A new variant of von Willebrand's disease (type I Padua): doublet-organized plasma von Willebrand factor oligomers in the presence of all size multimers.Haematologia (Budap). 1994; 26(2):97-109.H
Type I von Willebrand's disease (vWd) is characterized by a concomitant decrease in plasma of von Willebrand factor antigen (vWf:Ag) and vWf ristocetin cofactor activity (vWf:RCoF), associated with the presence of all-size multimers. As a rule, there is no evidence of intrinsic abnormality in vWf. We describe a family with type I vWd with an abnormal plasma vWf multimer pattern. Analysis of plasma vWf multimeric structure by short-SDS-agarose gel electrophoresis showed an abnormal banding pattern for each vWf oligomer, which was organized as a doublet instead of the normal triplet. The electrophoretic mobility of each component appeared to be normal. Multimeric analysis on a long gel showed all the bands that were detectable in normal subjects, but unlike normals the fast moving satellite stained as the major component. The platelet vWf multimer pattern was normal. The infusion of DDAVP normalized vWf:Ag, vWf:RCoF and VIII:C, but not the abnormal multimer pattern observed on both short- and long-gel electrophoresis. The return of factor VIII/vWf complex to the baseline condition was more rapid than that observed in normal subjects or classic type I vWd patients. Analysis of the subunit fragments in the patients' plasma vWf demonstrated a relatively greater proportion, compared to the normal counterpart, of a 115(140)-kD fragment, which derives from the aminoterminal region of the mature molecule; in contrast, no intact subunit was detectable. These findings indicate a new, previously unreported, variant of type I vWd, which is characterized by plasma vWf oligomers organized as doublets, instead of triplets. The reduced post-DDAVP half-life, and the abnormal subunit fragments of vWf, suggest a molecule characterized by an increased susceptibility to proteolytic degradation. As a result, the decrease in circulating vWf levels may be due to an instability of the abnormal vWf, rather than, or in addition to, a decrease in its synthesis.