FⅧ剂量对青少年重型血友病A的关节结构与功能的影响:43例前瞻性队列研究中期随访报告

目的 运用综合评估手段比较分析不同剂量FⅧ治疗下青少年重型血友病A患者的临床表型、关节结构与功能变化规律。方法 43例青少年（4~18岁）重型血友病A患者，分为按需组（n=7），低剂量预防组[FⅧ 10~15 U/kg，2~3次/周，且≤30 U/（kg·周），n=17]，中剂量预防组[FⅧ 15~20 U/kg，2~3次/周，且45~60 U/（kg·周），n=19]。比较分析其24月间临床出血表型[年出血率/年关节出血率/最严重单个关节年出血率]、关节影像评分（超声HEAD-US评分，IPSG MRI评分）、血友病关节健康评分量表（HJHS）、血友病功能独立性评分（FISH）及变化规律。使用Kruskal-Wallis检验、Wilcoxon和重复测量的方差分析进行统计检验。结果 低中剂量组的年出血率较按需组明显减少（P1=0.004，P2=0.000），中剂量较低剂量组减少32.87%。按需组、低剂量组和中剂量组的年关节出血率差异有统计学意义（P1=0.001，P2=0.000，P3=0.001）。按需组、低剂量组和中剂量组的最严重单个关节年出血差异有统计学意义（P1=0.016，P2=0.000，P3=0.005），按需组出血次数渐快增加，低剂量组维持不变，中剂量组则有减缓趋势。3组患者最严重单个关节影像学评分均有进展。低中剂量组的超声评分变化值进展较按需组延缓（P1=0.002，P2=0.000），按需组评分按原速率增长，低、中剂量组均有减缓趋势。低中剂量组的MRI评分变化值进展较按需组均有延缓（P1=0.041，P2= 0.000），按需、低剂量组评分增长加快，中剂量组速率保持不变。按需组的HJHS评分变化值较低中剂量组增加（P1=0.003，P2= 0.000）；按需组保持原有增长速度，低、中剂量组评分均出现负值趋势。按需组FISH评分降低0.29±3.09分，低中剂量组均回升，与按需组差异有统计学意义（P1=0.000，P2=0.000）。结论 两年中期随访结果显示，中国青少年低中剂量FⅧ的预防治疗在保护关节结构和功能方面明显优于按需治疗，中剂量可能稍优于低剂量预防。

Effect of FVIII doses on joint structure and function in adolescents with severe hemophilia A: mid-term results of a prospective cohort study

Objective To explore the clinical phenotype and changes in joint structure and function in adolescent patients with severe hemophilia A under different doses of FVIII. Methods Forty- three adolescents with severe hemophilia A aged 4-18 years were divided into on-demand group (n=7), low-dose group (FVIII dose of 10-15 U/kg, 2-3 times a week, and ≤30 U/kg a week; n=17), and intermediate-dose group (FVIII dose of 15-20 U/kg, 2-3 times a week, and 45-60 U/kg a week (n=19). The 3 groups were compared for their clinical bleeding phenotype, annual bleeding rate (ABR), annual joint bleeding rate (AJBR), annual the most severe joint bleeding rate, joint imaging scores (ultrasound HEAD-US score and IPSG MRI score), Hemophilia Joint Health Score (HJHS) and Functional Independence Score in Hemophilia (FISH) within 24 months. Results Compared with that in on-demand group, the ABR was significantly reduced in the low- and intermediate-dose groups (P=0.004 and 0.000, respectively), and was reduced by 32.87% in the intermediate-dose group as compared with the low-dose group. The AJBR (P<0.01) and annual the most severe joint bleeding rate (P<0.05) also differed significantly among the 3 groups. The number of bleeding episodes increased progressively with time in the on-demand group, remained stable in the low- dose group, and tended to decrease in the intermediate- dose group. The imaging scores of the most severe joints showed lesion progression in all the 3 groups. The ultrasound scores, which increased steadily in the on-demand group, showed significantly lowered increment rates in the low- and intermediate-dose groups (P=0.002 and 0.000, respectively). The MRI scores showed also delayed increment in the low- and intermediate-dose groups as compared with the on-demand group (P=0.041 and 0.000, respectively), and the increment was accelerated in the on-demand and low-dose group but remained stable in the intermediate-dose group. The increment of the HJHS scores was significantly higher in the on-demand group than in the low- and intermediate-dose groups (P=0.003 and 0.000, respectively), and the scores increased at a steady rate in the on-demand group but tended to decrease in the latter two groups. The FISH score was decreased by 0.29±3.09 in the on-demand group but was increased significantly in the low- and intermediate-dose groups compared with the on-demand group (P=0.000). Conclusion In Chinese adolescents with severe hemophilia A, low- and intermediate-dose FVIII prophylaxis , especially at the intermediate dose, is better than on-demand treatment for protecting joint structure and function.