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Hamostaseologie 2020; 40(01): 105-118
DOI: 10.1055/s-0039-3400260
Review Article
Georg Thieme Verlag KG Stuttgart · New York

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

Hamideh Yadegari
1   Institute of Experimental Haematology and Transfusion Medicine, University Clinics Bonn, Bonn, NRW, Germany
,
Johannes Oldenburg
1   Institute of Experimental Haematology and Transfusion Medicine, University Clinics Bonn, Bonn, NRW, Germany
› Author Affiliations
Further Information

Publication History

16 March 2019

26 September 2019

Publication Date:
22 January 2020 (online)

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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.

Zusammenfassung

Die Von Willebrand Erkrankung (VWE) ist die häufigsten erbliche Blutungsstörung, die durch Fehler im von Willebrand Faktor (VWF) verursacht wird. Diese Fehler können entweder zu einer Reduktion der VWF–Konzentration führen oder die Funktion des VWF beeinträchtigen. Wenn die VWF-Konzentration leicht bzw. mäßig reduziert ist, spricht man von einer VWE Typ 1, wenn praktisch kein VWF mehr nachweisbar ist von einer VWE Typ 3. Seit der Klonierung des VWF Gens (VWF) innerhalb der achtziger Jahre hat man viel über die Entstehung der VWE herausgefunden. Die genetische Basis des VWE Typ 3 ist relativ gut erklärt. VWF-verursachende Mutationen, die vorwiegend Null-Allele einschließen, wurden in mehr als 85% der Fälle identifiziert. Im Gegensatz dazu sind die genetischen Ursachen des VWE Typ 1 nur teilweise charakterisiert. Die VWF-Sequenzvariationen, die hauptsächlich Missense-Mutationen umfassen, werden nur bei ca. 65% der Patienten mit Typ 1 des VWE gefunden. Die Pathophysiologie der VWE des Typs 1 scheint zusätzlich noch durch genetische Faktoren beeinflusst zu werden, die außerhalb des VWF liegen. In dem hier vorliegenden Review werden ausführlich die genetischen Grundlagen sowie die molekularen Mechanismen diskutiert, die zu einer Reduktion der VWF-Konzentration führen.

Keywords

von Willebrand factor - von Willebrand disease - bleeding disorder - gene mutation

Schlüsselwörter

von-Willebrand-Faktor - von-Willebrand-Erkrankung - Blutgerinnungsstörung - Mutation

# Recipient of the Günter Landbeck Award, 2016.


 

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