title: High-dose erythropoietin alters platelet reactivity and bleeding time in rodents in contrast to the neuroprotective variant carbamyl-erythropoietin (CEPO).
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 microg/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.
authors.affiliation: Department of Molecular Neurobiology, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. agki@lundbeck.com
authors.forename: Agnete
authors.initials: A
authors.lastname: Kirkeby
authors.forename: Lars
authors.initials: L
authors.lastname: Torup
authors.forename: Louise
authors.initials: L
authors.lastname: Bochsen
authors.forename: Marianne
authors.initials: M
authors.lastname: Kjalke
authors.forename: Kristin
authors.initials: K
authors.lastname: Abel
authors.forename: Kim
authors.initials: K
authors.lastname: Theilgaard-Monch
authors.forename: Pär I
authors.initials: PI
authors.lastname: Johansson
authors.forename: Søren E
authors.initials: SE
authors.lastname: Bjørn
authors.forename: Jens
authors.initials: J
authors.lastname: Gerwien
authors.forename: Marcel
authors.initials: M
authors.lastname: Leist
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001760:Bleeding Time; D001798:Blood Proteins / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019007:P-Selectin / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044462:Receptors, Proteinase-Activated / Q000819:agonists; D011994:Recombinant Proteins
chemical_list: D001798:Blood Proteins; D018696:Neuroprotective Agents; D019007:P-Selectin; D044462:Receptors, Proteinase-Activated; D011994:Recombinant Proteins; C488171:carbamylated erythropoietin; C481941:protease-activated receptor 3, mouse; C481942:protease-activated receptor 4, mouse; D004921:Erythropoietin; D000244:Adenosine Diphosphate; D003094:Collagen