title: Intersection of mechanisms of type 2A VWD through defects in VWF multimerization, secretion, ADAMTS-13 susceptibility, and regulated storage.
abstract: Type 2A VWD is characterized by the absence of large VWF multimers and decreased platelet-binding function. Historically, type 2A variants are subdivided into group 1, which have impaired assembly and secretion of VWF multimers, or group 2, which have normal secretion of VWF multimers and increased ADAMTS13 proteolysis. Type 2A VWD patients recruited through the T. S. Zimmerman Program for the Molecular and Clinical Biology of VWD study were characterized phenotypically and potential mutations identified in the VWF D2, D3, A1, and A2 domains. We examined type 2A variants and their interaction with WT-VWF through expression studies. We assessed secretion/intracellular retention, multimerization, regulated storage, and ADAMTS13 proteolysis. Whereas some variants fit into the traditional group 1 or 2 categories, others did not fall clearly into either category. We determined that loss of Weibel-Palade body formation is associated with markedly reduced secretion. Mutations involving cysteines were likely to cause abnormalities in multimer structure but not necessarily secretion. When coexpressed with wild-type VWF, type 2A variants negatively affected one or more mechanisms important for normal VWF processing. Type 2A VWD appears to result from a complex intersection of mechanisms that include: (1) intracellular retention or degradation of VWF, (2) defective multimerization, (3) loss of regulated storage, and (4) increased proteolysis by ADAMTS13.
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201, USA.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Jacobi
authors.forename: Joan Cox
authors.initials: JC
authors.lastname: Gill
authors.forename: Veronica H
authors.initials: VH
authors.lastname: Flood
authors.forename: David A
authors.initials: DA
authors.lastname: Jakab
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Friedman
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Haberichter
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000071120:ADAMTS13 Protein; D005190:Family; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D055503:Protein Multimerization / Q000235:genetics / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D059748:Proteolysis; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014162:Transfection; D056728:von Willebrand Disease, Type 2 / Q000235:genetics* / Q000378:metabolism*; D014841:von Willebrand Factor / Q000235:genetics* / Q000378:metabolism*
chemical_list: D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human