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Hemophilia A and B: sharing differences
have circulating FVIII protein levels at almost 30% of nor- mal.
The mutations thought to be responsible for CRM+ HA are generally missense mutations found in the A2-domain of FVIII.8 At variance with HA, almost one-third of patients with HB are classified as CRM+ and can produce variable amounts of FIX protein.
The higher prevalence of less severe mutations (mis- sense mutations) in HB could provide a biological basis for a milder bleeding phenotype compared to HA, although clinical evidence is limited. Furthermore, this could also explain the lower prevalence of inhibitors in HB, mostly associated with stop codon or partial/whole gene dele- tion, probably together with the fact that FIX is smaller than FVIII, with less antigenic epitopes. Interestingly, it is well known that some missense mutations in mild HA are associated with inhibitor occurrence,9 while this has never been reported in patients with mild HB.
It is also interesting to note that for some FIX nonsense gene mutations in HB, usually categorized as null muta- tions, the mechanism of ribosome readthrough could restore translation impaired by mutations and could account for minimal full-length protein biosynthesis. This mechanism could be a modifier of clinical outcomes in this specific patient population.10
Finally, although rare, being implicated in just a small proportion of severe HB cases, it is worth noting the pos- sibility of a particular variant of HB: the hemophilia B Leyden.11 The molecular mechanism is likely to involve disruptions of sites in the proximal promoter of the F9 gene. In this condition, abnormal hemostasis is present after birth but spontaneously ameliorates at puberty, with a progressive recovery of FIX expression and normaliza-
tion of FIX level in adulthood.12 This effect is associated with rising post-pubertal growth hormone levels.13
Similar molecular mechanisms that can potentially improve the clinical presentation or outcomes, such as these two mechanisms just discussed for HB, have not yet been identified in HA patients.
Similarities and differences in hemophilia A and B clinical phenotype
The numerous bleeding episodes that individuals with severe hemophilia experience can lead to long-term dis- ability. Recurrent joint bleedings can result in severe arthropathy, muscle atrophy, pseudo-tumors, and lead to chronic pain and impaired mobility that often requires surgery and arthroplasty to improve joint function. HA and HB display similar clinical characteristics; however, several studies have reported on possible differences in bleeding frequency and factor consumption,14 clinical scores,15 and the need for orthopedic surgery.16,17
The possible different clinical evolution of HB was ini- tially suggested in 1959 by Quick18 and was based on 24 HB cases he had personally studied. He observed that HB, even in its most severe form, can be less incapacitating and disabling than HA, and that this difference was especially pronounced after adolescence. It should be kept in mind, however, that historically, in some studies, severe HB has been defined with a FIX <2% that could contribute to a less severe bleeding tendency compared to HA, usually defined with a FVIII <1%. However, forty years after Quick, a retrospective study reporting demographic char- acteristics, hospital admissions, and causes of death of patients with hemophilia was carried out in Scotland by Ludlam et al.19 They retrospectively studied 282 patients
Figure 1. Comparison of characteristics of hemophilia A and B. FIX: factor IX. 52Gouw et al. (2012); 7Belvini et al. (2005); 53Brummel-Ziedins and Mann. (2014); 54Nazeef and Sheehan (2016).
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