Interleukin 11 significantly increases plasma von Willebrand factor and factor VIII in wild type and von Willebrand disease mouse models

Interleukin (IL)-11 is a cytokine with thrombopoietic activity that has bee n shown to increase plasma von Willebrand factor (vWf) in preliminary clini cal studies. This led to further evaluation of the effect of recombinant hu man (rh)lL-11 on vWf and factor VIII (FVIII) secretion. In vitro, rhlL-11 d id not increase vWf production by cultured endothelial cells, which suggest s an indirect mechanism. Also, in vivo, plasma vWf was not elevated in mice shortly after a single intravenous (IV) bolus injection of 250 or 1000 mug /kg rhlL-11, The effect of continuous exposure to rhlL-11 was accessed by t reating wild type mice for 7 consecutive days with subcutaneous 250 mug/kg/ d rhlL-11. Platelet counts increased by 25% and 40% after 4 and 7 days, res pectively. Plasma vWf and FVIII levels increased 5-fold after 4 and 7 days. Surprisingly, no effect of rhlL-11 on vWf or FVIII messenger RNA was obser ved, which suggests that the regulation by rhlL-11 occurs after transcripti on, No increase in soluble P-selectin was observed after rhll-11 treatment, indicating that platelet activation is not the source of elevated vWf, Sim ilarly to wild type mice, vWf heterozygous mice responded to rhlL-11 treatm ent by a significant increase in platelet counts and vWf and FVIII levels. Importantly, in vWf-deficient mice, rhlL-11 also induced a significant incr ease in FVIII independent of vWf and was able to reduce skin bleeding time. These results suggest that a clinical evaluation of the effects of rhll-11 -induced vWf/FVIII elevation in maintaining hemostasis in mild hemophilia A or von Willebrand disease would be worthwhile, (C) 2001 by The American So ciety of Hematology.