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New variant of von Willebrand disease with defective binding to factor VIII
M Nishino, JP Girma, C Rothschild, E Fressinaud and D Meyer
INSERM U.143, Hopital de Bicetre, Paris, France.
A new variant of von Willebrand disease (vWD) was identified by a new
analytic method which characterizes the ability of plasma von Willebrand
Factor (vWF) to bind to purified factor VIII (F.VIII). vWF was isolated
from small amounts of plasma by immunoadsorption with a selected monoclonal
antibody to vWF previously coated onto wells of microtitration plates.
Plasma F.VIII was removed from immobilized vWF by washing with 0.4 mol/L
CaCl2; purified F.VIII was then added to the well. The amount of bound
F.VIII was estimated directly in the wells by a chromogenic assay and
immobilized vWF was estimated by an immunologic a pool of normal plasma,
ten control individuals, 13 with hemophilia A and five with type I vWD. In
all cases, the dose-response curves were linear and the slopes of the
regression lines were essentially the same. The method was then applied to
investigate the binding of vWF to F.VIII in two vWD patients (sister and
brother) who demonstrated significantly lower activity of F.VIII than of
vWF. The first patient, with a long history of epistaxis, bruising, and
hematomas, showed a slightly prolonged bleeding time (10 minutes); 15%
VIII:C and 39% of vWF:Ag and vWFRCo. Her brother, who has a bleeding
syndrome but no hematomas, showed similar data (bleeding time 9 minutes,
20% VIII:C, 53% vWF:Ag and vWFRCo). Similar levels of F.VIII were observed
in the two propositi by four different methods (one- and two-stage clotting
and chromogenic and immunologic assays). Sodium dodecyl sulfate (SDS) 1.4%
agarose gel electrophoresis showed that all multimers of vWF were present
in both patients. vWF binding to F.VIII was markedly decreased in the two
propositi. The abnormal binding of vWF to F.VIII was not corrected during
pregnancy or after infusion of 1-deamino (8-D- arginine) vasopressin
despite an increase in vWF levels. The qualitative abnormality of vWF in
both patients was associated with a subtle alteration of the multimeric
structure by SDS 3% agarose gel electrophoresis in which the two central
subbands of the quintuplet of individual oligomers were undetectable or
poorly visible. SDS- polyacrylamide gel electrophoresis under reducing
conditions demonstrated a single band of 275 Kd in the plasma of both
patients, and there was no evidence of a second band corresponding to
pro-vWF, the precursor of the mature vWF subunit, suggesting that
proteolytic processing of vWF was normal.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 74,
Issue 5,
pp. 1591-1599,
10/01/1989
Copyright © 1989 by The American Society of Hematology
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