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PubMed: 27515135

Title
Haptoglobin or Hemopexin Therapy Prevents Acute Adverse Effects of Resuscitation After Prolonged Storage of Red Cells.
Journal
Circulation
Volume
134
Issue
None
Pages
945-60
Date
2016-09-27
Authors
Liu Y | Graw JA | Zapol WM | Bloch DB | Bonventre JV | Colvin RB | Malhotra R | Mayeur C | Rechester O | Riley FE | Rosales I | Sabbisetti VS | Warren HS

Evidence 3e7f0fea93
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Tissue iron staining revealed greater cortical iron accumulation in the kidneys of mice resuscitated with SRBCs, SRBCs combined with albumin and SRBCs combined with hemopexin than in the kidneys of mice transfused with FRBCs (Figure 6A and B).

a(CHEBI:"iron(2+)") positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

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Kidney Cortex
MeSH
Hemorrhage
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a(CHEBI:"iron(2+)") positiveCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hpx)) View Subject | View Object

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MeSH
Kidney Cortex
MeSH
Hemorrhage
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a(CHEBI:"iron(2+)") positiveCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Alb)) View Subject | View Object

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Kidney Cortex
MeSH
Hemorrhage
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a(MESH:"Blood Transfusion") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

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Kidney Cortex
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Hemorrhage
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complex(a(MESH:"Blood Transfusion"), p(MGI:Alb)) positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

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Kidney Cortex
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Hemorrhage
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complex(a(MESH:"Blood Transfusion"), p(MGI:Hpx)) positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

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Kidney Cortex
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Hemorrhage
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Evidence 2cef310dce
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Splenic iron content was greater in mice after resuscitation with SRBCs than in FRBC-transfused mice.

a(CHEBI:"iron(2+)") positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

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Spleen
MeSH
Hemorrhage
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a(MESH:"Blood Transfusion") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

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Spleen
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Hemorrhage
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Evidence 0c6e1f1467
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Taken together, these results indicate that haptoglobin co-transfusion prevented stored blood transfusion-associated renal iron uptake and led to increased weight and greater iron- accumulation in the spleens of mice.

a(CHEBI:"iron(2+)") positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

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Spleen
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Hemorrhage
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a(MESH:"Blood Transfusion") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

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Spleen
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Hemorrhage
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Evidence d1e8be6066
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Only transfusion of SRBCs and haptoglobin prevented SRBC-induced renal iron accumulation (Figure 6A and B).

a(CHEBI:"iron(2+)") negativeCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) View Subject | View Object

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Kidney Cortex
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Hemorrhage
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complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) negativeCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

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Kidney Cortex
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Hemorrhage
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Evidence e4195e5513
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In comparison to mice transfused with SRBCs alone, the spleens of mice resuscitated with SRBCs and haptoglobin contained more iron (Figure 6D).

a(CHEBI:"iron(2+)") positiveCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) View Subject | View Object

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Spleen
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Hemorrhage
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complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

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Spleen
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Hemorrhage
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Evidence 4e72db901d
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Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24.

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

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

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

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

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

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

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

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

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Evidence ae16b3b1a0
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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.

a(CHEBI:heme) positiveCorrelation bp(MESH:"Lipid Peroxidation") View Subject | View Object

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a(CHEBI:heme) positiveCorrelation a(MESH:"Reactive Oxygen Species") View Subject | View Object

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a(MESH:"Reactive Oxygen Species") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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bp(MESH:"Lipid Peroxidation") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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

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Evidence e6ff4547ad
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Cell-free heme selectively triggers pro-inflammatory receptors such as TLR-4 and BACH-1, and activates proteasomes25.

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

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a(CHEBI:heme) positiveCorrelation act(p(PFAM:Proteasome)) View Subject | View Object

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a(CHEBI:heme) positiveCorrelation p(HGNC:BACH1) View Subject | View Object

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

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p(HGNC:BACH1) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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act(p(PFAM:Proteasome)) positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence ebfc4c9fb5
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The increase in hemopexin was associated with decreased plasma heme levels (Figure 3I).

a(CHEBI:heme) negativeCorrelation p(MGI:Hpx) View Subject | View Object

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Plasma
MeSH
Hemorrhage
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p(MGI:Hpx) negativeCorrelation a(CHEBI:heme) View Subject | View Object

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Plasma
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Hemorrhage
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Evidence 70df395f8b
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These results demonstrate that transfusion with SRBCs and simultaneous infusion of exogenous hemopexin results in decreased levels of circulating cell-free heme.

a(CHEBI:heme) negativeCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hpx)) View Subject | View Object

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Plasma
MeSH
Hemorrhage
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complex(a(MESH:"Blood Transfusion"), p(MGI:Hpx)) negativeCorrelation a(CHEBI:heme) View Subject | View Object

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Plasma
MeSH
Hemorrhage
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Evidence 3c78c9ecd7
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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.

a(MESH:"Blood Transfusion") positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

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

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

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Hemorrhage
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path(MESH:Hemolysis) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

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Hemorrhage
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Evidence f35204936d
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Hemoglobinuria was noted in mice resuscitated with SRBCs alone but not mice resuscitated with FRBCs or sham-treated mice (Figure 4A and B).

a(MESH:"Blood Transfusion") positiveCorrelation path(MESH:Hemoglobinuria) View Subject | View Object

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Plasma
MeSH
Hemorrhage
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path(MESH:Hemoglobinuria) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

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MeSH
Plasma
MeSH
Hemorrhage
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Results

Evidence fb65e19336
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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).

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

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

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Hemorrhage
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Evidence 69f2b627e9
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After resuscitation with SRBCs, only 58% of mice survived for 48 hours (SRBC vs. FRBC, P<0.05).

a(MESH:"Blood Transfusion") positiveCorrelation a(MESH:Mortality) View Subject | View Object

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Hemorrhage
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a(MESH:Mortality) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

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Hemorrhage
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Evidence 6a41e2f7ac
JSON

In animals resuscitated with SRBCs, plasma hemopexin levels significantly decreased from 147.1±11.4 mg/dl at baseline to 86.7±12.2 and 76.3±5. 4 mg/dl at two and four hours after resuscitation, respectively (p<0.05 for both, Figure 2A).

a(MESH:"Blood Transfusion") negativeCorrelation p(MGI:Hpx) View Subject | View Object

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Hemorrhage
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p(MGI:Hpx) negativeCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

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Hemorrhage
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Evidence dae193c772
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The increase in plasma haptoglobin levels from baseline to 48 hours after resuscitation was less in mice transfused with SRBCs compared to mice transfused with FRBCs (P<0.001).

a(MESH:"Blood Transfusion") negativeCorrelation p(MGI:Hp) View Subject | View Object

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Hemorrhage
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p(MGI:Hp) negativeCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

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Hemorrhage
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Evidence 06276d732e
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Markers of renal damage, including kidney KIM-1 and NGAL mRNA levels, urinary KIM-1 protein levels, and plasma NGAL concentration, were greater in mice after resuscitation with SRBCs or SRBCs and albumin than in mice transfused with FRBCs (Figures 4C–F).

a(MESH:"Blood Transfusion") positiveCorrelation p(MGI:Havcr1) View Subject | View Object

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Kidney
MeSH
Hemorrhage
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Results

a(MESH:"Blood Transfusion") positiveCorrelation r(MGI:Lcn2) View Subject | View Object

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Kidney
MeSH
Hemorrhage
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a(MESH:"Blood Transfusion") positiveCorrelation p(MGI:Lcn2) View Subject | View Object

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Plasma
MeSH
Hemorrhage
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Results

p(MGI:Havcr1) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

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Kidney
MeSH
Hemorrhage
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p(MGI:Lcn2) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

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Plasma
MeSH
Hemorrhage
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Results

r(MGI:Lcn2) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

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Kidney
MeSH
Hemorrhage
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Evidence 55c239c8ad
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Kidney sections of mice resuscitated with SRBCs showed more cortical Ki-67 positive cells per 20× field (1.08 mm field diameter) than those of mice resuscitated with FRBCs (SRBC vs. FRBC: 156.2±10.4 vs. 56.4±4.7, p<0.01).

a(MESH:"Blood Transfusion") positiveCorrelation p(MGI:Mki67) View Subject | View Object

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Kidney Cortex
MeSH
Hemorrhage
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p(MGI:Mki67) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

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Kidney Cortex
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Hemorrhage
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Evidence 9460dbe154
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Liver damage, measured by plasma levels of alanine transaminase (ALT) and aspartate transaminase (AST) at 48 hours after resuscitation, was greater after resuscitation with SRBCs compared to resuscitation with FRBCs (Figure 6E and F).

a(MESH:"Blood Transfusion") positiveCorrelation p(MGI:Gpt) View Subject | View Object

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Liver
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Hemorrhage
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a(MESH:"Blood Transfusion") positiveCorrelation p(MGI:Got1) View Subject | View Object

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Liver
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Hemorrhage
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p(MGI:Got1) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

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Liver
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Hemorrhage
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p(MGI:Gpt) positiveCorrelation a(MESH:"Blood Transfusion") View Subject | View Object

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Liver
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Hemorrhage
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Evidence 3c8ee2310d
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In contrast, all of the mice survived after SRBC-transfusion and treatment with hemopexin (SRBC+Hx vs. SRBC+Alb, P=0.018). Similarly the survival rate of mice resuscitated with SRBCs and co-infusion of haptoglobin was 96% (SRBC+Hp vs. SRBC+Alb, P=0.030).

a(MESH:Mortality) negativeCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hpx)) View Subject | View Object

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Hemorrhage
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a(MESH:Mortality) negativeCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) View Subject | View Object

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Hemorrhage
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complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) negativeCorrelation a(MESH:Mortality) View Subject | View Object

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Hemorrhage
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complex(a(MESH:"Blood Transfusion"), p(MGI:Hpx)) negativeCorrelation a(MESH:Mortality) View Subject | View Object

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Hemorrhage
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Evidence ea65be9de3
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Tubular regeneration, an indirect marker of tubular injury, was assessed by quantification of the number of Ki-67-positive renal tubular cells at 48 hours after resuscitation and by measuring the level of Ki-67 mRNA in kidney tissue (Figures 5C–E).

bp(GO:"tissue regeneration") positiveCorrelation p(MGI:Mki67) View Subject | View Object

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Kidney Tubules
MeSH
Hemorrhage
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p(MGI:Mki67) positiveCorrelation bp(GO:"tissue regeneration") View Subject | View Object

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Kidney Tubules
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Hemorrhage
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Evidence 64bb00e88d
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Co-administration of haptoglobin with SRBCs results in a prolonged increase in plasma hemoglobin levels for more than 48 hours after transfusion.

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

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

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Plasma
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Hemorrhage
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Evidence 44efc3b3fb
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Infusion of hemopexin together with SRBCs resulted in a 6.4-fold (95% CI [5.2 – 7.6]) increase in plasma hemopexin levels at four hours after transfusion (Figure 3D).

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

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Plasma
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Hemorrhage
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complex(a(MESH:"Blood Transfusion"), p(MGI:Hpx)) positiveCorrelation p(MGI:Hpx) View Subject | View Object

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Plasma
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Hemorrhage
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Evidence b7244f2bf4
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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).

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

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Plasma
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Hemorrhage
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complex(a(MESH:"Blood Transfusion"), p(MGI:Alb)) causesNoChange a(CHEBI:heme) View Subject | View Object

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Plasma
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Hemorrhage
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complex(a(MESH:"Blood Transfusion"), p(MGI:Alb)) causesNoChange p(MGI:Hpx) View Subject | View Object

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Plasma
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Hemorrhage
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complex(a(MESH:"Blood Transfusion"), p(MGI:Alb)) causesNoChange p(MGI:Hp) View Subject | View Object

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Plasma
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Hemorrhage
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Evidence 29a1622a85
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The renal expression level of IL-6 was greater 48 hours after resuscitation with SRBCs alone, SRBC and albumin, and SRBCs and hemopexin when compared to resuscitation with FRBCs (Supplemental Figure VI D).

complex(a(MESH:"Blood Transfusion"), p(MGI:Alb)) positiveCorrelation p(MGI:Il6) View Subject | View Object

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Kidney
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Hemorrhage
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complex(a(MESH:"Blood Transfusion"), p(MGI:Hpx)) positiveCorrelation p(MGI:Il6) View Subject | View Object

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Kidney
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Hemorrhage
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p(MGI:Il6) positiveCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hpx)) View Subject | View Object

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Kidney
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Hemorrhage
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p(MGI:Il6) positiveCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Alb)) View Subject | View Object

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Kidney
MeSH
Hemorrhage
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Evidence 5abfbffcd0
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Mice that were resuscitated with SRBCs and albumin or SRBCs and hemopexin showed a marked increase in HO-1 expression when compared to mice resuscitated with FRBCs.

complex(a(MESH:"Blood Transfusion"), p(MGI:Alb)) positiveCorrelation p(MGI:Hmox1) View Subject | View Object

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Kidney
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Hemorrhage
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complex(a(MESH:"Blood Transfusion"), p(MGI:Hpx)) positiveCorrelation p(MGI:Hmox1) View Subject | View Object

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MeSH
Kidney
MeSH
Hemorrhage
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p(MGI:Hmox1) positiveCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hpx)) View Subject | View Object

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MeSH
Kidney
MeSH
Hemorrhage
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Results

p(MGI:Hmox1) positiveCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Alb)) View Subject | View Object

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MeSH
Kidney
MeSH
Hemorrhage
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Results

Evidence fde4caccec
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Hemoglobinuria was present in mice resuscitated with SRBCs combined with albumin or hemopexin but not in mice resuscitated with SRBCs combined with haptoglobin (Figure 4A and B).

complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) negativeCorrelation path(MESH:Hemoglobinuria) View Subject | View Object

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MeSH
Plasma
MeSH
Hemorrhage
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Results

path(MESH:Hemoglobinuria) negativeCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) View Subject | View Object

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MeSH
Plasma
MeSH
Hemorrhage
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Results

Evidence a89ada69b5
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Co-infusion of haptoglobin but not albumin or hemopexin prevented SRBC-induced hemoglobinuria and kidney injury at 48 hours after resuscitation from hemorrhagic shock.

complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) negativeCorrelation path(MESH:Hemoglobinuria) View Subject | View Object

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MeSH
Kidney Cortex
MeSH
Hemorrhage
Text Location
Results

path(MESH:Hemoglobinuria) negativeCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) View Subject | View Object

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MeSH
Kidney Cortex
MeSH
Hemorrhage
Text Location
Results

Evidence 0f538fe7e7
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However, kidney KIM-1 and NGAL mRNA levels, urinary KIM-1 protein levels and NGAL plasma concentrations in mice transfused with SRBCs and haptoglobin were lower than in mice transfused with SRBCs given a co-infusion of albumin (Figures 4C–F).

complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) negativeCorrelation p(MGI:Havcr1) View Subject | View Object

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MeSH
Kidney
MeSH
Hemorrhage
Text Location
Results

complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) negativeCorrelation r(MGI:Lcn2) View Subject | View Object

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MeSH
Kidney
MeSH
Hemorrhage
Text Location
Results

complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) negativeCorrelation p(MGI:Lcn2) View Subject | View Object

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MeSH
Plasma
MeSH
Hemorrhage
Text Location
Results

p(MGI:Havcr1) negativeCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) View Subject | View Object

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MeSH
Kidney
MeSH
Hemorrhage
Text Location
Results

p(MGI:Lcn2) negativeCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) View Subject | View Object

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MeSH
Plasma
MeSH
Hemorrhage
Text Location
Results

r(MGI:Lcn2) negativeCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) View Subject | View Object

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MeSH
Kidney
MeSH
Hemorrhage
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Results

Evidence 7e8612fd3b
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The number of Ki-67 positive cells in kidneys from mice that received SRBCs and haptoglobin was similar to the number of Ki-67 positive cells in kidneys from mice that received FRBCs..

complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) negativeCorrelation p(MGI:Mki67) View Subject | View Object

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MeSH
Kidney Cortex
MeSH
Hemorrhage
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Results

p(MGI:Mki67) negativeCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) View Subject | View Object

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MeSH
Kidney Cortex
MeSH
Hemorrhage
Text Location
Results

Evidence 5005b6ac7e
JSON

Resuscitation with SRBCs and haptoglobin prevented the increase in SRBC-induced renal HO-1 expression (Figure 7F).

complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) negativeCorrelation p(MGI:Hmox1) View Subject | View Object

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

p(MGI:Hmox1) negativeCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) View Subject | View Object

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

Evidence 445f8d5c4d
JSON

Without adjusting for multiple comparison testing, IL-6 expression was lower in kidneys of mice resuscitated with SRBCs and haptoglobin compared to mice resuscitated with SRBCs and albumin (P<0.05).

complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) negativeCorrelation p(MGI:Il6) View Subject | View Object

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

p(MGI:Il6) negativeCorrelation complex(a(MESH:"Blood Transfusion"), p(MGI:Hp)) View Subject | View Object

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

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

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.