Transient Improvement in Erythropoiesis Is Achieved Via the Chaperone AHSP With Early Administration of Propranolol in Burn Patients

Abstract

Burn patients experience erythropoietin resistant anemia in which early commitment and late maturation of erythroblasts are defective. We previously showed that propranolol (Prop) treatment restores erythroid committed progenitors, but terminal maturation remains impaired. Hemoglobinization and maturation occurs during terminal erythropoiesis and these processes are aided by an erythroblast intrinsic functional protein called alpha hemoglobin stabilizing protein (AHSP). We evaluated the role of AHSP in PBMC (peripheral blood mono nuclear cell) derived erythroblasts and the implications of Prop in burn patients. Blood samples were collected at three time points from seventeen patients receiving standard burn care (SBC) or Prop. Five healthy volunteers provided control plasma (CP). PBMCs were placed in biphasic cultures with 5% autologous plasma (BP) or CP. Erythroblasts were harvested during mid and late maturation stages; the percentage of AHSP + erythroblasts, AHSP expression, and relative distribution of reticulocytes and polychromatophilic erythroblasts (PolyE) were determined by cytometry. During the second time point (7-10 days post burn), Prop cohort required 35% less transfusions. At mid maturation, PBMCs from Prop treated patients cultured in BP had 33% more AHSP + erythroblasts and 40% more AHSP expression compared to SBC. Furthermore, at late maturation, Prop had 50% more reticulocytes and 30% less PolyEs in CP versus BP compared to SBC (11% and 6% respectively). AHSP is positively associated with late stage maturation of PBMC derived erythroblasts in the presence of CP. Albeit transiently, this is more pronounced in Prop than SBC. Early administration of propranolol in burn patients supports erythropoiesis via the chaperone AHSP.

Temporal trends, predictors of blood transfusion and in‐hospital outcomes among patients with severe burn injury in the United States—A national database‐based analysis

“…7,8 Later, anemia may originate from chronic bleeding from unhealed wounds, augmented red cell damage, bone marrow suppression, erythropoietin (EPO)-resistant iron deficiency, and nutritional deficiencies. 3,9,10 In accordance with previous research, patient's age, full-thickness burn size and the number of operations have been identified as significant predictors of blood transfusion in adults with burns > 40% TBSA, studied retrospectively. 11 Another retrospective study in 89 adults with burns between 10% and 65% of the TBSA found that larger extent of burn and the use of therapeutic anticoagulation were significantly correlated with blood transfusion.…”

Adrenergic Modulation of Erythropoiesis After Trauma

“…There still is a need for further studies of the use of adrenergic modulation in specific trauma types and different age groups. The human studies of adrenergic modulation of erythropoiesis presented have been performed in both blunt trauma and burn patients ( Bible et al, 2014 ; Hasan et al, 2017a ; Loftus et al, 2018c ; Walczak et al, 2021 ). However, no studies to date have investigated the use of alpha agonists or beta antagonists and effects on erythropoiesis in patients subject to penetrating trauma.…”

“…In a study of burn patients who received propranolol during their hospital stay, evaluation of serial blood samples demonstrated increased numbers of erythroid progenitors and decreased MafB expression in multipotent progenitors ( Hasan et al, 2017a ). In a separate study, burn patients who received propranolol as part of their treatment were found to have greater numbers of erythroblasts and alpha hemoglobin stabilizing protein, which is associated with late stage maturation of erythroblasts, compared to patients who had not received propranolol ( Walczak et al, 2021 ). Burn patients who received propranolol also were found to have significantly fewer blood transfusion requirements during their hospitalization ( Walczak et al, 2021 ).…”

“…In a separate study, burn patients who received propranolol as part of their treatment were found to have greater numbers of erythroblasts and alpha hemoglobin stabilizing protein, which is associated with late stage maturation of erythroblasts, compared to patients who had not received propranolol ( Walczak et al, 2021 ). Burn patients who received propranolol also were found to have significantly fewer blood transfusion requirements during their hospitalization ( Walczak et al, 2021 ). A four-year retrospective cohort analysis of trauma patients administered non-selective beta blockade and/or clonidine demonstrated significantly higher hemoglobin at time of discharge compared to trauma patients who did not receive either medication; although notably this study did not separate groups into the medication received, the majority (81%) of patients had exclusively received a non-selective beta blocker ( Loftus et al, 2018c ).…”

β adrenergic signaling regulates hematopoietic stem and progenitor cell commitment and therapy sensitivity in multiple myeloma

“…Ficoll gradient isolated mononuclear cells were cultured for phase I expansion in serum-free expansion medium (SFEM) containing granulocyte macrophage colony-stimulating factor (GMCSF), stem cell factor (SCF), interleukin 3 (IL-3 – pluripotent hematopoietic colony-stimulating factor) or further expanded in phase II (day 6-16) by culture in SCF, HT (holo-transferrin), EPO (erythropoietin), and SFEM for all assays involving progenitor cells as previously described. 7 , 8 Cell death/viability were assessed by AnnexinV/DAPI flow cytometry. The CoMMpass MM trial (clinicaltrials gov.…”