Hemolytic anemia blunts the cytokine response to transfusion of older red blood cells in mice and dogs

Abstract

Background: Transfusion of red blood cells (RBCs) stored for longer durations induces hemolysis and inflammatory cytokine production in murine and canine models. Despite immune system activation by stored RBCs, human randomized trials suggest that fresher RBC transfusions do not improve clinical outcomes. We hypothesized that underlying recipient hemolysis may affect cytokine responses to older RBC transfusions. Study design and methods: C57BL/6 mouse cohorts were infused with anti-TER119 antibody to induce hemolysis, rabbit anti-platelet antiserum to induce immune thrombocytopenia (ITP), or appropriate control antibodies. Two days later, mice were transfused with fresh or stored RBCs. Furthermore, in a prospective, randomized, blinded trial, 38 client-owned dogs with primary autoimmune hemolytic anemia (AIHA) and two dogs with ITP, requiring RBC transfusion, were enrolled and randomized to receive fresh (≤7 days) or old (≥21 days) stored RBC transfusions. Monocyte chemoattractant protein (MCP)-1 levels were assessed at defined times after transfusion. Results: Prior immune-mediated hemolysis blunted the MCP-1 response to stored RBC transfusion in mice (361 ± 111 pg/ml vs. 6836 ± 1528 pg/ml in mice with immune hemolysis vs. ITP, respectively; mean ± SD; p < .0001). Although hemolysis markers increased after transfusion of older RBCs, the cytokine response was also muted in dogs with AIHA. No differences in morbidity or mortality were evident comparing dogs randomized to fresh or old RBCs. Conclusion:These data suggest that underlying hemolysis blunts inflammatory responses to old RBC transfusions. The canine data support randomized trial results suggesting a lack of clinical benefit with fresh RBC transfusions in subjects with underlying, baseline hemolysis.

Red blood cell transfusion‐induced non‐transferrin‐bound iron promotes Pseudomonas aeruginosa biofilms in human sera and mortality in catheterized mice

“…2 Because standard RBC units contain ˜200-250 mg of haemoglobin iron, rapid post-transfusion clearance of significant numbers of storage-damaged RBCs overwhelms the monocyte/macrophage system, 3 thereby releasing significant amounts of haemoglobin iron into the circulation in both animal models and humans. [4][5][6][7] The rate of iron release can be sufficient to saturate transferrin, the physiologic iron transporter in the circulation, thereby producing non-transferrin-bound iron (NTBI). 7 NTBI promotes proliferation and virulence of specific siderophilic bacterial species; thus, hepcidin-mediated elimination of NTBI may be an important mechanism of host defence.…”

“…the ‘RBC storage lesion’), thus impairing their transfusion quality and circulatory lifespan post‐transfusion 2 . Because standard RBC units contain ˜200–250 mg of haemoglobin iron, rapid post‐transfusion clearance of significant numbers of storage‐damaged RBCs overwhelms the monocyte/macrophage system, 3 thereby releasing significant amounts of haemoglobin iron into the circulation in both animal models and humans 4–7 . The rate of iron release can be sufficient to saturate transferrin, the physiologic iron transporter in the circulation, thereby producing non‐transferrin‐bound iron (NTBI) 7 .…”

Large Animal Models for Simulating Physiology of Transfusion of Red Cell Concentrates—A Scoping Review of The Literature

“…However, the study by Muenster et al exposed erythrocyte concentrates to oxygen or nitric oxide prior to transfusion [21]. (C) In 13 out of the 36 included studies, a total of 440 dogs were included, with only three studies describing a repeated use of the same animals [14,[42][43][44][45][46][47][48][49][50][51][52][53]. Study populations showed similar ranges compared to the other two species, with studies using six to 76 dogs per study [14,[42][43][44][45][46][47][48][49][50][51][52][53].…”

“…(C) In 13 out of the 36 included studies, a total of 440 dogs were included, with only three studies describing a repeated use of the same animals [14,[42][43][44][45][46][47][48][49][50][51][52][53]. Study populations showed similar ranges compared to the other two species, with studies using six to 76 dogs per study [14,[42][43][44][45][46][47][48][49][50][51][52][53]. In three out of 13 publications, male and female dogs were included in the same study [42,50,53].…”

“…Study populations showed similar ranges compared to the other two species, with studies using six to 76 dogs per study [14,[42][43][44][45][46][47][48][49][50][51][52][53]. In three out of 13 publications, male and female dogs were included in the same study [42,50,53]. For all studies in pigs and sheep, animals of only one sex were used for each study.…”