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)

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

› Institutsangaben

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

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Referenzen

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