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

Agnete Kirkeby; Lars Torup; Louise Bochsen; Marianne Kjalke; Kristin Abel; Kim Theilgaard-Monch; Pär I. Johansson; Søren E. Bjørn; Jens Gerwien; Marcel Leist

doi:10.1160/TH07-03-0208

Thrombosis and Haemostasis, Inhaltsverzeichnis

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)

Autoren

Agnete Kirkeby

¹H. Lundbeck A/S, Valby, Denmark
Lars Torup

¹H. Lundbeck A/S, Valby, Denmark
Louise Bochsen

²Department of Clinical Immunology, University Hospital of Copenhagen, Copenhagen, Denmark
Marianne Kjalke

³Novo Nordisk A/S, Måløv, Denmark
Kristin Abel

³Novo Nordisk A/S, Måløv, Denmark
Kim Theilgaard-Monch

⁴Department of Haematology, University Hospital of Copenhagen, Copenhagen, Denmark
Pär I. Johansson

²Department of Clinical Immunology, University Hospital of Copenhagen, Copenhagen, Denmark
Søren E. Bjørn

³Novo Nordisk A/S, Måløv, Denmark
Jens Gerwien^*

³Novo Nordisk A/S, Måløv, Denmark
Marcel Leist^*

⁵Faculty of Biology, University of Konstanz, Konstanz, Germany

Abstract

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.

Keywords

ADP - collagen - P-selectin - MPV - stroke

Volltext

Referenzen

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