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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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 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.

Detaljer

Författare
  • Agnete Kirkeby
  • Lars Torup
  • Louise Bochsen
  • Marianne Kjalke
  • Kristin Abel
  • Kim Theilgaard-Monch
  • Pär I. Johansson
  • Søren E. Bjørn
  • Jens Gerwien
  • Marcel Leist
Externa organisationer
  • H. Lundbeck A/S
  • Copenhagen University Hospital
  • Novo Nordisk A/S
  • University of Konstanz
Forskningsområden

Nyckelord

Originalspråkengelska
Sidor (från-till)720-728
Antal sidor9
TidskriftThrombosis and Haemostasis
Volym99
Utgivningsnummer4
StatusPublished - 2008 apr
PublikationskategoriForskning
Peer review utfördJa
Externt publiceradJa