Platelet transfusions in a murine model of neonatal polymicrobial sepsis: Divergent effects on inflammation and mortality

Davenport, Patricia; Fan, Hsuan-Hao; Nolton, Emily; Feldman, Henry A.; Lorenz, Viola; Canas, Jorge; Acosta-Zaldívar, Maikel; Yakah, William; Arthur, Connie M.; Martin, Camilia R.; Stowell, Sean R.; Koehler, Julia; Mager, Donald E.; Sola‐Visner, Martha

doi:10.1111/trf.16895

Cited by 10 publications

(8 citation statements)

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“…Thrombocytopenia is typically defined as a platelet count <150 000 platelets/µL of blood in humans and is common in preterm and low-birth-weight neonates, affecting 18% to 35% of neonatal intensive care unit patients. 1 There are conflicting data on whether the degree of thrombocytopenia is associated with major bleeding risk in neonates and on whether neonatal platelet transfusions increase or decrease the risk of major bleeding episodes. 2–4 A recent study of 1221 preterm infants noted a lower platelet count was significantly associated with increased risks of hemorrhage and mortality, 2 but whether platelet transfusions are beneficial in neonates may be dependent on many factors.…”

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confidence: 99%

Transfusion of Adult, but Not Neonatal, Platelets Promotes Monocyte Trafficking in Neonatal Mice

Maurya

Ture

et al. 2023

ATVB

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BACKGROUND: Thrombocytopenia is common in preterm neonates. Platelet transfusions are sometimes given to thrombocytopenic neonates with the hope of reducing the bleeding risk, however, there are little clinical data to support this practice, and platelet transfusions may increase the bleeding risk or lead to adverse complications. Our group previously reported that fetal platelets expressed lower levels of immune-related mRNA compared with adult platelets. In this study, we focused on the effects of adult versus neonatal platelets on monocyte immune functions that may have an impact on neonatal immune function and transfusion complications. METHODS: Using RNA sequencing of postnatal day 7 and adult platelets, we determined age-dependent platelet gene expression. Platelets and naive bone marrow–isolated monocytes were cocultured and monocyte phenotypes determined by RNA sequencing and flow cytometry. An in vivo model of platelet transfusion in neonatal thrombocytopenic mice was used in which platelet-deficient TPOR (thrombopoietin receptor) mutant mice were transfused with adult or postnatal day 7 platelets and monocyte phenotypes and trafficking were determined. RESULTS: Adult and neonatal platelets had differential immune molecule expression, including Selp . Monocytes incubated with adult or neonatal mouse platelets had similar inflammatory (Ly6C hi ) but different trafficking phenotypes, as defined by CCR2 and CCR5 mRNA and surface expression. Blocking P-sel (P-selectin) interactions with its PSGL-1 (P-sel glycoprotein ligand-1) receptor on monocytes limited the adult platelet-induced monocyte trafficking phenotype, as well as adult platelet-induced monocyte migration in vitro. Similar results were seen in vivo, when thrombocytopenic neonatal mice were transfused with adult or postnatal day 7 platelets; adult platelets increased monocyte CCR2 and CCR5, as well as monocyte chemokine migration, whereas postnatal day 7 platelets did not. CONCLUSIONS: These data provide comparative insights into adult and neonatal platelet transfusion–regulated monocyte functions. The transfusion of adult platelets to neonatal mice was associated with an acute inflammatory and trafficking monocyte phenotype that was platelet P-sel dependent and may have an impact on complications associated with neonatal platelet transfusions.

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confidence: 99%

Transfusion of Adult, but Not Neonatal, Platelets Promotes Monocyte Trafficking in Neonatal Mice

Maurya

Ture

et al. 2023

ATVB

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“…However, it is unclear whether these short-term morbidities fully explain the worse long-term neurodevelopmental outcomes or whether transfused platelets have direct harmful effects on the developing brain. It is now recognized that, in addition to their important hemostatic functions, platelets are active participants in immune and inflammatory responses, and recent animal studies have reported that platelet transfusions can alter neonatal immune responses . It is therefore possible that transfused platelets may have direct proinflammatory effects on the preterm brain, although this remains speculative.…”

Section: Discussionmentioning

confidence: 99%

Platelet Transfusion and Death or Neurodevelopmental Impairment in Children Born Extremely Preterm

Davenport,

Wood,

Heagerty

et al. 2024

JAMA Netw Open

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ImportanceInfants born extremely preterm receive transfusions at higher platelet count thresholds than older children and adults due to concerns for intracranial hemorrhage. A recent randomized trial comparing 2 platelet transfusion thresholds showed the higher threshold was associated with increased risk of long-term adverse neurodevelopmental outcomes.ObjectiveTo evaluate the association of platelet transfusion exposure with death and severe neurodevelopmental impairment (NDI) at 2 years’ corrected age in a cohort of infants born extremely preterm.Design, Setting, and ParticipantsAn observational cohort study and secondary analysis of the Preterm Erythropoietin Neuroprotection Trial, a randomized, placebo-controlled clinical trial of erythropoietin neuroprotection in neonates born extremely preterm, was conducted in 30 neonatal intensive care units in the US from December 1, 2013, to September 31, 2016. This analysis included 819 infants born extremely preterm at 24 to 27 completed weeks of gestation who had a documented outcome (death or neurodevelopmental assessment). Analysis was performed in April 2023.ExposuresAny platelet transfusion during neonatal intensive care unit hospitalization.Main Outcomes and MeasuresThe primary composite outcome was death or severe NDI evaluated at 2 years’ corrected age using the Bayley Scales of Infant Development–Third Edition (BSID-III) and the Gross Motor Function Classification System and was defined as the presence of severe cerebral palsy or a BSID-III composite motor or cognitive score 2 SDs below the mean. Confounding by indication for platelet transfusion was addressed with covariate adjustment and propensity score methods.ResultsOf the 819 infants included in the analysis (429 [52.4%] male; mean [SD] gestational age, 25.5 [1.1] weeks), 245 (30.0%) received at least 1 platelet transfusion during their initial hospitalization. The primary outcome occurred in 46.5% (114 of 245) of infants exposed to a platelet transfusion and 13.9% (80 of 574) of nonexposed infants with a corresponding odds ratio of 2.43 (95% CI, 1.24-4.76), adjusted for propensity score, gestational age at birth, and trial treatment group. The individual components of death and severe NDI were directionally consistent with the overall composite outcome.Conclusions and RelevanceThe findings of this study suggest that platelet transfusion in infants born extremely preterm may be associated with an increased risk of death or severe NDI at 2 years’ corrected age, although the possibility of residual confounding by indication cannot be excluded.

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“…In a neonatal model of polymicrobial sepsis (using the cecal slurry model), cecal slurry batches differed substantially in their bacterial composition and sepsis-related mortality. Interestingly, platelet transfusions (from adult donors) increased the mortality and the systemic inflammatory response (plasma cytokines) of postnatal day 10 (P10) newborn mice infected with a low-mortality batch, but attenuated the inflammatory response and decreased the mortality of newborn mice infected with a high-mortality batch [49 ▪ ]. These findings demonstrated that platelet transfusions can have either pro-inflammatory or anti-inflammatory effects in sepsis, depending on the type and/or severity of the infectious stimulus.…”

Section: Platelet Transfusions In Neonatesmentioning

confidence: 99%

Immunologic effects of red blood cell and platelet transfusions in neonates

Davenport

Sola‐Visner²

2022

Current Opinion in Hematology

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Purpose of ReviewPremature neonates are frequently transfused red blood cells (RBCs) or platelets to raise hemoglobin or platelet counts. However, these transfusions may have unintended effects on the immune system. This review will summarize the newest discoveries on the immunologic effects of RBC and platelet transfusions in neonates, and their potential impact on neonatal outcomes. Recent FindingsNeonatal RBC transfusions are associated with increases in plasma pro-inflammatory cytokines, but recent findings suggest sex-specific differential responses. At least one cytokine (monocyte chemoattractant protein-1) rises in females receiving RBC transfusions, but not in males. These inflammatory responses correlate with poorer neurodevelopmental outcomes in heavily transfused female infants, while preterm male infants seem to be more sensitive to severe anemia. Platelet transfusions in preterm neonates are associated with increased neonatal mortality and morbidity. The underlying mechanisms are unknown, but likely related to the immune/inflammatory effects of transfused platelets. Adult platelets are different from neonatal platelets, with the potential to be more pro-inflammatory. Early preclinical data suggest that platelet transfusions alter the neonatal systemic inflammatory response and enhance immune cell migration. SummaryRBC and platelet transfusions alter neonatal immune and inflammatory responses. Their pro-inflammatory effects might worsen neonatal disease or affect neurodevelopmental outcomes.

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Platelet transfusions in a murine model of neonatal polymicrobial sepsis: Divergent effects on inflammation and mortality

Cited by 10 publications

References 65 publications

Transfusion of Adult, but Not Neonatal, Platelets Promotes Monocyte Trafficking in Neonatal Mice

Transfusion of Adult, but Not Neonatal, Platelets Promotes Monocyte Trafficking in Neonatal Mice

Platelet Transfusion and Death or Neurodevelopmental Impairment in Children Born Extremely Preterm

Immunologic effects of red blood cell and platelet transfusions in neonates

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