Haptoglobin therapy has differential effects depending on severity of canine septic shock and cell-free hemoglobin level.
Journal
Transfusion
ISSN: 1537-2995
Titre abrégé: Transfusion
Pays: United States
ID NLM: 0417360
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
08
07
2019
accepted:
12
09
2019
pubmed:
23
10
2019
medline:
17
6
2020
entrez:
23
10
2019
Statut:
ppublish
Résumé
During sepsis, higher plasma cell-free hemoglobin (CFH) levels portend worse outcomes. In sepsis models, plasma proteins that bind CFH improve survival. In our canine antibiotic-treated Staphylococcus aureus pneumonia model, with and without red blood cell (RBC) exchange transfusion, commercial human haptoglobin (Hp) concentrates bound and compartmentalized CFH intravascularly, increased CFH clearance, and lowered iron levels, improving shock, lung injury, and survival. We now investigate in our model how very high CFH levels and treatment time affect Hp's beneficial effects. Two separate canine pneumonia sepsis Hp studies were undertaken: one with exchange transfusion of RBCs after prolonged storage to raise CFH to very high levels and another with rapidly lethal sepsis alone to shorten time to treat. All animals received continuous standard intensive care unit supportive care for 96 hours. Older RBCs markedly elevated plasma CFH levels and, when combined with Hp therapy, created supraphysiologic CFH-Hp complexes that did not increase CFH or iron clearance or improve lung injury and survival. In a rapidly lethal bacterial challenge model without RBC transfusion, Hp binding did not increase clearance of complexes or iron or show benefits seen previously in the less lethal model. High-level CFH-Hp complexes may impair clearance mechanisms and eliminate Hp's beneficial effect during sepsis. Rapidly lethal sepsis narrows the therapeutic window for CFH and iron clearance, also decreasing Hp's beneficial effects. In designing clinical trials, dosing and kinetics may be critical factors if Hp infusion is used to treat sepsis.
Sections du résumé
BACKGROUND
During sepsis, higher plasma cell-free hemoglobin (CFH) levels portend worse outcomes. In sepsis models, plasma proteins that bind CFH improve survival. In our canine antibiotic-treated Staphylococcus aureus pneumonia model, with and without red blood cell (RBC) exchange transfusion, commercial human haptoglobin (Hp) concentrates bound and compartmentalized CFH intravascularly, increased CFH clearance, and lowered iron levels, improving shock, lung injury, and survival. We now investigate in our model how very high CFH levels and treatment time affect Hp's beneficial effects.
MATERIALS AND METHODS
Two separate canine pneumonia sepsis Hp studies were undertaken: one with exchange transfusion of RBCs after prolonged storage to raise CFH to very high levels and another with rapidly lethal sepsis alone to shorten time to treat. All animals received continuous standard intensive care unit supportive care for 96 hours.
RESULTS
Older RBCs markedly elevated plasma CFH levels and, when combined with Hp therapy, created supraphysiologic CFH-Hp complexes that did not increase CFH or iron clearance or improve lung injury and survival. In a rapidly lethal bacterial challenge model without RBC transfusion, Hp binding did not increase clearance of complexes or iron or show benefits seen previously in the less lethal model.
DISCUSSION
High-level CFH-Hp complexes may impair clearance mechanisms and eliminate Hp's beneficial effect during sepsis. Rapidly lethal sepsis narrows the therapeutic window for CFH and iron clearance, also decreasing Hp's beneficial effects. In designing clinical trials, dosing and kinetics may be critical factors if Hp infusion is used to treat sepsis.
Identifiants
pubmed: 31639229
doi: 10.1111/trf.15567
pmc: PMC8216248
mid: NIHMS1706764
doi:
Substances chimiques
Haptoglobins
0
Hemoglobins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3628-3638Subventions
Organisme : NHLBI NIH HHS
ID : P01 HL103455
Pays : United States
Organisme : NHLBI NIH HHS
ID : 2R01HL098032
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL110849
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA CL090026
Pays : United States
Organisme : NHLBI NIH HHS
ID : 1R01HL125886
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL098032
Pays : United States
Organisme : NHLBI NIH HHS
ID : 5P01HL103455
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL125886
Pays : United States
Informations de copyright
Published 2019. This article is a U.S. Government work and is in the public domain in the USA.
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