation") positiveCorrelation p(HGNC:HBB) View Subject | View Object

Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24. PubMed:27515135

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Text Location
Introduction

path(MESH:"Vascular Diseases") positiveCorrelation p(HGNC:HBB) View Subject | View Object

There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246

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Introduction

path(MESH:"Vascular System Injuries") positiveCorrelation p(HGNC:HBB) View Subject | View Object

Hemolysis and the transfusion of banked blood or Hb-based therapeutics can result in varying quantities of circulating acellular Hb which can induce life threatening radical generating reactions in patients with a compromised vascular system [60]. PubMed:24486321

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Discussion

path(MESH:Anemia) negativeCorrelation p(HGNC:HBB) View Subject | View Object

The anemia in CEP mice was severe with significant reduction of Hb levels and RBC number (Table 1), regenerative with marked reticulocytosis (28.8±4.2%) (Table 1), and microcytic and hypochromic with reduced mean cell Hb content (9.95±0.64 pg in CEP vs. 14.5±0.18 in WT mice) (Table 1). PubMed:28143953

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Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Serum
MeSH
Porphyria, Erythropoietic
Text Location
Results

path(MESH:Anemia) decreases p(HGNC:HBB) View Subject | View Object

By day 1 following injection, plasma Hb concentrations in the anemia group were reduced to 0.5  0.3 g/l, which was not significantly different from the control value of 0.5  0.3 g/l (n  6, unadjusted P  0.93; Fig. 3A). PubMed:29351418

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MeSH
Plasma
Text Location
Results

path(MESH:Hematoma) negativeCorrelation p(HGNC:HBB) View Subject | View Object

The level of hemoglobin declined gradually over the time after the onset of ICH with a significant reduction at day 3. The contents of hemoglobin in the clot were 26.2 ± 5.2 mg/g at 4 hours, but were reduced to 13.9 ± 0.9 mg/g at day-3 (Fig. 2B, p<0.01). PubMed:27125525

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MeSH
Cerebral Hemorrhage
Text Location
Results

path(MESH:Hematoma) negativeCorrelation p(HGNC:HBB) View Subject | View Object

We found that hemoglobin contents in hematoma were significantly higher in the DFX treated group compare to the vehicle-treated group (15.9 ± 1.8 vs. 11.8 ± 0.8 mg/g, p<0.05, Fig. 5A). PubMed:27125525

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MeSH
Cerebral Hemorrhage
Text Location
Results

path(MESH:Hemolysis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Moreover they have demonstrated that released Hb plays an important role in exacerbating RBC hemolysis, establishing a damaging hemolysis/ oxidative cycle that drives further red cell damage, vascular injury, and thrombosis. PubMed:19276082

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

path(MESH:Hemolysis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Hemolysis and the transfusion of banked blood or Hb-based therapeutics can result in varying quantities of circulating acellular Hb which can induce life threatening radical generating reactions in patients with a compromised vascular system [60]. PubMed:24486321

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Discussion

path(MESH:Hemolysis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Hemolysis increases the concentration of Hb which, under oxidative stress, releases free heme. PubMed:24904418

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Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Malaria
Text Location
Review

path(MESH:Hemolysis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Haemoglobin and haem levels increase in plasma and urine when haptoglobin and haemopexin scavenging mechanisms are saturated during acute or chronic haemolysis. PubMed:25307023

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Cell Ontology (CL)
macrophage
MeSH
Plasma
MeSH
Urine
Text Location
Review

path(MESH:Hemolysis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Subsequent RBC lysis leads to release of acellular Hb, which, in turn, damages the alveolar epithelial cells. PubMed:26974230

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MeSH
Alveolar Epithelial Cells
Text Location
Introduction

path(MESH:Hemolysis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

The plasma hemoglobin levels at two and four hours after SRBC-transfusion were greater than the cell-free hemoglobin levels in the supernatant of the SRBCs before transfusion (Figure 1C, Supplemental Table I), providing evidence that hemolysis occurs in vivo during and after transfusion of SRBCs. PubMed:27515135

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Annotations
MeSH
Hemorrhage
Text Location
Results

path(MESH:Hemolysis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Red blood cell hemolysis in sickle cell disease (SCD) releases free hemoglobin. PubMed:28088643

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Annotations
MeSH
Erythrocytes
MeSH
Anemia, Sickle Cell
Text Location
Abstract

path(MESH:Hemolysis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. PubMed:29694434

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Text Location
Introduction

path(MESH:Hemolysis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Following MAC deposition on RBCs, intravascular hemolysis that leads to increasing levels of free hemoglobin was seen. PubMed:29929138

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Annotations
Cell Ontology (CL)
erythrocyte
Cell Ontology (CL)
neutrophil
Cell Ontology (CL)
platelet
MeSH
Hemoglobinuria, Paroxysmal
Text Location
Results

path(MESH:Hemolysis) increases p(HGNC:HBB) View Subject | View Object

Excessive intravascular hemolysis saturates scavenger mechanisms, resulting in free hemoglobin in plasma that irreversibly reacts with nitric oxide (NO) to form nitrate and methemoglobin. PubMed:29929138

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Cell Ontology (CL)
platelet
MeSH
Hemoglobinuria, Paroxysmal
Text Location
Discussion

path(MESH:Hemolysis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

In infectious diseases, such as malaria and sepsis, high amounts of cell-free hemoglobin and heme were found [8], suggesting that hemolysis during sepsis and systemic inflammation is of pathophysiological relevance. PubMed:29956069

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Annotations
Cell Ontology (CL)
hepatocyte
MeSH
Liver
MeSH
Sepsis
Text Location
Review

path(MESH:Hemolysis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Finally, a bi-directional crosstalk between hemolysis and coagulation was postulated with induction of tissue factor by cell-free hemoglobin as potentially central mechanism for hemolysis to trigger coagulation [87]. PubMed:29956069

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Cell Ontology (CL)
erythrocyte
MeSH
Microvessels
MeSH
Disseminated Intravascular Coagulation
Text Location
Review

path(MESH:Hemolysis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

In addition to inflammation, cell-free hemoglobin (Hb) released via hemolysis is a potent inducer of oxidative stress. PubMed:30505280

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Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

path(MESH:Inflammation) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24. PubMed:27515135

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Text Location
Introduction

path(MESH:Inflammation) positiveCorrelation p(HGNC:HBB) View Subject | View Object

There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246

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Introduction

path(MESH:Inflammation) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Our findings in the complex setting of critically ill pediatric cardiac surgery patients demonstrate that higher levels of free Hb and lower levels of haptoglobin are associated with serious postoperative clinical complications (infection, thrombosis, death), immunomodulation, and inflammation. PubMed:29603246

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Annotations
MeSH
Blood
MeSH
Anemia, Sickle Cell
Text Location
Discussion

path(MESH:Inflammation) positiveCorrelation p(HGNC:HBB) View Subject | View Object

During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. PubMed:29694434

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Text Location
Introduction

path(MESH:Inflammation) positiveCorrelation p(HGNC:HBB) View Subject | View Object

In infectious diseases, such as malaria and sepsis, high amounts of cell-free hemoglobin and heme were found [8], suggesting that hemolysis during sepsis and systemic inflammation is of pathophysiological relevance. PubMed:29956069

Appears in Networks:
Annotations
Cell Ontology (CL)
hepatocyte
MeSH
Liver
MeSH
Sepsis
Text Location
Review

path(MESH:Thrombophilia) positiveCorrelation p(HGNC:HBB) View Subject | View Object

High free hemoglobin was shown in patients with primary Cys89Tyr mutation in CD59 (Table 1) and it has been suggested in several ways that free hemoglobin may serve as a major mechanism for thrombophilia. PubMed:29929138

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Cell Ontology (CL)
erythrocyte
Cell Ontology (CL)
neutrophil
Cell Ontology (CL)
platelet
MeSH
Hemoglobinuria, Paroxysmal
Text Location
Results

rxn(reactants(a(CHEBI:"nitric oxide"), p(HGNC:HBB)), products(a(CHEBI:methemoglobin), a(CHEBI:nitrate))) hasReactant p(HGNC:HBB) View Subject | View Object

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path(MESH:Thrombosis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246

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Introduction

path(MESH:Thrombosis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

The median (and mean—data not shown) free Hb levels preoperatively and at all postoperative time points (immediately and 6 and 12 hr postoperatively) were higher (p50.057) in those who later developed a proven thrombosis (Fig. 3 displays the 12-hr data). PubMed:29603246

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MeSH
Anemia, Sickle Cell
Text Location
Results

path(MESH:Thrombosis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Our findings in the complex setting of critically ill pediatric cardiac surgery patients demonstrate that higher levels of free Hb and lower levels of haptoglobin are associated with serious postoperative clinical complications (infection, thrombosis, death), immunomodulation, and inflammation. PubMed:29603246

Appears in Networks:
Annotations
MeSH
Blood
MeSH
Anemia, Sickle Cell
Text Location
Discussion

path(MESH:Thrombosis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Children undergoing open heart surgery experience a progressively increasing risk of postoperative infection and thrombosis, increasing need for mechanical ventilation and inotropes, increasing Day 1 through Day 2 peak blood lactate, and decreased nadir mean arterial pressure as the levels of free Hb increase and the levels of haptoglobin decrease. PubMed:29603246

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MeSH
Blood
MeSH
Anemia, Sickle Cell
Text Location
Discussion

path(MESH:Thrombosis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. PubMed:29694434

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Introduction

rxn(reactants(a(CHEBI:"hydrogen peroxide"), p(HGNC:HBB)), products(a(HM:ferrihemoglobin))) hasReactant p(HGNC:HBB) View Subject | View Object

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rxn(reactants(p(HGNC:HBB)), products(a(CHEBI:methemoglobin))) hasReactant p(HGNC:HBB) View Subject | View Object

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Out-Edges 127

p(HGNC:HBB) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

Hemolysis increases the concentration of Hb which, under oxidative stress, releases free heme. PubMed:24904418

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Malaria
Text Location
Review

p(HGNC:HBB) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

Haemoglobin and haem levels increase in plasma and urine when haptoglobin and haemopexin scavenging mechanisms are saturated during acute or chronic haemolysis. PubMed:25307023

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Plasma
MeSH
Urine
Text Location
Review

p(HGNC:HBB) hasVariant p(HGNC:HBB, pmod(Ox)) View Subject | View Object

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p(HGNC:HBB) positiveCorrelation a(CHEBI:"iron trichloride") View Subject | View Object

Analysis of Hb release from ex vivo vessel chamber experiments revealed a significant (p  0.05; n  4) increase in Hb levels following FeCl3 treatment of isolated aorta in the presence of flowing blood (157  45 g/ml), whereas FeCl3 pretreatment of vessels prior to blood perfusion caused no hemolysis (Fig. 2A). PubMed:19276082

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

p(HGNC:HBB) positiveCorrelation a(CHEBI:"iron trichloride") View Subject | View Object

Analysis of the time course of hemolysis in whole blood revealed a rapid linear increase in Hb levels, peaking 10 min after FeCl3 addition (Fig. 2B), a time course consistent with the rapid hemolysis and vascular injury observed in the ex vivo aortic thrombosis model. PubMed:19276082

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Introduction

p(HGNC:HBB) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

Moreover they have demonstrated that released Hb plays an important role in exacerbating RBC hemolysis, establishing a damaging hemolysis/ oxidative cycle that drives further red cell damage, vascular injury, and thrombosis. PubMed:19276082

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Cell Ontology (CL)
erythrocyte
MeSH
Aorta
Text Location
Discussion

p(HGNC:HBB) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

Hemolysis and the transfusion of banked blood or Hb-based therapeutics can result in varying quantities of circulating acellular Hb which can induce life threatening radical generating reactions in patients with a compromised vascular system [60]. PubMed:24486321

Appears in Networks:
Annotations
Text Location
Discussion

p(HGNC:HBB) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

Subsequent RBC lysis leads to release of acellular Hb, which, in turn, damages the alveolar epithelial cells. PubMed:26974230

Appears in Networks:
Annotations
MeSH
Alveolar Epithelial Cells
Text Location
Introduction

p(HGNC:HBB) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

The plasma hemoglobin levels at two and four hours after SRBC-transfusion were greater than the cell-free hemoglobin levels in the supernatant of the SRBCs before transfusion (Figure 1C, Supplemental Table I), providing evidence that hemolysis occurs in vivo during and after transfusion of SRBCs. PubMed:27515135

Appears in Networks:
Annotations
MeSH
Hemorrhage
Text Location
Results

p(HGNC:HBB) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

Red blood cell hemolysis in sickle cell disease (SCD) releases free hemoglobin. PubMed:28088643

Appears in Networks:
Annotations
MeSH
Erythrocytes
MeSH
Anemia, Sickle Cell
Text Location
Abstract

p(HGNC:HBB) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. PubMed:29694434

Appears in Networks:
Annotations
Text Location
Introduction

p(HGNC:HBB) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

Following MAC deposition on RBCs, intravascular hemolysis that leads to increasing levels of free hemoglobin was seen. PubMed:29929138

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
Cell Ontology (CL)
neutrophil
Cell Ontology (CL)
platelet
MeSH
Hemoglobinuria, Paroxysmal
Text Location
Results

p(HGNC:HBB) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

In infectious diseases, such as malaria and sepsis, high amounts of cell-free hemoglobin and heme were found [8], suggesting that hemolysis during sepsis and systemic inflammation is of pathophysiological relevance. PubMed:29956069

Appears in Networks:
Annotations
Cell Ontology (CL)
hepatocyte
MeSH
Liver
MeSH
Sepsis
Text Location
Review

p(HGNC:HBB) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

Finally, a bi-directional crosstalk between hemolysis and coagulation was postulated with induction of tissue factor by cell-free hemoglobin as potentially central mechanism for hemolysis to trigger coagulation [87]. PubMed:29956069

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Microvessels
MeSH
Disseminated Intravascular Coagulation
Text Location
Review

p(HGNC:HBB) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

In addition to inflammation, cell-free hemoglobin (Hb) released via hemolysis is a potent inducer of oxidative stress. PubMed:30505280

Appears in Networks:
Annotations
MeSH
Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

p(HGNC:HBB) increases a(HM:ferrihemoglobin) View Subject | View Object

The results reported here indicate that, once exposed to oxidized plaque material, erythrocytes are lysed, the liberated hemoglobin is oxidized and heme dissociates from the resultant ferrihemoglobin. PubMed:20378845

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Cell Ontology (CL)
endothelial cell
MeSH
Plaque, Atherosclerotic
Text Location
Discussion

p(HGNC:HBB) positiveCorrelation path(MESH:"Vascular System Injuries") View Subject | View Object

Hemolysis and the transfusion of banked blood or Hb-based therapeutics can result in varying quantities of circulating acellular Hb which can induce life threatening radical generating reactions in patients with a compromised vascular system [60]. PubMed:24486321

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Text Location
Discussion

p(HGNC:HBB) increases path(MESH:"Vascular System Injuries") View Subject | View Object

Free hemoglobin (Hb) triggered vascular damage occurs in many hemolytic diseases, such as sickle cell disease, with an unmet need for specific therapeutic interventions. PubMed:26475040

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MeSH
Anemia, Sickle Cell
Text Location
Abstract

p(HGNC:HBB) increases path(MESH:"Vascular System Injuries") View Subject | View Object

Depending on the scale, rate, and site of hemolysis, the primary adverse effects triggered by free Hb are vascular dysfunction, oxidative tissue damage, and altered inflammatory response [1], PubMed:26475040

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MeSH
Anemia, Sickle Cell
Text Location
Abstract

p(HGNC:HBB) increases path(MESH:"Vascular System Injuries") View Subject | View Object

Several studies in animals have supported the idea that infusion of free Hb, stored RBC supernatant (preservation solution + plasma), and Hb-containing microvesicles causes vasoconstriction, vascular dysfunction, and vascular injury.12,16–18 PubMed:27308950

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MeSH
Arteries
Text Location
Introduction

p(HGNC:HBB) positiveCorrelation path(MESH:"Kidney Diseases") View Subject | View Object

Third, exposure to extracellular Hb, in the form of oxygen therapeutics or when Hb is released from old red blood cells, have also been reported to induce oxidative toxicity in kidney and brain tissues [65]. PubMed:24486321

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Discussion

p(HGNC:HBB) positiveCorrelation path(MESH:"Brain Diseases") View Subject | View Object

Third, exposure to extracellular Hb, in the form of oxygen therapeutics or when Hb is released from old red blood cells, have also been reported to induce oxidative toxicity in kidney and brain tissues [65]. PubMed:24486321

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deg(p(HGNC:HBB)) increases a(CHEBI:heme) View Subject | View Object

In that study, heme was shown to specifically bind to endothelial Toll-like receptors (TLR4) and trigger a cascade of inflammatory responses, which could be attributed to oxidation and degradation of cell-free Hb [73]. PubMed:24486321

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MeSH
Anemia, Sickle Cell
Text Location
Discussion

p(HGNC:HBB) increases a(CHEBI:heme) View Subject | View Object

Hemolysis increases the concentration of Hb which, under oxidative stress, releases free heme. PubMed:24904418

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Malaria
Text Location
Review

p(HGNC:HBB) increases a(CHEBI:heme) View Subject | View Object

Exposure to Hb and its oxidized products increases heme overload on the AT1 cells. Heme overload induces the expression of HO-1 and iron-sequestering proteins, such as ferritin. PubMed:26974230

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Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Discussion

p(HGNC:HBB) increases a(CHEBI:heme) View Subject | View Object

Toxicity of free hemoglobin is also caused by the release of cell-free heme, which produces lipid peroxidation and mitochondrial damage and increases the production of reactive oxygen species. PubMed:27515135

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Introduction

p(HGNC:HBB) increases a(CHEBI:heme) View Subject | View Object

Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. PubMed:28088643

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MeSH
Erythrocytes
MeSH
Anemia, Sickle Cell
Text Location
Abstract

deg(p(HGNC:HBB)) increases a(CHEBI:heme) View Subject | View Object

For instance, earlier studies have demonstrated that neutrophil elastase degrades the hemoglobin liberating free hemin that induces ROS production. PubMed:28716864

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Cell Ontology (CL)
neutrophil
MeSH
Serum
MeSH
Malaria
Text Location
Discussion

p(HGNC:HBB) positiveCorrelation p(HGNC:AMBP) View Subject | View Object

The expression of A1M is up-regulated by elevated levels of free Hb, heme and ROS [23]. PubMed:24489717

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p(HGNC:HBB) positiveCorrelation p(HGNC:AMBP) View Subject | View Object

This is consistent with our findings here that both heme and Hb were associated with increased levels of synovial fluid A1M. PubMed:30505280

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MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

p(HGNC:HBB) negativeCorrelation a(MESH:"haptoglobin-hemoglobin complex") View Subject | View Object

Because of its large molecular size, this complex is maintained in the intravascular space, preventing the association of otherwise free Hb with nitric oxide (NO; Reiter et al., 2002) and inhibiting the release of free heme (Melamed-Frank et al., 2001). PubMed:24904418

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Review

p(HGNC:HBB) decreases bp(MESH:Vasodilation) View Subject | View Object

Thus, the antioxidant, anticoagulant, anti-proliferative and vasodilating effects of the HMOX1 and biliverdin reductase systems probably compensate for the nitric oxide (NO) scavenging, vasoconstrictive, proliferative, inflammatory and pro-oxidant effects of circulating free haemoglobin, haem and haem-iron, which are discussed below (Rother et al, 2005). PubMed:25307023

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Cell Ontology (CL)
macrophage
Text Location
Review

p(HGNC:HBB) increases bp(GO:"cell proliferation") View Subject | View Object

Thus, the antioxidant, anticoagulant, anti-proliferative and vasodilating effects of the HMOX1 and biliverdin reductase systems probably compensate for the nitric oxide (NO) scavenging, vasoconstrictive, proliferative, inflammatory and pro-oxidant effects of circulating free haemoglobin, haem and haem-iron, which are discussed below (Rother et al, 2005). PubMed:25307023

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Annotations
Cell Ontology (CL)
macrophage
Text Location
Review

p(HGNC:HBB) increases path(MESH:Inflammation) View Subject | View Object

Thus, the antioxidant, anticoagulant, anti-proliferative and vasodilating effects of the HMOX1 and biliverdin reductase systems probably compensate for the nitric oxide (NO) scavenging, vasoconstrictive, proliferative, inflammatory and pro-oxidant effects of circulating free haemoglobin, haem and haem-iron, which are discussed below (Rother et al, 2005). PubMed:25307023

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Cell Ontology (CL)
macrophage
Text Location
Review

p(HGNC:HBB) increases path(MESH:Inflammation) View Subject | View Object

Free plasma haemoglobin and haem also scavenge NO and have multiple pro-inflammatory and pro-oxidant properties that mediate many of the adverse effects of haemolysis. PubMed:25307023

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Plasma
MeSH
Urine
Text Location
Review

p(HGNC:HBB) increases path(MESH:Inflammation) View Subject | View Object

Depending on the scale, rate, and site of hemolysis, the primary adverse effects triggered by free Hb are vascular dysfunction, oxidative tissue damage, and altered inflammatory response [1], PubMed:26475040

Appears in Networks:
Annotations
MeSH
Anemia, Sickle Cell
Text Location
Abstract

p(HGNC:HBB) increases path(MESH:Inflammation) View Subject | View Object

Extracellular hemoglobin and heme are pro-oxidative, proinflammatory, and cytotoxic [10–12], and can contribute to the pathology of hemolytic diseases. PubMed:26875449

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Review

p(HGNC:HBB) positiveCorrelation path(MESH:Inflammation) View Subject | View Object

Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24. PubMed:27515135

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Annotations
Text Location
Introduction

p(HGNC:HBB) positiveCorrelation path(MESH:Inflammation) View Subject | View Object

There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246

Appears in Networks:
Annotations
Text Location
Introduction

p(HGNC:HBB) positiveCorrelation path(MESH:Inflammation) View Subject | View Object

Our findings in the complex setting of critically ill pediatric cardiac surgery patients demonstrate that higher levels of free Hb and lower levels of haptoglobin are associated with serious postoperative clinical complications (infection, thrombosis, death), immunomodulation, and inflammation. PubMed:29603246

Appears in Networks:
Annotations
MeSH
Blood
MeSH
Anemia, Sickle Cell
Text Location
Discussion

p(HGNC:HBB) positiveCorrelation path(MESH:Inflammation) View Subject | View Object

During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. PubMed:29694434

Appears in Networks:
Annotations
Text Location
Introduction

p(HGNC:HBB) positiveCorrelation path(MESH:Inflammation) View Subject | View Object

In infectious diseases, such as malaria and sepsis, high amounts of cell-free hemoglobin and heme were found [8], suggesting that hemolysis during sepsis and systemic inflammation is of pathophysiological relevance. PubMed:29956069

Appears in Networks:
Annotations
Cell Ontology (CL)
hepatocyte
MeSH
Liver
MeSH
Sepsis
Text Location
Review

p(HGNC:HBB) decreases act(a(CHEBI:antioxidant)) View Subject | View Object

Thus, the antioxidant, anticoagulant, anti-proliferative and vasodilating effects of the HMOX1 and biliverdin reductase systems probably compensate for the nitric oxide (NO) scavenging, vasoconstrictive, proliferative, inflammatory and pro-oxidant effects of circulating free haemoglobin, haem and haem-iron, which are discussed below (Rother et al, 2005). PubMed:25307023

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Annotations
Cell Ontology (CL)
macrophage
Text Location
Review

p(HGNC:HBB) decreases act(a(CHEBI:antioxidant)) View Subject | View Object

Free plasma haemoglobin and haem also scavenge NO and have multiple pro-inflammatory and pro-oxidant properties that mediate many of the adverse effects of haemolysis. PubMed:25307023

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Plasma
MeSH
Urine
Text Location
Review

p(HGNC:HBB) decreases a(CHEBI:"nitric oxide") View Subject | View Object

Free plasma haemoglobin and haem also scavenge NO and have multiple pro-inflammatory and pro-oxidant properties that mediate many of the adverse effects of haemolysis. PubMed:25307023

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Plasma
MeSH
Urine
Text Location
Review

p(HGNC:HBB) decreases a(CHEBI:"nitric oxide") View Subject | View Object

In addition to cell-free Hb, membrane structural modification, externalization of phosphatidylserine,21 decreased cell membrane deformability,22,23 and increased endothelial adherence24 could alter vascular NO homeostasis. PubMed:27308950

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MeSH
Endothelium, Vascular
Text Location
Introduction

p(HGNC:HBB) negativeCorrelation a(CHEBI:"nitric oxide") View Subject | View Object

Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24. PubMed:27515135

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Text Location
Introduction

p(HGNC:HBB) decreases a(CHEBI:"nitric oxide") View Subject | View Object

Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. PubMed:28088643

Appears in Networks:
Annotations
MeSH
Erythrocytes
MeSH
Anemia, Sickle Cell
Text Location
Abstract

p(HGNC:HBB) decreases a(CHEBI:"nitric oxide") View Subject | View Object

Extracellular Hb exhibits a highly toxic nature by scavenging Nitric Oxide (NO) that reduces its bioavailability [1]. PubMed:28088643

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MeSH
Erythrocytes
MeSH
Anemia, Sickle Cell
Text Location
Introduction

p(HGNC:HBB) decreases a(CHEBI:"nitric oxide") View Subject | View Object

Some of the adverse effects caused by cell-free hemoglobin are a result of depletion of nitric oxide (NO), which may lead to vasoconstriction, inflammation, and platelet activation (10, 24). PubMed:28314763

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Introduction

p(HGNC:HBB) decreases a(CHEBI:"nitric oxide") View Subject | View Object

Another mechanism for platelet activation by RBC lysate is extracellular hemoglobin, which enhances platelet activation by lowering NO bioavailability [ 29]. PubMed:28458720

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MeSH
Veins
Text Location
Review

p(HGNC:HBB) decreases a(CHEBI:"nitric oxide") View Subject | View Object

Extracellular hemoglobin sequesters NO and thus promotes activation of endothelial cells and adhesion/aggregation of platelets [64]. PubMed:28458720

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Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Veins
MeSH
beta-Thalassemia
Text Location
Review

p(HGNC:HBB) decreases a(CHEBI:"nitric oxide") View Subject | View Object

The first process links the nitric oxide (NO) reactivity of oxyHb to a cascade of cell-free Hb extravasation, hemolysis-associated NO-depletion, and vasoconstriction.21–23 PubMed:29610666

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Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

p(HGNC:HBB) decreases a(CHEBI:"nitric oxide") View Subject | View Object

One of the mechanisms by which cell-free hemoglobin exerts its detrimental effects is its ability to effectively scavenge nitric oxide (NO), which in turn leads to perfusion disorders and an increased arterial and pulmonary arterial pressure [39, 40]. PubMed:29956069

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Arteries
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Sepsis
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Review

p(HGNC:HBB) positiveCorrelation complex(a(CHEBI:"nitric oxide"), p(HGNC:HBB)) View Subject | View Object

Release of hemoglobin (and ultimately heme), and arginase-1 into the plasma results in binding of nitric oxide and also reduction in L-arginine, respectively, causing a relative reduction in vasodilatory effect.[14,29] PubMed:26337933

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Cell Ontology (CL)
leukocyte
MeSH
Plasma
MeSH
Pulmonary Embolism
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Discussion

p(HGNC:HBB) decreases a(CHEBI:"L-arginine") View Subject | View Object

Release of hemoglobin (and ultimately heme), and arginase-1 into the plasma results in binding of nitric oxide and also reduction in L-arginine, respectively, causing a relative reduction in vasodilatory effect.[14,29] PubMed:26337933

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leukocyte
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Plasma
MeSH
Pulmonary Embolism
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Discussion

p(HGNC:HBB) increases bp(MESH:"Oxidative Stress") View Subject | View Object

Depending on the scale, rate, and site of hemolysis, the primary adverse effects triggered by free Hb are vascular dysfunction, oxidative tissue damage, and altered inflammatory response [1], PubMed:26475040

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Anemia, Sickle Cell
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Abstract

p(HGNC:HBB) increases bp(MESH:"Oxidative Stress") View Subject | View Object

Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. PubMed:28088643

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Erythrocytes
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Anemia, Sickle Cell
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Abstract

p(HGNC:HBB) positiveCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. PubMed:29694434

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p(HGNC:HBB) positiveCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

In addition to inflammation, cell-free hemoglobin (Hb) released via hemolysis is a potent inducer of oxidative stress. PubMed:30505280

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Knee
MeSH
Osteoarthritis, Knee
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Introduction

p(HGNC:HBB) increases a(MESH:"Toxic Actions") View Subject | View Object

Extracellular hemoglobin and heme are pro-oxidative, proinflammatory, and cytotoxic [10–12], and can contribute to the pathology of hemolytic diseases. PubMed:26875449

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Review

p(HGNC:HBB) increases path(HM:"Endothelial dysfunction") View Subject | View Object

Many studies have explored basic mechanisms of Hb or heme triggered endothelial damage and have suggested that oxidative reactions of Hb generate multiple toxic species such as free heme that is released from ferric Hb, iron, free radicals, and globin aggregation products [15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25]. PubMed:26475040

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Anemia, Sickle Cell
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Abstract

p(HGNC:HBB) increases path(HM:"Endothelial dysfunction") View Subject | View Object

Compared to wild-type (WT) mice, mice with 117 endothelial dysfunction have an increased vasoconstrictor response to infusion of 118 cell-free hemoglobin (25). PubMed:28314763

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p(HGNC:HBB) positiveCorrelation bp(MESH:"Erythrocyte Deformability") View Subject | View Object

Sickle cell disease (SCD) and malaria are paradigmatic hemolytic disorders, in which alteration in the structure of red blood cells (RBCs) leads to the release of Hb and heme into the circulation. PubMed:26675351

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Anemia, Sickle Cell
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Introduction

p(HGNC:HBB) increases bp(HM:"macrophage M1 polarization") View Subject | View Object

This is the case in a mouse model of SCD, which is hallmarked by hemolysis, increased circulating Hb/heme, and low levels of Hp and Hx and shows elevated hepatic macrophage iron levels and M1 polarization. PubMed:26675351

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macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
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Discussion

p(HGNC:HBB) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

Old blood transfusion resulted in systemic free Hb total exposure (AUC0–∞) of 4600 μmol heme-h/l, which was primarily cleared by the kidney within 24 h. PubMed:26794659

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Liver
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Results

p(HGNC:HBB) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

In old blood-transfused animals, strong Hb and iron deposition was observed in the tubule lumen and epithelial cells, respectively. PubMed:26794659

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epithelial cell
MeSH
Kidney Tubules
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Results

p(HGNC:HBB) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

In mice resuscitated with SRBCs, plasma hemoglobin levels were greater than in mice resuscitated with FRBCs or in sham-treated mice at two, four, and 24 hours after transfusion (Figure 1C). PubMed:27515135

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Hemorrhage
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Results

p(HGNC:HBB) negativeCorrelation a(MESH:Kidney) View Subject | View Object

Old blood transfusion resulted in systemic free Hb total exposure (AUC0–∞) of 4600 μmol heme-h/l, which was primarily cleared by the kidney within 24 h. PubMed:26794659

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Liver
Text Location
Results

p(HGNC:HBB) increases p(HGNC:HMOX1) View Subject | View Object

Immunofluorescence confirmed that renal Hb exposure triggered overexpression of HMOX1 and the unfolded protein response (UPR) chaperone HSP70 in tubule epithelial cells (Figure 2d). PubMed:26794659

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epithelial cell
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Kidney
Text Location
Results

p(HGNC:HBB) increases p(HGNC:HSPA5) View Subject | View Object

Immunofluorescence confirmed that renal Hb exposure triggered overexpression of HMOX1 and the unfolded protein response (UPR) chaperone HSP70 in tubule epithelial cells (Figure 2d). PubMed:26794659

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epithelial cell
MeSH
Kidney
Text Location
Results

p(HGNC:HBB) positiveCorrelation path(HP:"Paroxysmal nocturnal hemoglobinuria") View Subject | View Object

In cases of congenital hemoglobinopathies such as sickle cell disease, deficiencies in complement system regulators such as paroxysmal nocturnal hemoglobinuria, and many other disorders, erythrocytes can lyse and liberate large quantities of hemoglobin. PubMed:26875449

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Review

p(HGNC:HBB) increases a(HM:"oxidative reactions") View Subject | View Object

Extracellular hemoglobin and heme are pro-oxidative, proinflammatory, and cytotoxic [10–12], and can contribute to the pathology of hemolytic diseases. PubMed:26875449

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Review

p(HGNC:HBB) positiveCorrelation a(HM:"oxidative reactions") View Subject | View Object

The second biochemical process relates to the ability of Hb to facilitate oxidative reactions outside of the reducing environment of the RBC, leading to the accumulation of ferric metHb(Fe3+) in tissue.24 PubMed:29610666

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Cell Ontology (CL)
macrophage
MeSH
Mitochondria
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Discussion

p(HGNC:HBB) increases a(HM:"oxidative reactions") View Subject | View Object

This is a principal requirement for hemoglobin and hemin to induce adverse reactivity in tissues, including nitric oxide and oxidative reactions, release of free hemin, and molecular-signaling effects of hemin (reviewed by Schaer DJ et al.) [13] and Hill A et al. [14]. PubMed:29929138

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Cell Ontology (CL)
erythrocyte
Cell Ontology (CL)
neutrophil
Cell Ontology (CL)
platelet
MeSH
Hemoglobinuria, Paroxysmal
Text Location
Results

p(HGNC:HBB) increases act(p(MGI:Nfkb1)) View Subject | View Object

We also found that HbFe21 and HbFe31 activate NF-kB and mitogen-activated protein kinase pathways, as shown by phosphorylation of NF-kB p65 subunit and p44/42, respectively (Figure E3) as noted previously (31). PubMed:26974230

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Alveolar Epithelial Cells
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Results

p(HGNC:HBB) increases p(MGI:Hmox1) View Subject | View Object

We found a significant enrichment of HO-1 in the mitochondrial, but not in the cytosolic fractions after exposure to HbFe21 and HbFe31 (Figures 3A and 3B). PubMed:26974230

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Mitochondria
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Results

p(HGNC:HBB) causesNoChange p(MGI:Cox4i1) View Subject | View Object

Exposure to HbFe21 and HbFe31 did not alter the expression of cytochrome c oxidase IV protein (Figure 3A). PubMed:26974230

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Mitochondria
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Results

p(HGNC:HBB) negativeCorrelation path(MESH:Hematoma) View Subject | View Object

The level of hemoglobin declined gradually over the time after the onset of ICH with a significant reduction at day 3. The contents of hemoglobin in the clot were 26.2 ± 5.2 mg/g at 4 hours, but were reduced to 13.9 ± 0.9 mg/g at day-3 (Fig. 2B, p<0.01). PubMed:27125525

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Cerebral Hemorrhage
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Results

p(HGNC:HBB) negativeCorrelation path(MESH:Hematoma) View Subject | View Object

We found that hemoglobin contents in hematoma were significantly higher in the DFX treated group compare to the vehicle-treated group (15.9 ± 1.8 vs. 11.8 ± 0.8 mg/g, p<0.05, Fig. 5A). PubMed:27125525

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Cerebral Hemorrhage
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Results

p(HGNC:HBB) positiveCorrelation a(CHEBI:"desferrioxamine B") View Subject | View Object

We found that hemoglobin contents in hematoma were significantly higher in the DFX treated group compare to the vehicle-treated group (15.9 ± 1.8 vs. 11.8 ± 0.8 mg/g, p<0.05, Fig. 5A). PubMed:27125525

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Cerebral Hemorrhage
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Results

p(HGNC:HBB) increases rxn(reactants(a(CHEBI:"nitric oxide")), products(a(CHEBI:nitrate))) View Subject | View Object

Free Hb and Hb present in microvesicles oxidize vascular nitric oxide (NO) much faster than RBC-encapsulated Hb to form nitrate.14,15 PubMed:27308950

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p(HGNC:HBB) increases rxn(reactants(a(CHEBI:"nitric oxide")), products(a(CHEBI:nitrate))) View Subject | View Object

These data suggest that co-administration of human haptoglobin or hemopexin does 276 not attenuate the conversion of NO to nitrate that is mediated by cell-free murine 277 hemoglobin. PubMed:28314763

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p(HGNC:HBB) increases bp(MESH:"Blood Pressure") View Subject | View Object

Presence of any cell-free Hb limits NO diffusion from endothelium to smooth muscle cells for activation of guanylyl cyclase; as a consequence, mean arterial blood pressure increases.12,15 PubMed:27308950

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Arteries
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Introduction

p(HGNC:HBB) increases bp(MESH:"Blood Pressure") View Subject | View Object

SBP 315 increased 27±2 mmHg during the 40 minutes following infusion of hemoglobin in 316 db/db mice (Figure 4A). PubMed:28314763

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Diabetes Mellitus
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Introduction

p(HGNC:HBB) increases bp(GO:vasoconstriction) View Subject | View Object

Several studies in animals have supported the idea that infusion of free Hb, stored RBC supernatant (preservation solution + plasma), and Hb-containing microvesicles causes vasoconstriction, vascular dysfunction, and vascular injury.12,16–18 PubMed:27308950

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Arteries
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Introduction

p(HGNC:HBB) positiveCorrelation bp(GO:vasoconstriction) View Subject | View Object

Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24. PubMed:27515135

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p(HGNC:HBB) increases bp(GO:vasoconstriction) View Subject | View Object

Previous studies showed that db/db mice have enhanced 312 susceptibility to hemoglobin-induced vasoconstriction (25). PubMed:28314763

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Diabetes Mellitus
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Introduction

p(HGNC:HBB) increases a(CHEBI:nitrate) View Subject | View Object

The cell-free Hb in stored RBCs should actually increase nitrate by oxidizing NO to nitrate. PubMed:27308950

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Plasma
MeSH
Hypoxia
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Discussion

p(HGNC:HBB) positiveCorrelation path(MESH:"Platelet Aggregation") View Subject | View Object

Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24. PubMed:27515135

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p(HGNC:HBB) positiveCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) View Subject | View Object

Co-administration of haptoglobin with SRBCs results in a prolonged increase in plasma hemoglobin levels for more than 48 hours after transfusion. PubMed:27515135

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Plasma
MeSH
Hemorrhage
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Results

p(HGNC:HBB) increases a(CHEBI:"iron(2+)") View Subject | View Object

Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. PubMed:28088643

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Erythrocytes
MeSH
Anemia, Sickle Cell
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Abstract

p(HGNC:HBB) increases a(CHEBI:"iron(2+)") View Subject | View Object

Iron was also detected in the macrophages of the red pulp of CEP mice, while almost no iron deposit was observed in the spleen of Hjv–/– mice (Figure 4B), confirming that Hb and “free” heme are the likely source of macrophage iron accumulation. PubMed:28143953

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macrophage
MeSH
Serum
MeSH
Porphyria, Erythropoietic
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Results

p(HGNC:HBB) increases a(CHEBI:"iron(2+)") View Subject | View Object

Another pathogenic mechanism involves the release of iron from cell-free hemoglobin with consecutive radical formation, which in turn can modify lipids, proteins, and DNA, leading to inflammation [39]. PubMed:29956069

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Arteries
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Sepsis
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Review

p(HGNC:HBB) negativeCorrelation path(MESH:Anemia) View Subject | View Object

The anemia in CEP mice was severe with significant reduction of Hb levels and RBC number (Table 1), regenerative with marked reticulocytosis (28.8±4.2%) (Table 1), and microcytic and hypochromic with reduced mean cell Hb content (9.95±0.64 pg in CEP vs. 14.5±0.18 in WT mice) (Table 1). PubMed:28143953

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erythrocyte
MeSH
Serum
MeSH
Porphyria, Erythropoietic
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Results

p(HGNC:HBB) increases path(MESH:Hypertension) View Subject | View Object

Intravenous infusion of cell-free hemoglobin induces hypertension in mice 205 (24). PubMed:28314763

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p(HGNC:HBB) increases path(MESH:Hypertension) View Subject | View Object

One of the mechanisms by which cell-free hemoglobin exerts its detrimental effects is its ability to effectively scavenge nitric oxide (NO), which in turn leads to perfusion disorders and an increased arterial and pulmonary arterial pressure [39, 40]. PubMed:29956069

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Arteries
MeSH
Sepsis
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Review

p(HGNC:HBB) decreases a(HM:"Nitric oxide scavenging") View Subject | View Object

When mice 347 are infused with extracellular hemoglobin that has been extensively crosslinked and 348 only contains a small fraction of monomeric hemoglobin (as in the HBOCs, 349 PolyHeme), scavenging of NO is markedly reduced (25). PubMed:28314763

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Diabetes Mellitus
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Introduction

p(HGNC:HBB) decreases a(HM:"Nitric oxide scavenging") View Subject | View Object

Inhibition of extravasation of cross-linked extracellular 352 hemoglobin has been postulated as a possible mechanism of decreased NO353 scavenging in the muscular layer of arteries by high-molecular weight HBOCs. PubMed:28314763

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Arteries
MeSH
Diabetes Mellitus
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Introduction

p(HGNC:HBB) increases bp(MESH:"Platelet Activation") View Subject | View Object

Another mechanism for platelet activation by RBC lysate is extracellular hemoglobin, which enhances platelet activation by lowering NO bioavailability [ 29]. PubMed:28458720

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Veins
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Review

p(HGNC:HBB) positiveCorrelation bp(MESH:"Platelet Activation") View Subject | View Object

There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246

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p(HGNC:HBB) increases bp(MESH:"Platelet Aggregation") View Subject | View Object

When RBCs are damaged by high shear in continuous flow ventricular assist devices, free hemoglobin induces platelet aggregation, contributing to high risk of thrombotic complications [33]. PubMed:28458720

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Veins
MeSH
Acute Coronary Syndrome
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Review

p(HGNC:HBB) increases bp(MESH:"Platelet Aggregation") View Subject | View Object

Extracellular hemoglobin sequesters NO and thus promotes activation of endothelial cells and adhesion/aggregation of platelets [64]. PubMed:28458720

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Cell Ontology (CL)
erythrocyte
MeSH
Veins
MeSH
beta-Thalassemia
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Review

p(HGNC:HBB) increases bp(GO:"endothelial cell activation") View Subject | View Object

Extracellular hemoglobin sequesters NO and thus promotes activation of endothelial cells and adhesion/aggregation of platelets [64]. PubMed:28458720

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erythrocyte
MeSH
Veins
MeSH
beta-Thalassemia
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Review

p(HGNC:HBB) increases bp(MESH:"Whole Blood Coagulation Time") View Subject | View Object

Besides the effects of intact RBCs, free extracellular hemoglobin prolongs clotting time of fibrinogen due to impaired polymerization [73]. PubMed:28458720

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erythrocyte
MeSH
Veins
MeSH
beta-Thalassemia
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Review

p(HGNC:HBB) positiveCorrelation path(MESH:"Vascular Diseases") View Subject | View Object

There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246

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p(HGNC:HBB) positiveCorrelation path(MESH:Thrombosis) View Subject | View Object

There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246

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p(HGNC:HBB) positiveCorrelation path(MESH:Thrombosis) View Subject | View Object

The median (and mean—data not shown) free Hb levels preoperatively and at all postoperative time points (immediately and 6 and 12 hr postoperatively) were higher (p50.057) in those who later developed a proven thrombosis (Fig. 3 displays the 12-hr data). PubMed:29603246

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Anemia, Sickle Cell
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Results

p(HGNC:HBB) positiveCorrelation path(MESH:Thrombosis) View Subject | View Object

Our findings in the complex setting of critically ill pediatric cardiac surgery patients demonstrate that higher levels of free Hb and lower levels of haptoglobin are associated with serious postoperative clinical complications (infection, thrombosis, death), immunomodulation, and inflammation. PubMed:29603246

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Blood
MeSH
Anemia, Sickle Cell
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Discussion

p(HGNC:HBB) positiveCorrelation path(MESH:Thrombosis) View Subject | View Object

Children undergoing open heart surgery experience a progressively increasing risk of postoperative infection and thrombosis, increasing need for mechanical ventilation and inotropes, increasing Day 1 through Day 2 peak blood lactate, and decreased nadir mean arterial pressure as the levels of free Hb increase and the levels of haptoglobin decrease. PubMed:29603246

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Blood
MeSH
Anemia, Sickle Cell
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Discussion

p(HGNC:HBB) positiveCorrelation path(MESH:Thrombosis) View Subject | View Object

During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. PubMed:29694434

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p(HGNC:HBB) negativeCorrelation p(HGNC:HP) View Subject | View Object

However, patients who died had significantly higher plasma cell-free Hb and lower haptoglobin concentrations at all time points, preoperatively and immediately postoperatively and 6 and 12 hours postoperatively (Fig. 1 shows the 12-hr postoperative data). PubMed:29603246

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Anemia, Sickle Cell
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Results

p(HGNC:HBB) negativeCorrelation p(HGNC:HP) View Subject | View Object

Children undergoing open heart surgery experience a progressively increasing risk of postoperative infection and thrombosis, increasing need for mechanical ventilation and inotropes, increasing Day 1 through Day 2 peak blood lactate, and decreased nadir mean arterial pressure as the levels of free Hb increase and the levels of haptoglobin decrease. PubMed:29603246

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MeSH
Blood
MeSH
Anemia, Sickle Cell
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Discussion

p(HGNC:HBB) positiveCorrelation bp(MESH:Immunomodulation) View Subject | View Object

Our findings in the complex setting of critically ill pediatric cardiac surgery patients demonstrate that higher levels of free Hb and lower levels of haptoglobin are associated with serious postoperative clinical complications (infection, thrombosis, death), immunomodulation, and inflammation. PubMed:29603246

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Blood
MeSH
Anemia, Sickle Cell
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Discussion

p(HGNC:HBB) positiveCorrelation a(CHEBI:lactate) View Subject | View Object

Children undergoing open heart surgery experience a progressively increasing risk of postoperative infection and thrombosis, increasing need for mechanical ventilation and inotropes, increasing Day 1 through Day 2 peak blood lactate, and decreased nadir mean arterial pressure as the levels of free Hb increase and the levels of haptoglobin decrease. PubMed:29603246

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MeSH
Blood
MeSH
Anemia, Sickle Cell
Text Location
Discussion

p(HGNC:HBB) negativeCorrelation path(HP:"Elevated mean arterial pressure") View Subject | View Object

Children undergoing open heart surgery experience a progressively increasing risk of postoperative infection and thrombosis, increasing need for mechanical ventilation and inotropes, increasing Day 1 through Day 2 peak blood lactate, and decreased nadir mean arterial pressure as the levels of free Hb increase and the levels of haptoglobin decrease. PubMed:29603246

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MeSH
Blood
MeSH
Anemia, Sickle Cell
Text Location
Discussion

p(HGNC:HBB) positiveCorrelation bp(MESH:Vasoconstriction) View Subject | View Object

The first process links the nitric oxide (NO) reactivity of oxyHb to a cascade of cell-free Hb extravasation, hemolysis-associated NO-depletion, and vasoconstriction.21–23 PubMed:29610666

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macrophage
MeSH
Mitochondria
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Discussion

p(HGNC:HBB) increases a(CHEBI:methemoglobin) View Subject | View Object

The second biochemical process relates to the ability of Hb to facilitate oxidative reactions outside of the reducing environment of the RBC, leading to the accumulation of ferric metHb(Fe3+) in tissue.24 PubMed:29610666

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Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

p(HGNC:HBB) positiveCorrelation path(HM:"vaso-occlusive crisis") View Subject | View Object

Infusion of exogenous hemoglobin into SS-mice can markedly increase stasis compared to the amount of spontaneous stasis [5]. PubMed:29694434

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MeSH
Blood Platelets
MeSH
Anemia, Sickle Cell
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Results

p(HGNC:HBB) positiveCorrelation path(MESH:Thrombophilia) View Subject | View Object

High free hemoglobin was shown in patients with primary Cys89Tyr mutation in CD59 (Table 1) and it has been suggested in several ways that free hemoglobin may serve as a major mechanism for thrombophilia. PubMed:29929138

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Cell Ontology (CL)
erythrocyte
Cell Ontology (CL)
neutrophil
Cell Ontology (CL)
platelet
MeSH
Hemoglobinuria, Paroxysmal
Text Location
Results

p(HGNC:HBB) decreases p(HGNC:ADAMTS13) View Subject | View Object

One mechanism that may contribute to enhanced platelet thrombus formation is inhibition of the metalloprotease ADAMTS13 by free hemoglobin [20]. PubMed:29929138

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Cell Ontology (CL)
erythrocyte
Cell Ontology (CL)
neutrophil
Cell Ontology (CL)
platelet
MeSH
Hemoglobinuria, Paroxysmal
Text Location
Discussion

p(HGNC:HBB) positiveCorrelation path(HM:"endothelial lesions") View Subject | View Object

Endothelial injury may also be related to Free hemoglobin and its breakdown oxidative product heme, and MPs, which mediates direct proinflammatory, proliferative, and pro-oxidant effects on endothelial cells [22–24] both in PNH and congenital CD59 deficiency, but may be more pronounced in congenital CD59 deficiency and perhaps even more in the brain due to loss of CD59 in the endothelium of these patients. PubMed:29929138

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Cell Ontology (CL)
platelet
MeSH
Endothelium
MeSH
Hemoglobinuria, Paroxysmal
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Discussion

p(HGNC:HBB) increases p(RGD:Tnf) View Subject | View Object

Thus, the intravenous administration of hemoglobin in LPS-pretreated mice leads to a higher TNF- α concentration and an increased mortality; in turn, these effects could be inhibited by hemoglobin antibodies [33, 34]. PubMed:29956069

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Cell Ontology (CL)
hepatocyte
MeSH
Liver
MeSH
Sepsis
Text Location
Review

p(HGNC:HBB) positiveCorrelation a(MESH:Fibrin) View Subject | View Object

During DIC, fibrin strands within the fibrin mesh formed could cut red blood cells, resulting in the formation of schistocytes (strongly deformed red blood cells or fragments of red blood cells) and the release of hemoglobin. PubMed:29956069

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Cell Ontology (CL)
erythrocyte
MeSH
Microvessels
MeSH
Disseminated Intravascular Coagulation
Text Location
Review

p(HGNC:HBB) negativeCorrelation bp(GO:"regulation of glucose-6-phosphatase activity") View Subject | View Object

Nevertheless, the crosstalk between glucose and heme metabolism in sepsis is bidirectional since an excessive accumulation of cell-free heme following hemolysis influences the glucose metabolism by iron-driven oxidative inhibition of the glucose-6-phosphatase (a liver enzymes being important for endogenous glucose production via gluconeogenesis and glycogenolysis) [14]. PubMed:29956069

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erythrocyte
MeSH
Liver
MeSH
Sepsis
Text Location
Review

deg(p(HGNC:HBB)) positiveCorrelation complex(a(CHEBI:"iron(2+)"), a(CHEBI:heme), a(MESH:"Reactive Oxygen Species")) View Subject | View Object

Spontaneous decomposition of Hb via auto-oxidation leads to the formation of ROS, free heme groups and free iron, which are highly reactive and have the ability to damage lipids, proteins, and DNA (Olsson et al., 2012). PubMed:30505280

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Knee
MeSH
Osteoarthritis, Knee
Text Location
Introduction

p(HGNC:HBB) increases path(HM:"Oxidative damage") View Subject | View Object

These novel data support a role for A1M in the protection against oxidative damage due to extracellular Hb and heme in the joint in various knee arthropathies. PubMed:30505280

Appears in Networks:
Annotations
MeSH
Synovial Fluid
MeSH
Osteoarthritis, Knee
Text Location
Discussion

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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.