Page 27 - 2019_09-HaematologicaMondo-web

Hemophilia A and B: sharing differences
analysis of circulating osteoprotegerin (which plays a pro- tective role for the subchondral bone) and receptor activa- tor of nuclear factor-kB and RANK ligand (involved in osteoclast activation and bone erosions) showed a more favorable profile in HB patients. Consistent results were obtained with the histological analysis performed on syn- ovial tissue collected from these patients. Taken together, these data confirmed a less severe evolution of the arthropathy in HB patients and widened our understand- ing of the pathophysiological mechanisms underlying the different rate of joint deterioration and severity of disease.
Data published in 2018 by Mancuso et al.,27 reporting a study aimed at the development and validation of criteria to define clinically severe hemophilia (CSH), showed again that FIX deficiency is associated to a milder clinical phenotype when comparing patients with the same resid- ual factor activity. In this study, the authors evaluated the ability of residual circulating FVIII/FIX measured at diag- nosis using a one-stage clotting assay to discriminate a severe clinical phenotype (defined a priori as a CSH score >3). Importantly, the results showed a sensitivity of 0.87 [95% Confidence Interval (CI): 0.81-0.91] for FVIII but only 0.68 (95%CI: 0.43-0.87) for FIX, considering a cut-off of 1 IU/dL. In this study, 65.5% (156 of 238) of severe HA patients and 41.2% (13 of 31) of severe HB patients had a CSH score >3. The higher proportion of patients with HA with a severity score >3 suggests also in this cohort of patients the possible milder phenotype in patients with HB. Among patients with severe disease, the odds of hav- ing a clinically more severe form of bleeding symptoms in HA was 2.63 (95%CI: 1.23, 5.64). These results have been recently confirmed also in a study on HA and HB patients with mild disease.28
Orthopedic surgery
The need for orthopedic surgical treatment can be con- sidered a surrogate of severity of hemophilia disease. Chronic arthropathy is a consequence of recurrent bleed- ing into joints, hemarthrosis, which is a hallmark of severe hemophilia. The higher the number of bleeds in the joints, the higher the chance that a patient will develop permanent bone and cartilage damage requiring surgical intervention. In a retrospective national collection of data on hemophilia patients who underwent joint arthroplasty, Tagariello et al.17 found an Odds Ratio of 3.38 (95%CI: 1.97-5.77; P<0.001) when considering the risk of undergo- ing orthopedic surgery in HA compared to HB. This differ- ence was confirmed after adjustment for human immun- odeficiency virus, hepatitis C virus, and inhibitor status [Hazard Ratio (HR): 2.65; 95%CI: 1.62-4.33; P<0.001]. It is important to note that neither HA nor HB patients had been on regular primary prophylaxis during their lifetime before arthroplasty.
A study on a smaller cohort of patients from the Netherlands could not confirm these results.29 However, this Dutch analysis was based on a substantially lower number of arthroplasty interventions and patients were mostly on factor prophylaxis (77% in HA, 73% in HB).
A more recent study from the hemophilia treatment centers in the USA collected data on mild and moderate hemophilia patients who were exclusively treated with on-demand therapy.16 Patients with inhibitors were excluded. A total of 4,771 patients were included in the analysis; 289 (6%) had had orthopedic surgery, such as synovectomy (n=75), joint fusion or joint replacement
(n=126), and 123 had a different type of invasive orthope- dic procedure. Interestingly, in the regression analysis, the predicted number of joint bleeds for patients with factor activity <30% was greater for patients with HA. Also, the likelihood of undergoing an invasive orthopedic proce- dure was lower for HB patients (OR: 0.7, 95%CI: 0.5-0.9). These data are consistent with the Italian experience which has also suggested a more frequent progression to orthopedic surgery among patients with HA. Taken together, these results suggest a milder natural history of the disease in the individuals affected by HB. Table 1 sum- marizes the main clinical findings reported in the studies.
Potential mechanisms affecting the variability in disease severity between hemophilia A and hemophilia B Several possible underlying biological explanations for differences in disease severity can be hypothesized and are presented here. A summary of these mechanisms is
reported in Figure 2.
Associated prothrombotic abnormalities - the variable severity and frequency of bleeding that patients with hemophilia can experience, even at the same measured factor activity, has long been reported. The presence of an associated hypercoagulable state, such as gain-of-function mutations (FV Leiden or prothrombin G20210A) and other coagula- tion abnormalities (deficiencies of antithrombin, protein C, protein S), has been hypothesized to modulate the bleeding phenotype. However, the clinical relevance of such factors in modifying the clinical phenotype of severe hemophilia patients is still uncertain. In fact, a low prevalence of such prothrombotic factors in severe HA and HB patients with a milder phenotype30,31 has been reported and conflicting results from different studies have been seen.32-35 A more recent study investigating ETP as predictor of the clinical phenotype in severe hemophilia patients showed no differ- ences in the distribution of FV Leiden or prothrombin G20210A mutations between severe HA and HB patients.3
Extravascular distribution of FIX – a possible explanation for a milder phenotype in HB patients may lie in differ- ences in the molecular characteristics and different phar- macokinetics of FVIII and FIX proteins. FVIII resides exclu- sively in the intravascular space, and its residence time is determined exclusively by the rate of plasma clearance. In contrast, FIX also distributes extravascularly. Since the first pharmacokinetic studies of FIX concentrates, it has become evident that the volume of distribution of FIX, unlike FVIII, is around four times greater than the estimat- ed patient plasma volume and is similar to the central compartment plus the volume of the extracellular fluid. Significant extravascular FIX compartmentalization may increase the apparent volume of distribution, and poten- tially constitutes a mechanism for extended levels of bio- logically active FIX. In fact, pharmacokinetic studies showed that the PK of FIX is not linear and is most likely best represented by 3-compartment modeling. Assuming a multi-compartmental model implies that the drug in question, here specifically FIX, follows a complex disposi- tion, with receptor binding or compartmentalization in some extra-vascular space, with potential pharmacody- namicimplications.36
Even though there has not yet been a direct demonstra- tion of any clinical impact of such a mechanism, pre-clin-
haematologica | 2019; 104(9)
1705