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Discrepancy between IIA phenotype and IIB genotype in a patient with a
variant of von Willebrand disease
AS Ribba, O Christophe, A Derlon, G Cherel, V Siguret, JM Lavergne, JP Girma, D Meyer and G Pietu
INSERM U.143, Hopital de Bicetre, le Kremlin-Bicetre, France.
Type IIA and IIB von Willebrand disease (vWD) result from qualitative
abnormalities of von Willebrand factor (vWF) characterized by an absence in
plasma of high molecular weight vWF multimers and an abnormal reactivity of
vWF towards platelet glycoprotein (GP) Ib, which is decreased in type IIA
and increased in type IIB. In this report, we describe the case of a
patient having a IIA vWD phenotype associated with an intermittent
thrombocytopenia atypical in this subtype but observed in type IIB vWD. The
patient plasma vWF showed an absence of high molecular weight and
intermediate multimers and had a decreased binding capacity to GPIb. The
affinity of botrocetin was normal for plasma vWF from the propositus.
Analysis of the propositus vWF gene showed the presence of a substitution
Val 551 to Phe of the mature vWF subunit. This mutation is localized within
a 509-695 disulphide loop of the vWF that plays an important role in the
binding to GPIb and is where most of the molecular defects described so far
were associated with type-IIB vWD. We have reproduced the Val 551 Phe
substitution onto the vWF cDNA, expressed it in COS-7 cells, and performed
structural and functional analysis of the mutant recombinant protein
(rvWFPhe 551). The rvWFPhe 551 had a normal multimeric structure and showed
the capacity to spontaneously interact with GPIb. Botrocetin had a
decreased affinity for rvWFPhe 551. In conclusion, the Val 551 Phe mutation
modifies the affinity of vWF for platelet GPIb, as does a type IIB
mutation, and may be responsible for the thrombocytopenia of the patient
and the clearance of the high molecular weight and intermediate- sized
multimers of vWF from the plasma. The study of the rvWFPhe 551 has
confirmed the discrepancy between the IIA phenotype and the IIB genotype of
the patient.
Volume 83,
Issue 3,
pp. 833-841,
02/01/1994
Copyright © 1994 by The American Society of Hematology
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