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PubMed: 26875449

Title
Heme: Modulator of Plasma Systems in Hemolytic Diseases.
Journal
Trends in molecular medicine
Volume
22
Issue
None
Pages
200-213
Date
2016-03-01
Authors
Dimitrov JD | Lacroix-Desmazes S | Rayes J | Roumenina LT

Evidence 2170132632
JSON

Despite its damaging effects, heme induces the expression of HO-1, which degrades heme to anti-inflammatory, cytoprotective, and antioxidant products [25].

a(CHEBI:heme) increases p(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Serum
MeSH
Malaria
Text Location
Review

p(HGNC:HMOX1) increases deg(a(CHEBI:heme)) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Serum
MeSH
Malaria
Text Location
Review

Evidence ce05886c06
JSON

A recent Phase IIB clinical trial showed that preconditioning using hemin upregulated HO-1 in renal transplantation, launching further studies on clinical outcome [97].

a(CHEBI:heme) increases p(HGNC:HMOX1) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Serum
MeSH
Malaria
Text Location
Review

Evidence a078c9d855
JSON

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

a(CHEBI:heme) increases path(MESH:Inflammation) View Subject | View Object

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a(CHEBI:heme) increases a(HM:"oxidative reactions") View Subject | View Object

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Review

a(CHEBI:heme) increases a(MESH:"Toxic Actions") View Subject | View Object

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Review

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

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Review

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

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

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Evidence 483730575e
JSON

Heme is one of the factors capable of inducing stimulation and damage of endothelium, promoting the recruitment of neutrophils and sickle-cell erythro- cytes, and subsequently prompting a vaso-occlusive crisis.

a(CHEBI:heme) increases bp(GO:"endothelial cell activation") View Subject | View Object

Appears in Networks:
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MeSH
Anemia, Sickle Cell
Text Location
Review

a(CHEBI:heme) increases bp(GO:"neutrophil activation") View Subject | View Object

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

a(CHEBI:heme) increases path(HM:"vaso-occlusive crisis") View Subject | View Object

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

Evidence d026fee1ed
JSON

Taken sequentially, it appears that the release of heme under hemolytic conditions initiates the extrinsic pathway of coagulation through the upregulation of TF on endothelial cells and leukocytes, but subsequently blocks the propagation of coagulation by inhibiting FVIII and FV, and by inhibiting the conversion of fibrinogen into fibrin and fibrin clots.

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

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MeSH
Anemia, Sickle Cell
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Review

a(CHEBI:heme) decreases p(HGNC:F8) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

a(CHEBI:heme) decreases a(MESH:Fibrin) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

a(CHEBI:heme) positiveCorrelation bp(GO:"blood coagulation, extrinsic pathway") View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

a(CHEBI:heme) decreases p(HGNC:F5) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

bp(GO:"blood coagulation, extrinsic pathway") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

Evidence 53770d3977
JSON

Most studies concerning the pathophysiological roles of heme have focused on the protective effect of the heme-degrading enzyme, heme oxygenase 1 (HO-1) [25] (Box 2), and on the effect of this danger-associated molecule on cells, leading to oxidative stress, TLR4 signaling [26,27], and NLRP3 inflammasome activation [28] (Box 4).

a(CHEBI:heme) increases p(HGNC:TLR4) View Subject | View Object

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a(CHEBI:heme) increases bp(MESH:"Oxidative Stress") View Subject | View Object

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a(CHEBI:heme) increases p(HGNC:NLRP3) View Subject | View Object

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Evidence b44cdd18b1
JSON

Moreover, in vitro studies have demonstrated that heme binds to human platelets and induces platelet activation and aggregation [37–39].

a(CHEBI:heme) increases bp(MESH:"Platelet Aggregation") View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

a(CHEBI:heme) increases bp(GO:"platelet activation") View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

Evidence c2b064c7c2
JSON

For example, one of the severe complications of sickle-cell disease is vaso-occlusion, an outcome that can be triggered in mice upon heme administration [27,32].

a(CHEBI:heme) increases path(HM:"vaso-occlusive crisis") View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

Evidence 2398c3b13b
JSON

Heme may be implicated and contribute to the development of (i) bp(MESH:

a(CHEBI:heme) increases path(MESH:Atherosclerosis) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Serum
MeSH
Anemia, Sickle Cell
Text Location
Review

a(CHEBI:heme) decreases bp(MESH:"Erythrocyte Count") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
erythrocyte
MeSH
Serum
MeSH
Malaria
Text Location
Review

a(CHEBI:heme) increases path(HM:"vaso-occlusive crisis") View Subject | View Object

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

a(CHEBI:heme) increases path(MESH:"Acute Kidney Injury") View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Serum
MeSH
Anemia, Sickle Cell
Text Location
Review

a(CHEBI:heme) increases path(MESH:"Thrombotic Microangiopathies") View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Serum
MeSH
Atypical Hemolytic Uremic Syndrome
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Review

a(CHEBI:heme) increases path(MESH:"Vascular System Injuries") View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Serum
MeSH
Anemia, Sickle Cell
Text Location
Review

Evidence ae24ef20dc
JSON

Heme significantly reduced FVIII cofactor activity by inhibiting its interaction with activated factor IX(FIXa) in vitro.

a(CHEBI:heme) decreases act(p(HGNC:F8)) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

Evidence 3bac671d9d
JSON

From another perspective, in vitro assays have demonstrated that heme can also bind to fibrinogen and decrease its thrombin-mediated cleavage, thus affecting the final common coagulation pathway and reducing fibrin formation, important in clotting [44] (Figure 1).

a(CHEBI:heme) decreases a(MESH:Fibrin) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

Evidence d15a975711
JSON

Heme perturbs the enzymatic activity of thrombin, further contributing to the overall anticoagulant effect and decreased fibrin formation [45].

a(CHEBI:heme) decreases a(MESH:Fibrin) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

Evidence 47b9f63852
JSON

In contrast to the anticoagulant effect of heme on the intrinsic and terminal pathways of coagulation, heme can also trigger the extrinsic pathway of coagulation by upregulating tissue factor (TF) on the surface of human endothelial cells in vitro, as well as on leukocytes and perivascular cells in mice [50,51].

a(CHEBI:heme) increases p(MGI:F3) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

Evidence 33ac82896e
JSON

For example, the in vitro appearance of strong reactivity towards phospholipids of antibodies from normal human plasma following exposure to heme suggests that heme, when released in vivo, may perturb coagulation processes indirectly via its effects on antibodies.

a(CHEBI:heme) negativeCorrelation bp(MESH:"Antibody Specificity") View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

bp(MESH:"Antibody Specificity") negativeCorrelation a(CHEBI:heme) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

Evidence 806f028e30
JSON

Hemolytic diseases are often accompanied by dysregulation and overactivation of the complement system [72–74], which may be induced by free extracellular heme [33,75–77] (Figure 3B).

a(CHEBI:heme) increases bp(GO:"complement activation") View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

Evidence 719d7dec11
JSON

C3a and C5a anaphylatoxins, as well as the soluble membrane attack complex (sC5b9), are generated by incubation of heme with human serum or blood in vitro, via the alternative complement pathway [33,77] (Box 5).

a(CHEBI:heme) increases a(MESH:"Complement C5a") View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

a(CHEBI:heme) increases a(MESH:"Complement Membrane Attack Complex") View Subject | View Object

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Annotations
MeSH
Anemia, Sickle Cell
Text Location
Review

a(CHEBI:heme) increases a(MESH:"Complement C3a") View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

Evidence 1bf101bccc
JSON

Furthermore, the incubation of serum or whole blood with heme induces deposition of activation fragments (C3b, iC3b, C3dg) of complement component 3 (C3) at the surface of erythrocytes [77].

a(CHEBI:heme) increases p(HGNC:C3) View Subject | View Object

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

Evidence 749d22afd5
JSON

It is possible that heme-induced overactivation of the alternative complement pathway, and depo- sition of C3 fragments on erythrocyte membranes, participate in erythrophagocytosis of uninfected red blood cells in severe forms of malaria [77].

a(CHEBI:heme) increases bp(GO:"complement activation, alternative pathway") View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Malaria
Text Location
Review

a(HM:erythrophagocytosis) positiveCorrelation bp(GO:"complement activation, alternative pathway") View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Malaria
Text Location
Review

bp(GO:"complement activation, alternative pathway") positiveCorrelation a(HM:erythrophagocytosis) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Malaria
Text Location
Review

Evidence 0a84722faf
JSON

Heme exposure of other proteins in the alternative pathway (factors B, D, and H) does not appear to have any impact on their functions, thus implying that heme activates the alternative complement pathway by affecting C3 directly [33].

a(CHEBI:heme) increases bp(GO:"complement activation, alternative pathway") View Subject | View Object

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

a(CHEBI:heme) causesNoChange p(HGNC:CFB) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Malaria
Text Location
Review

a(CHEBI:heme) causesNoChange p(HGNC:CFD) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Malaria
Text Location
Review

a(CHEBI:heme) causesNoChange p(HGNC:CFH) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Malaria
Text Location
Review

Evidence 7ae37139da
JSON

The inhibitory effect of heme on the classical pathway is in agreement with in vitro functional assays showing that heme is capable of activating only the alternative pathway in human sera.

a(CHEBI:heme) increases bp(GO:"complement activation, alternative pathway") View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Serum
MeSH
Malaria
Text Location
Review

a(CHEBI:heme) decreases bp(GO:"complement activation, classical pathway") View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Serum
MeSH
Malaria
Text Location
Review

Evidence 100bfa2219
JSON

In contrast to its overactivating effects on the alternative pathway, heme inhibits the classical pathway. It binds to C1q, alters its electrostatic properties, and hampers the recognition of target molecules. This results in a reduction of classical pathway C3 convertase formation and C3b deposition.

a(CHEBI:heme) increases bp(GO:"complement activation, alternative pathway") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Serum
MeSH
Malaria
Text Location
Review

a(CHEBI:heme) decreases act(p(PFAM:C1q)) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Serum
MeSH
Malaria
Text Location
Review

a(CHEBI:heme) decreases bp(GO:"complement activation, classical pathway") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
erythrocyte
MeSH
Serum
MeSH
Malaria
Text Location
Review

Evidence 2fd40674d1
JSON

Moreover, exposure of endothelial cells to heme results in diminished surface expression of the negative complement regulators decay-accelerating factor (DAF) and membrane cofactor protein (MCP) [33], and hence reduces protection against complement.

a(CHEBI:heme) decreases p(HGNC:CD55) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Malaria
Text Location
Review

a(CHEBI:heme) decreases p(HGNC:CD46) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Malaria
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Evidence 3f2533cafe
JSON

Heme could suppress C1q binding to its main ligands, immunoglobulins and C-reactive protein (CRP), in a concentrationdepended manner.

a(CHEBI:heme) decreases act(p(PFAM:C1q)) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Malaria
Text Location
Review

Evidence c38a443d3f
JSON

The mechanism behind this erythrocyte loss is not well understood but may be related to reduced erythrocyte deformability, accelerated senescence, or to complement or antibody-mediated (anti-erythrocyte) erythrophagocytosis [79].

a(HM:erythrophagocytosis) decreases bp(MESH:"Erythrocyte Count") View Subject | View Object

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

bp(MESH:"Erythrocyte Count") positiveCorrelation bp(MESH:"Erythrocyte Deformability") View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Anemia, Sickle Cell
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Review

bp(MESH:"Erythrocyte Deformability") positiveCorrelation bp(MESH:"Erythrocyte Count") View Subject | View Object

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

Evidence 0dc71ec5a1
JSON

Plasmodium-mediated lysis of a single infected erythrocyte in vivo was shown to result in the lysis of 8–10 uninfected cells [78,79].

act(a(MESH:Plasmodium)) increases path(MESH:Hemolysis) View Subject | View Object

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

Evidence 303a3787f1
JSON

Indeed, the severe forms of malaria are associated with activation of the complement system [74].

bp(GO:"complement activation") association path(MESH:Malaria) View Subject | View Object

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

path(MESH:Malaria) association bp(GO:"complement activation") View Subject | View Object

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

Evidence 74dae37a90
JSON

Interestingly, a recent study demonstrated that, in severe hemolytic disease (sickle cell anemia), at least one third of plasma heme was associated with membrane vesicle structures (microparticles) that were generated from erythrocytes during hemolysis [24].

bp(MESH:Eryptosis) increases a(MESH:"Cell-Derived Microparticles") View Subject | View Object

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path(MESH:Hemolysis) increases a(MESH:"Cell-Derived Microparticles") View Subject | View Object

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Evidence d3ae229964
JSON

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.

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

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

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Evidence 04973a7d31
JSON

Molecular docking predicted the interaction of heme in close proximity to a thioester bond, known to be important for the activation of C3.

complex(a(CHEBI:heme), a(CHEBI:thioester)) increases p(HGNC:C3) View Subject | View Object

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Cell Ontology (CL)
erythrocyte
MeSH
Malaria
Text Location
Review

Evidence 6d3bd66b6e
JSON

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

p(HGNC:HPX) decreases a(CHEBI:heme) View Subject | View Object

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

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Evidence 0b10df7aff
JSON

In cases of extensive and chronic hemolysis, levels of haptoglobin and hemopexin in plasma decrease markedly [20,21].

p(HGNC:HPX) negativeCorrelation path(MESH:Hemolysis) View Subject | View Object

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p(HGNC:HP) negativeCorrelation path(MESH:Hemolysis) View Subject | View Object

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path(MESH:Hemolysis) negativeCorrelation p(HGNC:HP) View Subject | View Object

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path(MESH:Hemolysis) negativeCorrelation p(HGNC:HPX) View Subject | View Object

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Evidence b6848421b9
JSON

However, in contrast to its effect on C3, exposure of C1q to heme was demonstrated to inhibit its functions in vitro [89,90] (Figure 3B).

complex(a(CHEBI:heme), p(PFAM:C1q)) decreases act(p(HGNC:C3)) View Subject | View Object

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

Evidence f4fcf1feee
JSON

In the extrinsic pathway of coagulation, upregulated TF binds to activated factor VII (FVIIa), thus leading to activation of FX.

complex(p(HGNC:F3), p(HGNC:F7)) increases p(HGNC:F10) View Subject | View Object

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

Evidence 038c2cb057
JSON

Excess extracellular heme is weakly bound to albumin [22], /1-microglobulin (which can also degrade heme) [23] and, most likely, to other plasma proteins and lipoproteins; there is a dynamic nature to such interactions.

p(HGNC:AMBP) decreases a(CHEBI:heme) View Subject | View Object

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Evidence d99bb84173
JSON

This scenario may resemble that of paroxysmal nocturnal hemoglobinuria patients, who can be treated with complement C5- blocking antibody eculizumab [80]; in this example, extravascular hemolysis has been shown to occur in a small number of these patients despite treatment. It has been suggested that this is due to erythrophagocytosis of red blood cells deficient in the C3d-opsonized complement regulators – CD55 and CD59 [81,82].

p(HGNC:CD55) decreases path(MESH:Hemolysis) View Subject | View Object

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

p(HGNC:CD59) decreases path(MESH:Hemolysis) View Subject | View Object

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

Evidence 85d0c0b16f
JSON

In humans and mice, VWF protects FVIII from degradation by proteases in the circulation and controls FVIII catabolism [43].

p(HGNC:VWF) decreases deg(p(HGNC:F8)) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Review

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