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Platelet activation by Shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic uremic syndrome

Karpman, Diana LU orcid ; Papadopoulou, Domniki ; Nilsson, Kajsa ; Sjögren, Ann-Christine LU ; Mikaelsson, Carl and Lethagen, Stefan LU (2001) In Blood 97(10). p.3100-3108
Abstract
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... (More)
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. (Less)
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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
97
issue
10
pages
3100 - 3108
publisher
American Society of Hematology
external identifiers
  • pmid:11342436
  • scopus:0035874529
ISSN
1528-0020
DOI
10.1182/blood.V97.10.3100
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Emergency medicine/Medicine/Surgery (013240200), Paediatrics (Lund) (013002000)
id
57449c5b-3c24-45a9-8693-a0e0057de2f8 (old id 1119914)
date added to LUP
2016-04-01 12:32:19
date last changed
2025-04-04 14:14:48
@article{57449c5b-3c24-45a9-8693-a0e0057de2f8,
  abstract     = {{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.}},
  author       = {{Karpman, Diana and Papadopoulou, Domniki and Nilsson, Kajsa and Sjögren, Ann-Christine and Mikaelsson, Carl and Lethagen, Stefan}},
  issn         = {{1528-0020}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{3100--3108}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood}},
  title        = {{Platelet activation by Shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic uremic syndrome}},
  url          = {{http://dx.doi.org/10.1182/blood.V97.10.3100}},
  doi          = {{10.1182/blood.V97.10.3100}},
  volume       = {{97}},
  year         = {{2001}},
}