Accelerated clearance alone explains ultra-large multimers in von Willebrand disease Vicenza.
BACKGROUND
von Willebrand disease (VWD) Vicenza is characterized by low plasma von Willebrand factor (VWF) levels, the presence of ultra-large (UL) VWF multimers and less prominent satellite bands on multimer gels, and the heterozygous amino acid substitution R1205H in the VWF gene. The pathogenesis of VWD Vicenza has been elusive. Accelerated clearance is implicated as a cause of low VWF level.


OBJECTIVE
We addressed the question, whether the presence of ultra-large multimers is a cause, or a result of accelerated VWF clearance, or whether it is an unrelated phenomenon.


METHODS
We studied the detailed phenotype of three Hungarian patients with VWD Vicenza, expressed the mutant VWF-R1205H in 293T cells and developed a mathematical model to simulate VWF synthesis and catabolism.


RESULTS
We found that the half-life of VWF after DDAVP was approximately one-tenth of that after the administration of Haemate P, a source of exogenous wild-type (WT) VWF (0.81 + or - 0.2 vs. 7.25 + or - 2.38 h). An analysis of recombinant mutant VWF-R1205H showed that the biosynthesis and multimer structure of WT and mutant VWF were indistinguishable. A mathematical model of the complex interplay of VWF synthesis, clearance and cleavage showed that decreasing VWF half-life to one-tenth of normal reproduced all features of VWD Vicenza including low VWF level, ultra-large multimers and a decrease of satellite band intensity.


CONCLUSIONS
We conclude that accelerated clearance alone may explain all features of VWD Vicenza.
Gézsi
A
A
Central Immunology Laboratory, Semmelweis University, Budapest, Hungary.
Budde
U
U
Deák
I
I
Nagy
E
E
Mohl
A
A
Schlammadinger
A
A
Boda
Z
Z
Masszi
T
T
Sadler
J E
JE
Bodó
I
I
D019943:Amino Acid Substitution; D002460:Cell Line; D004587:Electrophoresis, Agar Gel; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D008297:Male; D010375:Pedigree; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014842:von Willebrand Diseases / Q000378:metabolism*; D014841:von Willebrand Factor / Q000737:chemistry / Q000378:metabolism
D011994:Recombinant Proteins; D014841:von Willebrand Factor