Descriptive and Epidemiological Study of Joint Damage in Non-Severe Hemophilia: Update of the Damage Study of the Mediterranean Group

Introduction: There is growing evidence indicating joint damage (JD) in non-severe hemophilia (nSH) patients. Although age and baseline factor (F) VIII/FIX levels have been proposed as good predictors of JD in mild hemophilia (MiH), data are scarce and in moderate hemophilia (MoH) are lacking. Besides, global hemostatic capacity (GHC) in this population and its contribution to JD has not been assessed.

Methods: We designed a cross-sectional, observational and multicenter study carried out in 12 Spanish hospitals (Mediterranean Group). We evaluated JD in nSH patients and its correlation with age, baseline FVIII/FIX and GHC. JD was defined as a HEAD-US score >0. Baseline FVIII (chromogenic assay), FIX (clotting assay) and GHC (assessed by thrombin generation test, TGT, Genesia^®, Stago) were evaluated in a central laboratory. Results were expressed as median (25^th-75^th percentiles). Categorical variables were expressed with percentage. A p value<0.05 was considered statistically significant.

Results: A total of 98 nSH patients were included: 10 (10.2%) MoH (9 HA: age= 35.6 [21.7-45.0] years old (YO); FVIII = 4.0 [4.0-5.0] IU/dL; 1 HB: FIX= 2 IU/dL) and 88 MiH (84 HA: age= 38.6 [19.0-52.1 YO]; FVIII= 15.5 [11.0-24.0] IU/dL; 4 HB: FIX= 30.0 [16.8-35.4] IU/dL). Target joints were observed in patients with MiH (7/88: 8.6% of the MiH patients). HEAD-US score was obtained in 73 patients (74.5% of the total participating patients): nine MoH patients presented a HEAD-US= 1 (0-6) (age: 32.7 [21.7-42.9] YO) while 64 MiH patients presented a HEAD-US= 0 (0-3) (age: 37.9 [17.8-48.7] YO) (comparison between MoH and MiH patients: HEAD-US: p=0.427, age: p= 0.614). Only 55.5% (5/9) MoH patients and 45.3% (29/64) MiH patients, presented JD (p=0.725). Baseline FVIII/FIX was 13.0 (7.0-20.0) IU/dL and 16.0 (11.0-22.5) IU/dL in patients with or without JD respectively (p= 0.311). These mild difference of number of patients with JD and degree of JD between MiH and MoH were corroborated by not detecting correlation between baseline FVIII/FIX levels and JD (r= -0.095; p= 0.426) (Figure 1). JD increased with age (r= 0.380; p= 0.001) reinforcing previous findings. GHC correlated with baseline FVIII/FIX (Table 1) but not with the degree of JD, suggesting that thrombin generation, with the used conditions, might not be helpful to predict JD in this population.

Conclusions: Around 50% of patients with nSH presented JD. This JD increased with age, supporting previous data. Although there was a correlation between baseline FVIII/FIX levels and thrombin generation, none of the TGT parameters were predictive of the degree of JD, enhancing that other variables might be influencing the development of JD in nSH patients. Of note, MiH individuals may develop severe JD due to presence of target joints. In summary, our results highlight the importance of evaluating JD in nSH in order to determine whether new protocols are required for the diagnosis, prevention, and treatment of JD in nSH patients.