Current and evolving features in the clinical management of haemophilia

Introduction

After the devastating consequences of acquired immunodeficiency syndrome (AIDS) and viral hepatitis epidemics due to the transmission of the human immunodeficiency (HIV) and hepatitis C (HCV) viruses through contaminated coagulation factor concentrates, leading to death of thousands of patients in the 1980s and 1990s, over the past three decades dramatic advances in the treatment and the overall management of haemophilia were achieved¹. These improvements of care, at least in high-income countries, presently warrant persons with haemophilia a highly satisfactory quality of life and a progressive increase in life expectancy, now approaching that of the general male population². Such advances rely upon the continuous improvement of factor concentrate safety and availability, from viral-inactivated plasmaderived products to the different generations of recombinant concentrates^1,3,4. Indeed, thanks to the implementation of techniques for inactivating or eliminating possible contaminating viruses from plasmaderived factor concentrates, together with rigorous criteria for selection of donors and the adoption of nucleic acid testing (NAT) of donations and plasma pools, no cases of blood-borne transmission of known virus from plasma products have been reported over the last 25 years¹. In parallel, rapid progresses in DNA recombinant technology led to the availability of products removing any trace of human or animal protein from the final formulation, and then from the culture medium and the whole purification process⁵. The availability of larger amounts of safe products, together with increasing evidence from literature of cost-effectiveness, made possible the diffusion of prophylaxis (i.e. regular infusion regimens of factor concentrates with the aim to prevent bleeding and bleeding-related complications), currently the standard of care in children with severe haemophilia, i.e. those with virtually absent residual factor (F) VIII/IX activity^1,6, but increasingly adopted even later in life with favourable clinical outcomes^7,8. These advances were significantly promoted thanks to the recognition, implementation and continuous improvement of a multidisciplinary approach in the delivery of care at specialised haemophilia treatment centres (HTCs)⁹. Indeed, comprehensive haemophilia care is multidisciplinary by nature, in order to face adequately the variable patients’ clinical needs from diagnosis onwards throughout life, including treatment of bleeding, education to home treatment, prevention and treatment of haemophilia- and treatment-related complications, as well of other co-morbidities. These clinical and organisational needs are presently even more complex in the light of the evolving scenario of ageing haemophilia patients¹⁰. Multi-centre and multi-national efforts in addressing unsolved clinical issues and improving the level of evidence for treatment recommendations have been strongly pursued, together with the development of documents setting basic elements of haemophilia care provision to make available or assisting healthcare providers in implementing care programs and encouraging practice harmonization around the world^9,11–16.

Although relevant challenges remain, in particular concerning venous access and patients with inhibitors¹⁷, and awaiting for further improvements by new factor concentrates with extended half-life on clinical trials¹⁸ and by developments in gene therapy overcoming previously disappointing findings¹⁹, the comprehensive management of haemophilia, well beyond the treatment of bleeding, may presently focus on warranting the best possible quality of life for patients and their families, tailoring treatment choices and regimens according to specific needs. In the following paragraphs, these aspects and open issues of modern management of haemophilia will be briefly reviewed.

Prophylaxis for all: between evidence and personalised treatment

In the third millennium two randomised clinical trials ([RCTs] the US Joint Outcome Study¹² and the Italian ESPRIT²⁰) unequivocally showed the superiority of prophylaxis over on-demand treatment in the management of children with severe haemophilia, in terms of lower bleeding rates and better joint outcomes and quality of life^12,20. These methodologically rigorous trials confirmed what had been long achieved over more than 40 years of clinical experience started in Northern Europe, reported in retrospective cohort studies^6,21,22 and in a large prospective international study, the Orthopedic Outcome Study²³, and recommended by the World Health Organization (WHO) and the World Federation of Hemophilia (WFH) since 1994²⁴. The role of prophylaxis in promoting health and social well-being of haemophiliacs, and reducing the burden of their condition, was stated among the European principles of haemophilia care by the European Association for Haemophilia and Associated Disorders (EAHAD) in 2009⁹. Thanks to the results from the RCTs, a grade 1A recommendation was assigned to the choice of prophylaxis in children with severe hemophilia in the first specific guideline published by the United Kingdom Hemophilia Centre Doctors’ Organization (UKHCDO)²⁵.

Both RCTs evaluated high-dose regimens, i.e. 25 IU/Kg e.o.d.¹² and 25 IU/Kg thrice weekly²⁰, respectively, started as “primary” or early “secondary prophylaxis”, i.e. in children without any clinical evidence of joint damage¹⁶. However, benefits of prophylaxis have been shown with a variety of dose regimens and even when started later in life⁷. Indeed, the lack of formal studies comparing clinical outcomes does not enable to define the optimal prophylaxis regimen^6,26. A series of studies report the feasibility and good clinical results with regimens individualised according to the bleeding tendency, including the lower dose in Dutch approach (FVIII 20–40 IU/Kg twice or thrice weekly or FIX 30–40 IU/kg once or twice weekly)²² or the Canadian escalating-dose regimen²⁷, or, more recently, according to the pharmacokinetics (PK)^26,28. However, few data concerning long-term outcomes of such personalised approaches, including prevention of arthropathy, and no comparisons with full-dose prophylaxis are presently available²⁶.

Individualised regimens may also facilitate the implementation of prophylaxis and adherence of families to treatment in small children, as well as reduce the impact of venous access problems, tailoring the frequency (and the dose) of concentrate infusions^6,27. Along this line, lower dose and individualised regimens are enabling the introduction of secondary²⁹ and even primary³⁰ prophylaxis in some developing countries, in which resources for factor concentrates are limited.

As regards the age at start of prophylaxis, increasing data are showing that prophylaxis is able to significantly reduce joint bleeding rates, and in parallel, improve health-related quality of life, even when started in adolescent or adult patients^15,28,31,32. In this respect, the definition of “tertiary prophylaxis”, i.e. started in patients with established joint damage, has been proposed¹⁶. Rigorous and long-term data on possible benefits on joint outcomes in such patients are still lacking, however a 5-year prospective study has been recently completed³³ and a 3-year randomised study is presently ongoing¹⁵. Therefore, data from these studies concerning the possibility of delaying the progression of arthropathy are eagerly awaited, being crucial for clearly assessing cost-effectiveness and cost-utility of such a highly expensive regimen in adolescents and adults and supporting clinical recommendations of prophylaxis “for all”³⁴. Optimal regimens of prophylaxis are even more uncertain in this setting, being extrapolated from those used in children, in whom PK, physical and social needs are largely different^7,32. On the other hand, whether generations of patients, presently in the adulthood with absent or minimal joint disease thanks to primary or early secondary prophylaxis, may safely discontinue such regimens or switch to less intensive modalities of treatment is presently unknown³⁵. A recent survey in 6 countries with different attitudes to the use of prophylaxis showed consistently higher quality of life in individuals on long-term prophylaxis when compared with those treated on-demand or on intermittent prophylaxis, with benefits continuing into adulthood³⁶. Available evidence supporting the different types of prophylaxis, according to the start of treatment and the clinical objectives of preventing or limiting the development and progression of hemophilic arthropathy, as recently revised by the WFH guidelines¹⁶, is summarised in Table I. Although clinical objectives are clearly different, the choice and the personalization of prophylaxis regimens are crucial for achieving and maintaining the best patient outcomes and, in particular, improvements of quality of life, irrespective of age. In the clinical practice, prophylaxis regimens are implemented and often adjusted by dose and/or frequency based on the observed bleeding pattern and, importantly, on other patient-specific factors, including times of expected physical activity, the status of musculoskeletal system and patient or family needs^6,27. On the whole, these clinical choices highly contribute to the effectiveness of prophylaxis, that results from a multi-dimensional assessment of outcomes, particularly in the long-term, including bleeding rates, muscle-skeletal status, laboratory parameters and, not last, health-related quality of life. Larger collection of data are needed for clarifying the clinical impact of less intensive (and less expensive) prophylaxis regimens, useful for overcoming the barrier of costs of treatment in low-income countries. However, only comprehensive evaluations in a lifetime perspective enable to highlight the actual cost-effectiveness and cost-utility of the huge investments for prophylaxis³⁷.

Table I.

Prophylaxis in haemophilia, clinical objectives and available evidence.

Type of prophylaxis	Definition^	Main clinical objective°	Evidence
Primary prophylaxis	Regular continuous* treatment started in the absence of documented osteochondral joint disease, determined by physical examination and/or imaging studies, and started before the second clinically evident large joint** bleed and age 3 years.	To prevent or minimize the incidence of hemophilic arthropathy, with its impact on psycho-physical development of children and quality of life	RCTs (JOS12, ESPRIT20) Prospective study (Canada27) Retrospective cohorts (Sweden21, Germany, the Netherlands22, US, UK) and comparisons (France vs. the Netherlands and Sweden; Norway vs. Sweden)#
Secondary prophylaxis	Regular continuous* treatment started after 2 or more bleeds into large joints** and before the onset of joint disease, documented by physical examination and imaging studies.	To reduce the frequency of bleeding, the development of target joints and hemophilic arthropathy, maintaining satisfactory levels of quality of life	Early: RCT (ESPRIT20) Prospective controlled study (Orthopedic Outcome Study23) Retrospective cohorts (Sweden, the Netherlands, Germany, US, UK) and comparison (France vs. the Netherlands and Sweden)#
Tertiary prophylaxis	Regular continuous* treatment started after the onset of joint disease documented by physical examination and plain radiographs of the affected joints.	To reduce the frequency of bleeding and stop or delay the progression of hemophilic arthropathy, improving quality of life; to prevent bleeding risk due to co-morbidities	Retrospective cohorts (UK, Italy31)# Prospective studies, short term28,32 Prospective study, long term (POTTER33) RCT (SPINART15)

^{^}according to the WFH guidelines, 2013 (ref. ¹⁶);

°In all cases, to prevent life-threatening bleeding episodes;

^*With the intent of treating for 52 weeks per year and receiving a minimum of an a priori defined frequency of infusions for at least 45 weeks (85%);

^**Large joints: ankles, knees, hips, elbows and shoulders;

^#For reviews of these studies see references 6 and 7.

Comprehensive care and the evolving scenario of ageing haemophilic patients

The WHO and the WFH recommendations, as well the European principles of care, clearly recognize the need for multidisciplinary teams at specialised HTCs, in order to deliver an optimal haemophilia care^9,16. According to the available clinical facilities and local organisation, the core group composed of haemophilia physicians, nurses, psychologists, social workers and laboratory specialists, also involves orthopaedic surgeons, physiotherapists and specialists in rehabilitation, hepatologists and infectious disease specialists, and other relevant medical personnel, in the frame of highly specialised comprehensive care centres (CCCs). This approach enables to achieve better clinical outcomes, including patients’ life expectancy, as shown in the developing world but even in high-income countries^38,39. Achieving or maintaining such an optimal standard of care is the main objective of national and international organisations and healthcare programs^9,16,40.

From a clinical point of view, as a consequence of their increased life expectancy, haemophilic patients and their treaters are now facing the new challenges arising from the age-related co-morbidities⁴¹. Indeed, together with joint disease and infectious complications (HIV infection and chronic hepatitis C), routinely managed over the last decades at HTCs and CCCs, ageing haemophilic patients develop the typical diseases of the elderly, previously only rarely seen, such as cardiovascular diseases, malignancies, renal diseases, prostatic hypertrophy, sexual dysfunction and neurologic problems. Few literature data presently support the management of such co-morbidities, that may significantly increase the bleeding risk due to organic lesions or the need for pharmacological interventions or invasive procedures⁴². The paradigm of these challenges is the management of ischemic heart disease in persons with haemophilia. In these cases, the use of antithrombotic drugs, often in combination in the acute phase, particularly when percutaneous coronary interventions are carried out, or for long-term secondary prevention should be balanced by specific prophylactic regimens to prevent excessive bleeding^42,43. Similarly, haemophilic patients with malignancies undergoing diagnostic or therapeutic invasive procedures or chemotherapy should receive adequate replacement treatment in order to minimise the bleeding risk⁴⁴. In this perspective, the multidisciplinary, comprehensive care for adult and ageing haemophiliacs should be updated and revisited. Haemophilia specialists are now learning to search for the close cooperation of other specialists (i.e., cardiologists, oncologists, neurologists, urologists) to define the most appropriate diagnostic and therapeutic strategies for identifying, preventing and treating age-related comorbidities^10,42. In the lack (and probably unfeasibility) of rigorous studies providing evidence-based approaches, international cooperation is crucial for improving our knowledge and expertise in this setting. Nevertheless, even “typical” haemophilia-related co-morbidities or complications should be confronted in the evolving perspective of the prolonged life expectancy of patients¹⁰. As regards the management of haemophilic arthropathy, increasing numbers of patients will need orthopedic surgeries, appropriate treatment for chronic pain, and prosthesis revision operations⁴². Similarly, addressing liver transplantation will be more frequently considered in patients with advanced HCV-related chronic hepatitis⁴⁵. Late-onset inhibitors represent another poorly investigated issue in elderly haemophilic patients, as recently highlighted by United Kingdom data demonstrating a second peak of incidence in patients aged ≥60 years⁴⁶.

Unsolved challenges in clinical management of haemophilia

The need for intravenous, frequent administration of factor concentrates and for an early start of prophylactic regimens in order to optimise clinical outcomes arises the crucial issue of venous access in haemophilic children. Indeed, the peripheral vein access is often unfeasible and, although individualization of dose and frequency of infusions enables to reach full-dose regimens later in life when children may have better peripheral accesses^6,26, central venous access devices (CVAD) are needed in relevant proportion of children starting prophylaxis^12,20,26. The placement of external or fully implantable central venous catheters, providing a stable and long-lasting venous access greatly facilitate home treatment and regular prophylaxis⁴⁷. However, an accurate specific training for caregivers is needed and CVAD complications (infections, occlusions) remain a major concern in the management of haemophilic children^47–48. A newer and possibly safer approach, i.e the arteriovenous fistula (AVF), has been proposed, with encouraging low rate of complications⁴⁹. However, AVF creation may be difficult in very small children (<2-year-old) and its maturation requires approximately 8 weeks. On the whole, this approach is practiced in few specialised centres and so far only one published relevant clinical experience about it⁴⁹. Peripherally inserted central venous catheters (PICC) are also being introduced in the management of haemophilic children. These devices, simply inserted (via US guide) and employed in many chronic diseases requiring long-term venous access, are associated with very low rates of complications (infection, occlusion, dislodgement, phlebitis) requiring their removal⁵⁰.

In the era of safe factor concentrates and of the diffusion of prophylaxis to prevent or reduce the impact of arthropathy, the most serious complication of hemophilia treatment remains the development of inhibitory alloantibodies in 25–30% of severe haemophilia A patients and in 3–5% of those with haemophilia B⁵¹. Inhibitors render the safe standard replacement therapy ineffective and, particularly, preclude prophylaxis feasibility, exposing children to higher morbidity and poorer quality of life, with a striking increase of economic burden of patient management⁵².

Intensive research has been devoted to unravel mechanisms of such an unfavorable immune response, in which a variety of genetic and environmental factors interplay, only in part presently elucidated (Table II)⁵³. Genetic predisposition relies upon F8/F9 causative mutations, family history, and ethnicity⁵⁴, but is being revealed more complex than previously thought, an increasing number of genes of immune response and intracellular signalling being identified, potentially relevant and requiring further specific evaluation⁵⁵. In this genetic background, the presentation of the exogenous, non-self, therapeutic protein may be not sufficient for triggering an immune response but, according to the “danger model”, the immune system is activated by alarm signals arising from the injured tissues to a greater extent than by the recognition of non-self⁵⁶. Consistent with this, an increased inhibitor risk in patients receiving intensive treatments at first exposure days (longer than 5 consecutive exposure days and/or FVIII doses higher than 35 IU/Kg) has been reported^57–59. On the other hand, the regular exposure to low doses of the antigen in the absence of danger signals by early prophylaxis might exert protective effects, inducing the tolerance of the foreign protein, as supported by some studies^57,60,61. However, the recent large prospective Research Of Determinants of INhibitor development (RODIN) study⁵⁹ showed that prophylaxis was only associated with decreased inhibitor incidence after 20 exposure days and that this association was more pronounced in patients with low-risk F8 genotypes than in those with high-risk F8 genotypes. Therefore, patients with “genetic” increased risk are likely to be less susceptible to protective effects of prophylaxis⁵⁹. On the whole, while the risk associated with the source of FVIII product (i.e. plasma-derived vs. recombinant concentrates) remains keenly debated, with conflicting results from cohort studies^57,62–64 and meta-analyses^65,66 and a randomised trial still ongoing¹³, the recognition of genetic and non-genetic (thus potentially modifiable) risk factors (Table II) is suggesting prediction models for identifying subjects at higher risk⁶⁷ and clinical approaches aimed to reduce the risk of inhibitor development⁶⁸, although presently far to be validated.

Table II.

Patient- and treatment-related factors associated with inhibitor development and eradication through immune tolerance induction in haemophilia A^{^}.

	Inhibitor development	Inhibitor eradication (ITI)
Patient-related factors	F8 mutations Ethnicity Family history F8 polymorphisms HLA-class II and immunogenotype	Inhibitor titer at ITI start Historical peak inhibitor titer Inhibitor peak titer during ITI
Treatment-related factors	Periods of intensive treatment Surgical procedures Dose of FVIII Prophylaxis*	Dose of FVIII
Unlikely	Age at first exposure Type of FVIII product (plasma-derived vs. recombinant) Switching between products Breastfeeding	Age at ITI start Time between inhibitor diagnosis and ITI start
Need for further data	Type of FVIII recombinant product Mode of infusion (bolus vs. continuous infusion) Extravasation of products Vaccinations Infections Amniocentesis, villocentesis	F8 mutations Ethnicity Type of FVIII product (plasma-derived vs. recombinant) Interruptions of treatment Infections and other immunologic challenges

^{^}in italics factors not consistently recognised; for reviews of these issues see references 53, 54, 70 and 71;

^*as a protective factor.

Even as regards the only available strategy to attempt inhibitor eradication, induction of immune tolerance (ITI), many questions are still unsolved^69–71. There is substantial agreement in recommending ITI in all children with persistent inhibitors interfering with standard FVIII replacement, as soon as possible after inhibitor diagnosis, in order to minimize the inhibitor-related morbidity burden, in particular on joint health^16,69–72. However, the optimal ITI regimen is still debated, high success rates (60–80%) being reported with heterogeneous protocols, in terms of dose and type of FVIII concentrate, interval of infusions and association of immunomodulating agents. According to the findings from a recent RCT in “good-prognosis” children (i.e. those aged <8 years, with a historical inhibitor peak titer lower than 200 BU/mL and starting ITI when inhibitor titer is lower than 10 BU/mL, within 24 months from inhibitor detection), in spite of similar success rates with a high-dose (the “Bonn” regimen, 200 IU/Kg daily) and a low-dose (50 IU/Kg thrice weekly) FVIII regimen, higher rates of bleeding episodes in patients on the low-dose arm raise concerns for choosing such regimen in this setting⁷³. Therefore, high-dose or intermediate-dose (100 IU/Kg) but daily regimens are suggested in “good-prognosis” children⁷², with the possibility of increasing FVIII dose in the case of intercurrent bleeding or detection of high inhibitor peaks, a putative negative predictor of ITI success^73,74. In this respect, in order to reduce the bleeding risk and possible negative effects on joint status in children attempting inhibitor eradication, prophylaxis regimens with bypassing agents, have been proposed while awaiting for ITI start and during ITI, until FVIII recovery is achieved^70,71. The administration of activated prothrombin complex concentrate (aPCC, 100 IU/Kg every 12 hours) was included in the original Bonn protocol, however more recently heterogeneous regimens with both aPCC and recombinant activated factor VII (rFVIIa) have been used, with the latter generally preferred in children and before ITI start, due to potential risk of anamnesis from FVIII traces in the aPCC⁷⁰. Avoiding immunologic “danger signals” from bleeding-related tissue damage through prophylaxis has been hypothesised to affect favorably ITI outcome, however in this respect no evidence is so far available⁷¹.

Even more debated is the optimal ITI regimen in “poor-risk” patients, in particular in those with long-standing inhibitors, in whom higher success rates are reported with high-dose regimens^70,71, as well the choice for the type of FVIII concentrate, in the lack of prospective/controlled studies comparing plasmaderived and recombinant concentrates. Presently, the same product associated with inhibitor development is usually adopted for attempting ITI^69–71. Also in the setting of inhibitor eradication, a better knowledge of predictors of ITI outcome (Table II) is becoming useful for optimizing the selection of candidates and regimens of treatment. Also in this case, improving pathophysiologic knowledge and clinical management may result in significant impact on cost-effectiveness of treatment and resource allocation, taking into account the highest costs of care for inhibitor patients⁷⁵. However, only some patient-related factors, including low inhibitor titer at ITI start - <10 BU/mL - and historical peak inhibitor titer < 200 BU/mL are consistently reported as predictors of ITI success^70–72, whereas other immunologic or genetic factors (including F8 mutations)⁷⁴ have been proposed but currently poorly investigated^70,71.

Consistent with the search for improving clinical outcomes and quality of life even in patients with inhibitors, growing experience with prophylactic regimens with both bypassing agents even in patients who are not candidate to ITI is extending the excellent results of prophylaxis in non-inhibitor patients in this setting^76–79. These clinical outcomes have been documented by rigorous studies, providing evidence of significant reductions in total, joint and target joint bleeding rates and of improved quality of life, although over short-term follow-up (3–12 months)^76,77. Due to such a limited observation period, these studies were not able to document effects in preventing or delaying joint deterioration and conflicting data are reported in retrospective case series^17,78,79. Therefore, prophylaxis is presently used by many physicians in inhibitor patients, although concerns about cost-effectiveness and the need for longer term assessment of efficacy (in particular with respect to joint outcomes) and safety are clearly highlighted⁸⁰.

The search for safety and overcoming current challenges

The need for safer and safer factor concentrates was the key for research and development of both plasmaderived and recombinant products over the last three decades¹. Current achievements rely upon plasmaderived concentrates, manufactured with rigorous policies for plasma collection, NAT screening and application of viral inactivation and elimination techniques (often in combination), and a variety of recombinant products, including new generation protein-free concentrates, i.e. without any addition of human or animal protein throughout the production process⁵. In spite of the high-level of safety of plasma-derived concentrates, documented by the lack of transmission of HCV, HIV or other clinically relevant infections over the last 25 years¹, many physicians continue to prefer recombinant products (particularly in children), thought to be safer with respect to known and, particularly, emerging or unknown pathogens^80,81. This attitude is also consistent with the search for the best possible treatment, although present economic constraints tend to influence therapeutic choices even in high-income countries^80,82. On the other hand, the ongoing and future development of replacement products is wholly based on recombinant technology. This search is devoted to overcome current treatment challenges thanks to factor concentrates with improved properties, in particular longer half-life products to obviate frequent administration and venous access problems, and/or reduced antigenicity/immunogenicity products to minimise inhibitor development^1,18. As recently reviewed in detail, some modified FVIII and FIX molecules with longer half-life are in advanced phase of clinical trials^18,83. The availability of such products will represent a relevant progress for countries that can afford costs of primary prophylaxis, being venous access problems the main barrier to its widespread adoption and adherence. These benefits will be associated ultimately with further improvements of quality of life of persons with hemophilia. A positive impact on the overall factor requirements (and hopefully on costs of treatment) might be obtained through the reduced dosage frequency and truly personalised regimens of prophylaxis with such products, although costs of longer half-life products are presently not predictable^83,84.

More advanced clinical development and encouraging results with modified FIX than FVIII concentrates^18,83 highlight the need for specific studies devoted to patients with haemophilia B. Indeed, due to the lower prevalence of hemophilia B, few patients have been included in clinical studies and the general practice is transferring results obtained in patients with haemophilia A. This is true for prophylaxis regimens but even more scarce information is available concerning inhibitor development and management, which are complicated by the additional morbidity of allergic reactions and unfavorable ITI outcome⁸⁵. Personalised management in haemophilia B might also be supported by several studies suggesting the different severity of the two forms of haemophilia, with less severe bleeding phenotype in haemophilia B than in haemophilia A⁸⁶.

Conclusions

In spite of significant persistent challenges, like the need for intravenous administration of replacement products and inhibitor development in approximately 30% of previously unexposed children, persons with haemophilia presently enjoy a highly effective and safe treatment⁸⁰, delivered through specialised centres, comprehensively addressing their demanding management. This results, at least in high-income countries, in an excellent quality of life for children born in the era of primary prophylaxis and their families, and in improved clinical outcomes in patients of all ages who predominantly receive long-term prophylaxis as replacement regimen. Thanks to these achievements, haemophilia in the third millennium can remove its historical hallmark of a crippling inherited bleeding disorder^1,6. Prophylaxis is the milestone of this pathway of continuous advances in the management of haemophilic patients, driven by the achievement of the best possible long-term quality of life and always requiring shared decisions between physicians, patients and their families⁸⁰. After the recognition of prophylaxis as the evidence-based treatment of choice in children, studies are being devoted to support its adoption in adolescents and adults and to validate individualised regimens, useful for facilitating long-term adherence and overcoming barriers to its diffusion, in particular venous access and costs. Indeed, in the present era of healthcare budget constraints, these regimens may improve cost-effectiveness of treatment and reduce the apparently insurmountable problem of costs. Along this line, in the near future extended half-life concentrates will provide further, possibly cost-effective, strategies for tailored treatment. Improving clinical outcomes and quality of life are key objectives even in the challenging management of inhibitor patients (searching for the optimal ITI or prophylaxis regimens) and of co-morbidities in elderly haemophiliacs. Again, personalised treatments represent the strategy for overcoming the limitations of unsolved issues and lack of evidence.