Influencing Factors and Predictors for Bleeding Outcomes in Severe-Type People with Hemophilia a (PwHA) on Extended Half-Life rFVIII-Fc Prophylaxis
Authors: Chang Chia-Yau , Lai Shiue-Wei , Cheng Mei-Mei , CHENG Chao-Neng , Liu Yen-Lin , Tsai Chen-Hua , Tsai Jia-Ruey , Ho Wan-Ling , Hu Shu-Hsia , Chen Yeu-Chin 
Published: December 2024

Introduction: In the past, we had ever reported that real-world severe-type people with hemophilia A (PwHA) got improved bleeding outcomes when they shifted to extended half-life (EHL) recombinant FVIII with Fc-fusion protein (rFVIIIFc) prophylaxis. EHL products showed not only effectiveness in preventing from joint bleeding and arthropathy, but also reducing injection burden. However, despite under regular prophylaxis therapy with EHL FVIII, some of PwHA had still experienced joint bleeding and zero bleeding rate can be achieved on some patients. Regarding bleeding outcomes of PwHA on rFVIIIFc prophylaxis, it existed evident inter-personal variation among patients; However, there were few reports on variation and correlates of bleeding outcome. We aimed to study whether there are clinical factors and pharmacokinetics-related factors influencing bleeding outcomes of real-world PwHA on rFVIIIFc prophylaxis.
Materials & Methods: Severe-type PwHA were retrospectively enrolled from two hemophilia centers, who were switched from rFVIII to rFVIIIFc after 2018. All of them received population pharmacokinetic study by WAPPS-hemo system after switching. Inclusion criteria were non-inhibitor PwHA, being on rFVIIIFc prophylaxis, having data of trough levels and bleeding frequency. Exclusion criteria were inhibitor patients, PwHA with on-demand therapy, or incomplete data. Bleeding frequency was obtained from bleeding records during study period from December, 2018 to July, 2020, with duration of at least &gt; 6 months, which was then annualized as annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR). Other clinical data were collected, including age, BW, BMI, Hct, ABO blood grouping, inhibitor history, HCV infection, week doses, and endogenous von Willebrand factor (VWF) levels. Pharmacokinetic data, including half lives, incremental recovery (IR), Time to 1%, etc. Data of dose regimen of rFVIIIFc prophylaxis were also collected, which were 30-35 iu/kg/dose every 3 days, 40-50 iu/kg/dose every 4 days, or 55-65 iu/kg/dose every 5 days or weekly as per regulations of National Health Insurance.
Results: There were totally 48 non-inhibitor patients (8 boys and 40 adults). The mean age was 34.6±15.9 years (range 8－64). Under rFVIIIFc prophylaxis, median ABR and AJBR was 1.4 and 1, respectively. For patients groups with ABR &lt; 1.4 and &gt;1.4, there were no significant difference in age, BW, BMI, Hct, ABO blood group, positive HCV infection, positive inhibitor history, endogenous VWF levels, weekly doses, dosing intervals, Time to 1%, half lives, and IR. For patients groups with AJBR &lt; 1 and &gt;1, there were the similar results as that of different ABR groups. However, patients groups with ABR &lt; 1.4 and &gt;1.4 had the mean ratio of VWF:activity/VWF:Ag of 0.97 and 0.88 (p&lt;0.05*), respectively; and patients groups with AJBR &lt; 1 and &gt;1 had the mean ratio of VWF:activity/VWF:Ag of 0.96 and 0.89 (p&lt;0.05*), respectively. By correlation analysis, ABR was significantly inversely correlated to ratio of VWF:activity/VWF:Ag. (P-rank=-0.3049, p-value&lt;0.05*) For patients with the ratio &lt; 0.942 and &gt; 0.942, there were no significant difference in age, BW, BMI, Hct, endogenous VWF levels, but there were significantly different in ABR as 3.39 and 1.11, respectively. (p&lt;0.01**) By univariate and multivariate linear regression for ABR, no variables, including age, BW, BMI, Hct, the proportion of ABO group, inhibitor history, endogenous VWF levels, half lives, weekly doses, dosing interval, Time to 1%, and IR, independently influenced ABR/AJBR, except the ratio of VWF:activity/VWF:Ag, which was proved as an independent predictor for ABR.
Conclusion: In our study, for patients with ABR &lt; 1.4 and patients with AJBR &lt; 1, both groups had significantly higher ratio of VWF:activity/VWF:Ag than the oppositive groups. ABR was found to be inversely correlated to ratio of VWF:activity/VWF:Ag. Many clinical factors, dosing regimen, and pharmacokinetic factors were proved to be unable to independently influence bleeding outcomes. Only ratio of VWF:activity/VWF:Ag was proved as a predictor for ABR.