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G. Castaman and D. Matino et al.
with hemophilia during the period between 1980 and 1994 who were treated predominantly with on-demand therapy. The authors found a lower rate of hospital admis- sions for patients with HB at all levels of severity, suggest- ing that these individuals have a milder bleeding pheno- type compared to HA patients.
Results consistent with these were obtained in the US a few years later in a cross-sectional study conducted between May 1998 and May 2002.20 Data collected from 4,343 males with hemophilia aged 2-19 years included age, bleeding frequency, family history, insurance status, orthopedic procedures, prophylaxis use, age at diagnosis and first hemophilia treatment center (HTC) visit, fre- quency of visits, hemophilia type, inhibitor status, race/ethnicity, body mass index. The authors highlighted the fact that overall, individuals with HB consistently reported fewer bleeding episodes, regardless of age or severity. Interestingly, among individuals with moderate factor deficiency, those affected by HA had a greater degree of range of motion limitation compared to persons with HB.
A survey conducted in 2006 aiming to describe prophy- laxis use in patients of all ages and severities with HA or HB in Canada also showed some differences between HA and HB treatment.21 Data on 2,663 individuals (2,161 hemophilia A, 502 hemophilia B), were returned by 22 Canadian HTC, totaling 98% of the Canadian hemophilia population. When comparing the use of prophylaxis, the authors reported that 32% of patients with severe HB were receiving prophylaxis compared with 69% of patients with severe HA. However, it is not clear if this difference is the result of a real or perceived difference in the clinical phenotype or just reflect the traditional thera- peutic approach to HB patients.
However, a subsequent study reported similar results. In a project aimed at constructing a composite score (Hemophilia Severity Score, HSS) to assess the severity of the disease, Schulman et al. evaluated 100 patients affected by HA (n=67) and HB (n=33).15 This was intended as a comprehensive measurement of the clinical severity of the disease and took into account the number of joint bleeds per year, the orthopedic joint score, and the annual con- sumption of FVIII. Interestingly, the HSS was higher for severe HA [median=0.50; interquartile range (IQR)=0.41- 0.68] than for severe HB (median=0.29; IQR=0.23-0.45) (P= 0.031). This result was not replicated in a subsequent external validation of the score in a smaller, single-center study in Italy. In this case, 65 consecutive hemophilia patients (57 with HA, 8 with HB) were enrolled, and no differences in HSS score were found between HA and HB (median=0.87 for severe HA vs. 0.91 in severe HB patients).22
An additional study that indirectly showed a possible difference in the clinical phenotype of severe HA com- pared to HB was published a few years later. This single- center, case-control study was carried out in Italy to eval- uate the role of genotype and endogenous thrombin potential (ETP) as possible predictors of the clinical pheno- type of patients affected by severe hemophilia.3 The authors evaluated patients displaying an extremely mild bleeding tendency (n=22) in comparison with those show- ing a typical bleeding tendency (n=50). In this study, the odds of having a milder form of the disease was five times higher in HB patients compared to persons affected by severe HA.3
More recently, a Canadian single-institute retrospective study evaluating possible differences between bleeding frequency and use of factor concentrate among adult patients with severe and moderate HA and HB was pub- lished.14 Sixty-eight HA patients (58 severe, 10 moderate) and 20 patients with HB (15 severe, 5 moderate) were studied between 2001 and 2003. Although no significant difference in terms of factor consumption was observed between the two groups, 10 of 68 (14.7%) HA patients had surgical procedures to correct musculoskeletal compli- cations compared to only 1 of 21 (4.7%) in the HB patient group. The bleeding events were also more frequent in the HA group. A total of 2,800 bleeding events were reported in the severe HA group (average 16/patient/year) while 502 total bleeds were reported among the severe HB patients (average 11/patient/year). The difference in the average number of bleeds per year was even more pro- nounced when considering patients with moderate factor deficiency: 4.6 for HA (n=10) and 1.06 for HB (n=5) patients.
However, a few years later, a study of pediatric HA and HB patients showed apparently contrasting results;23 over- all, this study showed a similar severity in the bleeding phenotype during the initial stage of the disease in severe and in moderate hemophilia A and B.
The cohort of patients in this analysis was made up of consecutive severe and moderate HA and HB patients from the PedNetHaemophilia Registry study and patients with severe HA from the RODIN study. A total of 582 patients with severe HA and 76 with severe HB were included and there was no difference in age at first expo- sure to clotting factor (0.81 vs. 0.88 years; P=0.20), age at first bleed (0.82 vs. 0.88 years; P=0.36), or age at first joint bleed (1.18 vs. 1.20 years; P=0.59).23 However, one should bear in mind that this study differed substantially from the others with respect to: a) age (pediatric population vs. adults); b) extensive use of prophylaxis (the authors reported a uniform intention to treat with continuous pro- phylaxis in 90% of patients born between January 1st 2000 and January 1st 2010); c) type of outcomes evaluated (bleeding characteristics during the early stage of the dis- ease compared to later-in-life bleeding phenotype and musculoskeletal complications). It is interesting to consid- er that for all parameters in this study there was a non-sig- nificant trend towards earlier age at bleeding in HA versus HB patients.
A robust support to the different frequencies of bleeding episodes among the two comes from two recent trials recruiting patients with HA and HB, all treated on demand, for phase III studies with recombinant long-act- ing products.24,25 These studies clearly showed that, at enrollment, the annualized bleeding rates in the year before entering the studies were significantly greater in HA patients.
A significant contribution to understanding the possible different evolution of the hemophilic arthropathy in HA and HB was produced by Melchiorre et al. in 2016.26 In this study, including mostly adult patients, the authors showed that the ultrasound score was significantly worse in HA when matched for age and frequency of hemarthro- sis. Likewise, the World Federation of Hemophilia clinical score in the HB group was lower [mean and Standard Deviation (SD): 48.6±16.2 vs. 22.6±16.4; P<0.0001], indi- cating a less severe arthropathy than in HA patients with a similar total number of hemarthrosis. In addition, the
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haematologica | 2019; 104(9)