Recessive von Willebrand disease type 2 Normandy: variable expression of mild hemophilia and VWD type 1.Acta Haematol. 2009; 121(2-3):119-27.AH
Missense mutations in the von Willebrand factor (VWF) gene impairing the binding to factor VIII (FVIII) do not impair the structure of VWF multimers nor the ability of VWF to aggregate platelets but causes an accelerated clearance of FVIII. Recessive VWD type Normandy (N) encompasses all patients with a deficiency in FVIII:coagulant activity (C) caused by a markedly decreased affinity of VWF for FVIII:C due to a FVIII binding defect in VWF but with normal or near normal VWF:antigen (Ag), VWF:ristocetin cofactor activity (RCo) and VWF:collagen binding (CB) levels, normal VWF:RCo/VWF:Ag ratio, normal VWF multimeric pattern and normal VWF-dependent platelet functions including ristocetin-induced platelet aggregation and bleeding time (BT) consistent with VWD type 1. The response to 1-deamino-8-D-arginine vasopressin (DDAVP) of VWF parameters is usually normal, but the degree of restricted response curves to DDAVP of FVIII:C depends on the severity of the FVIII binding defect to the mutated VWF. The homozygous mutations R816W and R854W are typically associated with severe and mild VWD 1/N, respectively. Homozygous or heterozygous/null mutations of C788, D879N or C1225G do not only dramatically decrease FVIII binding, but also induce a multimerization and secretion defect with a decrease in the large VWF multimers, lack of triplet structure and prolonged BT consistent with severe VWD 2E/N. The missense mutations Y795C and R763G either heterozygous or as a component of recessive VWD (double heterozygous) are responsible for the FVIII binding defect (VWD 1/N) and abnormal banding of VWF multimers leading to the presence of a smeary pattern with the presence of ultralarge VWF multimers.