SESSION TITLE: Sepsis and Septic Shock
SESSION TYPE: Original Investigation Slide
PRESENTED ON: Monday, October 28, 2013 at 07:30 AM - 09:00 AM
PURPOSE: The annexin A2 (A2) tetramer is a calcium-dependent, phospholipid-binding complex whose extracellular function is to serve as a co-receptor for tissue plasminogen activator (tPA) and plasminogen (Plg). On the endothelial cell surface, A2, in complex with, S100A10 (aka p11),forms the (A2-p11)2 heterotetramer, which enables tPA-mediated activation of Plg, and facilitates the generation of plasmin for clearance of fibrin from the vascular surface. In sepsis, a disorder characterized by a systemic inflammatory response to infection, coagulation and fibrinolytic pathways are known to be dysregulated. Based upon preliminary data suggesting that A2-deficient mice have increased survival compare to the wild type mice when subjected to the cecal ligation and puncture model of polymicrobial sepsis, we sought, in the current study, to understand the possible role of A2 in the human sepsis syndrome.
METHODS: Twenty-seven Medical Intensive Care Unit patients, diagnosed with sepsis, and 22 healthy controls were prospectively enrolled. Whole blood was obtained within 24 hours of diagnosis, and peripheral blood mononuclear cells (PBMC) were isolated via Ficoll-Paque density gradient centrifugation. PBMCs were used in a plasmin generation assay, which assesses cell surface, A2-dependent fibrinolytic capacity. The surface expression of annexin A2 was measured via flow cytometric analysis.
RESULTS: Assessment of plasmin generation capacity revealed a significant decrease in plasmin production among septic patients compared to the healthy controls (p= 0.001). This result was corroborated by flow cytometry analyses, which showed a decreased in cell surface A2 on PBMCs from septic subjects compare to healthy volunteers. Measurement of clot lysis times showed no difference in plasma-based fibrinolysis between septic subjects and healthy volunteers.
CONCLUSIONS: The results suggest a significant reduction in A2 expression in PBMCs from patients with sepsis. Because A2-deficient mice show a survival advantage in the setting of experimental sepsis, we postulate that depression of cell surface A2 expression may be an adaptive response in human sepsis.
CLINICAL IMPLICATIONS: Further research will evaluate the mechanistic basis for A2 regulation in sepsis, and whether A2 expression levels correlate with clinical outcome.
DISCLOSURE: The following authors have nothing to disclose: Julio Lanfranco, Huigen Chen, Kelly Harris, Dena Almeida, David Berlin, Katherine Hajjar
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