Table of Contents
Cover
Table of Contents
Half title page
Title page
Copyright page
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
2 Biosynthesis and organization of von Willebrand factor
Introduction
Molecular biology of VWF
Cell biology of VWF
3 von Willebrand factor structure and function
Introduction
Four functions of VWF
Structure of VWF
VWF domain structure
Biochemistry of VWF
Summary
Acknowledgements
4 Modulation of von Willebrand factor by ADAMTS13
Pathogenesis of TTP and discovery of ADAMTS13
ADAMTS13 structure, synthesis, and secretion
ADAMTS13 gene mutations
Autoantibodies against ADAMTS13
ADAMTS13 activity and regulation
ADAMTS13 interaction with VWF
ADAMTS13 and VWD
Conclusions
5 Animal models in von Willebrand disease
Genetic and phenotypic characterization of the different VWD animal models
Contribution of VWD animal models in improving VWD therapy
Contribution of VWD animal models in improving knowledge of VWF functions
Contribution of VWD animal models to improving knowledge of VWF biology
Concluding remarks
6 Classification of von Willebrand disease
The old nomenclature of VWD: some historical steps
Classification of VWD based on structural and functional abnormalities of VWF (1987)
The revised classification of VWD (1994)
Current classification. The updated revised classification (2006)
Acknowledgements
7 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
Conclusions
8 Clinical aspects of von Willebrand disease: bleeding history
Introduction
Bleeding history in VWD
Bleeding symptoms in VWD
Specific situations
Bleeding assessment tools
Conclusion
9 Laboratory diagnosis of von Willebrand disease: the phenotype
Screening diagnostic tests
Extended diagnostic tests
Special and/or newer diagnostic tests and processes
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
Future perspectives
10 Molecular diagnosis of von Willebrand disease: the genotype
Introduction
Molecular analysis
Range of genetic defects that contribute to VWD
VWF mutation analysis
Laboratory analysis
Mutation detection challenges
Mutation analysis resources
Acknowledgements
11 Clinical, laboratory, and molecular markers of type 1 von Willebrand disease
Introduction
The epidemiology of type 1 VWD
Clinical features of type 1 VWD
The laboratory diagnosis of type 1 VWD
The genetics of type 1 VWD
The role of ABO blood group and type 1 VWD
VWF gene mutations and type 1 VWD
Recurrent type I VWD candidate mutations
Noncoding sequence variants in type 1 VWD
Type 1 VWD and accelerated clearance of VWF
Future priorities in type 1 VWD characterization
12 Clinical, laboratory, and molecular markers of type 2 von Willebrand disease
Introduction
Clinical manifestations
Laboratory diagnosis
Molecular markers
Concluding remarks
13 Clinical, laboratory, and molecular markers of type 3 von Willebrand disease
General definition, history, and epidemiology
Clinical markers of type 3 VWD
Laboratory markers of type 3 VWD
Molecular markers of type 3 VWD
Treatment and prevention of bleeding in type 3 VWD
Future perspectives
Acknowledgements
14 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 VWD in childhood
VWD in adolescents
Treatment strategies in children
Conclusions
15 Women with von Willebrand disease
Epidemiology of VWD in women
The diagnosis of VWD in women
Clinical aspects of menorrhagia in women with VWD
Adolescent menorrhagia and VWD
Medical treatment of menorrhagia
Surgical treatment
Hemorrhagic ovarian cyst
Pregnancy
Treatment
Epidural anesthesia
Postpartum management
Neonates
Conclusion
16 On the use of desmopressin in von Willebrand disease
Summary
History
Mechanism of action
Modes of administration and dosage
Experience of desmopressin in VWD
Acquired von Willebrand syndrome
Pregnancy
Surgery
Menorrhagia
Conclusion
17 The use of plasma-derived concentrates
Introduction
VWF/FVIII concentrates
Thrombotic complications following VWF/FVIII concentrates
VWF concentrates devoid of FVIII
Conclusions
18 Prophylaxis in von Willebrand disease
Introduction
Prophylaxis in VWD
Experience in Sweden
Experience with prophylaxis in other cohorts
Planned or ongoing studies
The future of prophylaxis in VWD and recommendations
19 Pathophysiology, epidemiology, diagnosis, and treatment of acquired von Willebrand syndrome
General definition, history, and epidemiology
Pathophysiologic mechanisms for the management of AVWS
Lymphoproliferative diseases
Cardiovascular diseases
Thrombocythemia and other myeloproliferative disorders
Neoplasms
Immunologic diseases
AVWS in patients with other diseases
Current issues and future perspectives on AVWS
20 Gene therapy for von Willebrand disease
Introduction
Gene delivery approaches
Target cells
Conclusions and perspectives
Acknowledgements
Index
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Library of Congress Cataloging-in-Publication Data
Von Willebrand disease : basic and clinical aspects / edited by Augusto B. Federici ... [et al.].
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4051-9512-6 (hardcover : alk. paper)
1. Von Willebrand disease. I. Federici, Augusto B.
[DNLM:1. von Willebrand Diseases. WH 312]
RC647.V65V66 2011
616.1'57–dc22
2010036377
A catalogue record for this book is available from the British Library.
This book is published in the following electronic formats: ePDF 9781444329933; Wiley Online Library 9781444329926; ePub 9781444329940
Thomas C. Abshire MD
Senior Vice President
Medical Services and the Medical Science Institute;
Chief Medical Officer
BloodCenter of Wisconsin
Milwaukee, WI, USA
Luciano Baronciani PhD
Hospital Scientist
Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre
Department of Medicine and Medical Specialities
IRCCS Maggiore Policlinico Hospital
Mangiagalli and Regina Elena Foundation and University of Milan
Milan, Italy
Jennifer Barr BS
Department of Anatomy and Cell Biology
University of Iowa Carver College of Medicine
Iowa City, IA, USA
Javier Batlle MD
Chairman Servicio de Hematología y Hemoterapia.
INIBIC. C. Hospitalario Universitario A Coruña;
Associate Professor of Department of Medicine
School of Medicine
University of Santiago de Compostela
A Coruña, Spain
Margareta Blombäck MD PhD
Professor Emeritus
Department of Molecular Medicine and Surgery
Division of Clinical Chemistry and Blood Coagulation Research
The Karolinska Institute
Karolinska University Hospital
Stockholm, Sweden
Ulrich Budde MD
Director
Department of Hemostaseology
Medilys Laborgesellschaft mbH
c/o Asklepios Klinik Altona
Hamburg, Germany
Giancarlo Castaman MD
Consultant Haematologist
Department of Cell Therapy and Hematology
Hemophilia and Thrombosis Center
San Bortolo Hospital
Vicenza, Italy
Olivier D. Christophe PhD
Senior Researcher
INSERM Unit 770
Le Kremlin-Bicêtre, France
Marinee K.L. Chuah PhD
Professor
Flanders Institute for Biotechnology (VIB)
Vesalius Research Center
University of Leuven
Leuven;
Faculty of Medicine and Pharmacy
University Hospital Campus Jette
Free University of Brussels (VUB)
Brussels, Belgium
Cecile V. Denis PhD
Director of Research
INSERM Unit 770
Le Kremlin-Bicêtre, France
Jorge Di Paola MD
Associate Professor of Pediatrics and Genetics
Postle Family Chair in Pediatric Cancer and Blood Disorders
University of Colorado Denver School of Medicine
The Children’s Hospital
Aurora, CO, USA
Jeroen C.J. Eikenboom MD, PhD
Associate Professor
Department of Thrombosis and Hemostasis
Leiden University Medical Center
Leiden, the Netherlands
Emmanuel J. Favaloro PhD
Senior Hospital Scientist
Department of Haematology
Institute of Clinical Pathology and Medical Research (ICPMR)
Westmead Hospital
Westmead, NSW, Australia
Massimo Franchini MD
Head
Immunohematology and Transfusion Center
Department of Pathology and Laboratory Medicine
University Hospital of Parma
Italy
Edith Fressinaud MD, PhD
Consultant Haematologist
Centre National de Référence de la Maladie de Willebrand
Service d’Hématologie biologique
Hôpital Antoine Béclère
Clamart, France
Anne Goodeve BSc, PhD
Reader and Head, Haemostasis Research Group
Department of Cardiovascular Science
Faculty of Medicine, Dentistry and Health
University of Sheffield;
Principal Clinical Scientist
Sheffield Diagnostic Genetics Service
Sheffield Children’s NHS Foundation Trust
Sheffield, UK
Sandra L. Haberichter PhD
Associate Professor
Department of Pediatrics – Hematology/Oncology
Medical College of Wisconsin
Milwaukee, WI, USA
Paula D. James MD, FRCPC
Associate Professor, Hematologist
Queen’s University
Kingston, ON, Canada
Rezan A. Kadir MD, FRCS (ed), MRCOG, MD
Consultant Obstetrician and Gynaecologist
The Royal Free Hospital
London, UK
Peter A. Kouides MD
Medical and Research Director
Mary M Gooley Hemophilia Center
Rochester General Hospital
Rochester, NY, USA
Peter J. Lenting PhD
Director of Research
INSERM Unit 770
Le Kremlin-Bicêtre, France
Stefan Lethagen MD, PhD
Director of Copenhagen Haemophilia Centre
Thrombosis and Haemostasis Unit
Department of Haematology
Copenhagen University Hospital
Copenhagen, Denmark;
International Medical Director
Director of Medical & Science Haemostasis Department
Global Development
Novo Nordisk
Søborg, Denmark
María Fernanda López-Fernández MD
Head, Hemostasis and Thrombosis
Servicio de Hematología y Hemoterapia
Complexo Hospitalario Universitario de A Coruña
A Coruña, Spain
Pier Mannuccio Mannucci MD
Professor of Medicine
Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre
University of Milan and IRCCS Maggiore Hospital
Milan, Italy
Claudine Mazurier PhD
Head of Analytical Department, Preclinical Development
Laboratoire Français du Fractionnement et des Biotechnologies
Lille, France
Dominique Meyer MD
Professor of Haematology
Centre National de Référence de la Maladie de Willebrand;
University Paris-Sud
France
David Motto MD, PhD
Assistant Professor
Departments of Internal Medicine and Pediatrics
University of Iowa Carver College of Medicine
Iowa City, IA, USA
Ian Peake BSc, PhD
Sir Edward Mellanby Professor of Molecular Medicine
Department of Cardiovascular Science
University of Sheffield Medical School
Sheffield, UK
Almudena Pérez-Rodríguez PhD
Post-doctoral Investigator
Servicio de Hematología y Hemoterapia—INIBIC
Complexo Hospitalario Universitario de A Coruña
A Coruña, Spain
Inge Petrus PhD
Flanders Institute for Biotechnology (VIB)
Vesalius Research Center
University of Leuven
Leuven, Belgium
Jacob H. Rand
Hematology Laboratory
Department of Pathology
Montefiore Center
Bronx, NY, USA
Francesco Rodeghiero MD
Director
Department of Cell Therapy and Hematology
San Bortolo Hospital
Vicenza, Italy
Reinhard Schneppenheim MD, PhD
Director
Department of Pediatric Hematology and Oncology
University Medical Center Hamburg-Eppendorf
Hamburg, Germany
Alberto Tosetto MD
Senior Consultant
Department of Hematology
San Bortolo Hospital
Vicenza, Italy
Thierry VandenDriessche PhD
Group Leader
Flanders Institute for Biotechnology (VIB);
Vesalius Research Center
University of Leuven
Leuven;
Faculty of Medicine and Pharmacy
University Hospital Campus Jette
Free University of Brussels (VUB)
Brussels, Belgium
I feel very honored to have been asked to write the foreword to this book 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 a 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 bleedings.
To persuade 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 in 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 subgroups, and type 3 VWD are 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 diagnosis of the phenotypes, particularly with regard to the diagnosis of type 1 VWD, even if preanalytic 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, etc, 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 on trying to collate experience in multicenter studies on prophylaxis and diagnostic scores is very valuable and, of course, needs to be supported in order to solve the many difficulties that remain in the diagnosis and management of VWD.
Margareta Blombäck
Professor Emeritus
Karolinska Institutet
Sweden
1
Historical perspective on von Willebrand disease
Erik Berntorp1 and Margareta Blombäck2
1Malmö 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], that 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 in 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 at 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 the 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 seven 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 at childbirth. Intestinal bleeding had been the cause of death at early ages in some family members.
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 of von Willebrand syndrome for the condition.
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, that 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 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 h 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 h 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, nor 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 [20]).
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 from 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 from 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. In 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 in type 3 VWD. It includes desmopressin for most milder cases, new concentrates [38,39], and we are now anticipating development of recombinant VWF for therapeutic use.
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