de Kovel Marloes S, Escuriola-Ettingshausen Carmen, Königs Christoph, Ranta Susanna, Fischer Kathelijn
PedNet Haemophilia Research Foundation, Baarn, The Netherlands.
Hämophilie-Zentrum Rhein Main GmbH, Frankfurt, Germany.
J Thromb Haemost. 2024 Sep;22(9):2460-2469. doi: 10.1016/j.jtha.2024.05.030. Epub 2024 Jun 10.
Information on bleeding phenotype in nonsevere hemophilia may be used to determine target factor levels for prophylaxis or gene therapy in severe hemophilia.
To assess the association between endogenous factor level and bleeding phenotype in children with nonsevere (factor [F]VIII/FIX activity 1%-25%) hemophilia A (HA) and B without prophylaxis.
Data on annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), and onset of bleeding were extracted from the international PedNet cohort including children born since 2000. Mean ABR and AJBR were modeled and compared according to FVIII/FIX endogenous activity (1%-2%, 3%-5%, 6%-10%, 11%-15%, 16%-20%, and 21%-25%) using negative binomial regression. Onset of bleeding was analyzed using Kaplan-Meier survival curves.
Eight hundred twenty-five children (40% with moderate hemophilia; 87% with HA) with median follow-up of 7.4 years/child were included. The median age at onset of bleeding and median bleeding rates changed with increasing endogenous activity. From endogenous FVIII 1% to 2% to 21% to 25%, the age at onset of bleeding changed from a median of 1.4 to 14.2 years, ABR from 1.6 to 0.1/y, and AJBR from 0.5 to 0.0/y. From endogenous FIX 1% to 2% to 16% to 25%, the onset of bleeding changed from a median of 1.7 to 6.1 years, ABR from 0.5 to 0.1/y, and AJBR from 0.1 to 0.0/y. The negative correlation between AJBR and factor level was most strongly pronounced up to a factor level of 6% in HA and hemophilia B.
Endogenous factor activity of >5% was identified as a threshold to significantly lower joint bleeding rate, while FVIII levels >15% and FIX levels >10% were sufficient to achieve the goal of 0 bleeds in this pediatric cohort.
非重度血友病出血表型的信息可用于确定重度血友病预防或基因治疗的目标因子水平。
评估未接受预防治疗的非重度（因子[F]VIII/FIX活性为1%-25%）血友病A（HA）和B患儿内源性因子水平与出血表型之间的关联。
从国际PedNet队列中提取年化出血率（ABR）、年化关节出血率（AJBR）和出血发作的数据，该队列包括2000年以来出生的儿童。使用负二项回归，根据FVIII/FIX内源性活性（1%-2%、3%-5%、6%-10%、11%-15%、16%-20%和21%-25%）对平均ABR和AJBR进行建模并比较。使用Kaplan-Meier生存曲线分析出血发作情况。
纳入825名儿童（40%为中度血友病；87%为HA），每名儿童的中位随访时间为7.4年。出血发作的中位年龄和中位出血率随内源性活性的增加而变化。从内源性FVIII 1%到2%再到21%到25%，出血发作年龄从中位1.4岁变为14.2岁，ABR从1.6次/年变为0.1次/年，AJBR从0.5次/年变为0.0次/年。从内源性FIX 1%到2%再到16%到25%，出血发作从中位1.7岁变为6.1岁，ABR从0.5次/年变为0.1次/年，AJBR从0.1次/年变为0.0次/年。在HA和B型血友病中，AJBR与因子水平之间的负相关在因子水平达到6%之前最为明显。
内源性因子活性>5%被确定为显著降低关节出血率的阈值，而FVIII水平>15%和FIX水平>10%足以在该儿科队列中实现零出血的目标。
