Hemolytic uremic syndrome-associated Shiga toxins promote endothelial-cell secretion and impair ADAMTS13 cleavage of unusually large von Willebrand factor multimers.
Shiga toxin 1 (Stx-1) and Stx-2 produced by enterohemorrhagic Escherichia coli cause the diarrhea-associated hemolytic uremic syndrome (HUS). This type of HUS is characterized by obstruction of the glomeruli and renal microvasculature by platelet-fibrin thrombi, acute renal failure, thrombocytopenia, microvascular hemolytic anemia, and plasma levels of von Willebrand factor (VWF)-cleaving protease (ADAMTS13) activity that are within a broad normal range. We investigated the mechanism of initial platelet accumulation on Stx-stimulated endothelial cells. Stx-1 or Stx-2 (1-10 nM) stimulated the rapid secretion of unusually large (UL) VWF multimeric strings from human umbilical vein endothelial cells (HUVECs) or human glomerular microvascular endothelial cells (GMVECs). Perfused normal human platelets immediately adhered to the secreted ULVWF multimeric strings. Nanomolar concentrations (1-10 nM) of the Shiga toxins were as effective in inducing the formation of ULVWF-platelet strings as millimolar concentrations (0.1-20 mM) of histamine. The rate of ULVWF-platelet string cleavage by plasma or recombinant ADAMTS13 was delayed by 3 to 10 minutes (or longer) in the presence of 10 nM Stx-1 or Stx-2 compared with 20 mM histamine. Stx-induced formation of ULVWF strings, and impairment of ULVWF-platelet string cleavage by ADAMTS13, may promote initial platelet adhesion above glomerular endothelial cells. These processes may contribute to the evolution of glomerular occlusion by platelet and fibrin thrombi in diarrhea-associated HUS.
Nolasco
Leticia H
LH
Hematology Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
Turner
Nancy A
NA
Bernardo
Aubrey
A
Tao
Zhenyin
Z
Cleary
Thomas G
TG
Dong
Jing-Fei
JF
Moake
Joel L
JL
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000071120:ADAMTS13 Protein; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006463:Hemolytic-Uremic Syndrome / Q000378:metabolism*; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D008970:Molecular Weight; D010973:Platelet Adhesiveness; D011485:Protein Binding; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D022603:Shiga Toxins / Q000494:pharmacology*; D014470:Umbilical Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014841:von Willebrand Factor / Q000737:chemistry* / Q000378:metabolism*
D015295:Antigens, Tumor-Associated, Carbohydrate; C472766:Gb3 antigen; D011994:Recombinant Proteins; D022603:Shiga Toxins; D014841:von Willebrand Factor; D006632:Histamine; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human