Introduction: Recent data indicate joint damage (JD) in non-severe hemophilia (nSH), but evidences are still scarce. In nSH, the discrepancy on basal factor (F) VIII or FIX (FVII/FIX) levels between the coagulative (coag) and chromogenic (chrom) assays makes it difficult to predict the bleeding phenotype in this group of patients. The global hemostatic capacity (GHC) evaluated by thrombin generation test (TGT) or thromboelastometry (ROTEM®), might be useful in this field, although there are only few available data.

Objectives: To evaluate the JD in nSH patients as well as the correlation between JD, basal FVIII/FIX levels, age and GHC. We also aim to determine the degree of discrepancy between FVIII-chrom and FVIII-coag values in this group of patients.

Methods: Cross-sectional, prospective and pilot study in 9 Spanish hospitals was performed. nSH patients ≥12 years old without (or history) of prophylactic treatment were included. Patients with coagulation disorders other than hemophilia were excluded. JD (HEAD-US>0), basal levels of FVIII-chrom, FVIII/FIX-coag, fibrinogen Clauss (Fib), TGT (Genesia®), ROTEM® (exTEM, inTEM and fibTEM), platelet (PTS) and erythrocyte counts (ERY) were determined. Statistical analyses were two-sided and a p-value < 0.05 was considered statistically significant.

Results: A total of 56 patients: 6 moderate hemophilia (MoH) and 50 mild hemophilia (MiH) patients were included. The values of PTS, ERY and Fib were withing the normal ranges. The HEAD-US score was evaluated in 46 patients (6 MoH-A and 40 MiH-A patients; 276 joints in total) and indicated a higher % of patients with JD in the MoH group (100% of patients) vs. the 51.2% in the MiH (p=0.212). As expected, the median value of HEAD-US score was higher in MoH (MoH: 7.5 [5.0-12.0] vs. MiH: 1.0 [0.0-4.0], p= 0.019). Surprisingly, the median basal FVIII/FIX was similar between the groups with and without JD: 14.5 (11.0-20.0) IU/dL vs. 14.0 (11.0-17.0) IU/dL, respectively (p= 0.842). Another non-expected result was that 10% of MiH patients presented a target joint. No correlation was observed between HEAD-US score and GHC, age or basal FVIII/FIX levels. However, increasing basal FVIII/FIX levels affected the GHC by decreasing the CT-inTEM (clotting time: time to initiation of clot formation by the intrinsic pathway) (r= -0.715, p< 0.001), increasing the peak of thrombin generation (TG) (r= 0.334, p=0.014), shortening the time to reach the start tail (ST) of the TG curve (r= -0.271, p=0.048) and increasing the speed (velocity index, VI) of TG (r= 0.310, p= 0.024). As previously described, the increment of Fib incremented the lagtime (time to initiation of TG) and the time-to-peak of TG (r= 0.531, p<0.001 for both parameters), and also decreased the VI (r= -0.323, p= 0.022). Moreover as a typically described effect, increment of Fib increased the strength of the clot (Fib vs MCF-exTEM, MCF-inTEM and MCF-fibTEM (MCF=maximum clot firmness): r= 0.557, p= 0.006; r= 0.547, p= 0.008 and r= 0.417, p= 0.043, respectively). Increment in PTS decreased the clot formation time (CFT) and increased MCF (PTS vs CFT-inTEM and MCF-inTEM: r= -0.417, p= 0.034 and r= 0.638, p= 0.001, respectively). The degree of correspondence between FVIII-chrom and FVIII-coag was 79.5%.

Conclusions: Patients with nSH may present JD. Neither basal FVIII/FIX levels, nor GHC, nor age correlated in our study with the degree of JD though wider studies are needed to confirm these findings. Although correlation between basal levels of FVIII/FIX and GHC was observed, none of these variables were able to explain the degree of JD. Target joints can be observed in patients with MiH, therefore additional studies are necessary to clarify the need of new therapeutic intervention in this group of patients. Future studies should address the relationship between degree of JD (values of HEAD-US) and patients' quality of life (QoL) to stablish cutoff values of HEAD-US score that may affect the QoL. The unexpected high % of nSH patients with JD urges the need for larger studies on JD in this population to clarify the need of new type of therapeutic intervention in this group of patients.

No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.

Sign in via your Institution