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. 2015 May 20;13(4):644–650. doi: 10.2450/2015.0302-14

Tailoring care to haemophilia patients’ needs: which specialty and when?

Massimo Morfini 1,✉, Gary Benson 2, Victor Jiménez-Yuste 3, Rolf Ljung 4, Pier Mannuccio Mannucci 5, Gianluigi Pasta 6, Eduardo Remor 7, Silva Zupančić Šalek 8
PMCID: PMC4624542  PMID: 26057493

Introduction

To optimise care for patients with haemophilia, more is required than simply the prompt treatment of an acute bleed; to improve patients’ health and quality of life, the management of patients with haemophilia should also encompass psychosocial support, the prevention of bleeding and joint damage and the avoidance or management of disease and treatment complications such as inhibitor development or the possibility of blood-borne infections1. There is also a growing recognition that patients with haemophilia exhibit significant heterogeneity in terms of their clinical phenotype and response to treatment, and it should be remembered that, “there are not diseases but only patients”. Hence, to optimise treatment, the management should be considered on an individual basis and tailored to each patient and his needs.

The European Haemophilia Network (EUHANET) has published management guidelines and the criteria that must be met for centres to be classified as either European Haemophilia Treatment Centres or Comprehensive Care Centres2. In this respect, the World Federation of Hemophilia (WFH) recommends that the wide range and changing needs of patients and their families are best met through a multidisciplinary, comprehensive care team1. This team should comprise a medical director (preferably a paediatrician and/ or adult haematologist), a nurse co-ordinator and musculoskeletal, laboratory and psychosocial health experts. The comprehensive care team should also include, or have access to, other specialists including those with expertise in infectious diseases, chronic pain, hepatology, immunology and genetics1,2. However, results from a UK national audit3 and European surveys4,5 show that not all patients receive a high standard of comprehensive care, and many centres have limited or no access to the recommended specialists (Figure 1).

Figure 1.

Figure 1

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Access to specialist care for people with bleeding disorders: results reported in a survey of 35 European centres5.

Members of the Zürich Haemophilia Forum convened for their 12th meeting in November 2013 to discuss the components of the comprehensive care team and the importance of certain specialists in the optimisation of patients’ care and treatment outcome. In addition, they reviewed the changing needs of patients with haemophilia over time, especially as the increased life expectancy now achieved with modern care has resulted in a growing population of elderly patients, and considered how patients’ care should be tailored and adjusted according to these changing needs. This article summarises their discussions and recommendations.

Tailoring prophylaxis: pharmacokinetic modelling

Prophylaxis is considered the gold standard of treatment, although it is not always possible to provide it to all patients. The aim of prophylaxis is to prevent bleeding and joint damage and thereby preserve normal musculoskeletal function. Whenever possible, prophylaxis should be individualised to take into account the patient’s age and physical activity, venous access, the availability of replacement factor concentrates and bleeding frequency1. Regimens for prophylaxis with standard dosing recommendations have been successfully utilised to prevent bleeding and arthropathy6. However, the large inter-individual variability in the pharmacokinetic properties reported for factor VIII (FVIII) and factor IX (FIX) products may have a profound influence on the FVIII/FIX levels obtained for each patient when dosed under the same prophylactic regimen7. As such, tailored dosing based on the pharmacokinetic parameters of individual patients may help to ensure that optimal factor activity is obtained for each patient.

In order to tailor prophylaxis, population pharmacokinetic modelling8 may be useful for estimating which factors influence the variability in pharmacokinetic response, and allows prediction of an individual’s pharmacokinetics with less frequent sampling than more traditional intensive sampling. It is also useful for simulating dosing regimens and the prediction of trough factor levels. Several computer programmes are available for the estimation of individual pharmacokinetics. Of note, a study on the individualisation of therapy in haemophilia is ongoing, supported by Bayer HealthCare, in which new software for dose prediction (optiMs) is being tested9. The development of such programmes and the ability of centres to perform their own pharmacokinetic studies may be advantageous when tailoring prophylaxis for each patient. However, we suggest that a pragmatic approach should be used, and a combination of pharmacokinetic and clinical findings (e.g. changes in bleeding frequency) should be considered, to individualise prophylaxis.

Surveillance by imaging techniques: imaging experts

Early identification of joint disease is vital in order to initiate or modify treatment and thereby prevent arthropathy. Regular monitoring of haemophilia patients is therefore very important; the WFH recommends that patients should be seen by all members of the comprehensive care team at least yearly if they are adults, and every 6 months if they are children1. The emergence of new tools has advanced the diagnosis and detection of joint disease and the monitoring of treatment. However, the many tools available, and the presence of comorbidities related to haemophilia or ageing, have made it more difficult to decide which tool is the most appropriate to use for each individual10.

While several clinical or image-based scores to assess joint outcome have been validated, it is important to select one that is relevant to the age of the patient10. In particular, to evaluate the efficacy of prophylaxis (and enable tailoring of treatment when change is required), imaging of target and contralateral joints should be considered. In this respect, while the older, widely used X-ray scores (WFH “Pettersson” score11 and “Arnold-Hilgartner” score12) should not be forgotten, magnetic resonance imaging (MRI) has the advantage of being able to detect early changes in the soft tissues not seen by X-ray. The MRI scores available for use have recently been reviewed13, and as such, will not be further commented upon here. However, it is of note that MRI has been found to detect joint changes in patients on prophylaxis who have not experienced clinical bleeding14. This finding suggests that there may be a subgroup of patients who have different susceptibility to joint arthropathy; it may also offer an explanation as to why MRI scores correlate very well, but not perfectly, with orthopaedic scores. While MRI appears to be a promising tool, it should be noted that the applicability of MRI scores remains limited due to the lack of data from long-term follow-up studies, and further studies are required to establish whether the MRI findings can reliably predict future arthropathy13.

Ultrasound is also thought to be a useful imaging tool for monitoring treatment outcome in haemophilia. For clinical joint evaluations, an additive ultrasound scoring system has been developed: the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) system15. While ultrasound is less costly than MRI and may be used at the bedside, its utility is very user-dependent and operators need to use this method frequently to be able to make valid evaluations.

It is often asked whether ultrasound or MRI is the best imaging modality to use; in our opinion, this question is too simplistic: the most appropriate technique is dependent on the type of patient and the type of information required. The two methods are complementary and both can be valuable for clinical practice. For example, for younger patients who may be reluctant to undergo MRI (and who may require sedation in order to be imaged), ultrasound may be more appropriate; it also offers the advantage that all six major joints (knees, ankles and elbows) can be imaged at the same visit. Such screening may then inform on which patients/joints require closer monitoring with MRI.

The development of modern imaging techniques, such as ultrasonography and MRI, and associated scoring systems holds the promise for early detection and, therefore, treatment of joint disease. However, the occurrence of joint disease in the absence of clinical bleeding is very concerning and suggests that current thinking on prophylaxis and how best to prevent joint disease should be reconsidered. This finding also highlights that one dosing regimen for prophylaxis may not suit all and there is a need for individualised treatment.

Physiotherapy

A musculoskeletal expert, such as a physiotherapist, is recommended by the WFH as a core member of the comprehensive haemophilia care team1. While a European survey showed that no countries were without access to a physiotherapist, access was nevertheless reported as only sporadic in 12 of 35 countries5. In addition, physiotherapy provision at seven of 22 Comprehensive Care Centres audited in the UK was deemed to be inadequate3. It therefore appears that the provision of physiotherapy requires improvement in many European Comprehensive Care Centres.

All patients with haemophilia should be encouraged to engage in physical exercise1. However, before they do so, patients should consult with a musculoskeletal expert, such as a physiotherapist, who plays an important role in the evaluation, prevention and treatment of disease and any ensuing disability in patients with haemophilia. As the most appropriate physical activity differs from patient to patient, and may also change as they age, physiotherapists should discuss with each patient what the most suitable activity is for them, and advise on the need for any protective equipment1.

To enable all patients to pursue the sport/physical activity of their choice, prophylaxis should be tailored to take the desired form of exercise into consideration (in addition to a patient’s other needs and factors such as bleeding frequency and individual pharmacokinetics). For children, the moderate risk of increased bleeding associated with higher risk sports they may prefer (e.g. football) is transient and mostly mitigated by prophylaxis16. In addition, participation in physical activity and exercise provides not only physical benefits, but also supports the emotional and social well-being of children with haemophilia17. For adults, recommendations for a particular sport or physical activity comprise both the characteristics of the patient (including weight, age, previous physical activities and injuries) and of the sport (e.g. risk of injury or the biomechanical requirements of the sport)18. Physiotherapists should carry out evaluations, education, instruction and follow-up for each patient before the patient undertakes an activity; they may also advise on various auxiliary devices to help make the exercise easier and more comfortable to perform19. As patients get older, regular engagement in appropriate exercise and physical activity is key to maintaining their functional mobility. Being active appears to reduce the risk of falls, osteoporosis and fractures, and improves quality of life19.

For haemophilia patients with inhibitors, who tend to experience more pain, arthropathy and reduced mobility than haemophilia patients without inhibitors20, the theoretical principles and advice regarding rehabilitation and physiotherapy are very similar to those for patients without inhibitors. However, when a patient’s management plan must be drawn up, the key points to consider are the reduced efficacy of bypassing agents compared to FVIII/FIX replacement factor, and the need for any intervention to progress at a slow rate in order not to induce additional bleeding and to avoid overburdening other, already damaged, joints. The physiotherapist plays an important part in the individualised evaluation and prevention of disability and the treatment of complications for patients with inhibitors; physical activity has a role for all patients.

Orthopaedics

The WFH recognises the importance of orthopaedists as musculoskeletal experts who can address prevention as well as treatment of joint disease1. Access to orthopaedic specialists does not appear to be an issue (no countries in a European survey reported that they did not have access5; Figure 1). However, more often than not, orthopaedic surgery is thought of as a last resort once joint disease has progressed. Instead, surgery can be used to prevent deformity, and the surgeon should be considered a member of the rehabilitation and comprehensive care team.

While orthopaedic procedures fall within the definition of major surgery, experienced centres can perform such surgery with confidence in patients with haemophilia. However, when surgical treatment is indicated, all members of the comprehensive care team should be informed, so that the surgery can be considered in the context of any plans for treatment of concomitant illness (e.g. interferon therapy to eradicate hepatitis B/C infection). In such instances, it may be necessary to delay surgery.

Patients’ expectations, aims and needs differ with age, and should be taken into account when considering surgery. For example, the needs of a 20-year old patient with a painful ankle are different to those of a 55-year old patient who is pain free but has limited motion in his elbow. In addition, the treatment aims of surgery for a 27-year-old patient with knee arthropathy will be different to those for a 65-year old. It is often more important to decide when, and at which stage of joint disease a procedure should be carried out, rather than which procedure to perform.

Angiographic embolisation may be considered for joint bleeds that fail to respond well to treatment with replacement coagulation factor21; although the outcome of such treatment is still under evaluation, the short-term results have been promising. As far as concerns synoviorthesis, a published algorithm provides guidance on when it should be performed22, and current recommendations suggest that open or arthroscopic surgical synovectomy should be done if haemarthroses remain following three consecutive synoviortheses23. However, surgical synovectomy may sometimes be a preferred option; synoviorthesis is often painful and children/parents are reluctant to undergo the procedure again.

The gold standard of treatment for chronic arthropathy is joint replacement, but judgements on whether such a procedure should be performed, and when, should be based on the needs of the patients, and tailored accordingly. While total knee replacement has been reported to be a safe and effective procedure, providing marked pain relief and improved flexion and joint function24, there is sometimes reluctance to perform this in patients under 30 years of age. However, if total knee replacement is indicated (e.g. because of pain, functional impairment or malalignment), there is no gain to be had from waiting, and the patient’s age should not be the limiting factor. In these situations, for patients for whom surgery may be indicated due to functional impairment, it is important to explain to patients that although they may not be experiencing any pain, they need to think of their future mobility and joint function. For ankle arthropathy, ankle replacement may be the best option in order to achieve good functional outcome and reduce the impact on other adjacent joints (such as the knee). However, as it is not always possible to replace the ankle joint, arthrodesis may be considered as it is effective and provides a good functional outcome25.

Orthopaedic surgery should not only be considered as the last option, when other non-surgical treatment options have been explored, it should be considered and included when necessary, when tailoring patient care based on an individual’s current and future needs. Modern techniques and the use of modular components have resulted in significant improvements in patient quality of life; when required, total knee or hip replacements can be performed in younger patients with haemophilia to avoid years of pain.

Infectious diseases

Previously, the main focus on infectious diseases in haemophilia was human immunodeficiency virus (HIV) and hepatitis C. However, now that recombinant products are available, and they have a better safety profile, it appears that the importance of patients having access to infectious disease specialists is less well recognised. For example, the results of the European survey5 revealed that fewer countries reported access to infectious disease specialists compared with access to other specialists, such as paediatricians; two countries reported no access to infectious disease specialists at all, while seven countries reported sporadic access (Figure 1).

When considering comprehensive care and the prevention of infectious diseases, it is important that patients with haemophilia receive the same vaccinations as the general population, with the added recommendation that they should automatically receive vaccinations against hepatitis A and B. Patients with haemophilia, just like the general population, may contract sexually transmitted diseases (other than HIV and hepatitis) that require diagnosis and treatment, and it must not be assumed that joint pain in haemophilia is always due to the disease; the possibility of an infection should be considered. Infectious disease appears to be a specialty within haemophilia that requires re-defining and should involve more than just the management of HIV and hepatitis C with anti-viral treatment. In order to assess and evaluate potential risks, and diagnose them when they emerge, access to an infectious disease specialist should be available throughout the management of patients with haemophilia.

Psychosocial support

The importance of the provision of psychosocial support to optimise the care and well-being of patients with haemophilia (and their families) is well recognised by the WFH; it recommends that a psychosocial expert (preferably a social worker or a psychologist) should be a core member of the comprehensive care team1. However, it appears that the psychosocial worker is underutilised, mostly because of a lack of financial resources26. According to the European survey of 35 countries5, social and psychological support is often among that reported to be the least available to Haemophilia Centres; six countries reported that such support was not available at all, and it was only available sporadically in 14 countries (Figure 1). Furthermore, the UK audit of 22 Comprehensive Care Centres revealed that 11 did not have a dedicated social worker3.

The roles and tasks of psychosocial support professionals (i.e. counsellors, social workers, psychologists and psychiatrists) may differ greatly among countries, and even centres. We would like, in particular, to emphasise the importance of those professionals who are able to conduct assessments (of, for example, patients’ negative emotions and affect, mental health, self-care skills, treatment adherence, well-being and quality of life), perform psycho-educational interventions (e.g. assisting patients and families to cope with haemophilia, and empower patients to be effective partners in managing their own care) and provide training and conduct research.

The psychosocial support provided should be tailored to meet the needs of patients and their families, which may change as the patients grow older. For example, parents of infants and toddlers with haemophilia require support to help them cope with the diagnosis and to balance vigilance with overprotectiveness, while pre-adolescent patients (10–13 years of age) need help with how to manage their haemophilia on their own (and gain independence from treatment administered by their parents/caregivers). For adolescents, treatment adherence often becomes an issue, frequently mainly because teenagers do not want to appear different from their peers, and other challenges may arise including those associated with their sexuality (e.g. fear of pain, sexual performance or dysfunction). Adult patients may need support with financial concerns and application processes, for example, to obtain benefits or complete insurance claims. As patients grow older, they may need support regarding the acceptance of the changes that may come with ageing, such as the potential loss of independence or decrease in physical functioning, and cognitive deterioration may contribute to poorer adherence in elderly patients.

It is important to highlight that while many patients have the internal resources to cope well with haemophilia and its treatment burden, some require more support. Patients’ psychosocial needs require assessment and intervention on a per-patient basis, and psychologists and social workers (allied psychosocial professionals) can contribute to an integrated approach within the comprehensive care team. Psychosocial issues should not be neglected; it is important to combat them and enable patients to live normal lives.

Care of the older person

Prior to the 1970s, the life expectancy of patients with haemophilia was significantly shorter than that of the general population. Factors including improvements in the safety and availability of replacement therapy, the use of prophylaxis and improved treatments for patients with inhibitors has meant that life expectancy has now increased to the point that it reaches that of people without haemophilia27,28. However, this increase in life expectancy has meant that more patients are reaching old age and experiencing age-related clinical issues and haemophilia-related comorbidity, both of which have now become a focus of clinical attention and are being discussed in recent review articles29,30. For example, a case-control study of 39 elderly patients with haemophilia compared to 43 age-matched controls without haemophilia showed that elderly haemophilia patients have more comorbidities (mean 3.49 vs 2.07) and problems in daily living (e.g. dressing and bathing)31. Of note, over 80% of elderly patients with severe haemophilia had an impaired range of motion31; patients with haemophilia were reported to have a significant impairment in gait and balance, together with more pain, compared to the control population.

The above study highlighted that elderly patients with haemophilia may require more assistance in order to retain their physical and emotional independence. In this respect, the Milan Project for the Elderly Patient with Haemophilia, led by Elena Boccalandro, aimed to help patients with the management of their haemophilia as they age. The care team included a physiotherapist, geriatrician, haematologist and occupational therapist, and patients received training at workshops that sought to maintain and/or improve global motion function. Training was also provided on the use of aids and devices to improve and/or maintain proficiency in daily living. This was the first such project specifically designed for elderly patients with haemophilia, and we recommend that similar programmes be implemented in other centres in other countries.

As patients with haemophilia age, we believe they should be considered for the same interventions/ surgeries that are available to elderly patients without haemophilia (e.g. coronary stents). The role of the haematologist should be to facilitate these interventions and provide advice and support to other specialists treating their patients. However, as a second peak in the risk of inhibitor development appears to occur in elderly haemophilia patients32, questions arise as to how best to handle any surgery required for elderly patients in order to avoid inhibitor development; this requires an integrated approach by members of the comprehensive care team. For example, patients may be genotyped to assess whether they carry a high-risk mutation for inhibitors, and caution applied accordingly. The use of desmopressin for elderly patients with mild haemophilia may also be considered.

While it was previously proposed that patients with haemophilia may be at decreased risk of cardiovascular disease due to the potentially protective effect of a life-time long reduction in FVIII/FIX, recent findings suggest that cardiovascular disease, and its associated risk factors, are at least as prevalent, or more frequent, in patients with haemophilia33,34. Atrial fibrillation, the most common cardiac arrhythmia, is also as prevalent in patients with haemophilia aged over 60 years as in the general population, and requires careful clinical management in haemophilia patients to balance the need to reduce the risk of stroke with the risk of bleeding caused by anticoagulants35,36. It is now recommended that the screening for, and the treatment of, cardiovascular risk factors is integrated into haemophilia care, especially for patients aged over 40 years37, and we suggest that due to the increase in elderly patients with haemophilia and associated comorbidities, such as cardiovascular disease, new members are required in the comprehensive care team, which we believe should now include cardiovascular experts, geriatric specialists, and ophthalmologists (these specialists are not mentioned in recently updated haemophilia management guidelines1). Data from multinational and worldwide registries will aid the development of guidelines and/or recommendations for the treatment of age- and disease-related comorbidities in elderly patients with haemophilia.

Conclusions

Access to comprehensive care in haemophilia, with adherence to the involvement of all of the specialists recommended by the WFH, and other specialists who may be required as patients age, is key to the optimisation of patients’ care. As patients age, from childhood through to old age, different specialists may need to be involved in their care, and the comprehensive management plan should be individualised and adapted in accordance with patients’ changing needs.

Footnotes

Authorship contributions

All Authors contributed to the Twelfth Zürich Haemophilia Forum, on which the manuscript is based, approved the concept and design of the manuscript, critically reviewed the manuscript and approved its final version.

The Authors wish to thank Sharon Eastwood of PAREXEL, for medical writing assistance, financially supported by NovoNordisk Health Care AG in compliance with international guidelines for good publication practice.

Disclosure of conflicts of interest

MM has acted as a paid consultant for Bayer, Baxter, NovoNordisk and Pfizer advisory boards and received speaker fees from CSL Behring, Octapharma, Bayer and NovoNordisk. He has also received research grants from Bayer, Pfizer and Baxter. VJY has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Baxter, Bayer, CSL Behring, Grifols, NovoNordisk, Octapharma and Pfizer. RL has received consultancy or speaker fees from Bayer, Baxter, and NovoNordisk during the past 5 years. PMM has received speaker fees from Baxter, Bayer, Biotest, Grifols, Kedrion, NovoNordisk and Pfizer. GP has acted as a paid consultant to Faust Pharmaceuticals Incorporated and has received funding for research carried out and included in this work. ER has received speaker or consultancy fees from NovoNordisk. GB and SZS have no conflicts of interest to declare.

NovoNordisk Health Care AG provided financial support for the Twelfth Zürich Haemophilia Forum and for medical writing assistance, provided by Sharon Eastwood of PAREXEL, in compliance with international guidelines for good publication practice.

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