Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hematol. Aug 6, 2016; 5(3): 61-74
Published online Aug 6, 2016. doi: 10.5315/wjh.v5.i3.61
Changing insights in the diagnosis and classification of autosomal recessive and dominant von Willebrand diseases 1980-2015
Jan Jacques Michiels, Angelika Batorova, Tatiana Prigancova, Petr Smejkal, Miroslav Penka, Inge Vangenechten, Alain Gadisseur
Jan Jacques Michiels, Goodheart Institute and Foundation in Nature Medicine and Health, Blood Coagulation and Vascular Medicine Research Center, 3069 Rotterdam, The Netherlands
Jan Jacques Michiels, Blood Coagulation Research Laboratory, University Hospital Antwerp, B-2650 Edegem, Belgium
Angelika Batorova, Tatiana Prigancova, National Hemophilia Center, Department of Hematology and Blood Transfusion, Faculty of Medicine of Comenius University, University Hospital, Antolska 11, Bratislava, Slovakia
Petr Smejkal, Miroslav Penka, Department of Clinical Hematology, University Hospital and Department of Laboratory Methods, Faculty of Medicine, Masaryk University, Jihlavska 20, Brno 62500, Czech Republic
Inge Vangenechten, Alain Gadisseur, Hemostasis Research Unit, Antwerp University Hospital, 2650 Edegem, Belgium
Author contributions: Michiels JJ, Vangenechten I and Gadisseur A analysed the literature and wrote the manuscript; all authors participated in the prospective von Willebrand disease (VWD) research study to validate the European Clinical, Laboratory and Molecular classification of VWD.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Jan Jacques Michiels, MD, PhD, Investigator, Senior Internist, Goodheart Institute and Foundation in Nature Medicine and Health, Blood Coagulation and Vascular Medicine Research Center, Erasmus Tower, Veenmos 13, 3069 Rotterdam, The Netherlands.
Telephone: +31-62-6970534
Received: November 26, 2015
Peer-review started: November 30, 2015
First decision: January 15, 2016
Revised: March 29, 2016
Accepted: April 14, 2016
Article in press: April 18, 2016
Published online: August 6, 2016

The European Clinical Laboratory and Molecular (ECLM) criteria define 10 distinct Willebrand diseases (VWD): recessive type 3, severe 1, 2C and 2N; dominant VWD type 1 secretion/clearance defect, 2A, 2B, 2E, 2M and 2D; and mild type 1 VWD (usually carriers of recessive VWD). Recessive severe 1 and 2C VWD are characterized by secretion and multimerization defects caused by mutations in the D1-D2 domain. Recessive 2N VWD is a mild hemophilia due to D’-FVIII-von Willebrand factor (VWF) binding site mutations. Dominant 2E VWD caused by heterozygous missense mutations in the D3 domain is featured by a secretion-clearance-multimerization VWF defect. Dominant VWD type 2M due to loss of function mutations in the A1 domain is characterized by decreased ristocetin-induced platelet aggregation and VWF:RCo, normal VWF multimers and VWF:CB, a poor response of VWF:RCo and good response of VWF:CB to desmopressin (DDAVP). Dominant VWD type 2A induced by heterozygous mutations in the A2 domain results in hypersensitivity of VWF for proteolysis by ADAMTS13 into VWF degradation products, resulting in loss of large VWF multimers with triplet structure of each individual VWF band. Dominant VWD type 2B due to a gain of function mutation in the A1 domain is featured by spontaneous interaction between platelet glycoprotein Ib (GPIb) and mutated VWF A1 followed by increased proteolysis with loss of large VWF multimers and presence of each VWF band. A new category of dominant VWD type 1 secretion or clearance defect due to mutations in the D3 domain or D4-C1-C5 domains consists of two groups: Those with normal or smeary pattern of VWF multimers.

Keywords: Von Willebrand disease, Von Willebrand factor, ADAMTS13, DDAVP, Von Willebrand factor assays, Von Willebrand gene mutations

Core tip: The European Clinical Laboratory and Molecular criteria define at least 10 distinct phenotypes of von Willebrand diseases (VWD) that have significant therapeutic implications. High quality von Willebrand factor (VWF) multimeric analysis and responses to desmopressin of FVIII:C and VWF parameters are of critical diagnostic importance to document the contribution of VWF secretion, clearance, proteolysis and multimerization defects to real life phenotyping of each individual VWD patient.