title: Comparative response of plasma VWF in dogs to up-regulation of VWF mRNA by interleukin-11 versus Weibel-Palade body release by desmopressin (DDAVP).
abstract: Recombinant human interleukin-11 (rhIL-11), a glycoprotein 130 (gp130)-signaling cytokine approved for treatment of thrombocytopenia, also raises von Willebrand factor (VWF) and factor VIII (FVIII) by an unknown mechanism. Desmopressin (1-deamino-8-d-arginine vasopressin [DDAVP]) releases stored VWF and FVIII and is used for treatment of VWF and FVIII deficiencies. To compare the effect of these 2 agents, heterozygous von Willebrand disease (VWD) and normal dogs were treated with either rhIL-11 (50 microg/kg/d subcutaneously x 7 days) or DDAVP (5 microg/kg/d intravenously x 7 days). The rhIL-11 produced a gradual and sustained elevation of VWF and FVIII levels in both heterozygous VWD and normal dogs while DDAVP produced a rapid and unsustained increase. Importantly, rhIL-11 treatment produced a 2.5- to 11-fold increase in VWF mRNA in normal canine heart, aorta, and spleen but not in homozygous VWD dogs, thus identifying a mechanism for elevation of plasma VWF in vivo. Moreover, dogs pretreated with rhIL-11 retain a DDAVP-releasable pool of VWF and FVIII, suggesting that rhIL-11 does not significantly alter trafficking of these proteins to or from storage pools. The half-life of infused VWF is unchanged by rhIL-11 in homozygous VWD dogs. These results show that rhIL-11 and DDAVP raise plasma VWF by different mechanisms. Treatment with rhIL-11 with or without DDAVP may provide an alternative to plasma-derived products for some VWD and hemophilia A patients if it is shown safe in clinical trials.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, USA.
authors.forename: Eva H N
authors.initials: EH
authors.lastname: Olsen
authors.forename: Arlene S
authors.initials: AS
authors.lastname: McCain
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Merricks
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Fischer
authors.forename: Ivy M
authors.initials: IM
authors.lastname: Dillon
authors.forename: Robin A
authors.initials: RA
authors.lastname: Raymer
authors.forename: Dwight A
authors.initials: DA
authors.lastname: Bellinger
authors.forename: Scot A
authors.initials: SA
authors.lastname: Fahs
authors.forename: Robert R
authors.initials: RR
authors.lastname: Montgomery
authors.forename: James C
authors.initials: JC
authors.lastname: Keith
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schaub
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Nichols
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology / Q000627:therapeutic use*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005169:Factor VIII / Q000378:metabolism; D006207:Half-Life; D006321:Heart / Q000187:drug effects; D006579:Heterozygote; D017370:Interleukin-11 / Q000494:pharmacology / Q000627:therapeutic use*; D009206:Myocardium / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D020302:Weibel-Palade Bodies / Q000187:drug effects / Q000378:metabolism*; D014842:von Willebrand Diseases / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D014841:von Willebrand Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D017370:Interleukin-11; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D005169:Factor VIII; D003894:Deamino Arginine Vasopressin