Future needs for continuing innovation in hemophilia: improving outcomes for individuals of all severities, including women and those in resource-constrained regions.

Over recent decades, management of people with hemophilia (PwH) has been greatly improved by scientific advances that have resulted in a rich and varied therapeutic landscape. Nevertheless, treatment limitations continue to drive innovation, and emerging options have the potential to realize further improvement. We advocate four general principles to optimize benefits from innovation: individualizing the treatment approach, targeting 'normal,' making the most of available resources, and considering treatment affordability. Ultimately, all PwH-men and women, of all ages and severities, and worldwide-should have access to treatment that fully prevents bleeding, while allowing personal, social, family, and professional lives of choice. Clearly, we are not there yet, but developing goals/milestones based on the principles we describe may help to achieve this.

Reducing the risk of atherosclerotic cardiovascular disease in people with hemophilia: the importance of primary prevention.

Revolutionary advances in the treatment of hemophilia has led to a significant improvement in life expectancy. Associated with this has been an increase in age-related diseases especially atherosclerotic cardiovascular disease (CVD). While people with hemophilia (PWH) develop atherosclerosis at rates similar to those of the general population, rates of atherothrombosis and mortality related to CVD have been much lower, due to their hypocoagulable state. Changing treatment paradigms, aimed at reducing the risk of bleeding by improving hemostasis to levels approaching normality, has meant that the protection they are thought to have had may be lost. CVD risk factors are just as common in PWH as in the general population, but appear to be undertreated. In particular, primary prevention of CVD is vital in all individuals, but particularly in PWH as treatment of established CVD can be difficult. Active identification and management of CVD risk factors, such as obesity, physical inactivity, hypertension, and hypercholesterolemia, is required. In particular, statins have been shown to significantly reduce cardiovascular and all-cause mortality with few adverse events and no increased risk of bleeding in the general population, and their use needs urgent assessment in PWH. Further longitudinal research into preventing CVD in PWH, including accurate CVD risk assessment, is required to optimize prevention and management.

A preliminary application of a haemophilia value framework to emerging therapies in haemophilia.

INTRODUCTION: Emergence of new therapies are anticipated to improve clinical outcomes and quality of life of persons with haemophilia. Challenges in conducting randomized clinical trials in rare diseases have resulted in a lack of direct head-to-head comparisons to support value-based decision-making between different treatments. METHODS: We conducted a literature review for new and emerging haemophilia A and B therapies (extended half-life [EHL] replacement factor, non-replacement therapies [NRT], and gene therapies [GT]) to identify differentiating patient-centred outcomes defined previously in a haemophilia value framework. Since the literature included all publication types (e.g., surveys, modelling studies, commentaries/reviews), collected data were assigned level of evidence scores. RESULTS: Across different classes of therapies, bleeding was determined as the most frequently reported differentiating outcome, with EHL, NRT, and GT each demonstrating an advantage over comparator replacement therapies. EHL therapies for haemophilia A and B and NRT for haemophilia A showed good representation across Tier 1 outcomes (health status achieved/retained), while more publications were identified with Tier 2 (process of recovery) outcomes for NRT than EHL or GT. In Tier 3 (sustainability of health), frequency of breakthrough bleeds represented a differentiating outcome for EHL (both haemophilia A and B), NRT (haemophilia A only), and GT (haemophilia B only), whereas sustained good health was differentiating for most comparisons. CONCLUSIONS: We demonstrate the utility of the haemophilia value framework as a common core outcome set for effectively comparing therapies. Application of this framework will serve as a useful decision-making tool for patients, clinicians, and within health technology assessments. KEY POINTS OF CONSIDERATION: With the emergence of high-cost, paradigm changing treatments across multiple areas of medicine, we, the haemophilia community, need to be equipped to meet the growing demands for more rigorous evidence-based value assessments using the tools expected by assessors. The traditional access toolbox needs to evolve to meet the paradigm shift in treatment options. Value can no longer be defined by annualized bleed rates alone. To realize the full impact of new therapies, we need to utilize tools, such as a value framework, to organize evidence, identify data gaps, and assess patient-defined, meaningful outcomes across a multi-faceted dimension. The haemophilia value framework is an effective tool for organizing the available evidence and identifying gaps in the evidence. This can be used for assessing the value of emerging therapies in haemophilia utilizing data generated through randomized clinical trials and real world evidence generation. This is a call for incorporating the Value Framework into official submissions to authorities, as it captures a broader range of outcomes, including patient meaningful outcomes, in ways that better assess the potential benefits of new therapies.

Multidisciplinary Team Care of Patients with Hemophilic Arthropathy: A Qualitative Assessment of Contemporary Practice in the UK and Canada : Canada/UK: MDT Practices for Hemophilia.

We used a structured interview to explore approaches to comprehensive hemophilia and arthropathy care among 24 healthcare professionals (HCPs) from multidisciplinary teams (MDTs) in Canada and the UK. Represented MDTs typically comprise a hematologist, nurse, physiotherapist, and sometimes an orthopedic surgeon; pediatric (and some adult) MDTs also include a social worker/psychologist. HCPs emphasized the centrality of a team approach, facilitated through MDT meetings and involvement of all MDT members in patient care. In both countries, nurses and physiotherapists play critical, multifaceted roles. Respondents agreed that MDTs are crucial for successful transitioning, which can be facilitated by close collaboration between pediatric and adult MDTs, even when they are not co-located. Physiotherapists are instrumental in providing non-pharmacological pain relief. Hematologists or physiotherapists typically make orthopedic referrals, with the nurse, physiotherapist and hematologist working together in patient preparation for (and follow-up after) surgery. MDT best practices include a non-hierarchical team approach, ensuring that all MDT members know all patients, and regular MDT meetings. Together, these real-life insights from the MDT perspective emphasize the value of the MDT approach in comprehensive hemophilia care.

Hemophilia treatment in 2021: Choosing the"optimal" treatment using an integrative, patient-oriented approach to shared decision-making between patients and clinicians.

The mainstay of hemophilia treatment is to prevent bleeding through regular long-term prophylaxis and to control acute breakthrough bleeds. Various treatment options are currently available for prophylaxis, and treatment decision-making is a challenging and multifaceted process of identifying the most appropriate option for each patient. A multidisciplinary expert panel convened to develop a practical, patient-oriented algorithm to facilitate shared treatment decision-making between clinicians and patients. Key variables were identified, and an algorithm proposed based on five variables: bleeding phenotype, musculoskeletal status, treatment adherence, venous access, and lifestyle. A complementary, patient-focused preference tool was also hypothesized, with the aim of exploring individual patients' priorities, preferences, and goals. It is hoped that the proposed algorithm and the hypothesized patient preference tool will assist in selecting a treatment for each patient that is as efficient as possible in preventing bleeds while also accounting for the patient's expectations and priorities.

Practical considerations for nonfactor-replacement therapies in the treatment of haemophilia with inhibitors.

New therapeutic agents for haemophilia with inhibitors that are in development or already licensed are expected to provide transformative treatment options. Many of these new therapies are not based on simply replacing the missing factor; new strategies include bispecific antibody technology that mimics factor VIII coagulation function (emicizumab), and inhibition of anticoagulant proteins such as tissue factor pathway inhibitor (eg PF-06741086) and antithrombin (eg fitusiran). These agents are administered subcutaneously and should significantly reduce treatment burden and increase the ability to deliver prophylaxis for patients. Limited real-world data and validated practical guidance on these recently licensed/upcoming treatments resulted in the authors convening to discuss recommendations on their use. Emicizumab is currently the only licenced nonfactor therapy; thus, our recommendations focus on this product. Target candidates for emicizumab prophylaxis are difficult-to-treat patients with haemophilia A and inhibitors and/or venous access issues, frequent bleeds and target joints. In case of breakthrough bleeding while receiving emicizumab, patients still require treatment with bypassing agents; the adjunct treatment of choice is recombinant activated factor VII. This treatment is also recommended to prevent bleeds in patients with inhibitors undergoing surgery. Our recommendations on suitable laboratory assays and monitoring new products, as well as the benefit of patient-reported outcomes (such as pain and physical activity levels), are included. We also briefly discuss future treatment options for patients with haemophilia B and inhibitors. Although these nonfactor treatments offer great promise, further data and real-world evidence are needed.

Principles of care for acquired hemophilia.

OBJECTIVE: To establish clear priorities for the care of patients with acquired hemophilia A (AHA) by proposing 10 key principles of practical, holistic AHA management. METHOD: These principles were developed by the Zürich Haemophilia Forum, an expert panel of European hemophilia specialists comprising physicians and nursing and laboratory specialists. RESULTS: The 10 proposed principles for AHA care are as follows: (a) Improving initial diagnosis of AHA; (b) Differential diagnosis of AHA: laboratory assessment of patients with unusual bleeding; (c) Effective communication between laboratories, physicians, and specialists; (d) Improving clinical care: networking between healthcare professionals in the treating hospital and specialist hemophilia centers; (e) Comprehensive assessment of bleeding; (f) Appropriate use of bypassing agents; (g) Long-term follow-up and monitoring for efficacy and safety of immunosuppressive treatment; (h) Inpatient/outpatient settings; (i) Access to innovative and disruptive treatments; (j) Promotion of international collaborative research. CONCLUSION: The proposed principles for holistic AHA care aim to ensure swift diagnosis and optimal patient management. Key to achieving this goal is training for healthcare personnel in non-specialist hospitals and collaboration between different specialists. We hope these principles will increase awareness of AHA in the wider medical community and catalyze efforts toward improving its practical, multidisciplinary management.

Pharmacokinetics in routine haemophilia clinical practice: rationale and modalities-a practical review.

Prophylactic therapy with exogenous clotting factor concentrates in haemophilia A and B aims to achieve levels of circulating FVIII or FIX that are adequate for the prevention or reduction of spontaneous joint bleeding. Historically, a minimum trough level of at least 1% of the normal levels of circulating clotting factor has been targeted using standardised protocols. However, clearance of clotting factor varies between products and patients, and other pharmacokinetic (PK) parameters such as the frequency and magnitude of peaks may be important for ensuring optimal coverage. Thus, it is increasingly recognised that an individualised, PK-based approach to prophylaxis is necessary to achieve optimal protection. This review focuses on the clinical implications of using PK-guided, individualised prophylaxis in haemophilia to improve patient outcomes and considers practical methods of establishing patients' PK parameters. The most useful PK parameters will depend on the aim of the specific treatment (e.g. preventing activity-related and traumatic bleeds or addressing subclinical bleeding). In clinical practice, lengthy and frequent post-infusion sampling for PK analysis is costly and a significant burden for patients. However, a Bayesian analysis allows for the estimation of different PK parameters (e.g. half-life, factor concentrations over time, etc.) with only a minimum number of samples (e.g. 4, 24 and 48 h for haemophilia A), by using the patient's data to adjust a relevant population PK value towards the actual value. Numerous tools are available to aid in the practical use of Bayesian PK-guided dosing in the clinic, including the Web-based Application for the Population Pharmacokinetic Service hosted by McMaster University, Canada. The PK data can be used to determine the appropriate prophylaxis regimen for the individual patient, which can be monitored by assessment of the trough level at each clinic visit. Collection of PK data and subsequent PK-guided dosing should become standard practice when determining treatment strategies for people with haemophilia.

Achieving the unimaginable: Health equity in haemophilia.

Historically, treatment based on the availability of clotting factor replacement has resulted in an arcane guideline for the correction of factor deficiencies in people with haemophilia (PwH). While all other disease entities seek to restore function to a normal level, PwH are restricted to factor nadirs still equivalent to mild or moderate disease, resulting in continued risk of bleeding. A new treatment paradigm is needed based on the defined needs of PwH. A treatment model was developed by a panel of haemophilia providers, patient advocates and health economists to establish specific treatment milestones and targeted outcomes. The panel defined a series of treatment milestones to characterize the activity and outcomes linked to level of factor deficiency correction. All agreed that the ultimate goal should be 'functional cure' and 'health equity'. Seven levels to achieving a functional cure were identified, (a) Sustain life; (b) Minimal joint impairment; (c) Freedom from any spontaneous bleeds; (d) Attainment of 'normal' mobility; (e) Able to sustain minor trauma without additional intervention; (f) Ability to sustain major surgery or trauma; and (g) Normal haemostasis. A parallel set of patient-reported outcomes to achieve health equity was identified. These guidelines are now comparable with other disorders where the goal is to replace missing proteins to attain normal activity levels. As we are no longer limited by plasma supply due to the manufacture of recombinant factors, mimetics, and the early success of gene therapy, health equity is now achievable.

Inhibitors in haemophilia A and B: Management of bleeds, inhibitor eradication and strategies for difficult-to-treat patients.

The standard therapy for patients with haemophilia is prophylactic treatment with replacement factor VIII (FVIII) or factor IX (FIX). Patients who develop inhibitors against FVIII/FIX face an increased risk of bleeding, and the likelihood of early development of progressive arthropathy, alongside higher treatment-related costs. Bypassing agents can be used to prevent and control bleeding, as well as the recently licensed prophylaxis, emicizumab, but their efficacy is less predictable than that of factor replacement therapy. Antibody eradication, by way of immune tolerance induction (ITI), is still the preferred management strategy for treating patients with inhibitors. This approach is successful in most patients, but some are difficult to tolerise and/or are unresponsive to ITI, and they represent the most complicated patients to treat. However, there are limited clinical data and guidelines available to help guide physicians in formulating the next treatment steps in these patients. This review summarises currently available treatment options for patients with inhibitors, focussing on ITI regimens and those ITI strategies that may be used in difficult-to-treat patients. Some alternative, non-ITI approaches for inhibitor management, are also proposed.

Practical aspects of extended half-life products for the treatment of haemophilia.

Haemophilia A and haemophilia B are congenital X-linked bleeding disorders caused by deficiency of coagulation factor VIII (FVIII) and IX (FIX), respectively. The preferred treatment option for patients with haemophilia is replacement therapy. For patients with severe disease, prophylactic replacement of coagulation factor is the treatment of choice; this has been shown to reduce arthropathy significantly, reduce the frequency of bleeds and improve patients' quality of life. Prophylaxis with standard recombinant factor requires regular intravenous infusion at least two (FIX) to three (FVIII) times a week. Recombinant FVIII and FIX products with an extended half-life are in development, or have been recently licensed. With reported mean half-life extensions of 1.5-1.8 times that of standard products for FVIII and 3-5 times that of standard products for FIX, these products have the potential to address many of the unmet needs of patients currently treated with standard factor concentrates. For example, they may encourage patients to switch from on-demand treatment to prophylaxis and improve the quality of life of patients receiving prophylaxis. Indeed, extended half-life products have the potential to reduce the burden of frequent intravenous injections, reducing the need for central venous lines in children, promote adherence, improve outcomes, potentially allow for more active lifestyles and, depending on the dosing regimen, increase factor trough levels. Members of the Zürich Haemophilia Forum convened for their 19th meeting to discuss the practicalities of incorporating new treatments into the management of people with haemophilia. This review of extended half-life products considers their introduction in haemophilia treatment, including the appropriate dose and schedule of infusions, laboratory monitoring, patient selection, safety considerations, and the economic aspects of care.

Value of prophylaxis vs on-demand treatment: Application of a value framework in hemophilia.

INTRODUCTION: Therapeutic advances over the past 30 years have led to longer life expectancy and improved quality of life (QOL) for persons with hemophilia. Access to innovative therapy may be compromised if treatment decisions are driven solely by cost. New strategies are needed to assess true therapeutic values, along with financial cost, as physicians, policymakers, payers and manufacturers work together to improve patient care. AIM: To provide an evidence-based assessment of the value of prophylaxis vs on-demand therapy for hemophilia, based on a widely recognized three-tiered value framework approach for assessing a range of therapeutic interventions. METHODS: Data from six randomized clinical trials (ESPRIT, Joint Outcomes Study, SPINART, LEOPOLD II, ADVATE and POTTER) and four observational studies comparing primary and secondary prophylaxis vs on-demand therapy were applied to a hemophilia value framework. RESULTS: Both primary and secondary prophylaxis showed advantages in Tier 1 "Degree of health/recovery" outcomes, including measures of bleeding, musculoskeletal complications, pain, function/activity and QOL. Tier 2 "Process of Recovery" outcomes, also favoured prophylaxis, including measures of recovery time, return to normal activities, orthopaedic intervention and venous access. In Tier 3 "Sustainability of Health Recovery," measures of breakthrough bleeds, joint preservation, sustained productivity and QOL showed significant improvement with prophylaxis. CONCLUSION: The hemophilia value framework affirmed value of primary and secondary prophylaxis vs on-demand therapy, with clinical benefit demonstrated in all three tiers. This analysis also demonstrates clinical utility of the value framework process in the determination of optimal and cost-effective hemophilia care for all stakeholders.

Diagnosis and care of patients with mild haemophilia: practical recommendations for clinical management.

Mild haemophilia is defined by factor levels between 0.05 and 0.40 IU/mL and is characterised by traumatic bleeds. Major issues associated with mild haemophilia are that it may not present for many years after birth, and that awareness, even within families, may be low. Methodological problems exist in diagnosis, such as inconsistencies in results obtained from different assays used to measure factor levels in mild haemophilia. Advances in genetic testing provide insight into diagnosis as well as the likelihood of inhibitor development, which is not uncommon in patients with mild or moderate haemophilia and can increase morbidity. The management of patients with mild haemophilia is a challenge. This review includes suggestions around formulating treatment plans for these patients, encompassing the full spectrum from clinical care of the newly diagnosed neonate to that of the ageing patient with multiple comorbidities. Management strategies consider not only the vast differences in these patients' needs, but also risks of inhibitor development and approaches to optimally engage patients.

Haemophilia B: Where are we now and what does the future hold?

Research has been lacking on the natural history, complications, and treatment of haemophilia B, which is less common than haemophilia A and was recognized as a distinct clinical entity in 1947. Although the two diseases share the same clinical manifestations, they differ in causative mutation, risk of inhibitor development, and patient quality of life. Frequently debated is whether haemophilia B is as clinically severe as haemophilia A, with much of the published data on overall and haemophilia-specific health outcomes suggesting that haemophilia B may have a less severe clinical phenotype. However, although fewer haemophilia B than haemophilia A patients appear to experience bleeding, bleeds are just as severe. We review distinguishing characteristics of haemophilia B and its treatment, including management strategies for neonates, therapeutic approaches for patients who develop inhibitors, pharmacokinetics of factor IX concentrates administered as replacement therapy, and potential future treatments.

Partnering to change the world for people with haemophilia: 7th Haemophilia Global Summit, Madrid, Spain 22-24 September 2016.

The 7th Haemophilia Global Summit was held in Madrid, Spain, in September 2016. With a programme designed, for the 6th consecutive year, by a Scientific Steering Committee of haemophilia experts, the aim of the summit was to share optimal management strategies for haemophilia at all life stages and to provide an opportunity for specialists from across the haemophilia multidisciplinary care team to engage in discussion and debate with leading international experts on current and future areas of research. Topics covered ranged from the optimisation of haemophilia management, emerging issues in clinical care, practical approaches and future perspectives, in addition to patient engagement and empowerment in modern haemophilia care.

Outcome measures for adult and pediatric hemophilia patients with inhibitors.

Recent advancements in almost all aspects of hemophilia treatment have vastly improved patient care and management, and new and emerging treatments hold the promise of further progress. However, there remains a scarcity of data on long-term outcomes in hemophilia, particularly among those patients with inhibitors, for whom no validated outcome assessment tools are currently available. At the 15th Zürich Haemophilia Forum, an expert panel reviewed the most important outcome measures in inhibitor patients and considered the challenges associated with assessing outcomes in this population. A framework for outcome assessment in inhibitor patients incorporates traditional hemophilia outcome measures, such as bleed frequency and mortality, alongside measures of health, functioning, disability, social participation, quality of life, and economic considerations. It is important to remember that inhibitor patients differ in their clinical needs, perspectives, and priorities according to age, inhibitor status, degree of joint disease, and activity levels; as a result, the relative importance of different outcome measures will change throughout an inhibitor patient's life. Challenges inherent in measuring long-term outcomes in inhibitor patients include the small number of known patients, the subjective nature of many outcome assessment tools, and the risk of overburdening patients with repeated requests to complete questionnaires or participate in studies. Therefore, there is an urgent need to reach consensus on the most important and appropriate assessment tools for measuring outcomes in this population. These tools should ideally be standardized, easily applied, and internationally applicable in order to collect and generate quality outcome data.

Whole exome sequencing identifies a mutation in thrombomodulin as the genetic cause of a suspected platelet disorder in a family with normal platelet function.

Here, we describe a mother and son with a lifelong bleeding tendency and posttraumatic bleeding who were recruited to the UK Genotyping and Phenotyping of Platelets (GAPP) study with a suspected platelet function disorder. However, despite a clinically significant bleeding score, both had normal platelet counts and normal platelet function. The patients' blood was analyzed by light transmission aggregometry and genotyping by whole exome sequencing, as outlined by the GAPP study. Approximately 25 000 genetic variants were found for each patient as a result of sequencing and were filtered using a specialized bioinformatics pipeline. A heterozygous variant displaying autosomal dominant inheritance (c.1611 C>A) was found in the gene THBD which encodes the glycoprotein thrombomodulin. This sequence change results in a stop codon (p.Cys537Stop) and truncation of the protein and has been previously described in two other families with bleeding events which suggests it may be a recurrent mutation. In summary, this study shows that patients with a suspected platelet disorder but who present with a normal pattern of platelet aggregation should be investigated for defects in nonplatelet genes.

Beyond stopping the bleed: short-term episodic prophylaxis with recombinant activated factor FVII in haemophilia patients with inhibitors.

Preventing haemarthroses and arthropathy is a major challenge in patients with haemophilia and inhibitors, as treatment options are limited. One potential strategy is short-term episodic prophylaxis, which extends bypassing agent therapy beyond the resolution of bleeding to include the post-bleed inflammatory phase. At the 13th Zürich Haemophilia Forum, an expert panel reviewed the rationale behind this strategy, explored its current use with recombinant activated factor VII (rFVIIa) and considered treatment monitoring and optimisation. Two protocols are currently used for short-term episodic prophylaxis, both of which stipulate on-demand rFVIIa until resolution of bleeding, followed by daily dosing for ≥3 days to prevent re-bleeds. Short-term episodic prophylaxis should be individualised to optimise outcomes, perhaps through early treatment initiation or by combining rFVIIa with other treatments (e.g. factor VIII, tranexamic acid). Encouraging treatment compliance can also improve outcomes. Additionally, there is a need to develop objective clinical outcome measures, biomarkers and imaging protocols that can monitor treatment outcomes and joint disease in patients with inhibitors. A proactive approach incorporating a systematic package of care is needed. Currently, short-term episodic prophylaxis with rFVIIa may be an alternative treatment option to on-demand treatment for patients with inhibitors.