Progress in the contemporary management of hemophilia: The new issue of patient aging

EJINME-03552; No of Pages 6 European Journal of Internal Medicine xxx (2017) xxx–xxx

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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim

Narrative Review

Progress in the contemporary management of hemophilia: The new issue of patient aging Pier Mannuccio Mannucci a,⁎, Massimo Iacobelli b a b

Scientific Direction, IRCCS Ca' Granda Maggiore Policlinico Hospital, Milan, Italy Sintesi Research, Milan, Italy

a r t i c l e

i n f o

Article history: Received 2 March 2017 Received in revised form 10 May 2017 Accepted 11 May 2017 Available online xxxx Keywords: Hemophilia Aging Multimorbidity Polypharmacy

a b s t r a c t The management of inherited coagulation disorders such as hemophilia A and B has witnessed dramatic progresses since the last few decades of the last century. Accordingly, persons with hemophilia (PWH) now enjoy a life expectancy at birth not different from that of males in the general population, at least in high income countries. Nowadays, a substantial proportion of PWH are aging, like their peers in the general population. This outstanding progress is accompanied by problems that are in part similar to those of any old person (multiple concomitant diseases and the resulting intake of multiple drugs other than those specific for hemophilia treatment). In addition, older PWH suffer from the consequences of the comorbidities that developed when their treatment was at the same time poorly available and unsafe. Typical hemophilia comorbidities affect the musculoskeletal system following joint and muscle bleeds, but also the liver and kidney are often impaired due to previous bloodborne infections such as viral hepatitis and HIV. Thus, the comorbidities of hemophilia superimposed on the multimorbidity and polypharmacy associated with aging create peculiar problems in the current management of these patients, that demand the coordinated holistic intervention of internists, geriatricians and clinical pharmacologists in addition to the care traditionally provided by pediatricians and hematologists. © 2017 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.

1. Introduction Hemophilia A and B are rare bleeding disorders caused by mutations in the genes encoding coagulation factor VIII (FVIII) and factor IX (FIX) [1]. The prevalence of hemophilia A is 1 in 5000 male live births and that of hemophilia B is 1 in 40,000 [1,2]. Patients with plasma factor levels b 1 IU/dL (b1% of normal) are classified as severe hemophilia, those with levels between 1 and 5 IU/dL (1–5% of normal) and those with N5 but b 40 IU/dL (N 5%–b40% of normal) are moderate and mild hemophilia [3]. Although the bleeding phenotype may be heterogeneous [4,5], this classification reflects rather closely the severity of clinical symptoms [6]. Traditionally hemophilia A and B have been considered clinically indistinguishable from each other [7–9]. Recent evidence, however, suggests that severe hemophilia B may have a milder clinical phenotype than severe hemophilia A [8,9], reflected by less factor consumption, less deleterious gene mutations and less need for orthopedic surgery [9]. The latter is often necessary in poorly managed patients with hemophilia (PWH) because recurrent bleeding into muscles and joints is the hallmark of severe disease. The long-term consequences of these bleeds are the development of arthropathy through synovial hypertrophy, cartilage destruction and bone damage [10], that ⁎ Corresponding author. E-mail address: [email protected] (P.M. Mannucci).

leads to relevant physical and psychosocial handicaps [11]. This review provides a general overview of the current knowledge of the comorbidity and the multiple chronic diseases associated with aging that may occur in PWH who are becoming older as consequence of the improved management of hemophilia. 2. Progress in hemophilia treatment In the 1950s and the 1960s, fresh frozen plasma (FFP) was the mainstay of treatment for both hemophilia A and B. Each unit of FFP contains small amounts of FVIII and FIX, so that large volumes of intravenously administered FFP were needed to stop bleeding episodes and patients were usually hospitalized for each treatment. The first major progress in disease management took place in the 1960s, following the discovery by Judith Pool that it was possible to concentrate FVIII by cryoprecipitation of plasma [14,15], and in the 1970s following the introduction in the market place of lyophilized coagulation factors for both the hemophilias. This permitted the development of specialized treatment centres and enabled home treatment programmes. The decade also saw the initiation in Sweden of prophylaxis regimens [16], as well as the discovery in Italy of the synthetic drug desmopressin (DDAVP) for mild hemophilia A and von Willebrand disease. The 1980s were the gloomy years of AIDS and hepatitis, but these scourges fostered research that led to the cloning of FVIII and FIX genes, i.e., the

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Please cite this article as: Mannucci PM, Iacobelli M, Progress in the contemporary management of hemophilia: The new issue of patient aging, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.05.012

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basis for the production of FVIII and FIX by recombinant DNA technology [17,18]. Progress in viral inactivation methods also made plasma factors much safer [19] and indeed since the late 1980s no clinically relevant pathogen has been transmitted by coagulation factor products [20]. In the 1990s recombinant FVIII (rFVIII) and recombinant FIX became available, at least in high-income countries [21]. In addition, bypassing products such as an activated prothrombin complex concentrate (APCC, FEIBA) and recombinant activated FVII (rFVIIa, NovoSeven®, Novo Nordisk A/S) permitted treatment of bleeding episodes in PWH who had developed such a serious complication as anti-FVIII inhibitory antibodies (inhibitors). The 1990s also saw the introduction of immune tolerance induction therapy. First implemented in Bonn (Germany) and based upon repeated and long-lasting infusions of FVIII [22,23], this demanding therapeutic approach is able to eradicate inhibitors in approximately two thirds of cases, albeit with huge costs for the community and a heavy burden for patients [24,25]. Finally, the recent development of FVIII and FIX recombinant products with extended half-life (EHL-FVIII and EHL-FIX) promises to further improve treatment by reducing the number of intravenous injections needed to maintain a trough prophylactic level of replacement factor. Some EHL factor products are already licensed or in an advance stage of clinical development [26]. EHL-FVIII products have an average increase in half-life of no more than 1.5 times compared to the standard FVIII products [27–30], whereas EHLFIX products have a much more marked and clinically significant 3–5 fold increase compared to standard FIX products [31–33]. 3. Achievements of replacement therapy The forementioned availability of high-quality plasma-derived and recombinant factor products has greatly contributed to the improved quality of life and reduced morbidity in the hemophilia community. Further, life expectancy for PWH in high-income countries has matched that of the general population [35]. Comparing with the most frequent monogenic diseases (cystic fibrosis, thalassemia major, muscular dystrophy), PWH have a much better quality and expectancy of life [36]. The ultimate treatment goal in PWH is the prevention of bleeds, particularly of hemarthrosis with the resulting preservation of a normal joint status. To achieve this goal, patients with severe hemophilia A and B should be primarily managed with regularly spaced prophylactic infusions of coagulation factors or, when the latter treatment regimen is not available or feasible, with an aggressive and early demand treatment of the actual bleeding episodes with plasma-derived or recombinant FVIII or IX products. Several studies have demonstrated the superiority of prophylactic regimens with FVIII compared with on-demand treatment in severe hemophilia A [41–45]. The epitome of the efficacy of prophylaxis is a randomized study carried out in boys with normal baseline joint imaging, showing that prophylaxis with rFVIII administered every other day was effective in preventing structural joint damage (as detected by MRI). With this solid evidence of the efficacy of prophylaxis in patients with severe hemophilia A, in real-world clinical practice the dose and frequency of prophylactic FVIII infusions vary widely in PWH, ranging from alternate days [42] to three times a week [48] or two times a week [49]. Factor VIII half-life is 8–12 h and for FIX is 18–24 h [50], with much inter-individual but little intra-individual variations in pharmacokinetics [51]. In addition, there is some degree of patient heterogeneity in terms of clinical phenotype and responsiveness to treatment [40]. These characteristics led Canadian investigators to develop a tailored, dose-escalating prophylaxis regimen. All PWH were initially treated with rFVIII at a relatively large dose once weekly, until dosage escalation criteria were met when bleeding episodes were not satisfactorily prevented. If the criteria for dose escalation did apply, patients received rFVIII twice weekly and if any of the escalation criteria recurred again, rFVIII was given at alternate days. Results from the prospective clinical study carried out in boys with severe hemophilia A treated with this

tailored regimen showed minimal joint change on physical examination and minimal functional disability over the 13 year study duration [52, 53]. As expected, more subjects did escalate the frequency of infusions as they got older as a result of an increased bleeding frequency. Kaplan-Meier estimated probability of not escalating to the two times a week regimen was about 40% at 50 months and 20% at 150 months and the probability of not escalating further to the alternate day regimen was 40% at 150 months. Continued longitudinal evaluation of this cohort will yield further information regarding more long-term joint outcomes [53]. Furthermore, pharmacokinetic-driven approaches have been proposed to tailor prophylaxis regimens, using individual's pharmacokinetic (PK) responses to FVIII infusions to calculate dose and dosing frequency [54–56]. Dose regimens for prophylaxis are designed to keep the trough level of the replaced clotting factor above 1% of the normal level, because observational data indicate that the time per week spent by patients with FVIII/IX levels b1% is associated with an increased rate of bleeding [48]. A recent study has attempted to answer the question whether or not the rather cumbersome pharmacokinetic approach, that implies taking multiple blood samples in children is truly needed for the optimal tailoring of prophylaxis regimen, or whether a simpler fixed regimen is equally adequate. Results showed that the annualized bleeding rates for the fixed or tailored prophylaxis regimens were not different [57]. The rationale for prophylactic management of hemophilia originally developed in Sweden by the pioneer work of Nilsson and Blomback was based upon the transformation of the phenotype of severe hemophilia into that of moderate disease, because patients with moderate hemophilia typically bleed only in response to some trauma. Furthermore, patients with mild hemophilia bleed only in response to significant tissue injury induced by trauma or surgery. Thus, for the majority of mild and moderate hemophilia patients, replacement therapy is only employed on demand in order to control trauma related bleeding and to prevent bleeding before surgery or other invasive procedures. 4. The inhibitor complication Development of alloantibodies neutralizing the coagulant activity of FVIII is currently the most serious and challenging complication in the management of hemophilia A. Inhibitors compromise the ability to control hemorrhage, resulting in increased morbidity and disability for patients and costs for the community. A study from the UK examined the epidemiology of inhibitors in relation to age and previous treatments among patients with severe hemophilia A [24]. The highest incidence of inhibitors pertains to children aged b5 years previously untreated (or minimally treated) with factor replacement therapy (64.3 cases per 1000 treatment-years). The incidence was much smaller (5.3 per 1000 treatment-years) in treated patients at age 10–49 years, rising to 10.5 per 1000 treatment-years in PWH N 60 years of age [24]. Thus, the UK study shows that, at variance with previously untreated patients (PUPs), inhibitors are a rare event in previously treated patients (PTPs) with hemophilia A. Further, according to two recent meta-analyses, the pooled incidence rate of inhibitor development for the 25 studies providing follow-up data was 3 per 1000 person-years (95% confidence interval 1–4) [58,59]. Little is known about risk factors for inhibitors in PTPs, a field difficult to study due to the low incidence rate of this complication. There is no clear evidence of an increase of inhibitors when switching to and from the currently available factor concentrates, whether plasma-derived or recombinant [60]. With these preambles on the incidence of inhibitor in relation to age and treatment, it must be pointed out there are multiple risk factors for the development of this complication. In the high risk category of PUPs, residual plasma FVIII levels, gene mutations [61–63], early replacement therapy and the source of FVIII (i.e., human plasma or recombinant DNA technology) are the most clearly and consistently implicated risk factors [62,64–67]. The recently published Survey of Inhibitors in Plasma-

Please cite this article as: Mannucci PM, Iacobelli M, Progress in the contemporary management of hemophilia: The new issue of patient aging, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.05.012

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Product Exposed Toddlers (SIPPET) [68], a global randomized trial carried out in 264 PUPs from 14 countries of 5 continents, demonstrated that patients with severe hemophilia A treated with plasma-derived FVIII containing von Willebrand factor had a lower cumulative incidence of inhibitors than those treated with recombinant FVIII, i.e., 26.8% versus 44.5%. Thus, plasma-derived products should be preferred, at least in the early period of the first 50 treatments, i.e., at the time of the highest risk of inhibitor occurrence. FVIII may induce immunogenicity but it is also used for immune tolerance induction (ITI). Successful ITI leads to normalization of FVIII pharmacokinetics with consequent improvement in patient's quality of life. The International Immune Tolerance Study was a multicenter, randomized study specifically designed to test whether or not the overall response to ITI is dependent on the FVIII dosing regimen. The study compared a high daily dose and a low dose 3 times/week factor VIII regimens in 115 high-titer inhibitor subjects with severe hemophilia A [24]. Success, i.e., inhibitor eradication, did not differ between the two treatment arms, but the times taken to achieve this goal were much shorter with the high dose regimen. Thus, either regimen can be used successfully for ITI, but the high dose should be preferred when its more demanding and costly implementation is possible. 5. Aging with hemophilia and the role of the internist Before the advent of modern management as outlined above, PWH had a very short life expectancy (20–30 years) and many of them died at a young age due to life-threatening bleeding episodes. Today, this clinical picture has dramatically improved. A direct consequence of this scenario is the novel presence of a cohort of PWH who have become old and thus are often affected not only by the comorbidities of hemophilia (arthropathy, consequences of viral infections) but also by the multiple chronic diseases associated with aging. We define comorbidity as the presence of one or more additional clinical manifestation co-occurring in the same person as a consequence of a primary disease, multimorbidity as the co-existence of two or more long-term conditions with no apparent relationship with the primary disease. Older PWH are becoming more and more confronted with a number of comorbidities and multimorbidities. Some of them, listed below, are not peculiar of PWH, but are likely to be manifested at a younger age in them than in older people from the general population, and their management is somehow complicated by the presence of the lifelong coagulation defect typical of hemophilia [69]. Musculoskeletal problems are likely to develop early in PWH, with chronic pain, instability and loss of joint and muscle function that impairs their daily activities and worsen quality of life. Arthropathy is a leading cause of morbidity in PWH born before the 1970s, because this cohort had little or no access to replacement therapy in the first few years of their lives [70]. Moreover, impaired joint function and the resulting poor physical activity cause decreased bone mineral density and ultimately osteoporosis, with an increased risk of fractures. A recent meta-analysis of published case-control studies in PWH showed a significant reduction of the lumbar spine and hip bone mineral density, which appears to begin in childhood [71]. Cardiovascular disease are typical of aging. While the exact burden of cardiovascular disease in PWH is unknown, incidence rates from ischemic heart disease have risen throughout the last 20–30 years, suggesting that cardiac problems are becoming increasingly relevant [69]. It is now recognised that many risk factors, such as hypertension and overweight, occur frequently in PWH [72]. Their prevalence of hypertension is 49– 57% [73], higher than in the general population [72]. Atrial fibrillation is a common disorder in the aging general population. One European survey [74] among 3952 adult PWH revealed a similar prevalence in PWH as in the general population (3.4% in patients aged N60 years). Many cardiovascular drugs, typically anticoagulant and antiplatelet agents that have per se deleterious effects on hemostasis, may increase the bleeding tendency of PWH with a lifelong coagulation defect [69].

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Bloodborne viral infections (e.g. HIV and HCV) imply exposure of PWH to antiviral treatments, which may have adverse effects on their renal and liver functions. In HIV-infected PWH, combined antiretroviral therapy (cART) has dramatically reduced the high mortality rate seen before the advent of this treatment in the middle 1990s. However, cART increases the risk of such diseases previously rare in PWH as the metabolic syndrome, diabetes and atherothrombotic cardiovascular disease [75]. Exposure to nephrotoxic agents as therapy for these infections may place PWH at increased risk for renal disease [76]. Chronic renal disease may causes hypertension [76], which as seen before is more frequent in PWH than in the general population and is a risk factor for cerebral hemorrhage, a long-term threat for PWH owing to their coagulation defect. Chronic pain is prevalent in PWH [69]. The widely used paracetamol and non-steroidal anti-inflammatory drugs have adverse effects that may become more clinically significant with aging: gastrointestinal toxicity, paracetamol-induced liver dysfunction (particularly in association with excessive alcohol intake and viral liver disease), hypertension and renal insufficiency [77]. In addition, they impair platelet function, with a risk to increase the bleeding tendency. Opioids (hydrocodone-acetaminophen, morphine, fentanyl patch) are used in PWH but outcome data are scarce [78]. PWH are at least as vulnerable as other chronic pain populations to opioid-related adverse events and to develop abusive behaviors and addiction [79]. When cancer occurs in PWH chemotherapy may cause thrombocytopenia that aggravates the bleeding tendency [69]. Replacement therapy should be administered not only on an episodic basis at the time of diagnostic or therapeutic invasive procedures, but also as continuous prophylaxis when chemotherapy or radiotherapy is accompanied by severe thrombocytopenia [69]. Although most FVIII inhibitors develop at children age, they may also develop at a more advanced age, particularly when PWH receive intensive replacement therapy on the occasion of surgical or invasive procedures needed to tackle the aforementioned age-related problems. 6. Polypharmacy as a consequence of multimorbidity All in all, a brief account of the main clinical problems and their consequences and impact are in Table 1. There are no evidence-based guidelines for the treatments, trajectories and clinical outcomes of the forementioned medical and pharmacological problems in older PWH, owing to limited knowledge and very few previous data, particularly on drugs other than replacement therapy [69]. Thus, it is fundamental to collect more information about polypharmacy in older multimorbid PWH and on their effects on the natural clinical history and bleeding tendency of PWH. Furthermore, physicians dealing with a rare disease such as hemophilia must be informed and appropriately trained about this increasing problem in their aging patients, in order to update and optimize the interdisciplinary approach needed for the management of complex and chronic older patients taking multiple drugs. Indeed, there are several potentially negative consequences associated with polypharmacy in older PWH: - Bleeding tendency: as outlined above due to the coagulation defect, it may be enhanced by the use of multiple drugs that further impair the hemostatic system. - Medication non-adherence: inevitably accompanying polypharmacy, it is associated with treatment failure, disease progression and hospitalization [80,81]. - Adverse drug events (ADE): outpatients and hospitalized older patients often experience ADEs and approximately 10% of emergency room visits are attributed to ADEs [82]. Taking 5 or more drugs is associated with an increased risk of ADEs [82,83]. - Potentially inappropriate medications (PIM): some drugs are PIM for the elderly because they carry an increased risk of ADEs, old age being commonly associated with altered pharmacokinetics and

Please cite this article as: Mannucci PM, Iacobelli M, Progress in the contemporary management of hemophilia: The new issue of patient aging, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.05.012

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Table 1 Common comorbidities in older patients with hemophilia, associated consequences and impact on the health services. Medical problem

Management

Arthropathy

- Venous thromboembolism - Post-operative bleeding - Drug-drug interactions - Gastrointestinal bleeding - Combined antiretroviral - Metabolic syndrome therapy (cART) - Diabetes - Renal insufficiency - Atherothrombotic disease - Cardiovascular disease - Drug-drug interactions - Direct-acting antiviral - Liver dysfunction drugs - Renal insufficiency - Paracetamol - Drug addiction - Non-steroidal - Gastrointestinal toxicity anti-inflammatory drugs - Paracetamol-associated liver dysfunction - Opioids - Hypertension - Renal insufficiency - Gastrointestinal bleeding - Drug-drug interactions - Increased bleeding Anticoagulant/antiplatelet tendency - Drug-drug interactions medications

HIV infection

HCV infection Chronic pain

Atherosclerosis and ischemic cardiovascular disease Cancer

Risks

- Joint arthroplasty - Anti-inflammatory drugs

- Chemotherapy - Radiotherapy - Immunotherapy

- Increased bleeding associated with chemotherapy/radiotherapy and thrombocytopenia. - Drug-drug interactions

pharmacodynamics (i.e., delayed renal elimination of drugs and increased sensitivity to their anticholinergic and sedating effects) [84]. - Drug-drug interactions (DDI): older adults on polypharmacy are predisposed to DDIs. Specifically, a patient on 5–9 medications has a 50% probability of DDI, but this risk increases dramatically when a patient is taking 10 or more medications [80,85,86]. - Functional status: polypharmacy is associated in older patients with functional decline, with decreased physical and cognitive function and autonomy, poor self-care and inadequate dietary styles [82,87]. - Healthcare related costs: polypharmacy contributes to healthcare costs being associated with an increased risk of taking PIMs, and thus with an increased risk of outpatient visits, access to emergency room (ER) and hospitalizations, leading to marked cost increases [81]. All these issues related to the intake of multiple drugs are likely to be particularly cogent in older PWH, who often have some degree of preexisting impairment of such organs critical for drug metabolism and excretion as the liver and kidney. With this background, a new challenge is to implement a comprehensive approach aimed to provide optimal care for the aging PWH, uniquely characterized by the long-term consequences of a lifelong bleeding disorder superimposed on the problems generally experienced by older people. Thus their global assessment and management requires the acquisition of new elements that should be not only limited to clinical aspects but also include the integrated evaluation of functional, mood, cognitive and therapeutic domains. Moreover, the physicians at the hemophilia treatment centres should learn to act in closer cooperation with other specialties such internists, geriatricians and clinical pharmacologists, whose partnerships is definitely needed in order to optimize management. Particular care must be exerted when choosing drugs that should be tailored to patient age, functional status, comorbidities and, most importantly, the impaired hemostasis of these patients. Beside the professionals mentioned above, the nurses have a key role in the coordination and interpretation of the multiple expertise need to optimally managed older PWH.

7. Gene therapy to cure hemophilia Current treatment for hemophilia already provides excellent efficacy and safety, and this must be borne in mind in the development of new therapeutic approaches. Gene therapy has the potential to cure the disease by reducing disease severity from a severe phenotype to a moderate or mild one through the continuous production of FVIII or FIX after one (or more) administrations of a gene vector [50]. The first clinically significant results are available for hemophilia B. A Phase I–II dose escalation trial enrolled 10 patients with severe disease who received a single intravenous infusion of vector (an adeno-associated virus serotype 8) [88,89]. Results showed a dose dependent increase in FIX activity to 1–6% of normal value over a median period of 3.2 years, with 4–7% increase in the 6 patients who received a high vector dose, which resulted in a reduction of N 90% in bleeding episodes and of the use of prophylactic FIX concentrate. Severe side-effects have not been reported, with the exception of increased liver enzymes in four patients treated with the high vector dose, which resolved with prednisolone [88,89]. Other gene therapy clinical trials in hemophilia B based on different strategies are ongoing with promising preliminary results. There is, as yet, no similar fully published data for FVIII gene therapy. It is widely accepted that this most important therapeutic target is more problematic for a variety of reasons, including designing a vector cassette large enough to accommodate the larger FVIII cDNA, achieving adequate levels of transgene expression and preventing the far more frequent complication of anti-FVIII immunity [90]. The development of codon-optimised human FVIII cDNAs showed that shorter FVIII constructs can result in increased efficacy and might give rise to effective gene therapy [91]. Several groups are attempting to overcome the packaging limitations with the production of dual recombinant adeno-associated viral vectors for FVIII delivery [92] or by using lentiviral vectors for gene transfer [93]. 8. Conclusions The persons with hemophilia have witnessed fantastic improvements in their therapies in the last 40 years, starting from the 1970s when management of these diseases was defined “the success story of the decade”. These advances, quite unique in the context of the most frequent genetic disorders, have fortunately led to a significant aging of the population of PWH. The internists and geriatricians are thus going to have a larger and larger role in patient management, that in the past was mainly confined to the expertise of pediatricians and pediatric hematologists, who still maintain a fundamental role to guarantee an optimal transition from childhood to adulthood. Conflict of interest PMM, for lecture fees: Alexion, Shire, Bayer, CSL Behring, Grifols, Kedrion, LFB, Novo Nordisk; for advisory board membership Bayer and Kedrion. References [1] Mannucci PM, Tuddenham EG. The hemophilias – from royal genes to gene therapy. N Engl J Med 2001;344:1773–9. [2] Berntorp E, Shapiro AD. Modern haemophilia care. Lancet 2012;379:1447–56. [3] White GC, Rosendaal F, Aledort LM, et al. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 2001;85:560. [4] Aledort LM, Haschmeyer RH, Pettersson H, the Orthopaedic Outcome Study Group. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. J Intern Med 1994;236:391–9. [5] Jayandharan GR, Srivastava A. The phenotypic heterogeneity of severe hemophilia. Semin Thromb Hemost 2008;34:128–42. [6] Blanchette V, et al. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014;12:1935–9. [7] Makris M. Is VIII worse than IX? Blood 2009;114:750–1.

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Please cite this article as: Mannucci PM, Iacobelli M, Progress in the contemporary management of hemophilia: The new issue of patient aging, Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.05.012