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Blood, 1 July 2006, Vol. 108, No. 1, pp. 167-176.
Prepublished online as a Blood First Edition Paper on March 2, 2006; DOI 10.1182/blood-2005-08-3219.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Lipopolysaccharide from enterohemorrhagic Escherichia coli binds to platelets through TLR4 and CD62 and is detected on circulating platelets in patients with hemolytic uremic syndrome
Anne-lie Ståhl,
Majlis Svensson,
Matthias Mörgelin,
Catharina Svanborg,
Phillip I. Tarr,
Jody C. Mooney,
Sandra L. Watkins,
Roger Johnson, and
Diana Karpman
From the Department of Pediatrics, Clinical Sciences Lund, the Institute of Laboratory Medicine, Section for Microbiology, Immunology and Glycobiology, and the Department of Clinical and Experimental Infectious Medicine, Lund University, Lund, Sweden; the Division of Pediatric Gastroenterology and Nutrition, Washington University School of Medicine, St Louis, MO; the Children's Hospital and Regional Medical Center, Seattle, WA; the Department of Pediatrics, University of Washington School of Medicine, Seattle, WA; and the Public Health Agency of Canada, Laboratory for Foodborne Zoonoses, Guelph, Canada.
This study presents evidence that human platelets bind lipopolysaccharide (LPS) from enterohemorrhagic Escherichia coli (EHEC) through a complex of toll-like receptor 4 (TLR4) and CD62, leading to their activation. TLR4 colocalized with CD62 on the platelet membrane, and the TLR4 specificity of LPS binding to platelets was confirmed using C57BL/10ScN mice lacking Tlr4. Only platelets from TLR4 wild-type mice bound O157LPS in vitro. After in vivo injection, O157LPS bound to platelets from wild-type mice, which had lower platelet counts than did mice lacking TLR4. Mouse experiments confirmed that O157LPS binding to TLR4 is the primary event leading to platelet activation, as shown by CD40L expression, and that CD62 further contributes to this process. Activation of human platelets by EHEC-LPS was demonstrated by expression of the activated GPIIb/IIIa receptor, CD40L, and fibrinogen binding. In perfusion experiments, platelet activation on endothelial cells was TLR4 and CD62 dependent. O157LPS was detected on platelets from 12 of 14 children with EHEC-associated hemolytic uremic syndrome (HUS) and on platelets from 2 children before the development of HUS but not on platelets of EHEC-infected children in whom HUS did not develop (n = 3). These data suggest that O157LPS on platelets might contribute to platelet consumption in HUS. (Blood. 2006;108:167-176)
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