Diagnosis of Inherited von Willebrand Disease: A Clinical Perspective

ABSTRACT

von Willebrand disease (VWD) is the most frequent inherited disorder of hemostasis and is due to quantitative (types 1 and 3) or qualitative (type 2) defects of von Willebrand factor (VWF). Due to the large heterogeneity of VWF defects and to the external variables influencing VWF levels in the circulation, VWD diagnosis can be difficult, especially in relatively mild forms. Three criteria should be always satisfied for a correct VWD diagnosis: (1) a positive bleeding history since childhood; (2) reduced levels of VWF activity in plasma; and (3) autosomal dominant or recessive inheritance patterns within the family (in most cases). According to clinical prospective studies, a bleeding history in VWD patients should be derived from a detailed questionnaire, with calculated bleeding scores. The ristocetin cofactor activity is the most useful test for VWD screening in the general population because it reproduces in vitro the first VWF interactions with its platelet receptor; however other assays are required to identify and classify VWD types. The current classification (types 1, 2A, 2B, 2M, 2N, and 3) is important to understand the basic mechanisms of VWF defects, to determine the risk of bleeding, and to select the best therapeutic approach. Molecular screening can be important to confirm phenotypic diagnosis for tracking VWF defects within families. Compared with hemophilia, most VWD patients show relatively mild bleeding symptoms. Therefore, prenatal diagnosis is required only for women already known to be carriers of VWD type 3. No spontaneous bleedings usually occur at birth in severe type 3 VWD. Neonatal diagnosis of VWD should always be compared with other affected members within the same family. Given that young children with VWD type 3 might carry deletions of VWF gene that predispose to the alloantibodies to VWF, every new child with VWD type 3 should be investigated intensively for VWF gene deletions before starting extensive therapy with exogenous VWF concentrates.

KEYWORDS

Inherited von Willebrand disease - von Willebrand factor - bleeding score - ristocetin cofactor activity - genetic and molecular diagnosis

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