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Blood, 15 May 2001, Vol. 97, No. 10, pp. 3100-3108
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Platelet activation by Shiga toxin and circulatory factors as a
pathogenetic mechanism in the hemolytic uremic syndrome
Diana Karpman,
Domniki Papadopoulou,
Kajsa Nilsson,
Ann-Christine Sjögren,
Carl Mikaelsson, and
Stefan Lethagen
From the Departments of Pediatrics, Microbiology,
Immunology and Glycobiology, and Coagulation Disorders, Lund
University, Lund, Sweden.
Thrombocytopenia caused by platelet consumption in thrombi is a
major manifestation of hemolytic uremic syndrome (HUS) associated with
Shiga toxin (Stx) producing Escherichia coli. Platelets
have glycosphingolipid receptors capable of binding Stx, but a direct interaction between the toxin and platelets, leading to platelet activation, has not been reported. In this study, it is shown that Stx1
and its B (binding) subunit (Stx1B), at 10 pg/mL to 10 ng/mL, bound to
platelets. Toxin was internalized in platelets within 2 hours. This led
to increased platelet aggregation, as demonstrated by confocal
microscopy. Preincubation of Stx1B with anti-Stx1 antibody inhibited
this reaction. Stx1 induced morphologic changes in platelets seen on
scanning electron microscopy. In the presence of platelets and tumor
necrosis factor-pretreated human umbilical vein endothelial cells
(HUVEC), Stx1 and Stx1B induced the binding of platelets to the
endothelial cell membrane and were present at this binding site.
Incubation of Stx1 and Stx1B with whole blood increased fibrinogen
binding to platelets detected by flow cytometry. Fibrinogen binding was
partially inhibited by preincubation with anti-Stx1. Stx1 increased
platelet retention measured in a glass bead assay. In addition, plasma
from 17 patients with HUS, taken during the acute phase of the disease,
increased the retention of normal platelets and normalized after
recovery. Taken together, the results of this investigation show that
Stx1, Stx1B, and a factor or factors in the plasma of patients with HUS
activate platelets. The presence of Stx1 at the binding site of
platelets to HUVEC suggests that Stx may be directly involved in the
prothrombotic state seen in HUS.
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