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The effects of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor

Verkleij, Chantal J. N.; Nieuwdorp, Max; Gerdes, Victor E. A.; Mörgelin, Matthias LU ; Meijers, Joost C. M. and Marx, Pauline F. (2009) In Thrombosis and Haemostasis 102(3). p.460-468
Abstract
Epidemiological studies have shown a strong association between type 2 diabetes mellitus and cardiovascular diseases, and hypofibrinolysis may contribute to this phenomenon. The aim of this study was to determine the effect of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor (TAR). Hyperglycaemia was mimicked in vitro by incubation of TAFI with glyceraldehyde and in vivo by hyperglycaemic clamping of healthy volunteers. The effects of long-term hyperglycaemia in vivo on TAR were investigated by comparing TAFI from poorly regulated and tightly regulated patients with type 2 diabetes. In vitro glycated TAR showed an altered migration pattern on SDS-PAGE due to aggregation. Glycated TAFI showed decreased activity after activation... (More)
Epidemiological studies have shown a strong association between type 2 diabetes mellitus and cardiovascular diseases, and hypofibrinolysis may contribute to this phenomenon. The aim of this study was to determine the effect of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor (TAR). Hyperglycaemia was mimicked in vitro by incubation of TAFI with glyceraldehyde and in vivo by hyperglycaemic clamping of healthy volunteers. The effects of long-term hyperglycaemia in vivo on TAR were investigated by comparing TAFI from poorly regulated and tightly regulated patients with type 2 diabetes. In vitro glycated TAR showed an altered migration pattern on SDS-PAGE due to aggregation. Glycated TAFI showed decreased activity after activation by thrombin-thrombomodulin in a glyceraldehyde-dose-dependent manner and a reduced anti-fibrinolytic potential. In vivo, no differences in TAR parameters were found after hyperglycaemic clamping of healthy volunteers and between tightly and poorly regulated patients with type 2 diabetes. Moreover, TAR purified from poorly regulated and tightly regulated patients with type 2 diabetes migrated similarly on SDS-PAGE, indicating little or no glycation of the protein. Despite the deleterious effects of glycation of TAR in vitro on its function,TAFI was neither affected by hyperglycaemic clamping, nor by long-term hyperglycaemia in patients with type 2 diabetes. This is in contrast to fibrinolytic factors as plasminogen-activator inhibitor I and tissue-type plasminogen activator, which are affected. We therefore hypothesise that a normally functioning TAR under hyperglycaemic conditions may tip the haemostatic balance towards hypofibrinolysis, which may contribute to the development of cardiovascular diseases in type 2 diabetic patients. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
protein glycation, cardiovascular disease, diabetes mellitus, TAFI, hyperglycaemia
in
Thrombosis and Haemostasis
volume
102
issue
3
pages
460 - 468
publisher
F K Schattauer Verlag Gmbh
external identifiers
  • wos:000269890200007
  • scopus:70449338765
ISSN
0340-6245
DOI
10.1160/TH09-01-0016
language
English
LU publication?
yes
id
0fb84643-b6bf-46b5-9db1-fcca00791c55 (old id 1490256)
date added to LUP
2009-10-19 15:27:15
date last changed
2017-01-01 06:04:57
@article{0fb84643-b6bf-46b5-9db1-fcca00791c55,
  abstract     = {Epidemiological studies have shown a strong association between type 2 diabetes mellitus and cardiovascular diseases, and hypofibrinolysis may contribute to this phenomenon. The aim of this study was to determine the effect of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor (TAR). Hyperglycaemia was mimicked in vitro by incubation of TAFI with glyceraldehyde and in vivo by hyperglycaemic clamping of healthy volunteers. The effects of long-term hyperglycaemia in vivo on TAR were investigated by comparing TAFI from poorly regulated and tightly regulated patients with type 2 diabetes. In vitro glycated TAR showed an altered migration pattern on SDS-PAGE due to aggregation. Glycated TAFI showed decreased activity after activation by thrombin-thrombomodulin in a glyceraldehyde-dose-dependent manner and a reduced anti-fibrinolytic potential. In vivo, no differences in TAR parameters were found after hyperglycaemic clamping of healthy volunteers and between tightly and poorly regulated patients with type 2 diabetes. Moreover, TAR purified from poorly regulated and tightly regulated patients with type 2 diabetes migrated similarly on SDS-PAGE, indicating little or no glycation of the protein. Despite the deleterious effects of glycation of TAR in vitro on its function,TAFI was neither affected by hyperglycaemic clamping, nor by long-term hyperglycaemia in patients with type 2 diabetes. This is in contrast to fibrinolytic factors as plasminogen-activator inhibitor I and tissue-type plasminogen activator, which are affected. We therefore hypothesise that a normally functioning TAR under hyperglycaemic conditions may tip the haemostatic balance towards hypofibrinolysis, which may contribute to the development of cardiovascular diseases in type 2 diabetic patients.},
  author       = {Verkleij, Chantal J. N. and Nieuwdorp, Max and Gerdes, Victor E. A. and Mörgelin, Matthias and Meijers, Joost C. M. and Marx, Pauline F.},
  issn         = {0340-6245},
  keyword      = {protein glycation,cardiovascular disease,diabetes mellitus,TAFI,hyperglycaemia},
  language     = {eng},
  number       = {3},
  pages        = {460--468},
  publisher    = {F K Schattauer Verlag Gmbh},
  series       = {Thrombosis and Haemostasis},
  title        = {The effects of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor},
  url          = {http://dx.doi.org/10.1160/TH09-01-0016},
  volume       = {102},
  year         = {2009},
}