Current and Future Issues in Hemophilia Care E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 540

Veröffentlichungsjahr: 2011

Beschreibung

As haemophilia is a life-long condition, continuing supervision by a group of medical personnel is required. In many countries this is provided by comprehensive care haemophilia centres where staff of all specialities concerned with treatment- haematologists, paediatricians, nurses, physiotherapists, orthopaedic surgeons - have specialized knowledge.

This new book is a definitive resource on the current aspects and issues around haemophilia. Complications of haemophilia care are well covered in chapters on inhibitors, and musculoskeletal problems, as are all the latest developments in the field of haemophilia.

Leseprobe

Contents

Cover

Title Page

Copyright

Contributors

Preface

1: Introduction

1: History of Hemophilia

Introduction

History of hemophilia

Conclusions

References

2: Hemophilia Care in the Modern World

Introduction

Providing global care

An aging hemophilic population

Prophylaxis

Inhibitors

Future therapeutic strategies

Women with bleeding disorders

Conclusions

References

3: Comprehensive Care Model in Hemophilia

Introduction

Comprehensive care philosophy

Does the model work?

Improvements in care using HTCs

Cutting edge care and research at an HTC

The burden in the US

340B – unique US-based program

Conclusions

References

2: General Topics

4: When Should We Switch from On-Demand to Prophylaxis Regimen?

Introduction

International recommendations

Early prophylaxis in children and its continuation in adolescents and adults

Secondary prophylaxis in adolescents and adults

Conclusions

References

5: Prophylaxis in Children

Introduction

History of prophylaxis and current status in the United States

Current issues in prophylaxis

Future issues

Conclusions

References

6: Prophylaxis in Adults with Hemophilia

Introduction

Prophylaxis in children

Prophylaxis in adults

Conclusions

References

7: The Economics of Prophylaxis: Does Prophylaxis with Clotting Factor Represent Value for Money?

Introduction

Economics

Cost-utility analysis

Economic evaluation

Economic evaluations of prophylaxis in severe hemophilia

Why do the results differ so much?

Conclusions

References

8: The Transition of Care for the Young Adult Hemophilia Patient

Introduction

Physical development at puberty

Psychological maturation in adolescents

Issues affecting adolescents and young adults with hemophilia

Transition from pediatric to adult-orientated care for adolescents

Conclusions

References

9: Perinatal Clinical Care and Molecular Diagnosis in Hemophilia

Introduction

The genetic basis and inheritance of hemophilia

Molecular diagnosis of hemophilia

Genetic diagnosis of carriers

Prenatal diagnosis

Alternative and complementary prenatal testing procedures

Recommended mode of delivery

Neonatal manifestations of hemophilia

Prophylaxis in the neonate

Management of the hemophilic newborn

Conclusions

References

10: Managing the Mature Person with Hemophilia

Introduction

Complications due to hemophilia or its treatment

Impact of co-morbidities of aging on hemophilia

Conclusions

References

11: Quality of Life in Hemophilia

Introduction

What does health-related quality of life mean?

Importance of the evaluation of health-related quality of life

Quality of life assessment in hemophilia

Choosing a hemophilia PRO measure

Health-related quality of life instruments for hemophilia

Evidence of clinical indicators impacting HRQoL measured by PRO

Conclusions

References

3: Inhibitors

12: Immunology of Inhibitor Development

Introduction

Immunology of antibody responses to proteins

What do we know about antibody responses against FVIII in patients?

What have we learned from immune responses against FVIII in animal models?

Conclusions

References

13: Epidemiology of Inhibitors

Introduction

Hemophilia B versus hemophilia A

Severe, moderate, mild hemophilia

Incidences of inhibitors vary between and within families

Genetic and non-genetic risk factors

Early and late inhibitors

Assessment and comparison of incidences of early inhibitors

Assessment and comparison of incidences of inhibitors occurring in multitransfused patients

Future research challenges

Conclusions

References

14: Early Tolerization to Minimize Inhibitors in PUPs with Hemophilia A

Introduction

MIBS study group and development of inhibitors

Munich and Bremen experience

Discussion

Conclusions

References

15: Prediction of Inhibitors in Severe Hemophilia

Introduction

Endogenous (genetic) risk factors

Non-genetic factors

How to predict inhibitors

External validation

Acceptance of prediction score

Discussion

Conclusions

References

16: Genetic Basis for Inhibitor Development

Introduction

Inhibitors in patients with hemophilia A

The major histocompatibility complex and immune response genes

Inhibitors in patients with hemophilia B

Conclusions

References

17: Non-Genetic Risk Factors for Inhibitor Development

Introduction

First treatment exposure

Treatment regimens

Factor concentrates

Immune system challenges

Bleeding and surgery

Vaccination and infection

Antenatal issues and breast feeding

Conclusions

References

4: Inhibitor Treatment

18: Immune Tolerance Induction Programs

Introduction

Historical perspectives in ITI

Which ITI regimen to use?

When to start ITI?

Which product to use?

Who is the ideal patient for a successful ITI?

When to use bleeding prophylaxis during ITI and which bypassing agent to choose?

Central venous access devices

When to stop ITI?

Incomplete response or ITI failure

Immune tolerance in hemophilia B patients

Conclusions

References

19: Prophylaxis in Hemophilia A Patients with Inhibitors

Introduction

Clinical experience with bypassing agent prophylaxis

Application of bypassing agent prophylaxis

Outcome measures

Conclusions

References

20: Treatment of Bleeding in FVIII Inhibitor Patients

Introduction

Treatment of bleeding in FVIII inhibitor patients

Treatment of bleeding in FIX inhibitor patients

Surgery in patients with inhibitors

Immune tolerance induction (ITI)

Management of patients with inhibitors in the developing world

New approaches to inhibitor treatment on the horizon

Conclusions

References

21: Discordancy of Bypassing Therapy

Introduction

Mechanism of action

Efficacy of bypassing therapy to control bleeding in hemophilia

Potential reasons for a differential response

Conclusions

References

5: Joint Health and Disease

22: Experimental Studies on Hemarthrosis, Synovitis and Arthropathy

Introduction

Joint components

Pathophysiology of joint disease

Conclusions

References

23: Assessment of Joint Involvement in Hemophilia

Introduction

Physical examination

Radiologic scores

Conclusions

References

24: Imaging of the Hemophilic Joint

Introduction

Radiography

Ultrasonography

Magnetic resonance imaging

Other imaging techniques

Conclusions

References

25: Initial and Advanced Stages of Hemophilic Arthropathy, and Other Musculo-Skeletal Problems: The Role of Orthopedic Surgery

Introduction

Initial stages of hemophilic arthropathy

Hemarthrosis: the role of arthrocentesis

Hypertrophic hemophilic synovitis

Radiosynovectomy, chemical synovectomy and arthroscopic synovectomy

Articular contractures

Advanced hemophilic arthropathy

Other musculo-skeletal problems of hemophilia

Conclusions

References

26: Perioperative Thromboprophylaxis for Persons with Hemophilia Undergoing Orthopedic Surgery

Introduction

General prevalence of VTE after orthopedic surgery

General principles of orthopedic thromboprophylaxis

VTE in persons with congenital bleeding disorders: considerations in the surgical setting

VTE in persons with hemophilia and inhibitors

Thromboprophylaxis in hemophilic surgical patients: current practice

Conclusions

References

6: New Developments

27: New Technologies for the Pharmacokinetic Improvement of Coagulation Factor Proteins

Introduction

Less immunogenic drugs

More potent, longer-acting FVIII and FIX concentrates

Conclusions

References

28: Current and Future Approaches to Gene Therapy in Patients with Hemophilia

Introduction

Gene transfer vectors

Future approaches

Conclusions

References

29: New Developments in Hemophilic Arthropathy

Introduction

Experimental studies on hemophilic synovitis and arthropathy

Clinical studies on hemarthrosis, hemophilic synovitis and hemophilic arthropathy

Inhibitors

Hemophilic arthropathy in the elderly patient

Conclusions

References

30: Physiotherapy Evaluation and Intervention in the Acute Hemarthrosis: Challenging the Paradigm

Introduction

Key concepts regarding the physiotherapy evaluation

Physiotherapy intervention for the acute joint bleed

Conclusions

References

31: Laboratory Assays to Predict Response to Bypassing Agents

Introduction

The need for theranostic guidance in management of hemophilia patients with inhibitors

Calibrated automated thrombin generation

Translation of laboratory results to clinical practice

Prediction of response to bypassing agents

Individualized dose tailoring of bypassing agents during orthopedic surgery

Whole blood thromboelastometry

Complementary additional information on overall hemostatic capacity

Conclusions

References

32: Combination/Sequential Use of Bypassing Agents

Introduction

In vitro findings

In vivo findings

Discussion

Conclusions

References

Index

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Library of Congress Cataloging-in-Publication Data

Current and future issues in hemophilia care / edited by Emérito-Carlos Rodríguez-Merchán, Leonard A. Valentino. p. cm. Includes bibliographical references and index. ISBN-13: 978-0-470-67057-6 (hardcover : alk. paper) ISBN-10: 0-470-67057-6 (hardcover : alk. paper) 1. Hemophilia. I. Rodríguez-Merchán, E. C. II. Valentino, Leonard A. [DNLM: 1. Hemophilia A-prevention & control. 2. Hemophilia A-therapy. 3. Blood Coagulation Factors. WH 325] RC642.C87 2011 616.1′572–dc22 2011007517

A catalogue record for this book is available from the British Library

This book is published in the following electronic formats: ePDF 9781119979371; Wiley Online Library 9781119979401; ePub 9781119979388; Mobi 9781119979395

Contributors

Lydia Abad-Franch MDSpecialist in Family Medicine Hemostasis and Thrombosis Unit La Fe University Hospital Valencia, Spain

Louis M. Aledort MDThe Mary Weinfeld Professor of Clinical Research in Hemophilia Mount Sinai School of Medicine New York, NY, USA

Carmen Altisent MDUnitat d'Hemofília Hospital Universitari Vall d'Hebron Barcelona, Spain

Maria-Teresa Alvarez-Román MDConsultant Hematologist Hemostasis and Thrombosis Unit La Paz University Hospital Madrid, Spain

Jan Astermark MD, PhDAssociate Professor Lund University; Malmö Centre for Thrombosis and Haemostasis Skåne University Hospital Malmö, Sweden

Günter Auerswald MDKlinikum Bremen-Mitte Ambulanz für Thrombose und Hämostasestörungen, Prof.-Hess Kinderklinik Bremen, Germany

José A. Aznar MDHead of Hemostasis and Thrombosis Unit Department of Hematology and Hemotherapy La Fe University Hospital Valencia, Spain

Erik Berntorp MD, PhDProfessor of Hemophilia Lund University; Malmö Centre for Thrombosis and Haemostasis Skåne University Hospital Malmö, Sweden

Jan Blatny MD, PhDConsultant Hematologist Department of Pediatric Hematology Center for Thrombosis and Hemostasis Children's University Hospital Brno Brno, Czech Republic

Lisa N. Boggio MS, MDAssistant Professor of Medicine and Pediatrics Division of Hematology and Oncology Rush University Medical Center Chicago, IL, USA

Ana R. Cid MDHematologist Hemostasis and Thrombosis Unit La Fe University Hospital Valencia, Spain

Caroline Cromwell MDAssistant Professor of Medicine Division of Hematology/Oncology Mount Sinai School of Medicine New York, NY, USA

Donna M. DiMichele MDWeill Cornell Medical College; Deputy Director Division of Blood Diseases and Resources National Heart, Lung and Blood Institute New York, NY, USA

Gerard Dolan MB ChB, FRCP, FRCPathConsultant Haematologist Nottingham University Hospitals Nottingham, UK

Kathelijn Fischer MD, PhDPediatric Hematologist and Clinical Epidemiologist Van Creveldkliniek, Department of Hematology, and Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht, The Netherlands

Angela L. Forsyth PT, DPTPhysiotherapist Penn Hemophilia and Thrombosis Program Hospital of the University of Pennsylvania Philadelphia, PA, USA

Paul L.F. Giangrande BSc, MD, FRCP, FRCPath, FRCPCHConsultant Haematologist and Director Oxford Haemophilia and Thrombosis Centre Churchill Hospital Oxford, UK

Nicholas J. Goddard MB FRCSConsultant Orthopaedic Surgeon Department of Orthopaedic Surgery Royal Free Hospital London, UK

Alessandro Gringeri MD, MScDepartment of Medicine and Medical Specialities Fondazione IRCCS Cà Granda – Ospedale Maggiore Policlinico and University of Milan Milan, Italy

Narine Hakobyan PhDAssistant Professor Rush Hemophilia and Thrombophilia Center; Department of Pediatrics Rush Children's Hospital and Rush University Medical Center Chicago, IL, USA

Saturnino Haya MDHematologist Hemostasis and Thrombosis Unit Department of Hematology and Hemotherapy La Fe University Hospital Valencia, Spain

Christoph J. Hofbauer Dipl.-Ing. (FH)Department of Immunology TA BioTherapeutics Baxter Innovation GmbH Vienna, Austria

Frank M. Horling PhDManager Immunotoxicology Department of Immunology TA BioTherapeutics Baxter Innovation GmbH Vienna, Austria

Victor Jiménez -Yuste MD, PhDConsultant Hematologist Department of Hematology and Hemostasis Unit La Paz University Hospital; Associate Professor of Hematology School of Medicine Autonomous University Madrid, Spain

Karin Kurnik MDKlinikum Bremen-Mitte Ambulanz für Thrombose und Hämostasestörungen, Prof.-Hess Kinderklinik Bremen, Germany

Christine A. Lee MA, MD, DSc, FRCP, FRCPath, FRCOG ad eundemEmeritus Professor of Haemophilia University of London London, UK

Marilyn J. Manco-Johnson MDDirector, Hemophilia and Thrombosis Center; Professor of Pediatrics University of Colorado Denver Aurora, CO, USA

Mónica Martín-Salces MDConsultant Hematologist Hemostasis and Thrombosis Unit La Paz University Hospital Madrid, Spain

Carmen Martín-Hervás MD, PhDConsultant Radiologist Department of Musculo-Skeletal Radiology La Paz University Hospital; Associate Professor of Radiology School of Medicine Autonomous University Madrid, Spain

Prasad Mathew MB, BS, DCH, FAAPProfessor of Pediatrics Director, Ted R. Montoya Hemophilia Program and Pediatric Hemostasis University of New Mexico Albuquerque, NM, USA

Alec Miners BSc (Hons), MSc, PhDLecturer in Health Economics Faculty of Public Health and Policy London School of Hygiene and Tropical Medicine London, UK

Andrés Moret MSHemostasis and Thrombosis Unit La Fe University Hospital Valencia, Spain

Claude Negrier, MD, PhDProfessor Hematology Division Edouard Herriot University Hospital Lyon, France

Johannes Oldenburg MD, PhDProfessor and Director Institute of Experimental Hematology and Transfusion Medicine Haemophilia Center Bonn University Clinic Bonn Bonn, Germany

Anna Pavlova MD, PhDSenior Lecturer Institute of Experimental Hematology and Transfusion Medicine Haemophilia Center Bonn University Clinic Bonn Bonn, Germany

Pia Petrini MDAssociate Professor Department of Pediatrics Coagulation Unit Karolinska University Hospital Stockholm, Sweden

Felipe Querol MD, PhD, PTProfessor of Physiotherapy Hemostasis and Thrombosis Unit La Fe University Hospital Valencia, Spain

Savita Rangarajan FRCP, FRCPathConsultant Hematologist Comprehensive Care Centre for Haemophilia Haemostasis and Thrombosis Basingstoke and North Hampshire NHS Foundation Trust Basingstoke, UK

Birgit M. Reipert PhDAssociate Professor Director R&D Department of Immunology TA BioTherapeutics Baxter Innovation GmbH Vienna, Austria

Eduardo Remor PhDAssociate Professor Department of Psychobiology and Health Faculty of Psychology Autonomous University Madrid, Spain

Emérito-Carlos Rodríguez-Merchán MD, PhDConsultant Orthopedic Surgeon Department of Orthopedic Surgery and Hemophilia Unit La Paz University Hospital; Associate Professor of Orthopaedic Surgery School of Medicine Autonomous University Madrid, Spain

Hans-Peter Schwarz MD, PhDProfessor Vice President and Head TA BioTherapeutics Baxter Innovation GmbH Vienna, Austria

Mindy L. Simpson MDClinical Instructor of Pediatrics Pediatric Hematology/Oncology Rush University Medical Center Chicago, IL, USA

Benny Srensen MD, PhDDirector of HRU and Associate Professor Aarhus University, Denmark; Haemostasis Research Unit Centre for Haemophilia and Thrombosis Guy's and St Thomas' NHS Foundation Trust London, UK

Katharina N. Steinitz Mag Rer NatDepartment of Immunology TA BioTherapeutics Baxter Innovation GmbH Vienna, Austria

Jerome Teitel MDProfessor, University of Toronto Division of Hematology and Oncology St Michael's Hospital Toronto, ON, Canada

H. Marijke van den Berg MD, PhDPediatric Hematologist Meander Hospital, Amersfoort; Department of Chemistry and Haematology University Medical Center Utrecht Utrecht, The Netherlands

Johanna G van der Bom MD, PhDAssociate Professor of Clinical Epidemiology Department of Clinical Epidemiology and Jon J van Rood Center for Clinical Transfusion Medicine Leiden University Medical Center Leiden, The Netherlands

Francisco Vidal PhDUnitat de Diagnòstic i Teràpia Molecular Banc de Sang i Teixits Barcelona, Spain

Thynn Thynn Yee MD, FRCPConsultant Hematologist Katharine Dormandy Haemophilia Centre and Thrombosis Unit Royal Free Hospital London, UK

Leonard A. Valentino MDProfessor of Pediatrics, Internal Medicine, Immunology/Microbiology and Biochemistry Director, Hemophilia and Thrombophilia Center Rush University Medical Center Chicago, IL, USA

Guy Young MDPediatric Hematology and Oncology UCLA Health System Los Angeles, CA, USA

Nichan Zourikian BSc, PTPhysiotherapist Sainte-Justine Pediatric/Adult Comprehensive Hemostasis Center and Quebec Reference Center for Coagulation Inhibitors Sainte-Justine University Hospital Center Montreal, QC, Canada

Preface

Any text on hemophilia must acknowledge the roots of the disease. Hemophilia is an ancient bleeding disorder, first described in the 2nd century AD. Little attention was paid to this disease until the early 1900's when it was determined that Queen Victoria passed the gene down to several of her daughters, who carried the disease into several of the royal families of Europe. As such, the care of hemophilia has evolved from the time of Alexei, the son of Alexandra and Nicholas, Czar of Imperial Russia, to the current comprehensive model of care which has resulted in substantial decreases in morbidity and mortality and an improvement in the quality of life of patients with hemophilia. Many milestones mark the course of time for the disease but few so important as the discovery of cryoprecipitate in the 1960's which lead to development of advanced products to treat hemophilia including recombinant factor products essentially devoid of the risk of transmission of infectious diseases. These advancements laid the foundation for the development of treatment regimens designed to prevent bleeding and the complications of bleeding. Prophylaxis, initiated in young children, now has the potential to deliver patients into adolescence and adult life with normal joints, having nearly identical quality of life of their unaffected peers. This treatment comes at a price. The economic value of prophylaxis in hemophilia remains a matter of debate, especially in countries with limited resources available for healthcare. Adherence to prophylaxis and the transition to independence remains a major concern for providers of care. Management of patients at the ends of the age spectrum has attracted considerable attention. Key to optimal perinatal care and genetic counseling for carriers of hemophilia is an accurate molecular diagnosis and appropriate management of delivery to a healthy start to life of a boy with hemophilia.

This text attempts to address the current and future issues patients affected with the disease as well as the nurses, doctors and other care givers treating these patients must face in order to provide optimal care. In the first three chapters Cromwell and Aledort review the history of hemophilia, an appropriate starting place for any book such as this. Next Lee discusses the care of hemophilia in the modern world focusing on the worldwide improvements in diagnosis and care and the new problems of ageing with its associated co-morbidities. Finally the issues of inherited bleeding disorders in women are discussed. Mathew continues in this section to introduce the comprehensive care model but also draws attention to the necessities of funding in order to sustain the pinnacle of care that should be the goal of all nations and providers of hemophilia care in order to reduce morbidity and mortality and increase quality of life.

The next section delves into the day to day management issues that caregivers face with our patients. This begins with a discussion of prophylaxis in children by Manco-Johnson and moves to a review by Aznar and colleagues of the issues around changing from an on-demand regimen to prophylaxis. This is especially important in countries with limited resources. Miners deals with the economics of prophylaxis in the next chapter addressing the question, “Does prophylaxis with clotting factor represent value for money?” His conclusion, although not surprising, offers somewhat of a mandate to the bleeding disorders community and specifically to the manufacturers of clotting factor, to find ways to reduce the high cost of these life- and joint-saving biologicals. Jiménez-Yuste and colleagues address the difficult topic of prophylaxis for adult patients. Although many providers treating these patients feel there may be some benefit, the cost-effectiveness remains to be proven and represents a barrier to be overcome. As each of us has done (some better than others I suspect), we have transitioned from childhood to adulthood. This task is particularly problematic for patients with hemophilia as they face numerous obstacles, which, as Petrini discusses in the next chapter, “can have a significantly negative effect on morbidity and mortality in young adults.” The utility and effectiveness of programs to specifically assist young people with hemophilia during this vulnerable time await evaluation and more importantly, validation. As a congenital disease, hemophilia begins in neonates, not all of which are symptomatic. However, sub-optimal care at this fragile time can result in a lifetime of challenges for the boy with hemophilia. Altisent and Vidal reviews the management of pregnant women who are carriers of hemophilia and appropriate molecular diagnosis. Finally, this section ends with a discussion by Rangarajan and Yee on managing the mature person with hemophilia. This population brings many new challenges to hemophilia clinics across the globe including insuring links between hemophilia care providers and those in the areas of geriatrics, oncology, cardiology and primary care in order to provide a comprehensive and coordinated approach to care.

The development of alloantibodies against factor VIII or factor IX which inhibit the function of infused clotting factor is the most common, serious complication that must be faced by this population. Inhibitor development is only recently beginning to be understood. Reipert and her colleagues, leading researchers in this area, provide the reader with a state of the art review of the immunology of inhibitor formation. Van der Bom, in the next chapter, discusses the epidemiology of inhibitor formation including the evidence behind a multitude of putative risk factors and explains a framework for interpretation of publications describing rates of inhibitor development including potential confounding variables. The novel approach of Auerswald and Kurnik to prevent, or at least reduce, the likelihood of inhibitor development is presented in the next chapter. This provocative (and as yet unproven) approach involves administration of small doses of clotting factor to patients in the absence of “danger signals” and will be not only a frequent topic for discussion at future meetings but will also be more importantly, the focus of several national and international clinical trials. Next, Van der Berg and Fischer present provocative data on their model to predict inhibitor formation in a specific patient. If validated, this model could change the management decisions and the treatment paradigms used, especially in very young children with severe hemophilia. As noted previously, inhibitor development is complex and Oldenburg and Pavlova discuss the genetic basis for inhibitor formation followed by a discussion of the non-genetic risk factors by Boggio and Simpson.

The next section focuses on the difficult area of management of patients with inhibitors to factor VIII or factor IX. Optimally, immune tolerance should be undertaken in an attempt to eradicate the inhibitor and return the patient to his prior non-inhibitor state allowing the use of factor VIII or IX as replacement therapy. Blatny and Mathew first discuss immune tolerance programs designed to achieve this goal focusing on the important questions including which regimen to use, when to initiate and abort immune tolerance therapy, which product to use and how to identify the ideal patient for immune tolerance as well as discussing the issues around venous access and the control of bleeding. This is followed by the review by Valentino and Young on the use of prophylaxis in inhibitor patients and then the presentation of treatment guidelines by Giangrande and Teitel. Despite what is considered optimal treatment of bleeding, as many as 20–30% of hemorrhages may not respond to bypassing therapy. Astermark discusses the discordancy observed in the treatment of bleeding with bypassing agents and the factors which may play a role in these divergent responses. When bleeding is poorly controlled, such as that which occurs in patients with inhibitors, the joint is the main focus of morbidity. Valentino and Hakobyan discuss the experimental studies which shed light on the pathobiology of blood-induced joint disease. Berntorp then provides a review of the instruments available for the assessment of joint function and Martín-Hervás and Rodríguez-Merchán discuss imaging of the joints to better quantify not only the damage which occurs after bleeding but also to provide objective tools to assess the impact of new treatment modalities designed to reduced musculoskeletal morbidity including surgical interventions that are discussed by Rodríguez-Merchán and colleagues in the next chapter. Thrombosis is a major concern in patients undergoing orthopedic surgery and thromboprophyalxis in this population is reviewed by Dolan and colleagues next. Finally this section of inhibitor management concludes with a stimulating (and likely provocative) chapter on physiotherapy by Zourikian and Forsyth which focuses on the physiotherapy evaluation and intervention opportunities available during the acute bleeding episode.

The next section explores the new modalities that are on the horizon including a review of the new technologies in pre-clinical and clinical development for improvement in the pharmacokinetic profile of coagulation factors by Valentino and a discussion on gene therapy by Alvarez-Román and colleagues. The new developments in hemophilic arthropathy, including an assessment of the costs related to the occurrence of hemophilic arthropathy and management of arthropathy in elderly patients, are summarized by Rodríguez-Merchán and Valentino. In the next chapter, Sorensen and Negrier provide a rational for the use of an individualized “theranostic” approach utilizing global laboratory assays to tailor choices around the most suitable bypassing agent as well as to guide selection of effective dosages of bypassing agents. The last chapter in this section by Gringeri addresses the use of combination sequential therapy with bypassing agents, which have a synergistic effect in vitro and in vivo. Although this approach seems efficacious in children and in adults, care must be taken as adverse events are possible and this modality should be considered a salvage treatment due to its potential risks.

Finally, the management of the patient with hemophilia has as its goal the optimization of quality of life. Remor discusses the tools and instruments available to estimate quality of life and addresses the links of quality of life with health and well-being as well as the merits of the various disease-specific measures of quality of life.

Emérito-Carlos Rodriguez-Merchán and Leonard A. Valentino

1

Introduction

1

History of Hemophilia

Caroline Cromwell and Louis M. Aledort

Mount Sinai School of Medicine, New York, NY, USA

Introduction

The word hemophilia is derived from the Greek words “haima– : blood” and “philia – φιλoς: love or tendency to”. The history behind hemophilia is fascinating and complex. What is outlined here is a brief history of important events in development and discovery in this field.

History of hemophilia

Historical accounts are full of references to the disease. The first written description of hemophilia is found in the Babylonian Talmud, during the second century. In it is written “If she circumcised her first child and he died, and a second also died, she must not circumcise her third child” [1].What is fascinating is what is already understood and described from this decree. The familial nature was recognized. Rabbi Simon Ben Galaliel forbade a boy to be circumcised whose mother sisters’ sons had died after circumcision. In the twelfth century the physician Moses Maimonides enforced this ruling for sons of women who had married twice, thus indicating a further understanding of the maternal inheritance of this disease [2,3].

In the United States in 1803, Otto described a family in which the males had prolonged bleeding after trauma. He noted that unaffected females pass on the disorder to a proportion of their sons, whom he described as “bleeders”. In 1828 the disorder was coined “haemorrhaphilia”, meaning, “love of hemorrhages” (Brinkhous Handbook of Hemophilia) which eventually evolved into the name hemophilia. During the nineteenth century there were continued publications describing this condition and varied family pedigrees were extensively documented.

The royal history of hemophilia is well known. Queen Victoria of England is one of the most well-known historical figures in hemophilia (Figure 1.1). She transmitted the disorder to her eighth son, Leopold, and two of her daughters were carriers. Leopold was known to have suffered from severe major bleeding episodes. He died at the age of 31 from a cerebral hemorrhage after trauma. Perhaps the most well-known descendant of Queen Victoria is Alexis, son of Tsar Nicholas II of Russia. Historically it is thought that Alexis's illness allowed for the undue influence of Rasputin. Rasputin was thought to have healing powers. Through Alexis he gained access and influence over the royal family, and this was thought to contribute in part to the eventual downfall of the empire. This fascinating history is well documented in R.K. Massie's 1968 book Nicholas and Alexandra.

The conclusions drawn by astute physicians and caring doctors during those early times were that (1) hemophilia caused excessive bleeding; (2) that predominantly males were affected; and (3) The disorder was passed down through females.

Figure 1.1 Queen Victoria 1887.

(Reproduced from http://commons.wikimedia.org/wiki/File:Queen_Victoria_1887.jpg. Accessed 4 March 2011.)

As one can imagine, many varied therapies were historically attempted in patients with hemophilia, from the administration of oxygen, injection of sodium citrate, to splenectomy to the use of egg white extract [4]. A more scientifically based approach was the use of coagulant snake venom by R.G. Macfarlane in the 1930s, with some success [5]. The first treatment of hemophilia occurred in 1840. Samuel Lang performed a blood transfusion to treat a hemophilia patient. It would be many years until the process of blood transfusion was developed. However by the early 1920s, it was understood that blood transfusions appeared to ameliorate bleeding by providing something that was missing in the hemophiliac patient's blood. In 1939, Kenneth Brinkhouse described something which he termed antihemophilic factor, now called factor VIII. His work was instrumental in the advancement of the understanding of hemophilia. In 1944, Edwin Cohn, a biochemist, developed a process known as fractionation, allowing plasma to be separated into its different components. In 1952, Brinkhous developed the PTT test, which allowed for assessment of coagulation function. During this same time, it was discovered that there were two types of hemophilia. Previously it had been recognized that in certain cases the blood of two different hemophiliacs could be mixed, with correction of the clotting defect. Blood testing on Stephen Christmas, a child from Canada with hemophilia, revealed him to have a deficiency in factor IX as opposed to factor VIII. Factor IX deficiency became known as “Christmas” disease. Of great interest to note, recent investigation with novel DNA technologies have revealed the “royal disease” to be in fact, hemophilia B [6].

In 1964, Judith Graham developed cryoprecipitate. In the years that followed Kenneth Brinkhous (Figure 1.2) discovered how to purify factor VIII. Major changes in the treatment of hemophilia occurred during the 1970s. Large amounts of intermediate purity factor concentrates in lyophilized formulations became available. These concentrates were small volume, and easily injectable. This dramatically changed the face of treatment, as patients could receive treatment at home, either through self-administration or training of the caregiver. At the first sign of bleeding at home, these products could be administered, as opposed to wait for travel to a hospital. Hemophilia centers were able to focus on developing comprehensive care programs. These programs developed the concept of a team approach to care. The multi-faceted team was able to address all aspects of living with hemophilia, including the medical and psychosocial components. This was revolutionary at the time, and set the standard for the development of comprehensive care in other chronic illnesses. Orthopedic surgery became feasible in this patient population. Previously wheelchair-bound patients could have reconstructive orthopedic surgery. Great steps were made towards allowing a hemophiliac to live a fully functional life, to work, to go to school and to live.

Figure 1.2 Kenneth Brinkhous.

(Courtesy of UNC Chapel Hill.)

Ongoing discovery continued in the field of hemophilia treatment. In 1977, desmopressin was discovered, which became a mainstay of treatment for patients with mild hemophilia A and von Willebrand disease, although it was not licensed for this indication until the late 1980s in the United States. In the late 1970s, production of Factor VIII by pharmaceutical companies began on a large scale. Unfortunately transmission of hepatitis B and C was a devastating consequence for many patients treated with factor concentrates produced from pooled plasma. This heralded the era of HIV transmission. AIDS was first described in two patients with hemophilia in 1982. From the late 1970s to the mid-1980s, approximately half of the hemophilia population contracted HIV through blood products. In the ensuing years, heat treating which destroyed the HIV virus, became standard for production. It would still be many years until highly active retroviral therapy would be developed. Thousands of persons with hemophilia died of AIDS in the 1980s and 1990s. Further progress continued in the development of ways to inactivate blood-borne pathogens, such as implementation of the use of solvent detergent. These improvements in viral inactivation and viral screening have dramatically improved the safety of plasma derived products. There has been no transmission of HIV or hepatitis from plasma concentrates since 1987. Transmission of prions and subsequent variant Creutzfeldt–Jakob disease has been a concern since the discovery it could occur due to blood transfusion. However there has not been a case of transmission via plasma-derived products.

In 1984, the gene for factor VIII was located and cloned from human cells. This allowed for the development and production of recombinant factor VIII and eventually factor IX as well. Recombinant factor VIII was licensed by the US Food and Drug Administration (FDA) in 1992. Since that time the use of recombinant factor has become the mainstay in North America and Western Europe. However in the last few years new data have challenged the trend towards use of recombinant factors. Two studies of previously untreated patients with hemophilia A suggest that the incidence of inhibitors is higher with recombinant factor VII than with plasma derived products. It is postulated that this may be due to the presence of other proteins in plasma derived products, such as von Willebrand factor. Further study is ongoing to address this important issue.

The development of inhibitors in the patient with hemophilia is a much dreaded, devastating consequence. Two bypassing agents are available for this patient population, one recombinant. Activated prothrombin complex concentrates (aPCC) have been used since the 1980s. The risk of thrombosis in association with their use is well-documented. The FDA licensed recombinant human coagulation factor VIIa (rFVIIa) on 25 March 1999, for bleeding in patients with hemophilia A or B and inhibitors to factors VIII or IX. In addition to great strides in treating bleeding patients with inhibitors, major research has occurred in the area of inhibitor eradication through immune tolerance induction. Two large international registries have documented that immune tolerance induction with large and frequent doses of factor VIII was effective in approximately 70% of patients [7,8]. More study regarding dosing and timing of factor VIII infusions are ongoing. However neither of these issues addresses the prevention of inhibitors through the maintenance of tolerance, which is the ultimate goal.

Primary prophylaxis is an ongoing area of research. Studies have demonstrated that while this method may be expensive, it is more efficacious than on demand treatment [9]. Various options currently exist for the dose and dose interval. While primary prophylaxis may be an option in wealthier countries, in many areas of the world it is financially impossible.

Conclusions

To have to now address the issues of the aging hemophiliac demonstrates the advances that have been made in the treatment of this disease [10]. The field of biologics is constantly evolving, and the goal is to continue to produce more effective and less immunogenic therapies. Strides must be made to address the need of the underserved international patient and access to care. The ultimate goal in coming years will be the cure of hemophilia through gene therapy. Promising studies in animal models continue to fuel scientific drive to apply such technology in patients. Through continued international collaboration in clinical research, through the drive and passion of physicians and patients, we hope these goals will be reached.

References

1. Katzenelson JL. Hemophilia; with special reference to the Talmud. Harofe Haivri Heb Med J. 1958;1:165–78.

2. Seligsohn U. Hemophilia and other clotting disorders. Isr J Med Sci. 1973 Sep–Oct;9(9):1338–40.

3. Kavakli K, Aledort LM. Circumcision and haemophilia: a perspective. Haemophilia. 1998 Jan;4(1):1–3.

4. Ingram GI. The history of haemophilia. J Clin Pathol. 1976 Jun;29(6):469–79.

5. Macfarlane RG. Russell's viper venom,1934–64. Br J Haematol. 1967 Jul;13(4):437–51.

6. Rogaev EI, Grigorenko AP, Faskhutdinova G, Kittler EL, Moliaka YK. Genotype analysis identifies the cause of the “royal disease”. Science. 2009 Nov 6;326(5954):817.

7. Mariani G, Ghirardini A, Bellocco R. Immune tolerance in hemophilia-principal results from the International Registry. Report of the factor VIII and IX Subcommittee. Thromb Haemost. 1994 Jul;72(1):155–8.

8. DiMichele DM, Kroner BL. The North American Immune Tolerance Registry: practices, outcomes, outcome predictors. Thromb Haemost. 2002 Jan;87(1):52–7.

9. Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007 Aug 9;357(6):535–44.

10. Konkle BA, Kessler C, Aledort L, Andersen J, Fogarty P, Kouides P, et al. Emerging clinical concerns in the ageing haemophilia patient. Haemophilia. 2009 Nov;15(6):1197–209.

2

Hemophilia Care in the Modern World

Christine A. Lee

University of London, London, UK

Introduction

Hemophilia care in the modern world is described in the vision of the World Federation of Hemophilia (WFH) [1]. Their mission is to improve and sustain care to include all people with inherited bleeding disorders (IBDs). As they point out, this means those in the developing as well as the developed world, the young as well as the old, and both women and men.

Hemophilia care in the modern world has to embrace these challenges – the improved diagnosis and care around the world have introduced the new problems of an aging population with IBDs and co-morbidities; the benefit of primary prophylaxis is incontrovertible, but it needs to be tailored to the needs of young boys worldwide; the management of hemophilia requires the production of factor concentrates with prolonged efficacy and reduced immunogenicity; and the significance of IBDs in women has been increasingly recognized in the last two decades and these women now need to be identified and guided to clinical care.

Providing global care

The 2008 WFH Global Survey shows individuals from 72 countries worldwide with hemophilia, von Willebrand disease (VWD), rare factor deficiencies and inherited platelet disorders (Table 2.1). National hemophilia databases, including data on prevalence, treatment and outcome are essential for the care of hemophilia in the modern world. Such databases have been established in many countries including the UK, Italy, Germany, France, Spain, Australia, Canada, and the USA [2]. Advances in information technology open up many new possibilities [3].

Table 2.1 Male and female patients by disorder from the 2008 World Federation of Hemophilia Global Survey.

(Reproduced from Skinner MW. Building our global family – achieving treatment for all. Haemophilia 2010;16(suppl. 5):1–11.)

Databases support three basic functions – healthcare planning, epidemiologic research, and pharmacovigilance. In developing countries where the clinical service provision for hemophilia is poorly developed, basic prevalence data may be useful for planning purposes. This is well-illustrated by the change over time of the relationship of economic capacity to the number of adults with hemophilia (Figure 2.1). Improving care can result in more children surviving into adulthood [1].

Figure 2.1 Change over time of relationship of economic capacity to number of adults with hemophilia.

(Reproduced from Skinner MW. Building our global family – achieving treatment for all. Haemophilia 2010;16(suppl. 5): 1–10.)

There are increasing attempts to harmonize databases – hemophilia is a rare disorder and effective research depends on international co-operation. This is well-illustrated by EUHASS: European Adverse Event System. Adverse events are now rare and hemophilia is a rare disease so any reporting system needs to be multinational for the frequencies of adverse events to be meaningful. EUHASS is a collaboration of 56 sentinel centers in 27 European countries. It collects anonymized data on new inhibitors (antibodies to FVIII or IX), allergic reactions, infections, thromboses, cancers and deaths. The system was developed in parallel with the European Principles of Hemophilia Care and aims to raise awareness of adverse events, collect data and improve safety [4].

Table 2.2 Comparison of an intermediate dose to a high dose regimen: long-term follow-up results.

(Reproduced from Fischer K, Astermark J, van der Bom JG et al. Prophylaxis treatment for severe haemophilia: comparison of an intermediate-dose to a high-dose regimen. Haemophilia 2002;8;753–60.)

An aging hemophilic population

In 1937 Carroll Birch reported the natural history of hemophilia without treatment – in a cohort of 113 patients 82 died before 15 years of age and only eight survived beyond the age of 40 years [5]. This contrasts with a study published in 2007 from the UK in people with hemophilia uninfected with HIV – a median life expectancy of 63 years for those with severe hemophilia and 75 years for those with non-severe hemophilia was found [6]. This approaches that for the normal male population (Figure 2.2). People with hemophilia worldwide have benefited from both the general factors contributing towards health improvement as well as those due to the advances in hemophilia care including the availability of safe, effective concentrate, comprehensive care programs, home treatment and prophylaxis. In the general population, up to 88% over the age of 65 years have one or more chronic medical condition. [7] Thus, particularly in the developed world, the elderly population of people with hemophilia will present the complex co-morbidity of a tendency to bleed and the age-related problems of cardiovascular disease, neoplasia, renal and musculoskeletal problems. Studies are needed to explore these emerging health issues as there are currently few evidence based data of acute and chronic medical problems in older patients with hemophilia [8].

Figure 2.2 Survival in men in the UK who were not infected with HIV.

(Reproduced from Darby SC, Kan SW, Spooner RJ et al. Mortality rates, life expectancy, and causes of death in people with haemophilia A or B in the United Kingdom who were not infected with HIV. Blood 2007;110:815–25.)

Prophylaxis

The pioneering work in prophylaxis was in the 1950s and 1960s in Sweden and the Netherlands. This has provided over two decades of follow-up data [9,10]. The two regimens differed in the age at start of treatment and the intensity of treatment. The Swedish regimen was associated with a significantly lower rate of joint bleeding but the FVIII consumption was two-fold higher. After nearly 20 years of follow-up the extent of hemophilic arthropathy measured by the radiologic scale was similar for the two regimens (Table 2.2).

The beneficial role of primary prophylaxis in young boys with hemophilia is now proven without doubt. It is unfortunate that the Cochrane Collaboration review in 2006 challenged the evidence from the carefully conducted cohort studies [11]. In the USA definitive evidence was required from a randomized controlled trial that exposed young boys to the risk of life-threatening hemorrhage and unnecessary MRI scans [12].

There remain many questions for future research effort – how and when to initiate prophylaxis; the role of prophylaxis in the young adult; and the role of prophylaxis in other inherited bleeding disorders, particularly von Willebrand disease. World-wide the greatest barrier to the implementation of prophylaxis is the high cost. It is therefore important that treatment is individualized to maintain the required protective plasma factor level [13].

Inhibitors

The effectiveness of modern hemophilia treatment is challenged by the development of inhibitory antibodies and this remains the greatest therapeutic challenge. A systematic review commissioned by the British Department of Health and conducted by the School of Health and Related Research, the University of Sheffield in 2003, showed a great variability of inhibitor prevalence and the prevalence of inhibitor development ranged from 10% to 44% (Table 2.3). It was recognized that that a lower incidence was found following treatment with a single plasma derived (pd) product than with multiple pdFVIII preparations or single recombinant preparations [14]. Concentrate immunogenicity is complicated for a number of reasons – the method of inhibitor testing, the varied study populations, the different risk factors such as ethnicity, type of gene mutation and age at first treatment. There is continued debate about the role of von Willebrand factor as an immunomodulator [15].

Table 2.3 Prevalence of inhibitors in patients with severe hemophilia.

(Reproduced from Wight J and Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003;9:418–35.)

Author, DateThreshold FFVIII: C level for “severe”PrevalenceStrauss 19690.5%21% (16/77)Rasi 19901%17.3% (19/110)Sultan 19921%12.8% (198/1565)Aronis 19951%40% (19/49)Izquierdo-Ramirez 19881%44% (12/27)Ghosh 20011%8.2% (24/292)Ikkala 19712%16% (11/69)Yee 19992%10% (24/239)Ören 19992%41% (7/17)Rizza 20012%12.7% (196/1546)Schwarzinger 19875%17.5% (10/57)

To answer the question on different immunogenicity an independent, international, multicenter, prospective, controlled, randomized, open-label clinical trial is being carried out on inhibitor frequency in previously untreated patients (PUPs) or minimally blood component-treated (MBCTPs) when exposed to plasma-derived, von Willebrand factor-containing factor VIII (VWF/FVIII) concentrates or to rFVIII concentrates. This is the SIPPET study [16,17]. The truly global nature of hemophilia research is reflected in this study – there will be 80 centers from 24 countries on four continents. Thus a quarter of a century following the quest for recombinant products to overcome the problem of the viral epidemics of HIV and hepatitis there could be a return to pd FVIII to overcome inhibitor development.

Future therapeutic strategies

The adoption of prophylaxis as the “gold standard” brings with it the challenges of the need for frequent intravenous injections in small boys and the difficulties of venous access. For these reasons there has been focus on the production of bioengineered clotting factors with a prolonged half-life [18].

Even though the ultimate “cure” of hemophilia through gene therapy remains elusive, considerable progress has been made [17]. Promising results have been obtained with adeno-associated viral (AAV) vector delivery to the liver for FIX, FVIII and FVIIa genes in animal models. The short half-life of FVIIa has been overcome by gene transfer with AAV vector via the portal vein in the hemophilic dog. This would provide improved treatment for inhibitor patients. Furthermore, for non-inhibitor patients it could provide an attractive alternative to hemostatic therapy thus preventing immunologic challenge with FVIII and possible inhibitor development [19].

Women with bleeding disorders

Although hemophilia affects men other inherited bleeding disorders including VWD, rare bleeding disorders and inherited platelet disorders affect women (Table 2.1). In developed countries the number of women reported with inherited bleeding disorders is growing rapidly – from 1991–2007 the number of female patients treated in US hemophilia treatment centers increased from 2365 to 9041 (Figure 2.3).

Figure 2.3 Females treated for bleeding disorders at federally funded treatment centers in the United States, 1991–2007.

(Reproduced from Skinner MW. Building our global family – achieving treatment for all. Haemophilia 2010;16(suppl.5): 1–11.)

Bleeding disorders have a considerable impact on the health of women and their quality of life [20]. VWD is the most common inherited bleeding disorder worldwide with a prevalence of 1.3% [21]. Women experience early hemostatic challenge with menstruation and a systematic review of women with menorrhagia has shown a prevalence of VWD of 13% [22]. Outreach programs including Women Bleed Too in the UK, Project Red Flag in the US and the women's program of the Canadian Hemophilia Society have been established to both create awareness and to improve the quality of life and care for these women [23,24,25].

In many parts of the world, where first cousin marriage is common, the recessive rare bleeding disorders are a common cause of menorrhagia and bleeding in pregnancy. The WFH has realized the importance of this issue in the world and are encouraging innovative strategies and tools to reach these vulnerable populations where for the majority of women an inherited bleeding disorder remains a hidden condition to be suffered silently [1].

Conclusions

Within three-quarters of a century, the life expectancy for people with hemophilia has increased from less than 20 years to near 70 years in the developed parts of the world. Much of this achievement has been due to advances in clinical practice resulting from research in basic science. The challenge is to make these achievements possible in the developing world. Information technology allows for the development of databases, the most fundamental tool, after accurate diagnosis, for hemophilia care. The internet allows for the integration of such databases and as a resource to spread best practice. Worldwide, people with hemophilia can look forward to a bright future.

References

1. Skinner MW. Building our global family – achieving treatment for all. Haemophilia 2010;16(suppl. 5),110.

2. Hay CRM. National hemophilia databases. Textbook of Hemophilia, 2nd edition. Edited by Lee C, Berntorp E and Hoots K, 2010, Oxford: Blackwell Publishing.

3. Baker RI, Laurenson L, Winter M, et al. The impact of information technology on haemophilia care. Haemophilia 2004;10(Suppl. 4):41–6.

4. EUHASS, European Haemophilia Safety Surveillance System http://www.ehass.org

5. Birch C, La F. Haemophilia, clinical and genetic aspects. Urbana: University of Illinois, 1937.

6. Darby SC, Kan SW, Spooner RJ, et al. Mortality rates, life expectancy, and causes of death in people with haemophilia A or B in the United Kingdom who were not infected with HIV Blood 2007;110:815–25.

7. Hoffman C, Rice D, Sung HY. Persons with chronic conditions, their prevalence and costs. JAMA 1995;276:1473–9.

8. Dolan G. The challenge of an ageing haemophilic population. Haemophilia 2010;16(Suppl. 5),11–16.

9. Lofquist T, Nilsson IM, Berntorp, et al. Haemophilia prophylaxis in young patients – a long-term follow-up. J Int Med 1997;241:395–400.

10. Fischer K, Astermark J, van der Bom JG, et al. Prophylaxis treatment for severe haemophilia: comparison of an intermediate-dose to a high-dose regimen. Haemophilia 2002;8;753–60.

11. Stobart K, Iorio A, Wu JK. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with haemophilia A or B. Cochrane Database Syst Rev 2006;2:1–26.

12. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with haemophilia. N Engl J Med 2007;357:535–44.

13. Blanchette VS. Prophylaxis in the haemophilia population. Haemophilia 2010;16(Suppl. 5),181–8.

14. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003;9:418–35.

15. Auerswald G, Spranger T, Brackmann HH. The role of plasma-derived factor VIII/von Willebrand factor concentrates in the treatment of hemophilia A patients. Haematologica 2003;88:EREP05.

16. SIPPET study http://www.clinicaltrials.gov, Study NCT 01064284; EUDRACT n. 2009-011186-88.

17. Batorova A, High K, Gringeri A. Special lectures in haemophilia management. Haemophilia 2010;16:(Suppl. 5),22–8.

18. Saenko EL, Pipe SW. Strategies towards a longer acting factor VIII. Haemophilia 2006;12:42–51.

19. Margaritis P, Roy E, Aljamali MN, et al. Successful treatment of canine haemophilia by continuous expression of canine FVIIa. Blood 2009;113;3682–9.

20. Shankar M, Chi C, Kadir RA. Review of quality of life: menorrhagia in women with or without inherited bleeding disorders. Haemophilia 2008;14:15–20.

21. Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease. Blood 1987;69:454–9.

22. Shankar M, Lee CA, Sabin CA, et al. von Willebrand disease in women with menorrhagia: a systematic review. BJOG 2004;111:734–40.

23. Kadir RA, Nazzaro AM, Winikoff R, et al. Advocacy for women with bleeding disorders. Chapter 13 In: Inherited Bleeding Disorders in Women. Edited by Lee CA, Kadir RA and Kouides P, 2009 Oxford: Wiley-Blackwell.

24.www.womenbleedtoo.org.uk

25.www.projectredflag.org

3

Comprehensive Care Model in Hemophilia

Prasad Mathew

University of New Mexico, Albuquerque, NM, USA

Introduction

Comprehensive care in hemophilia requires a multidisciplinary team approach provided through hemophilia treatment centers (HTC) involving the management of the patient and his family through continuous supervision of the medical and psychosocial aspects of the disease. This type of care addresses the physical, emotional, educational, financial and vocational needs of the patient, while keeping the patient and his family abreast of the latest developments in the field of hemophilia [1]. Hemophilia cannot be optimally managed in a general hematology department due to its complexity. This reality is recognized by the World Health Organization (WHO), the World Federation of Hemophilia (WFH), and all developed countries. In 1973, the National Hemophilia Foundation (NHF) in the United States launched a two-year campaign to establish a nationwide network of hemophilia diagnostic and treatment centers. The idea was based upon providing a range of services (diagnostic and therapeutic) for patients with hemophilia under one roof. Subsequently, in 1975, the US Congress legislated, through Section 1131 of the Public Health Service Act, the establishment and funding for a network of 22 hemophilia diagnostic and treatment centers [2]. Today there are about 141 federally funded treatment centers and programs across the country [3].

Comprehensive care philosophy

The mainstay and backbone of optimal hemophilia care is a comprehensive care approach. The goal of comprehensive care is to address acute management of bleeding episodes, long-term management of arthropathy and other significant complications, and to provide psychosocial support and education needed to manage this disorder [4]. It thus involves a core team consisting of a hematologist, nurse, social worker, physical therapist, an orthopedic surgeon, and laboratory staff, among others. With the advent of highly active anti-retroviral therapy for human immunodeficiency virus (HIV) infection and newer agents for treatment of hepatitis C virus (HCV) infection, infectious disease specialists and hepatologists now are often part of the treatment team. Risk reduction counseling, ongoing education of patients regarding their bleeding disorder management, and empowering them in being advocates for their care, are key activities of comprehensive care [4,5]. Management of adults, many of whom need treatment for HIV and/or HCV infections, arthropathy, and counseling for issues related to aging (falls, prostatic hypertrophy, cardiovascular disease, cancer risk, etc.) are also handled by the HTC staff [6,7]. The WFH defines the functions of a comprehensive care program as one that performs diagnostic tests necessary for the definitive diagnosis of hemophilia and other inherited bleeding disorders, manages bleeding episodes with appropriate treatment products and first aid, and educates patients and families regarding safety precautions for the prevention and early identification of bleeding episodes. Furthermore, in this model, there is development and frequent reviews of an individualized management plan for each individual patient, monitoring and management of complications resulting from hemophilia and its treatment, as well as promoting regular physical exercise to maintain muscle and joint health while providing rehabilitative services for restoring function following bleeding episodes. In addition, it provides genetic counseling and genetic diagnostic services for patients and family members, educates, advises, and counsels patients, family members, health care workers, educators, and employers to ensure that the patients’ needs are met. It also conducts research to further knowledge and improve the management of bleeding disorders, often in collaboration with National and International hemophilia research centers [8].

Does the model work?

Comprehensive care results in significant improvement in the health of persons with hemophilia, with increased efficiency in delivering this care, while reducing the morbidity and mortality associated with this condition, and reducing use of healthcare resources [9,10]. In one of the earlier studies performed after the establishment of the initial 22 centers in the US, a five-year outcomes study showed that patients receiving care in a comprehensive care center experienced a decrease in the average number of days lost from work or school from 14.5 per year to 4.3 per year, and a decrease in the unemployment rate from 36% to 13%. This was accompanied by a decrease in the costs of care from about $15,800 per patient per year to $5932 per patient per year [11]. Today, the federally supported comprehensive HTCs are organized into 12 regions. Patients cared for in a comprehensive treatment center experience decreased morbidity and mortality, as well as a lower rate of unemployment, and reduced length of hospital stay and costs [12,13]. A Centers for Disease Control and Prevention (CDC) study of approximately 3000 people with hemophilia A and B, showed that those patients who visited an HTC were 30% less likely to die of hemophilia-related complications compared with those who did not receive care at an HTC, and were about 40% less likely to be hospitalized for bleeding complications [12,13].

As part of a comprehensive care set-up, HTCs in the US provide diagnostic services, treatment according to established treatment protocols, and follow recommendations provided through the Medical and Scientific Advisory committee (MASAC) of the National Hemophilia Foundation. In addition, they offer psychosocial and educational services, offer genetic counseling, refer patients for surgery as needed, consult for blood-borne disease prevention and treatment, and administer research and clinical trials to affected patients and their families [5]. Experience has shown that, through this approach, coalitions of patients, healthcare providers and governments can be built to achieve sustainable care. Clearly, with proper treatment, people with bleeding disorders can live nearly perfectly healthy lives, and history stands behind us to show that with research and constant striving to better the lives of people with bleeding disorders, one can achieve the vision that WFH has for the global bleeding disorder community, viz. the vision of “Treatment for All”; i.e. treatment will be available for all those with inherited bleeding disorders, regardless of where they live [14,15].

Improvements in care using HTCs

Epidemiological data show the benefits of improved hemophilia care through the years [16,17]. Hemophilia has moved from the status of a neglected and often fatal hereditary disorder to that of a defined group of disorders with a molecular basis for which safe and effective treatment is available. There are improved administration techniques and dosing regimens, a shift from on-demand treatment to prophylaxis, successful treatment protocols for immune tolerance induction in patients with inhibitors and enhanced approaches to overall patient management [16,18,19]. Improvements also include the introduction of virus inactivation methods for plasma derived clotting factor concentrates and the development of recombinant factor VIII therapy, which has essentially eliminated the risk of infectious disease transmission. Recombinant factor concentrates are recommended as the treatment of choice by several national guidelines today. All these developments have resulted in increased health-related quality of life and life expectancy for hemophilia patients who are transitioning from childhood to adulthood with healthy joints and an overall excellent health status. As a result, the ageing hemophilia population will be afflicted with age-related musculoskeletal disease, cardiovascular disease and cancer, among other “usual” disorders men experience as they age that were not previously observed in this population [20]. With respect to this, the spectrum of hemophilia care will need to be extended to diseases of older ages with the need of including further disciplines in comprehensive hemophilia care programs, such as cardiology, nephrology, oncology, etc. [20,21]. Despite these advances, the short half-life of factor VIII, requiring re-administration every 2 or 3 days and the development of inhibitors remains a challenge [22,23].

Cutting edge care and research at an HTC