Differences between developed and developing countries in paediatric care in haemophilia

Eighty per cent of people with severe haemophilia live in developing countries, where appropriate health resources are severely limited. In most of these countries, health insurance schemes are non-existent and where they do exist, they do not cover diseases, such as haemophilia, which are expensive to treat. India, for instance, with a population of over a billion would be expected to have 100 000 patients with severe haemophilia, however, a survey by the Haemophilia Federation of India (HFI) found only about 10 000 severe haemophiliacs throughout the country, suggesting a severe problem of underdiagnosis and ineffective management [1].

From a financial point they can be stratified into three tiers [2]. A very small proportion of extremely rich people can afford high cost health care, which they seek in their own countries, thus receiving standard haemophilia care. A substantial minority of people living in large cities can afford occasional use of clotting factor concentrate (CFC) if they have access to a government-owned specialized centres or a charitable hospital. They are educated and able to understand the importance of a multidisciplinary approach. But the majority comes from the rural population; they are extremely poor, do not have access to health care or are not diagnosed at all. To reach these patients, they must first be identified through structured programmes, which include training of medical manpower in this area. To achieve this the World Federation of Hemophilia (WFH) is running the Global Alliance Program (GAP). This article describes the situation for diagnosed PWH with some access to care.

In developed countries, despite easy access to products, new challenges exist: treating PWH with inhibitors, patients who migrated from a developing country or simply parents considering their children, who are on prophylaxis as regular persons with no need to accept any limitation of their activities. Every health care worker in the field of haemophilia care agrees on the fact that the availability of CFC makes the most important difference. There is also general agreement that multidisciplinary care is the most optimal way of treatment. The WFH supports haemophilia treatment centres (HTC’s) worldwide, in both developed and developing countries. They advocate the ideal situation, i.e. “Treatment for all”, which will be described in this article from the point of view of medical, rehabilitation and orthopaedic perspectives.

Developed countries – medical regimen

Prophylactic treatment began on a broader scale in Sweden during the 1950s. Twenty-five years of follow-up (n = 60) was published in 1992[3]. The Netherlands also has a long history with prophylactic regimens[4]; their strategy has differed from the Swedish with a later start, lower dosing, and longer dose intervals resulting in decreased concentrate cost. Overall, Swedish regimens have been more fixed and targeted trough levels of ≥1%, while Dutch regimens have been more tailored to individual bleeding phenotypes.

These regimens were compared in 2002 [5]. The median start time of prophylaxis was 2 and 5 years for the Swedish and Dutch cohort, respectively, with concentrate consumption twice as high in the Swedish cohort. Swedish patients experienced less annual haemarthroses (Swedish mean 0.2, Dutch 3.7) and were without joint disease (WFH and Pettersson scores), whereas the Dutch cohort had a median WFH score of 1 (range 0–2) and Pettersson score of 0 (range 0–5) and 54% had healthy joints by X-ray evaluation. Thus the more intensive and costly higher-dose Swedish regimen virtually abolished haemarthroses and haemophilic arthropathy (HA), whereas the intermediate-dose regimen had an almost comparable shorter-term outcome.

Early start is likely important as it appears to be an independent predictor of future joint disease. The challenge with early initiation (1–2 years) remains one of venous access, often requiring a central venous access device (CVAD). Issues with venous access and substantial variability in severe haemophilic phenotype (with resultant wide age range variation at first haemarthroses) are raised as contributing to overtreatment and/or unnecessary invasive procedures in some patients on early prophylaxis, started prior to the first haemarthroses. These issues are important from an economic and a societal perspective and were evaluated in the Canadian Haemophilia-Dose-Escalation Prophylaxis Trial [6]. The authors concluded that most boys with severe haemophilia A experienced little early bleeding and had good joint function with a tailored prophylactic approach resulting in less FVIII consumption than traditional regimens. Methods to tailor regimens include individual pharmacokinetics with computer-simulated dose levels and intervals to achieve a predetermined trough level.

Developed countries – rehabilitation (P.H. – Canada)

Modern treatment has allowed most children to grow up with little to no joint damage and to participate in a wide variety of activities. However, some joint or bleeding still occurs. Tailored prophylaxis appears to offer certain benefits, such as decreased cost and less frequent venous access, but relies on early and accurate bleed detection [6]. The issue of micro bleeding was raised in the US Joint Outcome Study as MRI findings were seen in some patients in the absence of reported joint bleeding [7]. More recent studies have pointed out the detrimental effects on cartilage of bearing weight on a joint with blood in it and the role of inflammation in increasing the risk of rebleeding [8].

Key issues in preventing arthropathy include early bleed detection and treatment, rest, non-weight bearing initially, and slow gradual progression to minimize risk of rebleeding. A significant challenge faced in treating toddlers is their natural instinct to run and jump as soon as pain subsides, thereby increasing the risk of rebleeding. Older children and adolescents may be reluctant to use crutches at school or to miss school. Children treated with prophylaxis are participating in a wide variety of activities and sports at competitive as well as recreational levels. Early return to sports/activities may result in rebleeding or persistent synovitis. Patients with mild haemophilia often come to clinic several days to weeks following an acute bleed prolonging their rehabilitation [9].

The main goals for physiotherapy in children with haemophilia in developed countries include education in bleed detection and prevention, evaluation of early joint changes, prevention of musculoskeletal deterioration, and preservation of activities and participation (school). Biannual musculoskeletal assessments for severe haemophilia and yearly for mild and moderate haemophilia help to identify early joint changes. Interprofessional team input along with involving the child and family in setting objectives for physiotherapy can result in better follow-through. Acute bleed-related pain is generally relieved by early effective factor administration and adequate rest. Short-term immobilization, such as a half cast or brace, can be useful to relieve pain and to reinforce rest especially for younger children. Gradual progression of range of motion and strengthening exercises is most often carried out at home with monitoring at the hospital or local clinic, which likely varies from developing countries where factor coverage during rehabilitation cannot be counted on. Hydrotherapy can be especially useful for gradual mobilization and ambulation of children with large muscle bleeds. Educating the child and family to monitor swelling (not just pain) as a key to progressing weight-bearing and return to activities is very important.

The physiotherapist can play a prime role in balancing physical fitness and reducing obesity risks with good choice of sports/activities to minimize significant injuries and maximize overall health.

Developed countries – orthopaedic surgery (G.P. – Italy)

The primary indication for surgical synovectomy is the recurrence of intra-articular bleeds despite a proper medical treatment (at least 6 months of efficient prophylactic treatment) or after failed synoviorthesis (chemical or radioactive). Surgical synovectomy can be performed by open or arthroscopic means and it is indicated in the presence of chronic synovitis regardless of the degree of radiographic changes. The goal of synovectomy is to remove the majority of the friable villous layer of the synovium, thus preventing the recurrence of joint bleeding and maintaining joint function. As open synovectomy has been effective in controlling synovitis and recurrent bleeding, it requires a large incision, prolonged hospitalization, protocolized rehabilitation, and large amount of factor replacement, and has been associated with a infection rate and reduced range of motion [10,11,12]. Long-term results on joint bleeding control and on overall joint function were satisfactory with these traditional techniques. Arthroscopic synovectomy represents a less invasive approach, with a low complication rate [13], and it has become the preferred alternative to the open technique. The use of arthroscopic synovectomy in persons with haemophilia was first attempted on knees and reported in 1983 [14,15], producing satisfactory results even after a prolonged follow-up with a significant reduction of joint bleeding recurrence and preservation of joint mobility [16]. This procedure, mainly performed in children or adolescents, allowed a significant reduction of bleeding rate and pain relief, suggesting that the beneficial effects of this surgery are greater if it is performed before the onset of severe radiological changes [17]. Additional data has been published suggesting that arthroscopic synovectomy is a cost-effective means of addressing target joint bleeding [18]. Associated musculoskeletal disorders (i.e. flat foot, axial deviation of lower limbs) have to be treated as soon as possible in order to reduce the likelihood of secondary joint disease.

Orthopaedic surgeons have to deal with two challenges: the management of haemophilic paediatric patients coming from countries where factor replacement therapy is not available and patients with inhibitors. Cases of severe arthropathy with severe joint involvement that we commonly encountered many years ago are now seen only in such patients. Patients with inhibitors have more severe and incapacitating degrees of arthropathy than those without [19], with fixed knee flexion deformity as a common problem. If conservative treatment fails, surgical procedures have to be considered, including supracondylar femoral extension osteotomy, joint distraction, posterior capsulotomy and arthroscopic release. Potential complications of these procedures are fractures, neurovascular lesions, knee instability, and recurrent deformity with continued growth [20]. In patients with an immature skeleton, anterior femoral stapling is a less invasive method to treat fixed knee flexion deformity, is well tolerated, and provides an excellent alternative to osteotomy by allowing gradual correction through growth manipulation [21]. Joint replacement surgery, as last resort, could be performed in such patients when marked joint destruction is present and pain or deformity compromises function. Relief of pain, reduction of the deformity, and dramatic improvement in functional status and quality of life can be achieved in most patients.

Developing countries – medical regimen (A.S. – India)

While multidisciplinary comprehensive care is extremely important in haemophilia [22], the critical role that replacement therapy with CFC plays in this process cannot be overemphasized [23]. The mode (prophylaxis vs. episodic) and quantity of replacement of CFC are the most important determinant of long-term musculoskeletal outcome [24,25]. Studies from Sweden and the Netherlands proved that a near normal musculoskeletal function in severe PWH is due to prophylaxis. A Canadian study has shown that prophylaxis started (even once a week) can reduce bleeding in such patients and that up to 40% of patients can continue this regimen later into childhood [6]. Most of these regimes are based on dosage of 25–40 IU/kg two to three times a week and require 3000–6000 IU/kg/yr of CFC and are deemed possible only in countries where CFC is available at 3–7 IU/capita [26,27]. Prophylaxis has therefore been mostly limited to the developed countries.

In developing countries the range of availability of CFC varies from <0.1 to ∼3.0 IU per capita. Therefore CFC replacement therapy in these countries has remained predominantly episodic, or On Demand, thus for the treatment of bleeding only [28]. This is even the case for those who nowadays are able to get access to 1000–2000 IU/kg/year. What outcome can patients in these countries expect? Unfortunately, data from several studies have shown that this mode of CFC replacement does not lead to adequate reduction in bleeding episodes so that most of these patients develop significant joint damage by the age of about 20 years with radiological joint scores of about 15–20 (Pettersson scale) [29]. The paramount question becomes whether alternative strategies for CFC replacement therapy can be considered, either found in developing countries with modest quantities of CFC, or in developed countries.

For the potential use of prophylaxis in developing countries, we will consider only those that are in the 1–2 IU/capita range or 1000–2000 IU/kg/year for individual patients. Such centres should be able to offer prophylaxis at lower doses to PWH. If they start with 10 IU/kg twice a week, this will require a total of about 1000 IU/kg/year. This could then be increased to 10–15 IU/kg two to three times per week depending on patient responses and local access and availability of CFC. It would still require total doses less than 2000 IU/kg/year. Is there data to support such doses and schedules? Practice at Utrecht in the 1970s and 1980s showed that the use of CFC between 15–30 IU/kg resulted in significant reductions of joint bleeding (4). It has more recently been reported that such doses used as secondary prophylaxis in older children also reduced the incidence of joint bleedings significantly [30]. A prospective observation multi-center international study (HYPERLINK "http://www.musfih.net" http://www.musfih.net) looking at the efficacy of episodic CFC replacement therapy over a wide range of doses from ∼100–2000 IU/kg/year has shown that a significant number of joint bleedings continue to occur over this entire range of doses and there may not be a significant difference between these doses when administered episodically (unpublished observations).

CFC replacement therapy aims at reducing the number of days a PWH is at risk of spontaneous haemorrhage. In a severe PWH the risk of bleeding in time can be considered 100% without any replacement therapy. Now if his factor level is raised to >1%, taken as a marker of successful replacement therapy, then even at 10 IU/kg/dose given twice a week, a severe PWH. A reduces this “time at risk” by >50% (taking a t½ of 10–12 hours for FVIII). As clinical efficacy often lasts beyond levels being maintained above 1%, it is likely that this reduction in risk time can be even greater. If this is enhanced to 10 IU/kg three times per week, this will then start reaching reduction risk times of >75%. If paradigms could be changed completely and find practical ways to administer CFC once a day then even with doses as low 5 IU/kg/day one could maintain >1% at all time with an annual dose well below 2000 IU/kg.

However, the use of such doses will also require that these patients be carefully monitored for their outcomes both in terms of their bleeding frequency and the development of joint and muscle disease. This may be measured by the Hemophilia Health and Joint Score (HJHS), by radiological (X-ray/ultrasonographic) assessments and collecting data on participation. This is critical for any long-term interpretation of the efficacy of this approach.

So what prevents centres that have access to modest doses of CFC from adopting such an approach? The most significant perhaps is the lack of concept among health care providers because of the often stated paradigm that prophylaxis should be considered when a country has access to ∼3 IU/capita and can administer higher than 25 IU/kg three times a week. Other factors that hinder implementation of prophylaxis in developing countries are lack of awareness among PWH, irregularity of access to CFC, local distribution and issues related to individual patients. However, all these are surmountable problems and should be addressed if we are to reduce the burden of bleeding related complications of haemophilia within the quantity of CFC that is already available.

Developing counties – rehabilitation (A.I. – Romania)

When the standard of care cannot be achieved, young PWH experience severe musculoskeletal complications, resulting in altered body functions, limited activities, and participation in society. Especially in the young age participation takes place in school activities, determining their possibilities in society at a later stage. Therefore, rehabilitation remains an inexpensive and efficient treatment option in order to minimize the detrimental effects of joint and muscle bleedings and to increase the functional independence and quality of life for PWH.

The first specialist that PWH consult is the haematologist who is often focused on replacement therapy only, thus not advising patients to start physical therapy or a more specific rehabilitation programme. Still today, young PWH in Romania are not yet evaluated for musculoskeletal complications and for functional limitations ever in their lives and they never were included in a rehabilitation programme. From this perspective, there is a big discrepancy between the patients from rural areas and those living in larger cities, giving access to university hospitals with rehabilitation departments.

The main goal of rehabilitation in developing countries is to restore joint and muscle function, which is different from developed countries where the goal is to prevent musculoskeletal complications. Following the detailed musculoskeletal and functional assessment, physical therapists, together with patient (and family) decide the goals of rehabilitation and develop a customized treatment. The first objective is often to decrease pain. Physiotherapists use ice cube massage, hydrotherapy, or electrotherapy suitable for children with haemophilia (pulsed ultrasound, phonophoresis with a hydrocortisone or Lidocaine) [31,32,33]. The use of kinesiotaping (elastic and adhesive tapes developed for re-educating the neuromuscular system, reduce pain, prevent injuries and to promote circulation and healing) shows good results in controlling pain and inflammation. To prevent or to correct joint deformities, physiotherapists use custom-made splints or orthotics. This is cheaper than the high-tech imported ones. As soon as acute bleeding has stopped and the pain subsides, the goal is to restore the muscle strength and joint range of motion (ROM). Patients start with isometric exercises at different joint angles, followed by isotonic and resistive exercises. In the Rehabilitation unit of the Elias Hospital, Bucharest, good results are seen in muscle training supervised by use of EMG-biofeedback. If ROM does not improve accordingly with strength, self-stretching exercise, then pool therapy or continuous passive motion (CPM) could be efficient [34]. As gait is the major determinant of functional independence, gait training becomes a key goal of rehabilitation. Physical therapists of the above mentioned unit start the gait training with body-weight support [35], in order to decrease the risk of re-bleeding and to re-learn a better gait pattern in young PWH.

Last but not least, an important role of the physiotherapist is to teach patients a safe home exercise programme, how to manage an acute bleed and to help patients understand that without regular physical activity, adolescents with haemophilia are often overweight and at greater risk of recurrent haemarthroses.

Developing countries – orthopaedic surgery (S.M. – India)

The articular problems of PWH begin early in infancy; the immature skeleton is very sensitive and severe structural deficiencies may develop quickly [36]. Untreated, this will result in handicaps in early life, while proper treatment is expensive, inadequate treatment is even more so, both to the individual and to the community [37]. Orthopaedic complications in young PWH range from septic arthritis, haemophilic (chronic) synovitis, pseudotumours, and advanced stages of HA, sometimes resulting in severe articular deformities.

In developing countries, surgical skill is more widely available than good haematologists or haematological laboratories. Thus many surgical procedures are performed without haemostatic assessment. Often, a patient or his family does not know that relatives died of a coagulation disorder, and even when a patient is known to have haemophilia, the surgeon is not told, for the fear he may not perform a much-needed operation. The results are often disastrous [38].

Kasper et al. [39] showed there was no significant difference in the frequency of bleeding complications between patients infused with doses ranging from 600 to 2500 IU/kg. In developing countries, it matters a great deal whether 600 or 2500 IU/kg will do the job. Several other studies have reported satisfactory haemostasis using doses between 300 and 400 IU/kg in surgical procedures of varying complexities [40]. This was possible when factor concentrate-saving measures, such as antifibrinolytic therapy, and local and general electrocautery were employed [41]. Continuous infusion also minimizes the use of factor concentrate during an operation [42].

Major haemarthroses must be aggressively treated to prevent synovitis. If no adequate haemostasis can be achieved, joint aspiration, short term splinting and early mobilisation till complete rehabilitation should be instituted. By definition, a post-bleeding synovitis is characterised as a CS after 3 months and especially of the knee joint, this is the clinical picture people recognise “haemophilia in developing countries.” It causes excessive growth within the epiphyseal plate of bone in the developing skeleton. Bone hypertrophy may lead to leg length discrepancies, angular deformities, and alteration of contour of developing skeleton. Chemical synoviorthesis provides a cost-effective way to deal this condition with 20% factor coverage during each session. Six injections of Oxytetracycline in all these joints at weekly intervals have shown excellent subjective and objective improvement [43].

HA is handled with a more conservative approach. In advanced arthropathy of the shoulder, arthrodesis is a reliable procedure. But in the presence of elbow joint destruction and limitation of movements this remains to be evaluated. Differential growth in this joint of both medial and lateral epicondyles leads to variable deformities. Excision of radial head and synovectomy improve ROM to a greater extent. Arthrodesis may be carried out when there is severe destruction of a joint surface. But treatment should be individualised depending upon the overall ability to carry out activities of daily living.

In young PWH, most commonly the knee joint is involved. Arthroscopic debridement in young patients in early stages is not possible in developing countries due to delayed presentations and lack of awareness. Serial cast correction and percutaneous release of hamstrings to correct contractures makes the PWH ambulatory with limited factor corrections [44]. The end-stage HA requires a more simple procedure like arthrodesis, but it puts stress on the other weight-bearing joints, leading to recurrent bleeds. In immature patients with knee arthrodesis recurrence of the deformity in the bony fusion must be avoided by regularly wearing an above knee splint. The most common deformities in ankles and feet include equinus and varus deformities. Supportive orthoses and wedged insoles often help to correct deformities. Ankle and triple arthrodesis are done to provide a lasting relief in case conservative treatment fails.

The intramuscular bleeds are usually managed conservatively with factor correction, rest, traction, and gradual mobilisation. Most of the neglected bleedings result in contractures and require various muscle release, tendon lengthening and tendon transfers. Meticulous haemostasis, reducing dead space and early mobilisation leads to a successful outcome. Patient compliance in these conditions is poor in developing countries.

The approach to pseudotumours is fast changing in the developing world due to better factor availability and affordability. Early surgical excision remains the hallmark of treatment and we are able to do more surgeries at selected tertiary care centres with better laboratory backups and CFC. Percutaneous treatment is less often practiced as these tumours are not so small when they present.

Surgery in PWH, although requiring a higher level of technical expertise, is as effective and safe (under cover of factor supplementation) as similar procedures in other patients. An effort from the WFH, government and medical community in forming and implementing better strategies is needed.

Statements (all authors):

Discussion (P.K. – the Netherlands)

This chapter is not a cookery book, nor a bible, but just a collection of experiences of eight different professionals from both developed and developing countries. Besides their statements just mentioned, they all put stress on early intervention, especially in children with haemophilia, no matter where they grow up.

Medical care

Disclosures

The authors stated that they had no interests which might be perceived as posing a conflict or bias.