Characteristics and Effected Factors of Break-through Bleedings in Tertiary Prophylaxis with Low and Intermediate-Dose in Chinese Adults with Severe Hemophilia

Background and Objective The characteristics of break-through bleedings (BTBs) in tertiary prophylaxis with low and intermediate-dose for chinese severe hemophilia A adults has not been reported, and with a depth understanding of the effected factors also help to further explore the resource-constrained individualizing prophylaxis, so as to find a suitable method to improve the efficacy of low and intermediate -dose prophylaxis. Methods Prospective observation and collect the case data; used the "Hemophilia Steward" APP to record the bleedings and injections accurately, analysis the correlation of BTB with own factors(age and body mass index ,BMI), past situation(bleeding phenotype, prophylactic time before follow-up, joint images, joint function, activity ability) and treatment regimen (dose, injection interval, the trough FVIII level, PK). Results There were 15 cases (Low-dose group) with the low-dose prophylaxis, median follow-up time 172 days (range,143-232 days) and 144 bleedings were recorded.There were 34 cases (Intermediate -dose group) with the intermediate -dose prophylaxis, median follow-up time 176.5 days (range,128-264 days) and 193 bleedings were recorded. Compared to Intermediate -dose group ,Low-dose group with less factor consumptions(107.06±42.58IU/kg/m vs 134.29±23.36IU/kg/m),but more BTBs and joint break-through bleedings(JBTBs)(18.15 /y vs 10.18 /y and 17.18 /y vs 6.25 /y),spontaneous breakthrough bleeding ratio was higher(75% vs 47.7%),more target joints and proportion of patents with target joint was higher(1 vs 0 and 80% vs 44.12%), target joints in the joint breakthrough bleeding accounted for a higher proportion(59.03% vs 41.45%),breakthrough bleed probability in 12-48 hours after injection was higher(64.68% vs 47.67%),and meaning a earlier breakthrough bleed time(40.08h vs 46.08h)(p <0.05,all of the above). The JBTBs in both groups were negatively correlated with the prophylactic dose(r=-0.539, p=0.038 and r=-0.418, p=0.014);4/9 (44.44%) in low-dose group and 8/23 (34.78%) in intermediate -dose group had a 72 hFVIII trough concentration of less than 1%;When prophylactic dose≤14 IU / kg / time, the JBTBs time was positively correlated with prophylactic dose(n=17, r=0.531, p=0.028).4 patients with intermediate-dose underwent PK testing and 27 bleedings were recorded, BTBs 9.6-16.4 times / year, half-life 6.64-8.70h, short half-life was the most likely causes of breakthrough bleeding in those patents. 15 /27 (55.56%) occurred in the FVIII concentration of less than 1%, 3/27 (11.11%) in 2% -3%, 1/27 (3.7%) in >3%. JBTBs in both groups were positively correlated with the bleeding phenotype(number of annual joint bleeding at the time of on-demand treatment, Pre-AJBR)(r=0.674, p=0.006and r=0.394, p=0.021), negatively correlated with FISH(r=-0.702, p=0.004 and r=-0.359, p=0.037); The correlation with age, BMI, prophylactic time before follow-up, joint images and joint function has not been observed( p >0.05). Conclusion Low and intermediate-dose tertiaryprophylaxis with the existence of insufficient dose that can not maintain the minimum effective valley concentration for adult sHA in china, meaning that lost of SHA were still not able to achieve the goal of preventing joint disease form progression. Although the prophylactic dose was the most important effected factor of the efficacy, reduce the target joint, improve bleeding phenotype and activity ability, adjust the dose and frequency based on individual PK parameters, schedule of work and prophylactic time reasonably and other non-factor approachs also can improve the efficacy.