Textbook of Von Willebrand Disease E-Book
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TEXTBOOK OF VON WILLEBRAND DISEASE Comprehensive resource summarizing recent research on von Willebrand disease, showing clinicians how to optimize management of patients with this disorder The newly revised and updated second edition of Textbook of von Willebrand Disease: Basic and Clinical Aspects, 2nd edition describes the important and complex role of von Willebrand factor (VWF) in hemostasis and thrombosis, covering not only the current understanding of its molecular biology, but also the association between genetic variants of VWF and different von Willebrand disease (VWD) phenotypes. The text also reviews the important area of the obstetric and gynecological manifestations of VWD, as well as how to manage patients with VWD for surgery. Many advances in agents are included in this updated edition, as well as the wide topics such as VWF in Angiogenesis, and VWF/ADAMTS13 as risk factors of thrombosis. Edited by a team of experts in VWD and an international team of contributors, Textbook of von Willebrand Disease covers sample topics such as: * VWF structure and function, biosynthesis and organization of VWF, modulation of VWF by ADAMTS13 and assessment of VWF clearance * Clinical, laboratory and molecular markers of different VWD types, from the mild forms of type 1 VWD and the moderate variants types 2A, 2B, 2M, 2N to the most severe type 3 VWD * Pediatric aspects of VWD and of women with VWD * Management of GI bleeds and appropriate therapies in surgery, and plasma-derived and recombinant VWF concentrates * Acquired von Willebrand Syndrome, cardiovascular causes of AVWS, gastrointestinal bleeds in VWD and AVWS, and prophylaxis in von Willebrand disease Providing complete and accessible coverage of the subject, Textbook of von Willebrand Disease: Basic and Clinical Aspects, 2nd edition is a valuable resource for hematologists in practice and in training, along with specialists in thrombosis, hemostasis, and bleeding/clotting disorders.
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Table of Contents
Cover
Table of Contents
Title Page
Copyright Page
List of Contributors
Foreword
Preface
1 Historical perspective on von Willebrand disease
Introduction
The scientist of the disease
First description of the disease: the Åland family
Other early clinical reports
The search for a new factor—the bleeding time factor
The end of the beginning
Recent scientific visits to Åland Islands
References
2 Biosynthesis and organization of von Willebrand factor
Introduction
Terminology
Molecular biology of VWF
Cell biology of VWF
References
3 Von Willebrand factor structure and function
Introduction
VWF function
Structure of VWF
VWF domain structure
Functional biochemistry of VWF
Summary
Acknowledgement
References
4 Regulation of von Willebrand factor expression
Introduction
VWF gene structure and chromosomal location
VWF expressing cells
VWF
promoter structure
Transcriptional activators
Transcriptional suppressors
NFY, a dual‐purpose transcription factor
Influence of regulatory sequence variants on VWF expression
Regulatory variants in the proximal regulatory region: the
VWF
promoter
Regulatory variants in the distal regulatory region:
VWF
enhancers
Epigenetic regulation of VWF expression
Posttranscriptional regulation of VWF expression
Splicing events and differential VWF expression in endothelial cells
MicroRNAs regulate VWF biosynthesis, maturation, and secretion
Physiological, pathological, and environmental factors affecting VWF expression
Hemodynamic shear stress regulates VWF expression
VWF is an acute‐phase reactant
Hormones raise blood VWF levels
Conclusion
References
5 Modulation of VWF by ADAMTS13
Introduction
VWF structure, synthesis, and function
ADAMTS13 structure
ADAMTS13 conformation/latency
ADAMTS13 function
Physiology and pathophysiology of the VWF‐ADAMTS13 axis
Summary
References
6 Assessment of VWF clearance
Introduction
Macrophage‐mediated VWF clearance
Endothelial cell contribution to VWF clearance
Conclusion
References
7 Classification of VWD
Classification of VWD
von Willebrand factor
Historical classification
Type 1 VWD
Type 1C VWD
Type 1 versus low VWF
Type 2 VWD
Type 3 VWD
Clinical classification of VWD
Genetic classification of VWD
Conclusion
Acknowledgement
Conflict of Interest
References
8 The epidemiology of von Willebrand disease
Introduction
Historical studies on the prevalence of VWD
Prevalence of bleeding patients in the general population
Bleeding score: A new diagnostic tool to assess clinically relevant VWD
The problem of diagnosing mild VWD
Prevalence of intermediate VWD
Prevalence of severe VWD
Prevalence of a mutant VWF gene
Conclusions
References
9 Clinical aspects of von Willebrand disease: bleeding history
Introduction
Bleeding history in VWD
Bleeding symptoms in VWD
Specific situations
Bleeding assessment tools
Conclusion
References
10 Laboratory diagnosis of von Willebrand disease: the phenotype
Screening diagnostic tests
Extended diagnostic tests
Qualitative changes in VWF
Diagnosis in neonates and young children
Diagnosis in pregnancy
Desmopressin trials as an aid to the diagnosis and functional characterization of VWD
An algorithmic approach to diagnosis of VWD
Future perspectives
References
11 Molecular diagnosis of von Willebrand disease: the genotype
Introduction and role of genetic testing in VWD
Techniques used in molecular analysis of VWD
Assessment of variant pathogenicity
Molecular spectrum of VWD
Challenges and future of VWD genotyping
Acknowledgments
References
12 Clinical, laboratory, and molecular markers of type 1 von Willebrand disease and low von Willebrand factor
Introduction
The epidemiology of type 1 von Willebrand disease
Clinical features of type 1 von Willebrand disease
The laboratory diagnosis of type 1 von Willebrand disease
The genetics of type 1 von Willebrand disease
The role of ABO blood group and type 1 von Willebrand disease
von Willebrand factor gene mutations and type 1 von Willebrand disease
Recurrent type I von Willebrand disease candidate mutations
Non‐coding sequence variants in type 1 von Willebrand disease
Type 1 von Willebrand disease and accelerated clearance of von Willebrand factor
Future priorities in type 1 von Willebrand disease characterization
References
13 Clinical and molecular markers of type 1C VWD
Introduction
Epidemiology
Clinical features
Laboratory diagnosis and studies on increased clearance in type 1 VWD
Genetics and the specific mutations of type 1C VWD
The role of glycans in increased VWF clearance
Summary
References
14 Clinical and molecular markers of VWD2A
Introduction
Pathophysiology
Clinical manifestations
Laboratory diagnosis
Molecular markers
Treatment
References
15 Clinical and molecular markers of VWD2B
Introduction
Pathophysiology
Clinical manifestations
Laboratory diagnosis
Molecular markers
Treatment
Conclusions
References
16 Clinical and molecular markers of type 2M VWD
Introduction
Clinical features of type 2M VWD
Laboratory classification of type 2M VWD
Problems with ristocetin in VWF assays
Genetic variants found in type 2M VWD
Treatment of type 2M VWD
Summary
Acknowledgements
Conflicts of Interest
References
17 Clinical and molecular markers of VWD2N
The VWF‐FVIII interaction
Laboratory diagnosis
Molecular analysis
Proposed algorithm for the diagnosis of type 2N
Clinical symptoms
Therapeutic options
Conclusions
References
18 Clinical, laboratory, and molecular markers of type 3 von Willebrand disease
General definition, history, and epidemiology
Epidemiology
Clinical markers of VWD3
Laboratory markers of VWD3
Molecular markers of VWD3
Additional VWF molecular markers found in 3WINTERS‐IPS patients
Treatment and prevention of bleeding in VWD3
Secondary long‐term prophylaxis
Future perspectives
Acknowledgments
References
19 Pediatric aspects of von Willebrand disease
Introduction
Diagnosis of VWD in childhood
Diagnosis of type 1 VWD versus low VWF levels as a risk factor for bleeding
VWD in neonates
Acquired VWS in childhood
VWD in adolescents
Treatment strategies in children
Conclusions
References
20 Women with von Willebrand Disease
Introduction
Gynecology
Obstetrics
References
21 The use of desmopressin in von Willebrand disease
History
Mechanism of action
Modes of administration and dosage
Experience of desmopressin in VWD
Conclusions
References
22 Plasma‐derived and recombinant VWF concentrates
Introduction
Plasma‐derived VWF/FVIII and VWF‐only concentrates
Recombinant VWF‐only concentrate
Conclusions
References
23 Pathophysiology, epidemiology, and management of acquired von Willebrand syndrome
General definition, history, and epidemiology
Pathophysiological mechanisms of AVWS occurring with underlying disorders
Diagnostic tests
Differentiation of AVWS from VWD
Lymphoproliferative disorders
Cardiovascular diseases
Myeloproliferative disorders
Immunological diseases
Other clinical conditions less frequently associated with AVWS
Hypothyroidisms and other very rare underlying diseases
Current issues and future perspectives on AVWS
References
24 Cardiovascular causes of AVWS
Von Willebrand factor: a sensor of blood flow
Epidemiology and pathophysiology of AVWS associated with cardiovascular diseases or devices
Diagnosis of AVWS associated with cardiovascular disorders
Pathophysiology of gastrointestinal angiodysplasia in AVWS associated with cardiovascular disorders
Management of AVWS associated with cardiovascular disorders
Conclusion
References
25 Von Willebrand factor regulation of angiogenesis and vascular integrity: implications for gastrointestinal angiodysplasia and beyond
Clinical evidence of gastrointestinal bleeds in von Willebrand disease and acquired von Willebrand syndrome
Gastrointestinal bleeding and angiodysplasia in von Willebrand disease and acquired von Willebrand syndrome: molecular mechanisms
References
26 Prophylaxis in von Willebrand disease
Introduction
Prophylaxis in von Willebrand disease. Rationale
Long‐term experience of prophylaxis in VWD
Prophylaxis in VWD. Guidelines
Discussion and future directions
References
27 Risk of thrombosis and antithrombotic treatment in von Willebrand disease patients
VWF and thrombosis in the general population
Thrombosis in von Willebrand disease patients
Thrombosis related to VWF concentrate treatment in VWD patients
Antithrombotic treatment in VWD patients
Remaining uncertainties regarding VWD treatment and risk of thrombosis
Conclusion
References
28 Novel functions for VWF beyond hemostasis
VWF: Traditional role in hemostasis and thrombosis
VWF beyond hemostasis: An adhesive glycoprotein
VWF: Affector of cells
Roles for VWF in non‐hemostatic disease pathogenesis
Conclusions
References
Index
End User License Agreement
List of Tables
Chapter 6
Table 6.1 Summary of association between VWF‐FVIII clearance receptor varia...
Chapter 7
Table 7.1 Types of VWD.
Table 7.2 Laboratory findings in VWD.
Chapter 8
Table 8.1 Epidemiological investigations of prevalence of von Willebrand di...
Table 8.2 Frequency of self‐reported hemorrhagic symptoms in the general po...
Table 8.3 Frequency of hemorrhagic symptoms in the 107 members with two or ...
Chapter 9
Table 9.1 Incidence (%) of bleeding symptoms both in patients with von Will...
Table 9.2 Published bleeding assessment tools.
Table 9.3 ISTH‐BAT bleeding score.
Chapter 10
Table 10.1 Typical laboratory patterns in von Willebrand disease (VWD).
a
Table 10.2 Diagnostic tests for the phenotyping of VWD.
Table 10.3 Test principles for the determination of von Willebrand factor (V...
Chapter 11
Table 11.1 Genetic variant interpretation resources.
Chapter 12
Table 12.1 Definition of type 1 von Willebrand disease.
Table 12.2 Influence of ABO blood group on von Willebrand factor.
Table 12.3 Von Willebrand factor gene mutations in type 1 von Willebrand di...
Table 12.4 Characteristics of the accelerated clearance type 1 von Willebra...
Chapter 13
Table 13.1 Glycosylation sites of VWF.
Chapter 14
Table 14.1 Suggestions for therapy of bleeding and surgery prophylaxis in t...
Chapter 15
Table 15.1 Mutations identified in exon 28 of VWF gene associated with type...
Table 15.2 Platelet count at baseline and during triggering situations, and...
Chapter 16
Table 16.1 Laboratory results found in VWD type 2M.
Chapter 17
Table 17.1 Phenotypic and clinical characteristics of a French cohort of 12...
Chapter 18
Table 18.1 Prevalence of type 3 von Willebrand disease (VWD3).
Table 18.2 Prevalence (%) of bleeding symptoms in patients with von Willebr...
Table 18.3 Clinical and laboratory characteristics of investigated subjects...
Table 18.4 Molecular genetic defects in VWD3.
Table 18.5 Plasma‐derived concentrates containing von Willebrand factor (VW...
Chapter 20
Table 20.1 Girls and women with HMB who require hemostatic testing.
Table 20.2 Commonly used medical treatments.
Table 20.3 Conditions for the use of regional block in women with inherited...
Chapter 21
Table 21.1 Recommended doses of desmopressin in Von Willebrand disease.
Table 21.2 General response to desmopressin in the different Von Willebrand...
Table 21.3 General flowchart for the use of desmopressin in Von Willebrand ...
Chapter 22
Table 22.1 Main characteristics of plasma‐derived VWF/FVIII and VWF‐only co...
Table 22.2 Treatment of von Willebrand disease with plasma‐derived VWF/FVII...
Chapter 23
Table 23.1 List of the pathogenic mechanisms that operate in different diso...
Table 23.2 Main diseases associated with AVWS in CLHH versus those publishe...
Table 23.3 Laboratory tests for the diagnosis of AVWS.
Table 23.4a Laboratory findings in AVWS associated with LPD at CLHH.
Table 23.4b Laboratory findings in AVWS associated with CVD at CLHH.
Table 23.4c Laboratory findings in AVWS associated with MPD at CLHH.
Table 23.4d Laboratory findings in AVWS associated with anti‐VWF antibodies...
Table 23.4e Laboratory findings in AVWS associated with liver disease at CL...
Table 23.4f Laboratory findings in AVWS associated with neoplasia at CLHH....
Table 23.4g Laboratory findings in AVWS associated with kidney diseases at ...
Chapter 26
Table 26.1 Frequency distribution of primary indication for prophylaxis, ch...
Table 26.2 Long‐term prophylaxis in VWD. Recommendations based on limited p...
Chapter 28
Table 28.1 VWF ligands with their corresponding VWF‐binding sites.
List of Illustrations
Chapter 1
Figure 1.1 Erik von Willebrand.
Figure 1.2 The Åland pedigree as originally described in 1926 [1]. The index...
Figure 1.3 VIII:C, VWF:Ag (VIIIR:Ag), VWF:RCo (VIIIR:RCF), and Duke bleeding...
Chapter 2
Figure 2.1 Domain structure of von Willebrand factor (VWF). (a) VWF is synth...
Figure 2.2 Intracellular processing of von Willebrand factor (VWF). The path...
Figure 2.3 von Willebrand factor (VWF) forms high‐molecular‐weight multimers...
Figure 2.4 Regulated storage of von Willebrand factor (VWF) in endothelial c...
Figure 2.5 Expression of VWF in AtT‐20 cells. (a) Propeptide‐deleted VWF is ...
Figure 2.6 von Willebrand factor (VWF)‐dependent Weibel–Palade body biogenes...
Chapter 3
Figure 3.1 This figure illustrates the multimer size dependency of binding t...
Figure 3.2 This figure provides the structural and functional relationships ...
Figure 3.3 This figure summarizes some of the functions of VWF and the regio...
Figure 3.4 This figure illustrates the localization of VWF variants on the c...
Chapter 4
Figure 4.1 VWF expression levels across different tissues in the human body....
Figure 4.2 Schematic representation of the transcriptional activators and re...
Figure 4.3 There are various factors that contribute to the positive or nega...
Chapter 5
Figure 5.1 VWF structure. (a) Schematic representation of multimeric VWF (VW...
Figure 5.2 ADAMTS13 structure. (a) Domain organization of ADAMTS13 in its “o...
Figure 5.3 ADAMTS13 function. (a) Under normal circumstances, multimeric VWF...
Chapter 6
Figure 6.1 Summary of putative VWF scavenger and lectin clearance receptors ...
Chapter 7
Figure 7.1 Structure of the VWF protein and corresponding domains.
Chapter 9
Figure 9.1 Odds ratio for type 1 von Willebrand disease associated with pres...
Chapter 10
Figure 10.1 Normal plasma and variants of von Willebrand disease (VWD) in a ...
Figure 10.2 Normal plasma and von Willebrand disease (VWD) variants in a dis...
Figure 10.3 Normal plasma and a von Willebrand disease variant in a disconti...
Figure 10.4 Densitometric visualization of von Willebrand factor multimers i...
Chapter 11
Figure 11.1 Structure and function of VWF (a) Structure of VWF precursor pro...
Chapter 12
Figure 12.1 Genetic mechanisms responsible for type 1 VWD and low VWF.
Chapter 13
Figure 13.1 DDAVP trial results for patients with type 1 compared to those w...
Figure 13.2 A comparison between mutation and glycosylation sites on VWF. (a...
Chapter 14
Figure 14.1 Frequency distribution of VWD phenotypes. (a) Frequency of VWD t...
Figure 14.2 Multimer patterns of 4 different subtypes of VWD2A, positioned a...
Figure 14.3 Pattern of changes in FVIII and VWF measurements after a test‐in...
Chapter 15
Figure 15.1 Location of the more frequent type 2B mutations in the A1 domain...
Chapter 16
Figure 16.1 A simplified algorithm that describes the results and the proces...
Figure 16.2 Healthy individuals with the 1472H variant have lower VWF:RCo/VW...
Figure 16.3 Cartoon of the
VWF
gene highlighting the A1 domain where type 2M...
Chapter 17
Figure 17.1 Proportion of VWD2N among patients with type 2 VWD in different ...
Figure 17.2 Variants identified in type VWD2N (according to de Jong A & Eike...
Figure 17.3 Molecular defect in a French cohort of 121 patients with type VW...
Figure 17.4 Proposed algorithm for the diagnosis of type VWD2N. *VWF genetic...
Figure 17.5 Type of bleeding manifestations observed in 99 patients belongin...
Chapter 18
Figure 18.1 Pedigree of family S of Föglö (historical picture Blombäk [113] ...
Figure 18.2 Bleeding‐free survival curves calculated according to bleeding s...
Figure 18.3 (a) Frequency of clinically relevant bleeding symptoms in male a...
Figure 18.4 Sample workflow and related results. In total, 213 subjects have...
Figure 18.5 Distribution of the 154 different unique variants identified in ...
Chapter 19
Figure 19.1 Proposed algorithm for diagnosis of von Willebrand disease (VWD)...
Chapter 20
Figure 20.1 Management of HMB flow chart.
Figure 20.2 Pregnancy changes in FVIII and VWF in women VWD..
Chapter 21
Figure 21.1 Chemical structure of the natural hormone vasopressin and its sy...
Figure 21.2 VWF: Ristocetin Cofactor activity (RCo) levels (IU/dL) in 15 pat...
Figure 21.3 Data from the European study on molecular and clinical markers f...
Figure 21.4 Data from the European study on molecular and clinical markers f...
Figure 21.5 Biologic response to desmopressin (a) in 26 patients with type 1...
Figure 21.6 Urinary flow (mL/h) and serum sodium (mmol/L) in 10 healthy volu...
Chapter 23
Figure 23.1 Pictorial representation of the four main pathogenetic mechanism...
Figure 23.2 Comparison of von Willebrand factor multimers of a patient with ...
Figure 23.3 Comparison of the von Willebrand factor multimer of a patient wi...
Figure 23.4 Comparison between von Willebrand factor (VWF) multimers in a pa...
Chapter 24
Figure 24.1 Pathogenesis of VWF HMW‐multimers defect associated with aortic ...
Figure 24.2 HMW‐multimers defect in plasma as a risk factor for angiodysplas...
Chapter 25
Figure 25.1 VWF angiostatic function. VWF promotes vascular stability and ex...
Figure 25.2 VWF in the pathogenesis of GI angiodysplasia and bleeding. (a) I...
Figure 25.3 VWF angiogenic function. During wound healing, the VWF heparin b...
Chapter 26
Figure 26.1 Indications for starting prophylaxis in VWD stratified according...
Chapter 28
Figure 28.1 Traditional hemostatic ligands interacting with VWF. VWFpp, VWF ...
Figure 28.2 VWF impacts a diverse range of hemostatic and non‐hemostatic cel...
Figure 28.3 Hemostatic and non‐hemostatic functions of VWF contribute to div...
Guide
Cover Page
Table of Contents
Title Page
Copyright Page
List of Contributors
Foreword
Preface
Begin Reading
Index
WILEY END USER LICENSE AGREEMENT
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Textbook of von Willebrand Disease
Basic and Clinical Aspects
Second Edition
Edited by
Augusto B. Federici, MD
Hematology and Transfusion MedicineL. Sacco University HospitalDepartment of Oncology and HematologyUniversity of MilanMilan, Italy
Erik E. Berntorp, MD, PhD
Department of Translational MedicineMalmö Centre for Thrombosis and HaemostasisLund UniversitySkåne University HospitalMalmöSweden
David Lillicrap, MD
Department of Pathology and Molecular MedicineRichardson LaboratoryQueen’s UniversityKingston, ON, Canada
Robert R. Montgomery, MD
Versiti Blood Research InstituteDepartment of PediatricsMedical College of WisconsinMilwaukee, WI, USA
This edition first published 2024© 2024 John Wiley & Sons Ltd
Edition HistoryBlackwell Publishing Ltd (1e, 2011)
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.
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Library of Congress Cataloging‐in‐Publication Data applied forISBN 9781119419488 (Hardback)
Cover Design: Dr. Luigi GhilardiniCover Images: Courtesy of Augusto B. Federici and Luigi Ghilardini
List of Contributors
Rezan Abdul KadirDepartment of Obstetrics and Gynecology, KatharineDormandy Haemophilia and Thrombosis UnitThe Royal Free NHS Foundation Trust and Institute forWomen’s Health, University College LondonLondonUK
Ferdows AtiqDepartment of HematologyErasmus University Medical CenterRotterdamThe Netherlands
Luciano BaroncianiAngelo Bianchi Bonomi Hemophilia and Thrombosis CentreIRCCS Maggiore Policlinico HospitalUniversity of MilanMilanItaly
Erik E. BerntorpDepartment of Translational Medicine, Malmö Centre forThrombosis and HaemostasisLund University, Skåne University HospitalMalmöSweden
Margareta BlombäckDepartment of Molecular Medicine and Surgery, Division ofClinical Chemistry and Blood Coagulation ReasearchThe Karolinska Institute, Karolinska University HospitalStockholmSweden
Ulrich BuddeHemostaseologyMedilys Laborgesellschaft mbHHamburgGermany
Giancarlo CastamanCenter for Bleeding Disorders and Coagulation, Department ofOncologyCareggi University HospitalFlorenceItaly
Pamela ChristophersonThrombosis and Hemostasis ProgramVersiti Blood Research InstituteMilwaukee, WIUSA
Heather CliftVersiti Blood Research InstituteMilwaukee, WIUSA
James T.B. CrawleyCentre for Haematology, Department of Immunologyand InflammationImperial College LondonLondonUK
Mélanie DanielFrench Reference Center for von Willebrand Disease (CRMW)University Hospital of LilleLilleFrance
Emmanuel J. FavaloroSydney Centres for Thrombosis and HaemostasisDepartment of HaematologyInstitute of Clinical Pathology and Medical ResearchWestmead HospitalWestmead, New South WalesAustralia
School of Dentistry and Medical Sciences, Faculty of Scienceand HealthCharles Sturt UniversityWagga Wagga, New South WalesAustralia
School of Medical Sciences, Faculty of Medicine and HealthUniversity of Sydney, Westmead HospitalWestmead, New South WalesAustralia
Augusto B. FedericiHematology and Transfusion MedicineL. Sacco University HospitalMilanItaly
Department of Oncology and HematologyUniversity of MilanMilanItaly
Veronica H. FloodVersiti Blood Research InstituteMilwaukee, WIUSA
Department of PediatricsMedical College of WisconsinMilwaukee, WIUSA
Massimo FranchiniDepartment of Transfusion Medicine and HematologyCarlo Poma HospitalMantovaItaly
Jessica GarciaDepartment of PediatricsUniversity of Texas Southwestern Medical CenterDallas, TXUSA
Elham GhorbanpourGenetics and Genome BiologySickkids Research InstituteTorontoCanada
Jenny GoudemandFrench Reference Center for von Willebrand Disease (CRMW)University Hospital of LilleLilleFrance
Sandra L. HaberichterVersiti Blood Research InstituteMilwaukee, WIUSA
Department of PediatricsMedical College of WisconsinMilwaukee, WIUSA
Paula D. JamesDepartment of MedicineQueen’s University, KingstonOntarioCanada
Maissaa JanbainDeming Department of internal Medicine, Section ofHematology and Medical OncologyTulane University School of MedicineNew Orleans, LAUSA
Frank W.G. LeebeekDepartment of HematologyErasmus University Medical CenterRotterdamThe Netherlands
David LillicrapDepartment of Pathology and Molecular Medicine,Richardson LaboratoryQueen’s UniversityKingstonCanada
Pier Mannuccio MannucciAngelo Bianchi Bonomi Hemophilia and Thrombosis CenterIstituto di Ricovero e Cura a Carattere Scientifico (IRCCS)Ca’ Granda Maggiore Policlinico Hospital FoundationMilanItaly
Robert R. MontgomeryVersiti Blood Research InstituteMilwaukee, WIUSA
Department of PediatricsMedical College of WisconsinMilwaukee, WIUSA
James S. O’DonnellIrish Centre for Vascular BiologySchool of Pharmacy and Biomolecular SciencesRoyal College of Surgeons in IrelandDublinIreland
National Coagulation CentreSt James’s HospitalDublinIreland
Jamie M. O’SullivanIrish Centre for Vascular Biology, School of Pharmacyand Biomolecular SciencesRoyal College of Surgeons in IrelandDublinIreland
Jorge Di PaolaDepartment of PediatricsWashington University School of Medicine in Saint LouisSaint Louis, MOUSA
Anastasis PetriCentre for Haematology, Department of Immunologyand InflammationImperial College LondonLondonUK
Anna M. RandiVascular Sciences, Imperial Centre for Translationaland Experimental MedicineNational Heart and Lung InstituteImperial College LondonLondonUK
Antoine RauchCHU Lille, Hematology TransfusionLilleFrance
Sophie SusenCHU Lille, Hematology TransfusionLilleFrance
Orla RawleyDepartment of Pathology and Molecular MedicineQueen’s UniversityKingston, OntarioCanada
Francesco RodeghieroHematologistHematology Project FoundationVicenzaItaly
Reinhard SchneppenheimDepartment of Pediatric Hematology and OncologyUniversity Medical CenterHamburg‐EppendorfGermany
Robert F. Sidonio, JrAflac Cancer and Blood DisordersEmory UniversityAtlanta, GAUSA
Laura L. SwystunDepartment of Pathology and Molecular MedicineQueen’s UniversityKingston, OntarioCanada
Alberto TosettoDepartment of HematologySan Bortolo HospitalVicenzaItaly
Yaoxian XuCentre for Haematology, Department of Immunologyand InflammationImperial College LondonLondonUK
Foreword
I feel very honored to have been asked to write the foreword to this textbook on von Willebrand disease (VWD). I am now the oldest living scientist to have experience in this area, and thus it may be of interest for readers to learn about some early experiences that I shared with the late Dr. Inga‐Marie Nilsson, which I have described below. Since I started working with VWD in the mid‐1950s, there has been enormous progress in the management of the disease in terms of knowledge about mechanisms, treatment, and underlying genetics. We have been able to follow this development in Stockholm because the hemophilia center here is currently responsible for the treatment of 40 patients with type 3 VWD (i.e., the most severe form).
In the 1950s, there were only a few known cases of the disease—which was mostly called “pseudohemophilia”—in addition to those cases known in the Åland Islands, where the disease was first identified by Erik von Willebrand. This was probably because most patients with type 3 VWD died young, either in utero or, if the patient was female and survived until puberty, as a result of menstrual bleeding. I remember some touching letters written at the end of the 19th century from a businessman to his wife, who was mostly bedridden owing to menstrual bleedings. This woman was an ancestor of a young woman from Stockholm with type 3 VWD, who is currently living a normal family life thanks to therapy in early childhood with the Swedish fraction I‐0 (which contained von Willebrand factor [VWF], factor VIII [FVIII], and fibrinogen) and later with commercial VWF‐containing concentrates.
When taking a bleeding history for a female in the 1950s, it was useful to ask whether she had been scolded in school for dropping blood onto her handiwork after pricking her finger with a sewing needle. We learned that it was useful to analyze blood groups in family investigations, as we found that a healthy child who showed no sign of having inherited the disease did not share the same father as the sick sibling. We made several mistakes—one girl was transfused with platelets during severe menstrual bleeding without success, but when treated with fraction I‐0, the bleeding stopped. It is possible that the platelet treatment was the reason why she later developed antibodies to VWD. At that time, there were no oral contraceptives, which have revolutionized the management of menorrhagia in patients with VWD. In this particular patient, we used testosterone and later hysterectomy (under prophylaxis of fraction I‐0) to deal with the menstrual bleeding.
Persuading doctors that a patient had to be treated with a concentrate was a difficult task. I remember the case of a 13‐year‐old boy who developed severe head trauma as a result of falling from a bicycle. Despite the fact that the boy had a bleeding chart saying that he should be treated immediately in the event of a trauma and the fact that I informed the doctor that the usual signs do not develop in bleeders immediately but sometimes several days later, the doctor refused to treat the boy with concentrates and he died from severe brain hemorrhage.
In 1958, we started prophylactic treatment for patients with hemophilia to avoid joint destruction. However, it was not until many years later that we realized that patients with type 3 VWD also required prophylaxis; therefore, some of them developed joint disabilities. We also did not know that the concentrates with which we treated our patients could contain hepatitis C virus, which has led to the premature death of some patients.
This book has become a very comprehensive and useful work into which many of the authors have put great efforts to make their chapters not only informative but also easy to understand. Progress, difficulties, and alternative ways to diagnose phenotypes and genotypes are described. Molecular diagnosis of type 1, type 2 and its variants, and type 3 VWD is presented. In addition, a chapter on gene therapy looking into the future is stimulating to read. Furthermore, many authors have endeavored to include all relevant literature, which is very useful for students.
A problem with regard to historical aspects is that the nomenclature has changed from FVIII‐related antigen to VWF antigen. Therefore, some of the early findings with regard to the level of VWF in patients with blood group O or A have not been observed. Nevertheless, the topic of how to proceed in diagnosis when the patient has blood group O or A has been thoroughly discussed. I have the impression that there still are problems with regard to the diagnosis of the phenotypes, particularly with regard to the diagnosis of type 1 VWD, even if pre‐analytic problems are taken into account, for example, the quality of methodology and the importance of telling the patient to rest and not to run or be stressed, before blood sampling. I made a serious mistake once when analyzing changes in VWF during the menstrual cycle—the volunteers were not well informed about resting before sampling and we therefore misinterpreted the results; there are not such great variations in FVIII and VWF during the menstrual cycle as initially suggested.
When investigating families with type 3 VWD, we found that the parents and siblings who were genetic carriers of VWD only had a phenotypically mild bleeding disorder, and often, but not always, the common analyses of VWD indicated a mild disorder. However, we recorded the usefulness of an increased ratio of FVIII/VWF:Ag for the diagnosis of what we called type 1 VWD in these families.
It must have been an enormous task for the editors to encourage all the authors to write, although possibly some welcomed the opportunity to put together their experience in a comprehensive chapter. The efforts to try to collate experience in multicenter studies on prophylaxis and diagnostic scores are very valuable and, of course, need to be supported in order to solve the many difficulties that remain in the diagnosis and management of VWD.
Margareta BlombäckProfessor EmeritusKarolinska InstitutetSwedenJanuary 2019
Preface
Erik von Willebrand described a novel bleeding disorder in 1926, and in his original publication, he provided an impressive description of the clinical and genetic features of von Willebrand disease (VWD). In contrast to hemophilia, the epitome of inherited bleeding disorders, both sexes were affected, and mucosal bleeding was the predominant symptom. The history of VWD is fascinating because it demonstrates how good clinical observations, genetic studies, and biochemical skills can improve the basic understanding of a disease and its management. The continuous efforts of scientists and clinicians over the last 85 years have significantly furthered the understanding of the structure and function of von Willebrand factor (VWF), the protein that is absent, reduced, or dysfunctional in patients with VWD. Such basic information about VWF will undoubtedly improve both the diagnosis and the treatment of VWD. Determination of both the phenotype and the genotype is now readily available in many countries, and treatment is becoming more specific and directed by the type and subtype of VWD. Therapeutic agents must correct the dual defect of hemostasis, i.e. the abnormal platelet adhesion due to reduced and/or dysfunctional VWF and the associated low level of factor VIII (FVIII). Desmopressin (DDAVP) is the treatment of choice for type 1 VWD because it induces the release of VWF from cellular compartments. VWF concentrates that are virally inactivated, with or without FVIII, are effective and safe in patients unresponsive to DDAVP. The recombinant VWF was under evaluation in clinical trials when the first edition of this book was published and is now used to manage VWD patients in most developed countries. Retrospective and prospective clinical studies, including bleeding history and laboratory markers for diagnosis, as well as the use of DDAVP and VWF concentrates to treat or prevent bleeding in patients with VWD, have been essential to provide international guidelines for the management of VWD such as those published in 2021 by ASH/ISTH/WFH societies. More efforts should be devoted to promote awareness of VWD especially in developing and low‐income countries where high costs for laboratory diagnosis cannot be afforded. More simplified clinical and diagnostic approaches should be designed.
In 2026, we are going to celebrate the first century since the original description of VWD by Erik von Willebrand. The second edition of this book has been organized to report the most updated basic and clinical aspects of inherited and acquired defects of VWF. All the important advances have been described in more chapters by the most experts who have contributed directly to the improved management of VWD patients. For these reasons, the editors decided to propose a new title for this second edition of the book: Textbook of von Willebrand Disease: Basic and Clinical Aspects. The editors hope that a book specifically devoted to VWD can be useful to the hematologists of the 21st century who would like to manage VWD patients in a more comprehensive way using the most updated and evidence‐based recommendations.
The editors would like to dedicate this Textbook on VWD to three pioneers in VWD research who made pivotal and original contributions to this field: Arthur Bloom, Inga Maria Nilsson, and Theodore S. Zimmerman. Another special dedication must be attributed to J. Evan Sadler who pioneered the study of the two proteins VWF/ADAMTS13 involved in VWD basic mechanisms and classification. Their lifelong devotion to research on VWD and other bleeding disorders should stimulate further studies on these topics of hematology.
The Editors
Augusto B. Federici
Erik E. Berntorp
David Lillicrap
Robert R. Montgomery
16 January 2024
1Historical perspective on von Willebrand disease
Erik E. Berntorp1 and Margareta Blombäck2
1Department of Translational Medicine, Malmö Centre for Thrombosis and Haemostasis, Lund University, Skåne University Hospital, Malmö, Sweden
2Department of Molecular Medicine and Surgery, Division of Clinical Chemistry and Blood Coagulation Reasearch, The Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
Introduction
The history of von Willebrand disease (VWD) and its causative factor, the von Willebrand factor (VWF), spans almost a century and was recently comprehensively reviewed by the late professor Birger Blombäck, who described the first publication by Erik von Willebrand [1], the gene cloning in 1985, and the discovery of the specific metalloprotease, ADAMTS13 [2], which degrades VWF. The purpose of this review is to describe the early history of the understanding of the disease and the first steps in the replacement therapy for its severe forms. Also, we describe in greater detail the findings of a group of different families investigated on the Åland Islands.
The scientist of the disease
Erik Adolf von Willebrand (Figure 1.1) was born in Vasa, Finland, in 1870. He qualified as a medical doctor in 1896 and specialized initially in physical therapy and later in internal medicine in Helsinki. Erik von Willebrand devoted much of his professional life to an interest in blood, especially its coagulation properties. In 1899, he defended a doctoral thesis that dealt with his investigation of the changes that occur in blood following a serious hemorrhage. From 1908 until his retirement in 1935, Erik von Willebrand worked at the Deaconess Institute in Helsinki, where he headed the Department of Internal Medicine between 1922 and 1931. Erik von Willebrand was known for his modesty and integrity, and in his obituary it was said that he “usually preferred to discuss his observations of nature rather than his personal achievements.” He died in September 1949, at the age of 89 years.
First description of the disease: the Åland family
In 1926, Erik von Willebrand first described the inherited bleeding disorder in Finska Läkaresällskapets Handlingar (in Swedish). He identified features that suggested that this disease was distinct from classic hemophilia and other bleeding disorders known at the time, such as anaphylactoid purpura, thrombocytopenic purpura, and hereditary thrombasthenia, described by Glanzmann. What differentiated this bleeding disorder from classic hemophilia was that it was not frequently associated with muscle and joint bleeding, and it affected both women and men. He stressed that a prolonged bleeding time was its most prominent characteristic. He concluded that the condition was a previously unknown form of hemophilia, and called it “hereditary pseudohemophilia.” Erik von Willebrand also discussed the pathogenesis of the condition and felt that the bleeding could best be explained by the combined effect of a functional disorder of the platelets and a systemic lesion of the vessel walls.
The original observations leading to this new disease were made in several members of a large family (identified as family S) living on the island of Föglö in the Åland archipelago in the Baltic Sea. The index case was a girl aged 5 years, named Hjördis S, who had marked and recurrent bleeding tendencies and was brought to Helsinki for consultation. Both her mother and father were from families with histories of bleeding. The girl was the ninth of 11 children, of whom 7 had experienced bleeding symptoms. Four of her sisters had died from uncontrolled bleeding at an early age. Hjördis herself had experienced several severe episodes of bleeding from the nose and lips and following tooth extractions, as well as bleeding in her ankle. At the age of 3 years, she bled for 3 days from a deep wound in her upper lip. The bleeding was so severe that she almost lost consciousness and had to be hospitalized for 10 weeks. At the age of 14 years, Hjördis bled to death during her fourth menstrual period.
Hjördis came from a large family (Figure 1.2). Intrigued by their history, Erik von Willebrand studied the family further with the help of coworkers. He published the pedigree and his clinical and laboratory evaluation in his 1926 paper. He found that 23 of the 66 family members had bleeding problems. The most prominent problem among the affected family members was mucosal bleeding: epistaxis, followed by profuse bleeding from oral lesions, easy bruising, and, in females, excessive bleeding during menstruation and childbirth. Intestinal bleeding had been the cause of death at early ages in some family members.
Figure 1.1 Erik von Willebrand.
In further studies, Erik von Willebrand found two families related to Hjördis S and one unrelated family in whom bleeding symptoms similar to those observed in Hjördis were common [3, 4]. In the 1930s, Jürgens, together with von Willebrand [5, 6], reinvestigated the patients in Åland and concluded that the disease was due to some impairment of platelet function, including platelet factor 3 deficiency. This observation led to the disease being called von Willebrand–Jürgens thrombopathy, and, although this condition is not officially recognized today, von Willebrand did not dismiss the notion that factors in blood plasma might also be important in the pathogenesis of the disease.
Other early clinical reports
In 1928, Dr. George R. Minot of Boston described five patients from two families with prolonged bleeding times and symptoms similar to the Åland family members. This may have been one of the first descriptions of VWD [7–9]. In the following years, numerous cases similar to those described by von Willebrand were reported, usually under the name of pseudohemophilia. In 1953, Alexander and Goldstein [10] found a dual defect in two patients with hereditary pseudohemophilia. They confirmed the earlier findings of prolonged bleeding time, normal platelet count and function, and abnormal nail bed capillaries. However, they also found a decreased FVIII level (5–10% of normal) and they observed a prolonged coagulation time that was normalized by normal plasma. The prolonged bleeding time, however, was not normalized and this was later explained by the fact that infusion of a restricted volume of plasma does not provide a sufficient amount of VWF [11]. Larrieu and Soulier [12] also found low FVIII activity and a prolonged bleeding time in pseudohemophilia, but otherwise normal clotting factors and platelet parameters. They proposed the name von Willebrand syndrome for the condition.
Figure 1.2 The Åland pedigree as originally described in 1926 [1]. The index case, Hjördis, is the ninth sibling in family S (Fam S). unaffected male; unaffected female; male with mild bleeding disease; female with mild bleeding disease; female with severe bleeding disease; † bled to death.
The search for a new factor—the bleeding time factor
The first demonstration of the VWF was during the 1950s through a joint effort by Margareta and Birger Blombäck, working in Stockholm with the purification of fibrinogen, and Inga Marie Nilsson, who had established a clinical coagulation unit in Malmö. It was found that fibrinogen purified from Cohn fraction I of human plasma, when specifically obtained in fraction I‐0 (AHF‐Kabi), was heavily contaminated with an antihemophilic factor, which is plasma factor VIII (FVIII) [13].
At that time, Dr. Nilsson had a 15‐year‐old female patient named Birgitta who had a severe hemorrhagic diathesis. When she began to menstruate, the condition worsened and she received frequent blood transfusions. However, Birgitta developed serious side‐effects from the transfusions and they were stopped. As a consequence, other treatment options had to be considered, and a hysterectomy was planned. Her coagulation evaluation had shown a prolonged bleeding time and a somewhat prolonged coagulation time but normal platelet count and function. FVIII activity was low. Since fraction I‐0 had a high concentration of FVIII, it was decided that its effects should be tested in Birgitta. To the surprise of the treating physicians, not only did FVIII activity increase as expected but the bleeding time was also normalized [14]. Subsequently, a hysterectomy was successfully performed under the cover of fraction I‐0. According to modern classification, this patient had type 3 VWD. She is now well and has been on regular prophylaxis with VWF concentrate for many years.
In June 1957, Inga Marie Nilsson, Erik Jorpes, Margareta Blombäck, and Stig‐Arne Johansson visited Åland and studied 16 patients who had been examined 25–30 years previously by von Willebrand. No patients who had severe forms of the disease were still living. In their investigation, they found FVIII activity to be reduced in 15 of 16 cases [15]. The father of Hjördis had a normal level. The Duke bleeding time varied, with two patients having a definite prolongation and three patients having a moderate prolongation. Platelet counts were normal and, in contrast to Jürgens’ earlier observation, the platelets themselves were normal with respect to platelet factor 3. One of the patients was given fraction I‐0, which normalized the FVIII level and the bleeding time. It could be concluded that the Åland family had the same disease described by several other authors in Europe and the USA [16]. At the same time, Jürgens visited the islands (Erik Jorpes had told him of his team’s research plan) and took samples from many of the same patients, and confirmed the decreased FVIII levels [17].
The findings by the Swedish group confirmed what had been documented in a number of Swedish families [18]. The observation was also made that FVIII increased during the first 24 hours after infusion of fraction I‐0 in patients with VWD, in contrast to what is seen in hemophilia [19]. The results of fraction I‐0 infusion in a patient with severe VWD are shown in Figure 1.3. The bleeding time is reduced or normalized; factor VIII clotting activity (VIII:C) increases steadily during the first 24 hours, whereas the VWF (VIIIR:Ag and VIIIR:RC according to old nomenclature) displays a pharmacokinetic profile as expected and as later shown. Control experiments and further studies [11, 20, 21] revealed that the bleeding time factor was a plasma factor not earlier described. Fraction I‐0 prepared from patients with severe hemophilia A not only corrected the bleeding time in VWD, but also stimulated the production of FVIII activity, whereas fraction I‐0 prepared from patients with VWD had no such effect. Purified fibrinogen had no effect on the bleeding time. Still, there was the possibility that the shortening of the bleeding time was due to platelets or platelet factors contaminating fraction I‐0. This turned out to be unlikely, since the effect on bleeding time was the same whether the fraction had been prepared from platelet‐rich or platelet‐poor plasma. Infusion of a platelet suspension from a normal donor to a patient with VWD had no effect on either bleeding time or bleeding tendency or did injection of fraction I‐0 into a patient with thrombocytopenia. From these findings, it was concluded that the impaired hemostasis in VWD was due to lack of a plasma factor, the bleeding time correcting factor, or the VWF, which occurs not only in normal plasma but also in hemophilia A plasma. This factor not only corrected the prolonged bleeding time but apparently increased the level of FVIII. Thus, platelets or platelet factors were not identical with the bleeding time factor, which had been proposed by both Rudolf Jürgens and Erik von Willebrand to be responsible, together with a vascular defect, for the bleeding diathesis. These findings have since been widely confirmed. The claim that a previously unknown factor in plasma had been discovered was communicated at the Congress of the International Society of Hematology in Rome in 1958 (see also Ref. [20]).
Figure 1.3 VIII:C, VWF:Ag (VIIIR:Ag), VWF:RCo (VIIIR:RCF), and Duke bleeding time (BT) in a patient with severe von Willebrand disease after infusion of human fraction I‐0 (AHF‐Kabi) [16]. Bleeding time is shortened and VIII:C is successively increased after the initial post‐infusion peak during the first 24 hours, whereas the von Willebrand factor (VIIIR:Ag and VIIIR:RC) displays a pharmacokinetic profile as expected.
Reproduced from Nilsson and Holmberg [16].
At first, it was not understood how a plasma factor could affect primary hemostasis and shorten the bleeding time. However, Borchgrevink [22] found decreased platelet adhesiveness in vivo, and Salzman [23] demonstrated decreased platelet adhesiveness to glass in VWD. Borchgrevink employed the method suggested by Hellem [24], which used a slow flow and could not discriminate between samples from patients with or without VWD. Salzman modified this method and introduced a higher flow, making it more specific for VWD. It was also shown that normal or hemophilic plasma can normalize the reduced platelet adhesiveness as well as the bleeding time in VWD [23, 25, 26]. In studies using electron microscopy, Jörgensen and Borchgrevink [27] demonstrated a decreased adhesion of platelets to disrupted endothelium in VWD. This observation indicated that the plasma factor lacking in VWD exerted its action in primary hemostasis via the platelets by enhancing their adhesiveness.
During the 1960s, cases of VWD were reported in several countries. The disease was thought to be uniform and was defined as an autosomal dominant inheritable hemorrhagic disease characterized by a prolonged bleeding time, decreased FVIII clotting activity, decreased platelet adhesiveness as measured by the Salzman method, and progressive increase of FVIII activity after infusion of plasma and FVIII concentrate [16].
However, returning to the earlier papers by Erik von Willebrand and Rudolf Jürgens, the findings on the Åland islands showed what appeared to be a discrepancy between the original family S and some of the others investigated; the original von Willebrand family having “pure” VWD while in other families there were also platelet function defects. Thus, in 1977, Dag Nyman (originally from Åland) and collaborators [28] traveled from Stockholm to Åland to undertake a thorough investigation using new laboratory methods [28]. They found that the families described as having VWD could be divided into four categories: (i) the survivors with a mild disorder from the original family S had the characteristics of type 1 VWD, that is they had similarly decreased levels of VWF:Ag and ristocetin cofactor activity in addition to normal or decreased levels of FVIII, and the platelet aggregation was normal; (ii) one family had a platelet function defect (pure cyclooxygenase defect); (iii) one family had a mixture of VWD and a cyclooxygenase defect; and (iv) one family had a platelet function defect of the aspirin type. These findings, of course, made it easier to investigate the genetic defects of the original VWD (family S).
In the beginning of the 1990s, Zhang and collaborators [29] investigated the DNA sequence of 24 patients with type 3 VWD living in Sweden. They found a cytosine deletion in exon 18 of the VWF gene in most of those of Swedish origin and an insertion in exon 28 in those of Finnish origin. Most patients with type 3 VWD were homozygous or double heterozygous for the mutations. Most of the parents had type 1 VWD and were heterozygous. As the Åland population is primarily of Swedish origin, the researchers also investigated family S and found that the surviving members who had type 1 VWD were heterozygous with respect to the mutation in exon 18. There was a small boy with severe VWD whose family was related long ago to another family with VWD from Åland. He was homozygous for the mutation in exon 18 [30].
The end of the beginning
After the publication by Erik von Willebrand in 1926, it took some 30 years until it was clear that a new plasma factor responsible for the hemostatic impairment in VWD had been detected. At that time, a factor concentrate had been produced that was effective in the replacement of VWF: fraction I‐0 (or, later, AHF‐Kabi). Studies using this concentrate and concentrates purified from different types of bleeding disorders, helped scientists to find and prove the presence of the VWF. This was the end of the beginning.
In 1971, VWF was first detected immunologically and named “FVIII‐related antigen” [31]. Since 1985, the VWF has been cloned [32–35], the primary amino‐acid sequence has been determined [36], and the complex molecular structure and multiple functions are becoming understood in detail. The metalloprotease ADAMTS13 that cleaves VWF was discovered in 2001 [2]. VWD is no longer a uniform disease [37]. The treatment armamentarium has been developed and includes prophylactic treatment with concentrates, especially in type 3 VWD. It includes desmopressin for most milder cases, new concentrates [38, 39], including recombinant VWF [40], for therapeutic use.
Recent scientific visits to Åland Islands
Many scientific visits have been organized since the report by Erik von Willebrand and pioneering visits were performed by Margareta Blombäck, Inga Marie Nilsson, and others during the 1950s when blood sampling was performed from the family members concerned. In more recent years, scientific conferences have been organized, among them in 2016—90 years after the first case of VWD was diagnosed in a patient from the Åland Islands in 1926 [41]. Sixteen experts in the field from Europe and North America convened to share knowledge and expertise on current trends and challenges in VWD. Topics included the storage and release of VWF, epidemiology and diagnostics in VWD, treatment of VWD, angiogenesis, and VWF inhibitors. Delegates also visited the house where Hjördis was living until her far too early death and her grave. A more obvious and realistic historic journey of a previously deadly bleeding disorder cannot be described.
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