A case of compound type 2N/type 1 von Willebrand disease linked to a novel von Willebrand factor exon 18 mutation A2311G encoding for Met 771 val

Abstract number: P0100

Friedman^* K. D., Gruppo† R. A., Ebert^* D. D., Kakela^* J. K., Bellissimo^* D. B., Endres^* J. L., Wetzel^* N., Montgomery‡ R. R.

^*Blood Center of Southeastern Wisconsin, USA; †Cincinnati Children's Hospital Medical Center, USA; ‡Medical College of Wisconsin, USA

Type 2N von Willebrand disease (2N VWD) is a qualitative disorder of von Willebrand factor (VWF) characterized by defective stabilization of plasma factor VIII (F-VIII) by VWF. Clinically, the F-VIII level is lower than the VWF antigen (VWF:Ag), with shortened F-VIII survival after desmopressin (DDAVP) stimulation. The D' and D3 domains of VWF (encoded by VWF exons 18–24) contain the factor VIII binding domain. Family and genetic studies in 2N VWD suggest a recessive inheritance pattern with patients carrying two defective VWF alleles, one encoding for a qualitatively defective interaction of F-VIII with VWF, and the other being similarly defective or encoding for quantitatively decreased VWF production. We describe a case of type 2N VWD associated with a novel mutation in exon 18. The patient developed bleeding after tonsillectomy, and moderate VWD was diagnosed. He has since had epistaxis and trauma related hemarthrosis. Mother gives a history of mucosal bleeding, but the father and brother are asymptomatic. The patient's F-VIII/VWF ratio was only 0.53 (>2 SD below the mean of 37 other patients with VWF:Ag under 35 U dL^-1). VWF ristocetin cofactor (VWF:RCo) level was depressed commensurate with VWF:Ag, and VWF multimers were normal. We studied the logarithmic decay of endogenous VWF:Ag and F-VIII for a period of 4 h after DDAVP. While VWF half-life appears to be over 12 h, F-VIII half-life was only 2 h. Severely decreased binding of recombinant F-VIII by patient VWF (VWF:FVIIIB) was observed in a microtiter assay developed in our laboratory, confirming the 2N VWD phenotype. Family studies (see table) indicate the mother has type 1 VWD and the father is an asymptomatic 2N VWD carrier.

Sequence analysis of VWF exons 18–24 of the patient and father identified a unique mutation not listed in the ISTH VWD database (heterozygous A2311G, encoding substitution of Methionine 771 by Valine) in an area of the VWF sequence in which expression studies have located defects in F-VIII binding by VWF. Thus this affected child appears to be a 2-N/Type 1 VWD compound heterozygote with a previouslyunreported mutation associated with the 2N phenotype.

Table 1