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Clinical, epidemiological and molecular aspects of hemolytic uremic syndrome

Sartz, Lisa LU (2010) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2010:94.
Abstract
Hemolytic uremic syndrome (HUS) is the most common cause of acute renal

failure in children in the western world. HUS is characterized by the triad of

hemolytic anemia, thrombocytopenia and renal failure. There are two main

subtypes of HUS; typical or D+ (D stands for diarrhea) HUS associated with

enterohemorrhagic E. coli (EHEC) infection, which accounts for about 90% of all

HUS cases, and atypical HUS. Atypical HUS may be associated with uncontrolled

activation of the alternative pathway of complement, and in about 70% of cases

mutations are found in complement regulators or proteins.

In this thesis an epidemiological investigation of a large outbreak of... (More)
Hemolytic uremic syndrome (HUS) is the most common cause of acute renal

failure in children in the western world. HUS is characterized by the triad of

hemolytic anemia, thrombocytopenia and renal failure. There are two main

subtypes of HUS; typical or D+ (D stands for diarrhea) HUS associated with

enterohemorrhagic E. coli (EHEC) infection, which accounts for about 90% of all

HUS cases, and atypical HUS. Atypical HUS may be associated with uncontrolled

activation of the alternative pathway of complement, and in about 70% of cases

mutations are found in complement regulators or proteins.

In this thesis an epidemiological investigation of a large outbreak of EHEC

infections affecting 30 individuals in southern Sweden in 2002 is described. The

source of infection was traced to locally produced contaminated cold-smoked

fermented sausage.

Studies of whole blood from patients with D+HUS demonstrated the presence of

platelet-leukocyte complexes and microparticles bearing tissue factor as well as

complement C3 and C9.

Platelet-leukocyte complexes and the release of blood-cell derived microparticles

bearing tissue factor could be induced by incubation of whole blood with Shiga

toxin and O157LPS. Similarly, incubation of whole blood with Shiga toxin and

O157LPS induced deposition of C3 and C9 on platelet-leukocyte complexes via

the alternative pathway. C3 and C9 were also present on microparticles,

particularly those released from platelets and monocytes. Simultaneous incubation

with both Shiga toxin and O157LPS increased tissue factor and complement

deposition. The release of blood cell-derived microparticles bearing tissue factor

and complement components could promote prothrombotic and inflammatory

mechanisms and thus contribute to the pathogenesis of D+HUS.

Complement mutations were investigated in two kindreds with atypical HUS. A

novel C3 mutation (V1636A) with increased affinity for factor B was found.

Additional mutations and rare polymorphisms were found in C3, factor H, factor I

and MCP. The clinical and pathological phenotypes were described, in which

different variants of chronic thrombotic microangiopathy could be attributed to

common complement mutations. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • docent Tullus, Kjell, Department of Paediatric nephrology Great Ormond Street Hospital for children, London, UK
organization
publishing date
type
Thesis
publication status
published
subject
keywords
O157, C3, microparticles, Shiga toxin, epidemiology, EHEC, hemolytic uremic syndrome, complement, tissue factor, atypical HUS
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2010:94
pages
192 pages
publisher
Lund University
defense location
Belfragesalen, D15, Biomedicinskt Centrum (BMC), Lund
defense date
2010-10-22 09:00
ISSN
1652-8220
ISBN
978-91-86671-10-5
language
English
LU publication?
yes
id
a1af21da-9202-48c6-9640-c2c90b5dc472 (old id 1692018)
date added to LUP
2010-10-21 11:35:09
date last changed
2018-05-29 09:41:12
@phdthesis{a1af21da-9202-48c6-9640-c2c90b5dc472,
  abstract     = {Hemolytic uremic syndrome (HUS) is the most common cause of acute renal<br/><br>
failure in children in the western world. HUS is characterized by the triad of<br/><br>
hemolytic anemia, thrombocytopenia and renal failure. There are two main<br/><br>
subtypes of HUS; typical or D+ (D stands for diarrhea) HUS associated with<br/><br>
enterohemorrhagic E. coli (EHEC) infection, which accounts for about 90% of all<br/><br>
HUS cases, and atypical HUS. Atypical HUS may be associated with uncontrolled<br/><br>
activation of the alternative pathway of complement, and in about 70% of cases<br/><br>
mutations are found in complement regulators or proteins.<br/><br>
In this thesis an epidemiological investigation of a large outbreak of EHEC<br/><br>
infections affecting 30 individuals in southern Sweden in 2002 is described. The<br/><br>
source of infection was traced to locally produced contaminated cold-smoked<br/><br>
fermented sausage.<br/><br>
Studies of whole blood from patients with D+HUS demonstrated the presence of<br/><br>
platelet-leukocyte complexes and microparticles bearing tissue factor as well as<br/><br>
complement C3 and C9.<br/><br>
Platelet-leukocyte complexes and the release of blood-cell derived microparticles<br/><br>
bearing tissue factor could be induced by incubation of whole blood with Shiga<br/><br>
toxin and O157LPS. Similarly, incubation of whole blood with Shiga toxin and<br/><br>
O157LPS induced deposition of C3 and C9 on platelet-leukocyte complexes via<br/><br>
the alternative pathway. C3 and C9 were also present on microparticles,<br/><br>
particularly those released from platelets and monocytes. Simultaneous incubation<br/><br>
with both Shiga toxin and O157LPS increased tissue factor and complement<br/><br>
deposition. The release of blood cell-derived microparticles bearing tissue factor<br/><br>
and complement components could promote prothrombotic and inflammatory<br/><br>
mechanisms and thus contribute to the pathogenesis of D+HUS.<br/><br>
Complement mutations were investigated in two kindreds with atypical HUS. A<br/><br>
novel C3 mutation (V1636A) with increased affinity for factor B was found.<br/><br>
Additional mutations and rare polymorphisms were found in C3, factor H, factor I<br/><br>
and MCP. The clinical and pathological phenotypes were described, in which<br/><br>
different variants of chronic thrombotic microangiopathy could be attributed to<br/><br>
common complement mutations.},
  author       = {Sartz, Lisa},
  isbn         = {978-91-86671-10-5},
  issn         = {1652-8220},
  keyword      = {O157,C3,microparticles,Shiga toxin,epidemiology,EHEC,hemolytic uremic syndrome,complement,tissue factor,atypical HUS},
  language     = {eng},
  pages        = {192},
  publisher    = {Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Clinical, epidemiological and molecular aspects of hemolytic uremic syndrome},
  volume       = {2010:94},
  year         = {2010},
}