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High-dose erythropoietin alters platelet reactivity and bleeding time in rodents in contrast to the neuroprotective variant carbamyl-erythropoietin (CEPO)

Kirkeby, Agnete LU ; Torup, Lars; Bochsen, Louise; Kjalke, Marianne; Abel, Kristin; Theilgaard-Monch, Kim; Johansson, Pär I.; Bjørn, Søren E.; Gerwien, Jens and Leist, Marcel (2008) In Thrombosis and Haemostasis 99(4). p.720-728
Abstract

The haematopoietic hormone erythropoietin (EPO) has neuroprotective properties and is currently being explored for treatment of stroke and other neurological disorders. Short-term, high-dose treatment with EPO seems to improve neurological function of stroke patients but may be associated with increased thrombotic risk, whereas alternative non-erythropoietic neuroprotective derivatives of EPO, such as carbamylated EPO (CEPO), may be devoid of such side-effects. We investigated the effects of short-term, high-dose treatment with EPO and CEPO on platelet function and haemostasis in healthy mice and rats. Animals received three daily doses of EPO or CEPO (50 μg/kg), and blood was compared with respect to alterations in haematology and... (More)

The haematopoietic hormone erythropoietin (EPO) has neuroprotective properties and is currently being explored for treatment of stroke and other neurological disorders. Short-term, high-dose treatment with EPO seems to improve neurological function of stroke patients but may be associated with increased thrombotic risk, whereas alternative non-erythropoietic neuroprotective derivatives of EPO, such as carbamylated EPO (CEPO), may be devoid of such side-effects. We investigated the effects of short-term, high-dose treatment with EPO and CEPO on platelet function and haemostasis in healthy mice and rats. Animals received three daily doses of EPO or CEPO (50 μg/kg), and blood was compared with respect to alterations in haematology and platelet reactivity. In rats, treatment with EPO increased the haematocrit to >50% and the mean platelet volume by 37%,while CEPO had no effect on these parameters. Platelets from EPO-treated rats showed an increased sensitivity to thrombin receptor agonist peptides and elevated plasma levels of soluble P-selectin (sP-selectin) were found in treated mice. Further indicators of platelet hyperreactivity in EPO, but not CEPO-treated animals, were significantly increased aggregatory responses to collagen in whole blood and platelet-rich plasma (PRP). The increased platelet reactivity was paralleled by a decreased bleeding time after tail transection in rats. Samples from EPO-treated rats showed an attenuated response to ADP in whole blood aggregometry and thrombelastography (TEG) platelet mapping but not in apyrase-treated PRP, suggesting involvement of ADP receptor desensitization. These findings suggest that while EPO affects various aspects of platelet function, CEPO is devoid of such effects. © 2008 Schattauer GmbH.

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Please use this url to cite or link to this publication:
author
publishing date
type
Contribution to journal
publication status
published
keywords
ADP, Collagen, MPV, P-selectin, Stroke
in
Thrombosis and Haemostasis
volume
99
issue
4
pages
9 pages
publisher
F K Schattauer Verlag Gmbh
external identifiers
  • Scopus:43749105165
ISSN
0340-6245
DOI
10.1160/TH07-03-0208
language
English
LU publication?
no
id
1d65ff2c-0fa4-4d40-b3e6-26bd40209818
date added to LUP
2016-06-02 09:43:12
date last changed
2016-11-07 15:01:13
@misc{1d65ff2c-0fa4-4d40-b3e6-26bd40209818,
  abstract     = {<p>The haematopoietic hormone erythropoietin (EPO) has neuroprotective properties and is currently being explored for treatment of stroke and other neurological disorders. Short-term, high-dose treatment with EPO seems to improve neurological function of stroke patients but may be associated with increased thrombotic risk, whereas alternative non-erythropoietic neuroprotective derivatives of EPO, such as carbamylated EPO (CEPO), may be devoid of such side-effects. We investigated the effects of short-term, high-dose treatment with EPO and CEPO on platelet function and haemostasis in healthy mice and rats. Animals received three daily doses of EPO or CEPO (50 μg/kg), and blood was compared with respect to alterations in haematology and platelet reactivity. In rats, treatment with EPO increased the haematocrit to &gt;50% and the mean platelet volume by 37%,while CEPO had no effect on these parameters. Platelets from EPO-treated rats showed an increased sensitivity to thrombin receptor agonist peptides and elevated plasma levels of soluble P-selectin (sP-selectin) were found in treated mice. Further indicators of platelet hyperreactivity in EPO, but not CEPO-treated animals, were significantly increased aggregatory responses to collagen in whole blood and platelet-rich plasma (PRP). The increased platelet reactivity was paralleled by a decreased bleeding time after tail transection in rats. Samples from EPO-treated rats showed an attenuated response to ADP in whole blood aggregometry and thrombelastography (TEG) platelet mapping but not in apyrase-treated PRP, suggesting involvement of ADP receptor desensitization. These findings suggest that while EPO affects various aspects of platelet function, CEPO is devoid of such effects. © 2008 Schattauer GmbH.</p>},
  author       = {Kirkeby, Agnete and Torup, Lars and Bochsen, Louise and Kjalke, Marianne and Abel, Kristin and Theilgaard-Monch, Kim and Johansson, Pär I. and Bjørn, Søren E. and Gerwien, Jens and Leist, Marcel},
  issn         = {0340-6245},
  keyword      = {ADP,Collagen,MPV,P-selectin,Stroke},
  language     = {eng},
  number       = {4},
  pages        = {720--728},
  publisher    = {ARRAY(0x9ade010)},
  series       = {Thrombosis and Haemostasis},
  title        = {High-dose erythropoietin alters platelet reactivity and bleeding time in rodents in contrast to the neuroprotective variant carbamyl-erythropoietin (CEPO)},
  url          = {http://dx.doi.org/10.1160/TH07-03-0208},
  volume       = {99},
  year         = {2008},
}