The treatment of haemophilia in the UK has changed significantly over the last few decades. Haematology doctors treating patients with haemophilia still have older patients with fused joints, who are unable to mobilise without aid, due to significant bleeding episodes and haemarthoses. Alongside them, there are ever increasing younger patients who have had prophylaxis throughout their lives, and have pristine joints, having never experienced a joint bleed. The treatment of haemophilia has moved during the last decades from using cryoprecipitate, to plasma-derived factor VIII concentrate, to the currently used recombinant factor VIII (rFVIII) concentrate. We are now in a very exciting era with new treatments emerging, such as long-acting factor VIII concentrates, gene therapy, bispecific antibodies mimicking factor VIII, and RNAi technologies that can favourably alter haemostatic balance.
Current practice in the UK is that all children should be commenced on regular prophylaxis with rFVIII concentrate as soon as feasible, often after the first few bleeding episodes, and ideally before a joint bleed occurs. It is now well accepted that primary prophylaxis significantly reduces the risk of joint bleeding – both haemarthoses but also small sub-clinical or microbleeds.1–4 The clear aim is to reduce and/or prevent haemophilic arthopathy, and so improve the quality of life. In our facility, which is a comprehensive care haemophilia centre, discussion of prophylaxis starts from the very first time that the baby/child attends, often just after the pint of diagnosis. Our aim is to initiate prophylaxis as soon as reasonable and practicable, and certainly not to wait for a joint bleed. Naturally in cases of intracranial or other life-threatening bleed, prophylaxis will be initiated immediately after the acute management of the bleeding episode.
There are different schools as to how to initiate prophylaxis. One approach would be to start once a week, and slowly escalate to twice week, and then three times a week or alternate days. Another approach would be to start directly on 3/week or alternate days treatment.
No one size fits all, and an individual approach is needed, taking into account the family surroundings, the ability of the parents/carers to treat the child at home, the proximity of a haemophilia treating centre, the need for a central venous access device, such as a port-a-cath, or not. If the parents/carers can be taught to administer treatment via peripheral access, that would be ideal, but often a port-a-cath is needed for young children, which following the surgical insertion, can dramatically simplify administration of rFVIII in the community. The first 50 episodes of treatment will be closely monitored, as the risk to develop an inhibitor to factor VIII is higher. Following the initial high-risk period, the children and then the adult patients will be seen in clinic every four to six months, unless there are emergent additional problems.
Historically we have tended to adopt
a broad ‘one size fits all’ approach to prophylaxis, bearing in mind that there are clear differences in children and which require more discussion to consider the best approach. Nonetheless, the standard regime for prophylaxis has been to recommend treatment with factor VIII concentrate every alternate day or at least three times a week at a dose of 25–40 units per kilogram to maintain a trough level greater than 1IU/dl. In simple terms, currently accepted targets for optimal prophylaxis, particularly for our adult cohort, have been maintaining the minimum factor VIII level of 1IU/dl, aiming to reduce/minimise bleed rate, preventing or delay arthropathy and joint deterioration and so improve the quality and predictability of life for our patients.
As clinicians, we base such prophylactic regimes on the presumption that factor VIII has a half life of approximately 12 hours. Hence, on this basis and simple extrapoliations, infusions can be recommended in the range of 25 to 40U/kg alternate days or at least three times a week. However, this basic ‘one-size fits all’ approach does not take into account the variability that we see in people with haemophilia. Such variability importantly includes levels of activity, personal wishes and circumstances. If we consider two simple scenarios of men with severe haemophilia, it is clear that the treatment regime best-suited for an active sports-focused 20-year-old man with pristine joints is not going to be the same as a sedentary office worker at the age of 50 who has evidence of haemophilic arthropathy.
A second important point that we tend to overlook is that although we assume the half life of factor VIII is approximately 12 hours, this does not take into account that there is a considerable range in the population in terms of factor VIII half life and clearance. Studies have demonstrated clearly that within the population of patients with severe haemophilia A, the half-life of factor VIII may vary between 8 and 25 hours.5 Therefore, a simple application of this principle tells us that a one size fits all approach of infusing every alternate day will not necessarily be the optimal treatment regime for patients – those with a short half life of significantly under 12 hours will require higher doses or more frequent administration, whereas those with significantly longer half-lives could manage with the lower doses or have the opportunity to increase the treatment interval.
When one considers these issues, it is quite clear one single approach to prophylaxis cannot address the needs of all our patients with severe haemophilia optimally. This has led to the increasing view that prophylactic treatments need to be tailored or personalised to the individual bearing in mind the personal circumstances, personal wishes, comorbidities of our patients and also their individual pharmacokinetic handling of factor VIII concentrates. Furthermore, we can see from first principles that extended half life therapies will potentially magnify such variations. Indeed, it is fair to say, the advent of extended half life therapies has further thrown the view of the benefits of personalised therapy into sharp relief.
Allied to these evolving therapeutic concepts is also the increasing appreciation amongst haemophilia clinicians that a trough level of 1IU/dl is not optimal. It is well accepted now, based on extrapolating bleeding data from a Dutch population at various severities of haemophilia,6 that rates of bleeding could be progressively improved with higher trough levels. Acceptance and belief in the position, therefore, that higher trough levels may be required for some individuals with particularly frequent bleeding problems in problematic joints is gaining increasing traction.
Personalising and optimising treatment
Bearing in mind this increasing change in presumptions in terms of prophylaxis care, we need to consider how we can personalise, and so optimise, prophylactic treatment. Although we are now thinking differently about what constitutes optimal prophylaxis, the basic tenants of personalised approaches remain simple and obvious – that is, reducing and keeping bleeding rate as low as possible, optimising the infusion interval and optimising factor VIII consumption.
The first approach that is widely used is clinically based and relies upon changing treatment regimes in response to observed patterns of bleeding and clinical response to treatment. This approach of personalisation is the most simple and is already, by default, employed widely.
However, it is arguably better to employ a more evidence-based approach to personalising treatment. This would entail assessing patient need and preferences but also determining treatment dose and frequency based on knowing how that individual handles factor VIII pharmacokinetically. Pharmacokinetic analysis can be performed two ways, using either traditional individual PK analysis using multiple time points or using a Bayesian population pharmacokinetic approach using fewer time points.
The latter approach is simpler and less time-consuming but does come with some limitations. It assumes one pharmacokinetic model for a population, requires population data to compile and there continues to be debate about whether such models are product specific. By contrast, individual pharmacokinetic analysis is more time-consuming though intrinsically may provide a best-fit model because of variation in compartmental modelling factor VIII.
In our centre, we have employed both approaches and continue to assess the practicality of using both. Although some manufacturers provide product-specific Bayesian modelling from traditional individual pharmacokinetic modelling, they are not available for all therapies.
An important programme development in this field for population modelling that is not product-specific has been provided by McMaster University (WAPPS; www.wapps-hemo.org/), and participation is freely accessible.
Nonetheless, some form of pharmacokinetic analysis can significantly help in discussing, changing and amending prophylaxis regimes for individuals by providing an evidential base of the changes.
We have found at our centre that employing pharmacokinetic modelling has engaged many of our patients with haemophilia in active discussions to consider their personal preferences and choices, which allow us to develop an optimised treatment programme together. It has allowed us to extend the treatment interval in some individuals, whereas in others who value best joint health above frequency of infusion to optimise/maximise trough levels and, in yet others, significantly increase frequency to daily to provide them with safe and secure protection from bleeding in the most cost-effective manner. For many individuals, a combination of opportunities has allowed an extension of treatment interval and also an increase in trough levels.
The advent of extended half life therapies has provided still greater opportunities for both extending interval and raising trough levels. In such settings, the principle of personalised approach, allows us to increasingly achieve and maximise the benefits of the new generation therapy.
Individualising therapy and personalising the approach clearly, we would argue, is a rational way forward for the effective management of prophylactic regimes for people with severe haemophilia. By closely involving our patients, we have been able to achieve a better patient outcome and we have found that patient concordance with the treatment regimes has improved. Our experience has taught us that a ‘one-size fits all approach’ is clearly not ideal not just from a theoretical point of view but also practically and that, equally, in purely practical terms personalising prophylaxis has brought considerable cost effective improvements in the quality of care that we provide for our patients.
Furthermore, as part of our aim to holistically review our patients and have a more personalised approach, in addition to regular clinical review by the haemophilia doctors and nurses, in our centre we also have a full time physiotherapy team committed to the review and assessment of our patients. This service is adding to the more accurate review of how the patient is doing, and with frequent joint assessments, it offers personalised physiotherapy sessions with advice on the best exercise regimens to fit each patient’s needs. In short, our aim is increasingly to assess each person as an individual and review needs globally.
In conclusion, prophylaxis with factor VIII has clearly been shown to have a benefit for all patients with haemophilia A, and it is supported by contemporary guidance.7 Prophylaxis will prevent haemarthrosis, which is the cause of haemophilic arthropathy, and also prevent other severe bleeding problems.
We are now aiming to offer tailored prophylaxis to all of our patients, taking into account each patient’s individual circumstances and ensure that patients have their own individual prophylaxis plan, which fits their needs. Personalised care ensures that the schedule for individuals will be amended as circumstances change during their lifetime, in order to adapt to their activity and requirements over time. This approach offers more patient-focused care, and, we hope, a better quality of life.
- All children with severe haemophilia A should be on prophylaxis in order to prevent haemarthrosis and other bleeding episodes.
- Adults with severe haemophilia A should also be advised to remain or initiate prophylaxis in order to prevent bleeding episodes.
- Prophylaxis should be ideally tailored to the individual’s health needs and life style.
1 Manco-Johnson MJ et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007;357:535–44.
2 Manco-Johnson MJ et al. Physical therapy and imaging outcome measures in a haemophilia population treated with factor prophylaxis: current status and future directions. Haemophilia 2004;10(Suppl 4):88–93.
3 Gringeri A et al. Primary and secondary prophylaxis in children with haemophilia A reduces bleeding frequency and arthropathy development compared to on-demand treatment: a 10-year, randomized, clinical trial. J Thrombosis Haemost 2009;7(Suppl. 2):114–15.
4 Manco-Johnson MJ et al. Prophylaxis usage, bleeding rates and joint outcomes of hemophilia 1999– 2010: a surveillance project. Blood 2017, doi.org/10.1182/blood-2016-02-683169.
5 Björkman S et al. Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight. Blood 2012;119:612–18.
6 Den Uijl IE et al. Clinical severity of haemophilia A: does the classification of the 1950s still stand? Haemophilia 2011;17(6):849–53.
7 Richards M et al. A United Kingdom Haemophilia Centre Doctors’ Organization guideline approved by the British Committee for Standards in Haematology: guideline on the use of prophylactic factor VIII concentrate in children and adults with severe haemophilia. Br J Haematol 2010;149(4):498–507.