The Current Understanding of Molecular Pathogenesis of Quantitative von Willebrand Disease, Types 1 and 3

Abstract

Von Willebrand disease (VWD), the most prevalent congenital bleeding disorder, arises from deficiencies in quantity or quality of von Willebrand factor (VWF). The quantitative deficiencies of VWF are considered to be either VWD type 1 (mild/moderate reduction of VWF) or type 3 (virtual absence of VWF). Following cloning of the VWF gene (VWF) in the 1980s, significant progress has been made in our understanding of the pathogenesis of VWD. The genetic basis of type 3 VWD is well defined. VWF causative variations comprising predominantly null alleles have been identified in more than 85% of cases. In contrast, the molecular mechanisms in type 1 disease are only partially characterized. The VWF sequence variations, including mostly missense alterations, are found in only approximately 65% of type 1 VWD patients. It appears that genetic elements outside of VWF may contribute to the pathophysiology of type 1 VWD. This review discusses in detail the current understandings of the genetic basis and molecular mechanisms causing quantitative deficiencies of VWF.

Nonhuman primate genetic models for the study of rare diseases

“…Von Willebrand’s disease (VWD) represents the most commonly inherited disorder of human coagulation and afflicts up to 1% of the population [ 116 ]. It occurs in multiple primary types, with type 1 representing reduced quantity of Von Willebrand’s factor (VWF), type 2 representing reduced function of VWF, and type 3 representing an absence of VWF [ 116 ]. Each of these types can lead to bleeding due to VWF’s role in platelet adhesion and aggregation.…”

Age-Associated Increase in Thrombogenicity and Its Correlation with von Willebrand Factor

“…Deficiencies of VWF, either quantitative or qualitative, are associated with the most common inherited bleeding disorder known as Von Willebrand disease (VWD) [ 48 , 49 , 50 ]. There are four main types of VWD based on phenotypic analysis of the VWF: Type 1, Type 2, Type 3, and platelet-type [ 51 , 52 , 53 ]. The most common and mildest form of VWD is Type 1 (quantitative) that is caused by low VWF production or accelerated clearance [ 53 ].…”

“…There are four main types of VWD based on phenotypic analysis of the VWF: Type 1, Type 2, Type 3, and platelet-type [ 51 , 52 , 53 ]. The most common and mildest form of VWD is Type 1 (quantitative) that is caused by low VWF production or accelerated clearance [ 53 ]. Type 2 VWD (qualitative) is characterized by defects in VWF (abnormal function), and it accounts for 20–40% of VWD cases [ 51 ].…”

“…Type 2 VWD (qualitative) is characterized by defects in VWF (abnormal function), and it accounts for 20–40% of VWD cases [ 51 ]. Whereas Type 3 (qualitative) VWD is a total quantitative deficiency of VWF and is the most severe form of VWD that represents 5% of VWD cases [ 53 ]. In platelet-type VWD, a gain of function mutation within platelet surface receptor for VWF leads to exaggerated platelet-VWF interaction, resulting in thrombocytopenia and consequently prolonged bleeding time [ 52 ].…”

A Homozygous Deep Intronic Variant Causes Von Willebrand Factor Deficiency and Lack of Endothelial-Specific Secretory Organelles, Weibel–Palade Bodies

“…In our cohort of type 3 VWD patients, the mutation detection rate was about 94%, following completing genetic diagnostic tests including multiplex ligation-dependent probe amplification (MLPA) as well as Sanger DNA sequencing of the promotor, coding regions, and conserved consensus splice site (ss) (exon/intron borders) of VWF [ 20 , 27 ]. It is proposed that the causative mutations in type 3 mutation-negative cases or heterozygous cases might be located within deep intronic regions or distant regulatory sequences [ 28 ]. Nevertheless, to date, there is no report of confirmation of any gene variant outside of the VWF coding region or its consensus ss in type 3 VWD patients.…”