Characterization of post-traumatic immunosuppression and its partial reversal by autologous salvaged blood transfusion
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Documentary evidence of post-traumatic immunosuppression (PTI) is traceable back to 1856. Although improved hygiene has ameliorated many risks, vulnerability to systemic infection following major surgery or closed injury persists. Underlying mechanisms remain enigmatic and few effective treatments exist. Knee replacement surgery offers an ideal clinical model to characterize immune status after sterile trauma in terms of blood biomarkers. The main objective was to identify biomarkers of PTI, and establish how these were altered by anti-coagulated salvaged blood transfusion. A prospective non-randomized cohort study involved 43 patients undergoing primary total knee arthroplasty, 25 of whom received anti-coagulated salvaged blood transfusions collected post-operatively, and 18 non-transfused patients. Biomarkers of sterile trauma included haematological values, Damage-Associated-Molecular-Patterns (DAMPs), cytokines, and chemokines. Salvaged blood was analysed within one hour and six hours after commencing collection. Biomarker levels were expressed as fold-changes over pre-operative values. Two groups of biomarkers were revealed: the first were termed as 'common biomarkers of sterile trauma' that were common to all 43 patients with no differences in changes between the two cohorts; whereas the second were termed as 'Salvaged Blood Sensitive Biomarkers of sterile trauma' as these were reversed by anti-coagulated salvaged blood re-infusion. The former included the following: leukocytosis, monocytosis, neutrophilia, erythropenia, decreased haemoglobin and haematocrit values, thrombocytopenia, lymphopenia, and also decreased numbers of eosinophils and basophils; increased levels of: Interleukin (IL)-6, IL-1-Receptor-Antagonist (IL-1RA), IL-8, Heat-Shock-Protein-(HSP)-70, Calgranulin-S100-A8/9, alpha-Defensins, Heat Stable Antigen (CD24), Sialic Acid Binding Ig-Like Protein-10 (Siglec-10), Soluble CD14, Lysozyme and Anaphylatoxin C5a; and, decreased levels of Soluble IL-6 Receptor, Soluble gp130 and High Mobility Group Box Protein-1 (HMGB-1). SBS-BST included increased levels of: IL-1-beta, IL-2, IL-17A, Interferon-gamma (IFN-gamma), Tumour-Necrosis-Factor-alpha (TNF-alpha), Annexin-A2, ADAM-17 and IL-22; and decreased levels of: IL-4, IL-5, IL-10, and IL-13. Analyses of salvaged blood revealed two groups of biomarkers. The first group was termed as 'Stable biomarkers of salvaged blood' that had no additional production during the collection period in the bag, and were assumed to have been continuously synthesized in-vivo within the wound site. Stable biomarkers included: sustained high levels of certain DAMPs including: Calgranulin-S100-A8/9, alpha-Defensin, HSP-27, HSP-60, HSP-70, alpha-Defensins IL-9; and low levels of IL-13. The second group termed as 'Dynamic biomarkers of salvaged blood', since on-going synthesis or reduction was observed during ex-vivo collections of salvaged blood. These included: increasing levels of Annexin-A2, IL-1-beta, IL-1RA, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IFN-gamma, TNF-alpha, Transforming-Growth-Factor-Beta-1 (TGF-Beta-1), Monocyte-Chemotactic-Protein-1, Macrophage-Inflammatory-Protein-1-alpha, IL-22, ADAM-17, Soluble CD14, Lysozyme; and, decreasing levels of HMGB-1 and Keratinocyte Growth Factor. This study also indicated that sterile trauma human enhanced levels of antimicrobial proteins, including soluble CD14, Lysozyme, Calgranulin and alpha-Defensin. Furthermore elevated levels of Siglec-10 and soluble CD24 suggested enhanced regulation of autoimmune reaction to neoantigens exposed by necrotic tissues. This study showed that whereas early salvaged blood reflected suppressed immune status associated with PTI, it developed immunostimulatory properties ex-vivo that upon reinfusion subsequently reversed PTI. The detailed characterisations of immunostimulatory constituents of salvaged blood responsible for this phenomenon and their therapeutic potential have yet to be performed.
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