Thromb Haemost 2008; 99(04): 720-728
DOI: 10.1160/TH07-03-0208
Platelets and Blood Cells
Schattauer GmbH

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

Agnete Kirkeby
1   H. Lundbeck A/S, Valby, Denmark
,
Lars Torup
1   H. Lundbeck A/S, Valby, Denmark
,
Louise Bochsen
2   Department of Clinical Immunology, University Hospital of Copenhagen, Copenhagen, Denmark
,
Marianne Kjalke
3   Novo Nordisk A/S, Måløv, Denmark
,
Kristin Abel
3   Novo Nordisk A/S, Måløv, Denmark
,
Kim Theilgaard-Monch
4   Department of Haematology, University Hospital of Copenhagen, Copenhagen, Denmark
,
Pär I. Johansson
2   Department of Clinical Immunology, University Hospital of Copenhagen, Copenhagen, Denmark
,
Søren E. Bjørn
3   Novo Nordisk A/S, Måløv, Denmark
,
Jens Gerwien*
3   Novo Nordisk A/S, Måløv, Denmark
,
Marcel Leist*
5   Faculty of Biology, University of Konstanz, Konstanz, Germany
› Author Affiliations
Further Information

Publication History

Received: 20 March 2007

Accepted after major revision: 06 February 2008

Publication Date:
25 November 2017 (online)

Summary

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.

* These authors have contributed equally to this work.


 
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