- Email: [email protected]
Comprehensive care for hemophilia and other inherited bleeding disorders
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Comprehensive care for hemophilia and other inherited bleeding disorders David Page National Director of Health Policy, Canadian Hemophilia Society Montreal, Canada
A R T I C LE I N FO
A B S T R A C T
Keywords: Comprehensive care Hemophilia History Development
The World Federation of Hemophilia (WFH) states in its Guidelines for the Management of Hemophilia, Second Edition [1], that people with hemophilia are best managed in a comprehensive care setting. That team is typically comprised of a core group including a hematologist, nurse coordinator, physiotherapist, social worker, specialized lab technologist and data manager, and as needed, by other specialists. Hemophilia is an X-linked congenital bleeding disorder caused by a deficiency of coagulation factor VIII (FVIII) in hemophilia A or factor IX (FIX) in hemophilia B. There are a number of other disorders that are now typically treated in these comprehensive care centers including von Willebrand disease (VWD), rare factor deficiencies (I, II, V, V & VIII, VII, X, XI and XIII), and inherited platelet function disorders. Models of comprehensive care delivery for hemophilia and other inherited bleeding disorders were first defined in the 1960s and have been in constant evolution ever since. Comprehensive care for hemophilia and other inherited bleeding disorders was made possible by the discovery of cryoprecipitate for the treatment of hemophilia A in the mid-1960s and, in the decade that followed, the development of lyophilized clotting factor concentrates. It was quickly realized that treatment at home was far preferable to frequent visits to Emergency Departments or out-patient. Tragically, the same clotting factor concentrates that revolutionized treatment and dramatically improved quality of life exposed thousands of people with hemophilia to HIV-AIDS and hepatitis C in the late 1970s and 1980s [2]. The model of comprehensive care was forced to add specialists in infectious disease and hepatology. At the same time, the crisis accelerated the development of recombinant FVIII and IX clotting factors; these entered the clinic in 1993 and 1997 respectively. The proven safety of both recombinant and plasma-derived products spurred on the expansion of prophylactic care to more patients. Today, with the success of a comprehensive care model that keeps patients out of the hospital (and out of sight), and promises a normal lifespan, there is an emerging impression among many health system managers that the problem of hemophilia is “solved.” In 2019, however, even the best care and treatment remains highly burdensome and not entirely efficacious. Emerging innovative therapies are promising yet dramatically different in their modes of action, dosing and administration. Much of what has been learned in terms of management of the disease over the last 50 years may no longer be relevant. Rather than one type of treatment for all, there may well be many different therapies. Comprehensive care centres will not become obsolete. It will remain critically important that specialized staff be able to foster long-term relationships with patients and their families. Indeed, they will need to expand their knowledge and expertise in order to be able to continue to deliver the standards of care so carefully developed since the 1960s.
The World Federation of Hemophilia (WFH) states in its Guidelines for the Management of Hemophilia, Second Edition [3], that people with hemophilia are best managed in a comprehensive care setting. Comprehensive care, the Guidelines write, promotes both physical and psychosocial health and the quality of life of the person. As hemophilia is a rare disorder that is complex to diagnose and treat, optimal care requires much more than the treatment of acute bleeding. The Guidelines state, “The wide-ranging needs of people with hemophilia and their families are best met through the coordinated delivery of comprehensive care by a multidisciplinary team of healthcare professionals,
in accordance with accepted protocols that are practical, and national treatment guidelines, if available.” That team is typically comprised of a core group including a hematologist, nurse coordinator, physiotherapist, social worker, specialized lab technologist and data manager, and augmented, as needed, by an orthopedist, dentist, psychologist and other specialists, including infectious disease following the widespread blood-borne infections with HIV and HCV in the 1970s and 1980s. More recently, the need to integrate an OB-GYN into the team to provide support around menorrhagia and childbirth has been recognized. Hemophilia is an X-linked congenital bleeding disorder caused by a
E-mail address: [email protected]. https://doi.org/10.1016/j.transci.2019.08.005
1473-0502/ © 2019 Published by Elsevier Ltd.
Please cite this article as: David Page, Transfusion and Apheresis Science, https://doi.org/10.1016/j.transci.2019.08.005
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
D. Page
deficiency of coagulation factor VIII (FVIII) in hemophilia A or factor IX (FIX) in hemophilia B. The deficiency is the result of mutations of the respective clotting factor genes. Hemophilia A has an estimated frequency of approximately one in 10,000 births; hemophilia B, one in 50,000 births. As many as 30–40% of all cases are the result of spontaneous mutations and therefore there is no prior family history. The severe forms of hemophilia affect mainly males, though female carriers often have symptoms of bleeding, which can in some cases be severe. Hemophilia A and B are the most common severe inherited bleeding disorders; however, there are a number of other disorders that are now typically treated in the comprehensive care centres first developed for the treatment of hemophilia. These include von Willebrand disease (VWD), under-diagnosed but thought to affect up to 1 in 1,000 people with symptoms severe enough to require treatment, rare factor deficiencies including deficiencies in factors I, II, V, V & VIII, VII, X, XI and XIII, and inherited platelet function disorders. In addition, people who develop acquired inhibitors to coagulation proteins, and hence a severe bleeding tendency, are often treated in these centres. Hemophilia is generally labelled based on clotting factor levels. Severe forms of the disease occur at levels less than 1% of normal, moderate forms between 1% and 5%, and mild forms between 5% and 40%, though other factors can affect the severity of symptoms both positively and negatively. Bleeding can occur anywhere in the body; however, it is bleeding into joints, especially the ankles, knees and elbows, that is most common and debilitating. Acute bleeding into joints and muscles, when not controlled, can be excruciatingly painful over many days and even weeks. The consequence of repeated hemorrhages into joints and muscles is severe hemophilic arthropathy at a young age. Some bleeds, notably those into the brain, can be life-threatening. When optimally treated with coagulation products delivered in a comprehensive care setting, people with hemophilia can lead full and productive lives. Innovative non-factor therapies, including monoclonal antibodies like emicizumab and RNA-interference therapies like fitusiran, as well as gene therapy, hold out the promise of life-changing advances in care in the very near future. Models of comprehensive care delivery for hemophilia and other inherited bleeding disorders were first defined in the 1960s and have been in constant evolution ever since. The concept has spread around the world from Europe, North America and Australia and is now well established on every continent. The greatest barriers to efficacious treatment in many countries are the limited access to accurate laboratory diagnosis and to coagulation therapies. The WFH estimates that 75% of people with hemophilia have little or no access to adequate care. Comprehensive care for hemophilia and other inherited bleeding disorders was made possible by the discovery of cryoprecipitate for the treatment of hemophilia A in the mid-1960s and, in the decade that followed, the development of lyophilized clotting factor concentrates for both hemophilia A and B. These products were major therapeutic advances over previously available fresh frozen plasma (FFP) because of their higher concentration of the missing clotting proteins, factors VIII and IX. They were efficacious in stopping bleeding rapidly after onset and reduced both the immediate pain and suffering as well as the long-term damage to joints. In addition, the new therapies presented an opportunity to prevent bleeding rather than to simply treat bleeding that was already occurring. However, the median half-life of infused FVIII is only 12 h; that of FIX18 h. Therefore, preventative, or prophylactic, treatments were needed two or three times per week to maintain clotting factor levels above 1% of normal, the critical point above which the majority of spontaneous (no apparent cause) bleeding could be largely prevented. Through the vision of Inge-Marie Nilsson in Sweden, prophylactic treatment of bleeding in boys with severe hemophilia, beginning at the age of 1–2 years, started in 1967. Twentyfive years later, the men had maintained very close to normal joint function [4]. It was quickly realized that treatment at home was far preferable to frequent visits to Emergency Departments or out-patient
clinics for those patients with the severe forms of hemophilia A and B. Home treatment involved considerable expertise on the part of the patient or his caregiver: determining which bleeds required treatment and which did not, and the ability to intravenously infuse the coagulation product safely. Cryoprecipitate, stored at minus 20 degrees C, needed to be thawed quickly and infused immediately as the factor VIII it contained degraded rapidly. While more concentrated in factor VIII than FFP, it nevertheless represented a high volume to be transfused. A single unit of 15–20 mL of cryoprecipitate contains 150–200 International Units (IUs) of FVIII. A typical dose of 1000 IUs, enough to raise FVIII levels in a 70-kg adult to 15% of normal, therefore required 5 to 7 units, or over 100 mL in volume. Lyophilized factor VIII was more concentrated. Early preparations containing 1000 IUs of FVIII or IX were typically diluted in 20 mL of sterile water. In those years, both cryoprecipitate and factor concentrates frequently caused severe allergic reactions, ranging from urticaria to anaphylaxis; therefore, patients and caregivers also needed to be equipped and trained to respond urgently with adrenaline. A 1972 crossover study by Strawczynski [5] at the Montreal Children’s Hospital in Canada compared two groups of children receiving cryoprecipitate in hospital or at home, administered by a nurse. The children being treated at home reported bleeds more quickly and were treated sooner, missed fewer days of school and required less treatment. More than 95% of the families preferred home treatment. The cost of providing care at home was one-fifth the cost of hospital care. Providing access to these improved therapies and the educational needs involved with home management led to the development of hemophilia treatment centres (HTC), centred around the services of the nurse coordinator and hematologist. Quickly, other disciplines were added to the teams. A dedicated physiotherapist was critical to preserving joint function. Psychosocial support in the form of a social worker and/or psychologist to help families face the considerable challenge of a chronic disease requiring frequent and burdensome care in the home was also essential. Almost every country claims the first HTC. Many people agree, however, that the first detailed description of comprehensive care was in a 1966 text edited by Rosemary Biggs at the University of Oxford [6]. Alison Street, then Vice President Medical of the World Federation of Hemophilia, wrote in 2012, “They recognized that treating patients in a specialized centre provided better clinical and cost outcomes and called them ‘comprehensive care centres.’ Such improved outcomes were critically dependent on collaboration between laboratory personnel, haematologists, surgeons and physiotherapists [7].” In 1975 in the United States, the Public Health Service Act established and funded Hemophilia Diagnostic and Treatment Centers [8]. These centers provided, at minimum:
• A coagulation laboratory of recognized high standards; • A blood bank providing all of the blood components needed by hemophiliacs; • A multidisciplinary hemophilia care team including a hematologist, • • •
an internist, a pediatrician, an orthopedic surgeon, a physical therapist, a dentist, a social worker, and a registered nurse; Formal linkages with mental health, genetic counselling, and rehabilitative services; A training course in self-therapy (home care) and updated hemophilia concepts for patients and family members; An outreach program to enable every hemophiliac within the area served to receive services of the program [9].
A study conducted in 11 of these centres between 1976 and 1981 found that the people treated in this network had improved health, decreased hospitalization, decreased absenteeism, and a decrease in the unemployment rate from 36 percent to 13 percent. This was accompanied by decreased costs of care. The authors concluded, “In this model of a chronic handicapping illness, the early application of 2
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Table 1 XXX. European Haemophilia Treatment Centres (EHTC) …
European Haemophilia Comprehensive Care Centres (EHCCC) …
provide care for patients, including diagnosis, treatment, follow-up and rehabilitation provide patients with safe and effective treatment products
provide all the services of EHTCs and …
provide a 24 h emergency treatment service provide basic diagnostic and monitoring laboratory support during normal working hours for the more common inherited bleeding disorders have access to multidisciplinary support, locally or in conjunction with an EHCCC offer specific treatment for patients with inhibitors and immune tolerance in collaboration with an EHCCC provide advisory service, including genetic counselling, to patients and healthcare professionals promote information and training programs on inherited bleeding disorders to patients and healthcare professionals
co-ordinate the delivery of hemophilia services both in hospital and in the community including liaison with affiliated EHTCs provide a 24 -h advisory service for patients, families, hospital doctors, general practitioners and affiliated EHTCs health care professionals provide specialist care for patients with inhibitors, including surgery provide a diagnostic and reference laboratory service with a full repertoire of tests for the diagnosis and monitoring of inherited disorders of hemostasis provide a 24 h laboratory service for clotting factor assays and inhibitors screens have access to orthopaedic and/or rheumatology service with provision of surgery have access to physiotherapy service have access to a specialised obstetric and gynaecological service for the management of hemophilia carriers and women with VWD and other hereditary bleeding disorders have access to paediatric facilities if children are treated have access to a genetic diagnosis service providing also carrier detection and antenatal diagnosis have access to dental service have access to hepatology and infectious diseases service for patients with HIV and/or viral hepatitis offer professional psychological support have access to a social worker and welfare advice collate data (e.g. product usage, patient demographics) participate in research, including clinical trials
Bleeding Disorders [13]. The Vision was to promote the provision of comprehensive care to all individuals with inherited bleeding disorders, guided by clear standards, facilitated by engagement with stakeholders, and driven by needs and best practice, resulting in best outcomes. The focus of the standards themselves was on the structural and resource requirements necessary for a hemophilia treatment centre to effectively provide care, and on its functions and responsibilities. The Standards document stated that, “Effective programs …
comprehensive care is preferable to the previous emphasis on end-stage rehabilitative efforts [10].” Health authorities recognized the value of comprehensive care centres. In Canada in 1979, the government of Quebec created four hemophilia treatment centres for the province. At the same time, it decreed that only patients registered in those centres would have access to clotting factor concentrates, thus recognizing the importance of specialized knowledge in the management of these conditions and in the prescribing of blood products that were expensive, administered at home and carried a risk of adverse reactions. By the end of the 1970s, comprehensive care centres were established across Canada. Tragically, the same clotting factor concentrates that revolutionized treatment and dramatically improved quality of life exposed thousands of people with hemophilia to HIV-AIDS and hepatitis C in the late 1970s and 1980s [11]. The model of comprehensive care was forced to change, adding specialists in infectious disease and hepatology. For many patients, the focus of care shifted to the life-and-death issues of immune challenges and liver disease before the advent of efficacious treatments that are available today. At the same time, the crisis accelerated the development of recombinant FVIII and IX clotting factors; these entered the clinic in 1993 and 1997 respectively. The proven safety of both recombinant and plasma-derived products spurred on the expansion of prophylactic care to more patients. In the 21st century, the focus returned to the preservation of joint health. In 2007, Manco-Johnson published the landmark study proving that prophylaxis with recombinant factor VIII prevented joint damage and decreased the frequency of joint and other hemorrhages in young boys with severe hemophilia A [12]. This reinforced the importance of comprehensive care. It was only with the multidisciplinary resources of a comprehensive care centre that the challenge of maintaining the necessary compliance in administering a burdensome IV treatment in the home environment could be successfully met. Efforts began to better define comprehensive care and the standards required to achieve it. In 2007, the Canadian Hemophilia Standards Group, comprised of health care providers and patients, published the Canadian Comprehensive Care Standards for Hemophilia and Other Inherited
• deliver comprehensive care through an integrated, multidisciplinary team; • partner with patients to foster and facilitate self-management and independence; • have the capacity to tailor management to the individual’s needs and abilities; • adhere to guidelines and standards; • regularly participate in quality assurance; • consult with other programs; • participate in collaborative research.” A self-assessment in 2010 by the Canadian HTCs found that 22 of 24 centres adhered to 92% of the standards. A large number of centres, however, failed to adhere to a key standard due to a lack of core team members. This finding was validated several years later in an evaluation conducted by the Canadian Hemophilia Society [14]. Nine of 25 centres lacked designated resources in physiotherapy and psychosocial support. Similar situations are thought to prevail in centres in many countries. In Europe, an extensive deliberative process led by the European Haemophilia Network (EUHANET) between 2008 and 2013 involving health care providers and patients led to the European Guidelines [15], developed in order to set quality standards for European Haemophilia Centres and criteria for their certification. It defined two levels of service delivery: European Haemophilia Treatment Centres (EHTC) providing basic services for at least 10 people with severe hemophilia A or B or VWD type 3, and European Haemophilia Comprehensive Care Centres (EHCCC), able to provide more specialized care for at least 40 3
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innovative therapies are promising yet dramatically different in their modes of action, dosing and administration. Much of what has been learned in terms of management of the disease over the last 50 years—protocols for factor replacement therapy, peaks and troughs of FVIII and IX, perhaps even home treatment—may no longer be relevant. Rather than one type of treatment for all, there may well be many different therapies, depending on age, severity of disease and appetite for change. Comprehensive care centres will not become obsolete. It will remain critically important that specialized staff be able to foster long-term relationships with patients and their families. Indeed, they will need to expand their knowledge and expertise in order to be able to continue to deliver the standards of care so carefully developed since the 1960s.
people with severe hemophilia A or B and VWD type 3. Their respective services are summarized in Table 1. Several countries in Europe, including Ireland and the U.K. have well-defined audit systems to evaluate centres’ capacity to respect accepted comprehensive care standards. Every three or four years, a team of external experts—physician, nurse, physiotherapist, patient—visit the centre, meet all staff, verify performance indicators against standards and conduct a patient survey. Recommendations for improvements are issued. Inherited bleeding disorders remain rare diseases and research on them is not abundant. While the value of comprehensive care programmes and the pertinence of the standards that underlie them appear self-evident to the professionals who provide care and to the patients who benefit from it, they remain largely unproven in this era of evidence-based medicine. To attempt to overcome this lack of research on the superiority of standards-based comprehensive care over alternate models, the U.S. National Hemophilia Foundation partnered with McMaster University in Canada between 2014 and 2016 “to identify evidence-based best practices in hemophilia care delivery [16].” The researchers used the term “integrated care” in place of “comprehensive care.” The guideline was developed based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach [17]. The systematic analysis concluded, “The Guideline panel suggests that the integrated care model be used over non-integrated care models for persons with hemophilia (PWH) (conditional recommendation, moderate certainty in the evidence). For PWH with inhibitors and those at high risk for inhibitor development, the same recommendation was graded as strong, with moderate certainty in the evidence. The panel suggests that a hematologist, a specialized hemophilia nurse, a physical therapist, a social worker and round-the-clock access to a specialized coagulation laboratory be part of the integrated care team, over a care team that does not include all of these components (conditional recommendation, very low certainty in the evidence). Based on available evidence, the integrated model of care in its current structure, is suggested for optimal care of PWH. There is a need for further appropriately designed studies that address unanswered questions about specific outcomes and the optimal structure of the integrated care delivery model in hemophilia [18].” With the HIV-hepatitis tragedy of the 1980s becoming a distant memory for the general public, with the current availability of a wide range of clotting factor therapies (at least in the well-resourced countries of the world), and with the success of a comprehensive care model that keeps patients out of the hospital (and out of sight), and promises a normal lifespan, there is an emerging impression among many health system managers that the problem of hemophilia is “solved.” In 2019, however, even the best care and treatment remains highly burdensome and not entirely efficacious. Quality of life is compromised. Emerging
References [1] Guidelines for the management of hemophilia. Haemophilia 2012. https://doi.org/ 10.1111/j.1365-2516.2012.02909.x. Epub 6 JUL. [2] EVATT BL. The tragic history of AIDS in the hemophilia population, 1982–1984. J Thromb Haemost 2006;4(Issue 11, September). [3] Guidelines for the management of hemophilia. Haemophilia 2012. https://doi.org/ 10.1111/j.1365-2516.2012.02909.x. Epub 6 JUL. [4] Nilsson IM, et al. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992;232(July (1)):25–32. [5] Hemophilia home care cuts costs, hospitalizations. Strawczynski H. MD of Canada; 1972. October. [6] Biggs RMc, Farlane RC. Treatment of haemophilia and other coagulation dis- orders. Oxford, UK: Blackwell Scientific; 1966. [7] Developing models of haemophilia care A. STREET. Haemophilia 2012;18(Suppl. 4):89–93. https://doi.org/10.1111/j.1365-2516.2012.02876.x. [8] PL 9463: the Public Health Service Act establishing the hemophilia diagnostic and treatment center program. No. 1131 of Public Law 9463. Washington, DC: Govt Printing Office; 1975. [9] S.S.M.I.T.H. PETER, P.E.T.E.R.H. MD, LEVINE MD. The benefits of comprehensive care of hemophilia: a five-year study of outcomes. Am J Public Health 1984;74(June). No. 6. [10] S.S.M.I.T.H. PETER, P.E.T.E.R.H. MD, LEVINE MD. The benefits of comprehensive care of hemophilia: a five-year study of outcomes. American Journal of Public Health 1984;74(June). No. 6. [11] EVATT BL. The tragic history of AIDS in the hemophilia population, 1982–1984. J Thromb Haemost 2006;4(Issue 11, September). [12] Manco-Johnson Marilyn J, et al. Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. N Engl J Med 2007;357:535–44. [13] Canadian Comprehensive Care Standards for Hemophilia and Other Inherited Bleeding Disorders. https://www.hemophilia.ca/comprehensive-care-standards/. [14] Page D, et al. Penny wise, pound foolish: an assessment of Canadian Hemophilia/ inherited bleeding disorder comprehensive care program services and resources. Haemophilia 2016:1–6. https://doi.org/10.1111/hae.12913. [15] Giangrande Paul, Calizzani Gabriele. The European standards of Haemophilia Centres. Blood Transfus 2014(Suppl 3):s525–30. https://doi.org/10.2450/2014. 0056-14s. [16] Pai M, et al. NHF-McMaster Guideline on Care Models for Haemophilia Management. Haemophilia 2016;22(Suppl. 3):6–16. [17] Grading of Recommendations, Assessment, Development and Evaluation. https:// cebgrade.mcmaster.ca/aboutgrade.html. [18] Pai M, et al. NHF-McMaster Guideline on Care Models for Haemophilia Management. Haemophilia 2016;22(Suppl. 3):6–16.
4
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Comprehensive care for hemophilia and other inherited bleeding disorders David Page National Director of Health Policy, Canadian Hemophilia Society Montreal, Canada
A R T I C LE I N FO
A B S T R A C T
Keywords: Comprehensive care Hemophilia History Development
The World Federation of Hemophilia (WFH) states in its Guidelines for the Management of Hemophilia, Second Edition [1], that people with hemophilia are best managed in a comprehensive care setting. That team is typically comprised of a core group including a hematologist, nurse coordinator, physiotherapist, social worker, specialized lab technologist and data manager, and as needed, by other specialists. Hemophilia is an X-linked congenital bleeding disorder caused by a deficiency of coagulation factor VIII (FVIII) in hemophilia A or factor IX (FIX) in hemophilia B. There are a number of other disorders that are now typically treated in these comprehensive care centers including von Willebrand disease (VWD), rare factor deficiencies (I, II, V, V & VIII, VII, X, XI and XIII), and inherited platelet function disorders. Models of comprehensive care delivery for hemophilia and other inherited bleeding disorders were first defined in the 1960s and have been in constant evolution ever since. Comprehensive care for hemophilia and other inherited bleeding disorders was made possible by the discovery of cryoprecipitate for the treatment of hemophilia A in the mid-1960s and, in the decade that followed, the development of lyophilized clotting factor concentrates. It was quickly realized that treatment at home was far preferable to frequent visits to Emergency Departments or out-patient. Tragically, the same clotting factor concentrates that revolutionized treatment and dramatically improved quality of life exposed thousands of people with hemophilia to HIV-AIDS and hepatitis C in the late 1970s and 1980s [2]. The model of comprehensive care was forced to add specialists in infectious disease and hepatology. At the same time, the crisis accelerated the development of recombinant FVIII and IX clotting factors; these entered the clinic in 1993 and 1997 respectively. The proven safety of both recombinant and plasma-derived products spurred on the expansion of prophylactic care to more patients. Today, with the success of a comprehensive care model that keeps patients out of the hospital (and out of sight), and promises a normal lifespan, there is an emerging impression among many health system managers that the problem of hemophilia is “solved.” In 2019, however, even the best care and treatment remains highly burdensome and not entirely efficacious. Emerging innovative therapies are promising yet dramatically different in their modes of action, dosing and administration. Much of what has been learned in terms of management of the disease over the last 50 years may no longer be relevant. Rather than one type of treatment for all, there may well be many different therapies. Comprehensive care centres will not become obsolete. It will remain critically important that specialized staff be able to foster long-term relationships with patients and their families. Indeed, they will need to expand their knowledge and expertise in order to be able to continue to deliver the standards of care so carefully developed since the 1960s.
The World Federation of Hemophilia (WFH) states in its Guidelines for the Management of Hemophilia, Second Edition [3], that people with hemophilia are best managed in a comprehensive care setting. Comprehensive care, the Guidelines write, promotes both physical and psychosocial health and the quality of life of the person. As hemophilia is a rare disorder that is complex to diagnose and treat, optimal care requires much more than the treatment of acute bleeding. The Guidelines state, “The wide-ranging needs of people with hemophilia and their families are best met through the coordinated delivery of comprehensive care by a multidisciplinary team of healthcare professionals,
in accordance with accepted protocols that are practical, and national treatment guidelines, if available.” That team is typically comprised of a core group including a hematologist, nurse coordinator, physiotherapist, social worker, specialized lab technologist and data manager, and augmented, as needed, by an orthopedist, dentist, psychologist and other specialists, including infectious disease following the widespread blood-borne infections with HIV and HCV in the 1970s and 1980s. More recently, the need to integrate an OB-GYN into the team to provide support around menorrhagia and childbirth has been recognized. Hemophilia is an X-linked congenital bleeding disorder caused by a
E-mail address: [email protected]. https://doi.org/10.1016/j.transci.2019.08.005
1473-0502/ © 2019 Published by Elsevier Ltd.
Please cite this article as: David Page, Transfusion and Apheresis Science, https://doi.org/10.1016/j.transci.2019.08.005
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
D. Page
deficiency of coagulation factor VIII (FVIII) in hemophilia A or factor IX (FIX) in hemophilia B. The deficiency is the result of mutations of the respective clotting factor genes. Hemophilia A has an estimated frequency of approximately one in 10,000 births; hemophilia B, one in 50,000 births. As many as 30–40% of all cases are the result of spontaneous mutations and therefore there is no prior family history. The severe forms of hemophilia affect mainly males, though female carriers often have symptoms of bleeding, which can in some cases be severe. Hemophilia A and B are the most common severe inherited bleeding disorders; however, there are a number of other disorders that are now typically treated in the comprehensive care centres first developed for the treatment of hemophilia. These include von Willebrand disease (VWD), under-diagnosed but thought to affect up to 1 in 1,000 people with symptoms severe enough to require treatment, rare factor deficiencies including deficiencies in factors I, II, V, V & VIII, VII, X, XI and XIII, and inherited platelet function disorders. In addition, people who develop acquired inhibitors to coagulation proteins, and hence a severe bleeding tendency, are often treated in these centres. Hemophilia is generally labelled based on clotting factor levels. Severe forms of the disease occur at levels less than 1% of normal, moderate forms between 1% and 5%, and mild forms between 5% and 40%, though other factors can affect the severity of symptoms both positively and negatively. Bleeding can occur anywhere in the body; however, it is bleeding into joints, especially the ankles, knees and elbows, that is most common and debilitating. Acute bleeding into joints and muscles, when not controlled, can be excruciatingly painful over many days and even weeks. The consequence of repeated hemorrhages into joints and muscles is severe hemophilic arthropathy at a young age. Some bleeds, notably those into the brain, can be life-threatening. When optimally treated with coagulation products delivered in a comprehensive care setting, people with hemophilia can lead full and productive lives. Innovative non-factor therapies, including monoclonal antibodies like emicizumab and RNA-interference therapies like fitusiran, as well as gene therapy, hold out the promise of life-changing advances in care in the very near future. Models of comprehensive care delivery for hemophilia and other inherited bleeding disorders were first defined in the 1960s and have been in constant evolution ever since. The concept has spread around the world from Europe, North America and Australia and is now well established on every continent. The greatest barriers to efficacious treatment in many countries are the limited access to accurate laboratory diagnosis and to coagulation therapies. The WFH estimates that 75% of people with hemophilia have little or no access to adequate care. Comprehensive care for hemophilia and other inherited bleeding disorders was made possible by the discovery of cryoprecipitate for the treatment of hemophilia A in the mid-1960s and, in the decade that followed, the development of lyophilized clotting factor concentrates for both hemophilia A and B. These products were major therapeutic advances over previously available fresh frozen plasma (FFP) because of their higher concentration of the missing clotting proteins, factors VIII and IX. They were efficacious in stopping bleeding rapidly after onset and reduced both the immediate pain and suffering as well as the long-term damage to joints. In addition, the new therapies presented an opportunity to prevent bleeding rather than to simply treat bleeding that was already occurring. However, the median half-life of infused FVIII is only 12 h; that of FIX18 h. Therefore, preventative, or prophylactic, treatments were needed two or three times per week to maintain clotting factor levels above 1% of normal, the critical point above which the majority of spontaneous (no apparent cause) bleeding could be largely prevented. Through the vision of Inge-Marie Nilsson in Sweden, prophylactic treatment of bleeding in boys with severe hemophilia, beginning at the age of 1–2 years, started in 1967. Twentyfive years later, the men had maintained very close to normal joint function [4]. It was quickly realized that treatment at home was far preferable to frequent visits to Emergency Departments or out-patient
clinics for those patients with the severe forms of hemophilia A and B. Home treatment involved considerable expertise on the part of the patient or his caregiver: determining which bleeds required treatment and which did not, and the ability to intravenously infuse the coagulation product safely. Cryoprecipitate, stored at minus 20 degrees C, needed to be thawed quickly and infused immediately as the factor VIII it contained degraded rapidly. While more concentrated in factor VIII than FFP, it nevertheless represented a high volume to be transfused. A single unit of 15–20 mL of cryoprecipitate contains 150–200 International Units (IUs) of FVIII. A typical dose of 1000 IUs, enough to raise FVIII levels in a 70-kg adult to 15% of normal, therefore required 5 to 7 units, or over 100 mL in volume. Lyophilized factor VIII was more concentrated. Early preparations containing 1000 IUs of FVIII or IX were typically diluted in 20 mL of sterile water. In those years, both cryoprecipitate and factor concentrates frequently caused severe allergic reactions, ranging from urticaria to anaphylaxis; therefore, patients and caregivers also needed to be equipped and trained to respond urgently with adrenaline. A 1972 crossover study by Strawczynski [5] at the Montreal Children’s Hospital in Canada compared two groups of children receiving cryoprecipitate in hospital or at home, administered by a nurse. The children being treated at home reported bleeds more quickly and were treated sooner, missed fewer days of school and required less treatment. More than 95% of the families preferred home treatment. The cost of providing care at home was one-fifth the cost of hospital care. Providing access to these improved therapies and the educational needs involved with home management led to the development of hemophilia treatment centres (HTC), centred around the services of the nurse coordinator and hematologist. Quickly, other disciplines were added to the teams. A dedicated physiotherapist was critical to preserving joint function. Psychosocial support in the form of a social worker and/or psychologist to help families face the considerable challenge of a chronic disease requiring frequent and burdensome care in the home was also essential. Almost every country claims the first HTC. Many people agree, however, that the first detailed description of comprehensive care was in a 1966 text edited by Rosemary Biggs at the University of Oxford [6]. Alison Street, then Vice President Medical of the World Federation of Hemophilia, wrote in 2012, “They recognized that treating patients in a specialized centre provided better clinical and cost outcomes and called them ‘comprehensive care centres.’ Such improved outcomes were critically dependent on collaboration between laboratory personnel, haematologists, surgeons and physiotherapists [7].” In 1975 in the United States, the Public Health Service Act established and funded Hemophilia Diagnostic and Treatment Centers [8]. These centers provided, at minimum:
• A coagulation laboratory of recognized high standards; • A blood bank providing all of the blood components needed by hemophiliacs; • A multidisciplinary hemophilia care team including a hematologist, • • •
an internist, a pediatrician, an orthopedic surgeon, a physical therapist, a dentist, a social worker, and a registered nurse; Formal linkages with mental health, genetic counselling, and rehabilitative services; A training course in self-therapy (home care) and updated hemophilia concepts for patients and family members; An outreach program to enable every hemophiliac within the area served to receive services of the program [9].
A study conducted in 11 of these centres between 1976 and 1981 found that the people treated in this network had improved health, decreased hospitalization, decreased absenteeism, and a decrease in the unemployment rate from 36 percent to 13 percent. This was accompanied by decreased costs of care. The authors concluded, “In this model of a chronic handicapping illness, the early application of 2
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Table 1 XXX. European Haemophilia Treatment Centres (EHTC) …
European Haemophilia Comprehensive Care Centres (EHCCC) …
provide care for patients, including diagnosis, treatment, follow-up and rehabilitation provide patients with safe and effective treatment products
provide all the services of EHTCs and …
provide a 24 h emergency treatment service provide basic diagnostic and monitoring laboratory support during normal working hours for the more common inherited bleeding disorders have access to multidisciplinary support, locally or in conjunction with an EHCCC offer specific treatment for patients with inhibitors and immune tolerance in collaboration with an EHCCC provide advisory service, including genetic counselling, to patients and healthcare professionals promote information and training programs on inherited bleeding disorders to patients and healthcare professionals
co-ordinate the delivery of hemophilia services both in hospital and in the community including liaison with affiliated EHTCs provide a 24 -h advisory service for patients, families, hospital doctors, general practitioners and affiliated EHTCs health care professionals provide specialist care for patients with inhibitors, including surgery provide a diagnostic and reference laboratory service with a full repertoire of tests for the diagnosis and monitoring of inherited disorders of hemostasis provide a 24 h laboratory service for clotting factor assays and inhibitors screens have access to orthopaedic and/or rheumatology service with provision of surgery have access to physiotherapy service have access to a specialised obstetric and gynaecological service for the management of hemophilia carriers and women with VWD and other hereditary bleeding disorders have access to paediatric facilities if children are treated have access to a genetic diagnosis service providing also carrier detection and antenatal diagnosis have access to dental service have access to hepatology and infectious diseases service for patients with HIV and/or viral hepatitis offer professional psychological support have access to a social worker and welfare advice collate data (e.g. product usage, patient demographics) participate in research, including clinical trials
Bleeding Disorders [13]. The Vision was to promote the provision of comprehensive care to all individuals with inherited bleeding disorders, guided by clear standards, facilitated by engagement with stakeholders, and driven by needs and best practice, resulting in best outcomes. The focus of the standards themselves was on the structural and resource requirements necessary for a hemophilia treatment centre to effectively provide care, and on its functions and responsibilities. The Standards document stated that, “Effective programs …
comprehensive care is preferable to the previous emphasis on end-stage rehabilitative efforts [10].” Health authorities recognized the value of comprehensive care centres. In Canada in 1979, the government of Quebec created four hemophilia treatment centres for the province. At the same time, it decreed that only patients registered in those centres would have access to clotting factor concentrates, thus recognizing the importance of specialized knowledge in the management of these conditions and in the prescribing of blood products that were expensive, administered at home and carried a risk of adverse reactions. By the end of the 1970s, comprehensive care centres were established across Canada. Tragically, the same clotting factor concentrates that revolutionized treatment and dramatically improved quality of life exposed thousands of people with hemophilia to HIV-AIDS and hepatitis C in the late 1970s and 1980s [11]. The model of comprehensive care was forced to change, adding specialists in infectious disease and hepatology. For many patients, the focus of care shifted to the life-and-death issues of immune challenges and liver disease before the advent of efficacious treatments that are available today. At the same time, the crisis accelerated the development of recombinant FVIII and IX clotting factors; these entered the clinic in 1993 and 1997 respectively. The proven safety of both recombinant and plasma-derived products spurred on the expansion of prophylactic care to more patients. In the 21st century, the focus returned to the preservation of joint health. In 2007, Manco-Johnson published the landmark study proving that prophylaxis with recombinant factor VIII prevented joint damage and decreased the frequency of joint and other hemorrhages in young boys with severe hemophilia A [12]. This reinforced the importance of comprehensive care. It was only with the multidisciplinary resources of a comprehensive care centre that the challenge of maintaining the necessary compliance in administering a burdensome IV treatment in the home environment could be successfully met. Efforts began to better define comprehensive care and the standards required to achieve it. In 2007, the Canadian Hemophilia Standards Group, comprised of health care providers and patients, published the Canadian Comprehensive Care Standards for Hemophilia and Other Inherited
• deliver comprehensive care through an integrated, multidisciplinary team; • partner with patients to foster and facilitate self-management and independence; • have the capacity to tailor management to the individual’s needs and abilities; • adhere to guidelines and standards; • regularly participate in quality assurance; • consult with other programs; • participate in collaborative research.” A self-assessment in 2010 by the Canadian HTCs found that 22 of 24 centres adhered to 92% of the standards. A large number of centres, however, failed to adhere to a key standard due to a lack of core team members. This finding was validated several years later in an evaluation conducted by the Canadian Hemophilia Society [14]. Nine of 25 centres lacked designated resources in physiotherapy and psychosocial support. Similar situations are thought to prevail in centres in many countries. In Europe, an extensive deliberative process led by the European Haemophilia Network (EUHANET) between 2008 and 2013 involving health care providers and patients led to the European Guidelines [15], developed in order to set quality standards for European Haemophilia Centres and criteria for their certification. It defined two levels of service delivery: European Haemophilia Treatment Centres (EHTC) providing basic services for at least 10 people with severe hemophilia A or B or VWD type 3, and European Haemophilia Comprehensive Care Centres (EHCCC), able to provide more specialized care for at least 40 3
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innovative therapies are promising yet dramatically different in their modes of action, dosing and administration. Much of what has been learned in terms of management of the disease over the last 50 years—protocols for factor replacement therapy, peaks and troughs of FVIII and IX, perhaps even home treatment—may no longer be relevant. Rather than one type of treatment for all, there may well be many different therapies, depending on age, severity of disease and appetite for change. Comprehensive care centres will not become obsolete. It will remain critically important that specialized staff be able to foster long-term relationships with patients and their families. Indeed, they will need to expand their knowledge and expertise in order to be able to continue to deliver the standards of care so carefully developed since the 1960s.
people with severe hemophilia A or B and VWD type 3. Their respective services are summarized in Table 1. Several countries in Europe, including Ireland and the U.K. have well-defined audit systems to evaluate centres’ capacity to respect accepted comprehensive care standards. Every three or four years, a team of external experts—physician, nurse, physiotherapist, patient—visit the centre, meet all staff, verify performance indicators against standards and conduct a patient survey. Recommendations for improvements are issued. Inherited bleeding disorders remain rare diseases and research on them is not abundant. While the value of comprehensive care programmes and the pertinence of the standards that underlie them appear self-evident to the professionals who provide care and to the patients who benefit from it, they remain largely unproven in this era of evidence-based medicine. To attempt to overcome this lack of research on the superiority of standards-based comprehensive care over alternate models, the U.S. National Hemophilia Foundation partnered with McMaster University in Canada between 2014 and 2016 “to identify evidence-based best practices in hemophilia care delivery [16].” The researchers used the term “integrated care” in place of “comprehensive care.” The guideline was developed based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach [17]. The systematic analysis concluded, “The Guideline panel suggests that the integrated care model be used over non-integrated care models for persons with hemophilia (PWH) (conditional recommendation, moderate certainty in the evidence). For PWH with inhibitors and those at high risk for inhibitor development, the same recommendation was graded as strong, with moderate certainty in the evidence. The panel suggests that a hematologist, a specialized hemophilia nurse, a physical therapist, a social worker and round-the-clock access to a specialized coagulation laboratory be part of the integrated care team, over a care team that does not include all of these components (conditional recommendation, very low certainty in the evidence). Based on available evidence, the integrated model of care in its current structure, is suggested for optimal care of PWH. There is a need for further appropriately designed studies that address unanswered questions about specific outcomes and the optimal structure of the integrated care delivery model in hemophilia [18].” With the HIV-hepatitis tragedy of the 1980s becoming a distant memory for the general public, with the current availability of a wide range of clotting factor therapies (at least in the well-resourced countries of the world), and with the success of a comprehensive care model that keeps patients out of the hospital (and out of sight), and promises a normal lifespan, there is an emerging impression among many health system managers that the problem of hemophilia is “solved.” In 2019, however, even the best care and treatment remains highly burdensome and not entirely efficacious. Quality of life is compromised. Emerging
References [1] Guidelines for the management of hemophilia. Haemophilia 2012. https://doi.org/ 10.1111/j.1365-2516.2012.02909.x. Epub 6 JUL. [2] EVATT BL. The tragic history of AIDS in the hemophilia population, 1982–1984. J Thromb Haemost 2006;4(Issue 11, September). [3] Guidelines for the management of hemophilia. Haemophilia 2012. https://doi.org/ 10.1111/j.1365-2516.2012.02909.x. Epub 6 JUL. [4] Nilsson IM, et al. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992;232(July (1)):25–32. [5] Hemophilia home care cuts costs, hospitalizations. Strawczynski H. MD of Canada; 1972. October. [6] Biggs RMc, Farlane RC. Treatment of haemophilia and other coagulation dis- orders. Oxford, UK: Blackwell Scientific; 1966. [7] Developing models of haemophilia care A. STREET. Haemophilia 2012;18(Suppl. 4):89–93. https://doi.org/10.1111/j.1365-2516.2012.02876.x. [8] PL 9463: the Public Health Service Act establishing the hemophilia diagnostic and treatment center program. No. 1131 of Public Law 9463. Washington, DC: Govt Printing Office; 1975. [9] S.S.M.I.T.H. PETER, P.E.T.E.R.H. MD, LEVINE MD. The benefits of comprehensive care of hemophilia: a five-year study of outcomes. Am J Public Health 1984;74(June). No. 6. [10] S.S.M.I.T.H. PETER, P.E.T.E.R.H. MD, LEVINE MD. The benefits of comprehensive care of hemophilia: a five-year study of outcomes. American Journal of Public Health 1984;74(June). No. 6. [11] EVATT BL. The tragic history of AIDS in the hemophilia population, 1982–1984. J Thromb Haemost 2006;4(Issue 11, September). [12] Manco-Johnson Marilyn J, et al. Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. N Engl J Med 2007;357:535–44. [13] Canadian Comprehensive Care Standards for Hemophilia and Other Inherited Bleeding Disorders. https://www.hemophilia.ca/comprehensive-care-standards/. [14] Page D, et al. Penny wise, pound foolish: an assessment of Canadian Hemophilia/ inherited bleeding disorder comprehensive care program services and resources. Haemophilia 2016:1–6. https://doi.org/10.1111/hae.12913. [15] Giangrande Paul, Calizzani Gabriele. The European standards of Haemophilia Centres. Blood Transfus 2014(Suppl 3):s525–30. https://doi.org/10.2450/2014. 0056-14s. [16] Pai M, et al. NHF-McMaster Guideline on Care Models for Haemophilia Management. Haemophilia 2016;22(Suppl. 3):6–16. [17] Grading of Recommendations, Assessment, Development and Evaluation. https:// cebgrade.mcmaster.ca/aboutgrade.html. [18] Pai M, et al. NHF-McMaster Guideline on Care Models for Haemophilia Management. Haemophilia 2016;22(Suppl. 3):6–16.
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