Engaging the Ashwell-Morell Receptor Elicits Protection Against Organ Damage and Disseminated Intravascular Coagulopthy in Fatal Sepsis

PRABHJIT GREWAL; WON HO YANG; CHERI MANN; DAVID DITTO; RICARDO LARDONE; DZUNG LE; NISSI VARKI; JAMEY MARTH

Seattle

Congreso; 2011 Meeting of the Society for Glycobiology; 2011

Society for Glycobiology

The Ashwell-Morell receptor (AMR) of hepatocytes rapidly clears from blood circulation exogenously administered glycoproteins bearing glycan ligands that include galactose and N-acetylgalactosamine.  Although the AMR is conserved throughout mammalian radiation, endogenous ligands and a biological purpose of this prototypical lectin have only recently been discovered.  We previously identified circulating platelets and von Willebrand factor (VWF) as endogenous AMR ligands and found that 70% of blood platelets are rapidly removed from circulation by the AMR during sepsis induced by Streptococcus pneumoniae (SPN) infection.  This AMR-dependent platelet clearance activity is induced during SPN infection by the SPN-encoded NanA neuraminidase.  Hemostatic adaptation by the AMR reduces the onset of disseminated intravascular coagulation (DIC) - a lethal complication of sepsis, and significantly improves the probability of host survival.  Therefore our findings challenge the assumption that the early thrombocytopenia of sepsis, which is typically a clinical hallmark of infection, is due to the consumption of coagulation factors, and instead suggest that AMR-mediated platelet clearance is a host response to reduce the potential for DIC.  We have now developed an approach to further discover novel AMR ligands in vivo and to determine the role of platelet clearance in the therapeutic activity of the AMR during sepsis.  Our findings will be presented and further indicate that engagement of the AMR early during infection by intravenous administration of neuraminidase promotes a selective and transient hypo-thrombotic state that involves platelet clearance and which minimizes disseminated intravascular coagulopathy while increasing the frequency of host survival.  At present, there are no therapeutic agents in the clinic with similar anti-coagulant and therapeutic potency, and which can greatly inhibit organ damage and failure.  Neuraminidase-induced AMR clearance activity appears to provide an effective anticoagulant therapy for multiple indications including preservation of organ health and function during the onset and progression of sepsis.