title: The interaction between factor H and Von Willebrand factor.
abstract: Complement factor H (fH) is a plasma protein that regulates activation of the alternative pathway, and mutations in fH are associated with a rare form of thrombotic microangiopathy (TMA), known as atypical hemolytic uremic syndrome (aHUS). A more common TMA is thrombotic thrombocytopenic purpura, which is caused by the lack of normal ADAMTS-13-mediated cleavage of von Willebrand factor (VWF). We investigated whether fH interacts with VWF and affects cleavage of VWF. We found that factor H binds to VWF in plasma, to plasma-purified VWF, and to recombinant A1 and A2 domains of VWF as detected by co-immunoprecipitation (co-IP) and surface plasmon resonance assays. Factor H enhanced ADAMTS-13-mediated cleavage of recombinant VWF-A2 as determined by quantifying the cleavage products using Western-blotting, enhanced cleavage of a commercially available fragment of VWF-A2 (FRETS-VWF73) as determined by fluorometric assay, and enhanced cleavage of ultralarge (UL) VWF under flow conditions as determined by cleavage of VWF-platelet strings attached to histamine stimulated endothelial cells. Using recombinant full-length and truncated fH molecules, we found that the presence of the C-terminal half of fH molecule is important for binding to VWF-A2 and for enhancing cleavage of the A2 domain by ADAMTS-13. We conclude that factor H binds to VWF and may modulate cleavage of VWF by ADAMTS-13.
authors.affiliation: Division of Internal Medicine, Benign Hematology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Shuju
authors.initials: S
authors.lastname: Feng
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Liang
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Cruz
authors.forename: Hangoc
authors.initials: H
authors.lastname: Vu
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.forename: Naresh
authors.initials: N
authors.lastname: Pemmaraju
authors.forename: Jing-Fei
authors.initials: JF
authors.lastname: Dong
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kroll
authors.forename: Vahid
authors.initials: V
authors.lastname: Afshar-Kharghan
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D017242:Complement Factor H / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D014841:von Willebrand Factor; D017242:Complement Factor H