Abstract
目的
利用新的关节综合评估手段研究重型血友病A患儿凝血因子Ⅷ（FⅧ）低中剂量预防治疗的疗效。
方法
47例接受F Ⅷ治疗的重型血友病A患儿（FⅧ活性≤2%），其中18例低剂量预防治疗（FⅧ 10 U/kg，每周2~3次）、20例中剂量预防治疗（FⅧ 15~30 U/kg，每周3次）和9例按需治疗（出血时根据血友病诊断与治疗中国专家共识标准输注FⅧ治疗）患儿。随访180 d，观察临床出血表型、关节结构、关节功能、活动能力四方面指标变化并进行相关性研究，使用Kruskal-Wallis、t检验及Spearman等级相关系数进行统计学分析，P < 0.05为差异具有统计学意义。
结果
低中剂量预防治疗组均较按需治疗组明显改善临床出血表型（P < 0.01），且中剂量预防治疗组改善优于低剂量预防治疗组（P < 0.05）。而且在关节影像结构及功能综合评估方面，血友病关节健康评分（HJHS）总分变化、血友病功能独立性评分量表（FISH）总分变化，最严重单个靶关节彩超和同一最严重单个靶关节HJHS变化4个指标，低中剂量预防治疗组的变化值有明显小于按需治疗组的优势（均P < 0.05），中剂量预防治疗组有可能有优于低剂量预防治疗组的趋势。重型血友病A患儿，年靶关节出血次数（ATJBR）与其彩超评分变化、ATJBR与其HJHS变化、年关节出血次数（AJBR）与FISH总分变化均无相关性（P>0.05）。
结论
FⅧ低中剂量预防治疗较按需治疗明显改善临床出血表型及延缓血友病患儿关节损伤的进展，但临床出血表型不足以全面反映病情进展。
Keywords: 重型血友病A, 预防治疗, 关节综合评估, 相关性
Abstract
Objective
To study the effect of low-and intermediate-dose factor Ⅷ (FⅧ) for prophylactic treatment of severe hemophilia A in children by comprehensively evaluating the outcomes of the joints.
Methods
Forty-seven children with severe hemophilia A (FⅧ activity ≤2%) were enrolled in this study. Eighteen of the children received prophylactic treatment with low-dose FⅧ (10 U/kg, 2-3 times a week), 20 received prophylactic treatment with intermediate-dose FⅧ (15-30 U/kg, 3 times a week), and 9 received on-demand treatment with FⅧ infusion when bleeding occurred according to the Chinese Expert Consensus on the Diagnosis and Treatment of Hemophilia. The children were followed up for 180 days to observe the changes in the indexes of clinical bleeding phenotype, joint structure, joint function, and joint mobility, and the correlation of these indexes were analyzed.
Results
Compared with on-demand treatment, prophylactic treatment with low-and intermediate-dose FⅧ significantly improved the clinical hemorrhage phenotype (P < 0.01), and the improvement was significantly more conspicuous with intermediate-dose prophylactic treatment (P < 0.05). Comprehensive evaluation of the joint structure and function changes showed that compared with on-demand treatment, prophylactic treatment with low-and intermediate-dose FⅧ resulted in significant improvements in the total score of Hemophilia Joint Health Score (HJHS), Functional Independence Score in Hemophilia (FISH), the single most severe target joint ultrasound and HJHS score of the target joint (P < 0.05) and prophylactic treatment with intermediate-dose FⅧ appeared to produce better outcomes of the joint than low-dose FⅧ. No correlation was found between annual target joint bleeding rate (ATJBR) and ultrasound score, between ATJBR and HJHS change, or between annual joint bleeding rate (AJBR) and the total score of FISH (P>0.05).
Conclusion
Compared with on-demand treatment, prophylactic treatment with low-and intermediate-dose FⅧ can significantly improve the bleeding phenotype and delay the progression of joint injury, but the clinical hemorrhagic phenotype is not sufficient to monitor the disease progression.
Keywords: severe hemophilia A, prophylactic treatment, comprehensive evaluation of joint, correlation
重型血友病A患儿以自发性出血为主要临床表现，出血可见于各个部位，其中关节出血最常见，约占出血事件的80%[1]。血友病患儿累及的关节主要见于双侧肘关节、膝关节和踝关节[2]。患儿反复出血可导致慢性关节病变，甚至导致残疾[3-4]。血友病A目前无根治手段，主要是输注凝血因子Ⅷ（Factor Ⅷ，FⅧ）替代治疗，一种为按需治疗，另一种为预防治疗[5]。1994年开始，世界血友病联盟和世界卫生组织就已经开始提倡重型血友病A患者行FⅧ预防治疗[6-7]。目前重型血友病A患儿标准治疗方式是输注FⅧ预防治疗，旨在控制患儿关节出血，避免关节损伤，维护正常肌肉骨骼功能[8-10]。按照预防治疗FⅧ用药的剂量和频率不同，可分为足剂量（20~40 U/kg，3次/周或1次/隔日）、中剂量（15~30 U/kg，每周3次）及低剂量（10 U/kg，每周2~3次）预防治疗方案[10]。欧美等发达国家推荐足剂量预防治疗方案可实现几乎零出血及有效保护关节功能[11-12]，但因子用量和费用较高，不适用于中国等资源有限国家国情。此前国外以及我国多个研究数据证实低中剂量预防治疗亦可明显减少年出血次数（ABR）和年关节出血次数（AJBR），且可短期改善关节活动能力[13-17]，尚未见基于关节评估层面评价疗效的报道。近年证实，ABR和AJBR等临床出血表型与关节影像及功能的损害呈弱相关，其原因不仅是临床出血表型属于主观指标，欠可靠；更因为亚临床出血才是关节损害更重要原因[11, 18]。因此，需要利用新进的关节综合评估手段研究低中剂量预防治疗重型血友病A患儿疗效及相关性分析，为我国等资源有限国家血友病诊疗指南的修订提供依据。
1. 资料和方法
1.1. 研究对象
将2016年3月~2017年3月于南方医科大学南方医院血友病中心门诊接受FⅧ治疗的47例重型血友病A患儿（FⅧ：C≤2%）纳入本次研究。根据中国儿童血友病专家指导意见[10]标准分为低剂量预防治疗、中剂量预防治疗和按需治疗组。其中，低剂量预防治疗组（F Ⅷ 10 U/kg，每周2~3次[10]）18例，年龄为8.8±3.6岁，体质量为33.3±13.4 kg；中剂量预防治疗组（FⅧ 15~30 U/kg，每周3次[10]）20例，年龄为7.7±2.9岁，体质量为26.7± 11.0 kg；另外9例采用按需治疗（出血时根据血友病诊断与治疗中国专家共识[5]标准输注FⅧ治疗）的重型血友病A患者作为对照组，年龄为9.7±5.1岁，体质量为32.8±18.0 kg。所有患儿均为男性，暴露日均>150 d，抑制物检测阴性，无关节/滑膜手术病史。患儿及其监护人均获得了知情同意。
1.2. 研究方法
本研究为单中心、前瞻性、观察性研究。对低中剂量预防治疗及按需治疗3组患儿进行180 d以上随访观察研究。除了ABR、AJBR和靶关节年出血次数（ATJBR）等临床出血表型的传统评价指标，采用国际新进的血友病关节综合评估方法：血友病关节健康评分（HJHS 2.1）、关节超声影像学（彩色多普勒超声，彩超）、血友病功能独立性评分量表（FISH），研究重型血友病A患儿在低中剂量预防治疗方案下的关节结构、功能以及活动能力变化等疗效指标。
1.3. 评估指标
1.3.1. 靶关节
参照国际标准定义[9]：半年内AJBR≥3次的关节为靶关节；若连续一年内某关节AJBR≤2次，则不再视为靶关节。
1.3.2. 临床出血表型
包括ABR、AJBR、和ATJBR。入组患儿利用本中心自行设计的并正式上线的国内第1个“血友管家”APP进行出血及治疗记录，通过后台收集到患儿随访时间内出血次数、关节出血次数和靶关节出血次数然后进行年化处理，公式如下：ABR/AJBR/ ATJBR=参与随访时间内出血次数、关节出血次数和靶关节出血次数÷参与随访时间×365.25。
1.3.3. 关节彩超影像变化
使用关节彩超对患儿最严重单个靶关节进行结构评定。关节彩超可发现关节积液、滑膜、关节软骨及骨质等部分病变[19]。参照Doria的评分标准[20]将最严重单个靶关节的检查结果进行量化评分，分别在患儿入组时和随访6月后的最严重单个靶关节进行评分，评估患者关节结构状态变化情况（关节超声影像变化=随访6月后彩超得分-入组时彩超得分，正值则表示关节功能恶化，负值则表示关节功能好转）。操作人员均经Doria教授培训确保准确。
1.3.4. 关节功能变化
采用我们参与验证的国际HJHS 2.1关节功能评估方法[21]。HJHS2.1主要对患者的双侧肘关节、膝关节和踝关节进行关节肿胀、肌肉萎缩、肌力、关节疼痛、关节摩擦音、关节伸展度和步态等方面进行评分。本研究以HJHS2.1表分别测评患者入组时和随访6月后的关节功能状态，评估患者关节功能状态变化情况（HJHS变化值=随访6月后HJHS得分-入组时HJHS得分，正值则表示关节功能状态恶化，负值则表示关节功能状态好转）。
1.3.5. 活动能力评分
使用FISH对患儿的日常活动能力进行量化评分[22]。本研究以FISH量表分别对患者入组时和随访6月后的活动能力进行评分，评估患者活动能力变化情况（FISH变化值=随访6月后FISH得分-入组时FISH得分，如为正值则活动能力改善，如为负值则活动能力下降）。
1.4. 统计学方法
采用统计软件IBM SPSS 22.0进行数据分析。P < 0.05为差异具有统计学意义。对两组变量进行对比时，使用Kruskal-Wallis及t检验；分析两项评估指标相关性时使用Spearman等级相关系数。
2. 结果
2.1. 一般资料
47例患儿均按要求完成了180 d的随访。按照预防治疗剂量和频率，预防治疗的38例患儿分为18例低剂量预防治疗组及20例中剂量预防治疗组，9例按需治疗患儿作为对照。3组患儿的年龄、体质量、体质量指数、首次出血年龄、首次关节出血年龄和诊断年龄等相关一般资料无统计学差异（P>0.05，表 1）。
1.
三组重型血友病A患儿的一般资料比较
Comparison of general data among the 3 groups of children with severe hemophilia A (Mean±SD)
| Parameters | On-demand group | Low-dose group | Intermediate-dose group | P |
| Case | 9 | 18 | 20 | |
| Age (year) | 9.7±5.1 | 8.8±3.6 | 7.7±2.9 | 0.602 |
| Weight (kg) | 32.8±18.0 | 33.3±13.4 | 26.7±10.9 | 0.353 |
| Body mass index (kg/m2) | 18.1±3.6 | 18.5±4.7 | 16.0±2.5 | 0.160 |
| Age of first bleeding (year) | 1.1±0.8 | 1.3±1.2 | 1.2±0.7 | 0.705 |
| Age of first joint bleeding (year) | 1.6±1.2 | 1.8±1.2 | 1.6±0.9 | 0.864 |
| Age at diagnosis (year) | 2.7±3.7 | 1.5±1.9 | 1.1±0.8 | 0.447 |
2.2. 临床出血表型
低剂量预防治疗组和中剂量预防治疗组与按需治疗组比较，临床出血表型（ABR、AJBR、ATJBR）均明显改善（低剂量预防治疗组：ABR减少79.99%，AJBR减少77.82%，ATJBR减少75.00%；中剂量预防治疗组：ABR减少87.79%，AJBR减少86.07%，ATJBR减少85.25%），均有明显差异（P < 0.01）；且中剂量预防治疗组较低剂量治疗组出血次数更少（P=0.010，0.018，0.018，表 2）。
2.
按需治疗组和低中剂量预防治疗组的临床出血表型比较
Comparison of clinical hemorrhage phenotype among the 3 groups (Mean±SD)
| On-demand group | Low-dose group | Intermediate-dose group | P1 | P2 | P3 | |
| P1: Comparison between the on-demand group and the low-dose group; P2: Comparison between the on-demand group and the intermediate-dose group; P3: Comparison between the low-dose group and the intermediate-dose group. | ||||||
| ABR | 38.89±27.30 | 7.78±4.05 | 4.75±2.40 | 0.009 | 0.006 | 0.010 |
| AJBR | 26.56±16.54 | 5.89±3.25 | 3.70±2.15 | 0.006 | 0.003 | 0.018 |
| ATJBR | 20.00±12.31 | 5.00±3.09 | 2.95±1.20 | 0.006 | 0.003 | 0.018 |
2.3. 关节功能及活动能力变化
与入组时基线水平相比较，按需治疗组、低剂量预防治疗组、中剂量预防治疗组随访180 d后的HJHS总分均增加及FISH总分均降低。低剂量和中剂量预防治疗组的HJHS总分及FISH总分变化均明显低于按需治疗组（P < 0.05）。中剂量预防治疗组的HJHS和FISH总分变化均有小于低剂量预防治疗组趋势，但180 d内低剂量预防治疗组与中剂量预防治疗组两者无明显差异（P>0.05，表 3）。
3.
按需治疗组和低中剂量预防治疗组的HJHS总分及FISH总分变化比较
Comparison of variation of HJHS and FISH scores among the 3 groups (Mean±SD)
| On-demand group | Low-dose group | Intermediate-dose group | P1 | P2 | P2 | |
| P1: Comparison between the on-demand group and the low-dose group; P2: Comparison between the on-demand group and the intermediate-dose group; P3: Comparison between the low-dose group and the intermediate-dose group. | ||||||
| Variation of the total score of HJHS | 3.33±0.87 | 2.00±1.46 | 1.50±2.54 | 0.019 | 0.046 | 0.469 |
| Variation of the total score of FISH | -2.78±0.97 | -0.78±0.43 | -0.60±0.60 | 0.000 | 0.000 | 0.296 |
2.4. 最严重单个靶关节彩超影像及功能变化
按需治疗组、低剂量预防治疗组和中剂量预防治疗组的最严重单个靶关节超声及HJHS评分均有增加。低剂量预防治疗组和中剂量预防治疗组的超声及HJHS评分增加值均明显低于按需治疗组（P≤0.01）。中剂量预防治疗组的最严重单个靶关节超声及HJHS评分变化均有小于低剂量预防治疗组趋势，但180 d内低剂量预防治疗组和中剂量预防治疗组两组尚无统计学差异（P>0.05，表 4）。
4.
按需治疗组和低中剂量预防治疗组的最严重单个靶关节彩超及其HJHS评分变化的比较
Comparison of variation of ultrasonic and HJHS score of the most severe target joint among the 3 groups (Mean±SD)
| On-demand group | Low-dose group | Intermediate-dose group | P1 | P2 | P3 | |
| P1: Comparison between the on-demand group and the low-dose group; P2: Comparison between the on-demand group and the intermediate-dose group; P3: Comparison between the low-dose group and the intermediate-dose group. | ||||||
| Variation of ultrasonic score of the most serious target joint | 2.00±0.71 | 0.78±0.65 | 0.55±1.15 | 0.000 | 0.002 | 0.451 |
| Variation of HJHS Score of the most serious target joint | 1.22±0.67 | 0.50±0.62 | 0.15±0.93 | 0.010 | 0.005 | 0.187 |
2.5. 三组重型血友病患儿的临床出血表型与最严重单个靶关节HJHS及其彩超和FISH总分变化相关性分析
按需治疗、低剂量预防治疗和中剂量预防治疗3组重型血友病A患儿，ATJBR与其彩超评分变化、ATJBR与其HJHS变化、AJBR与FISH总分变化均无相关性（r=0.270，P=0.060；r=0.257，P=0.081；r=0.247，P=0.094，图 1~3）。
1.
ATJBR与其彩超评分变化的相关性
Correlation between ATJBR and changes of ultrasonic scores.
3.
AJBR与FISH总分变化的相关性
Correlation between AJBR and changes of FISH total score.
2.
ATJBR与其HJHS评分变化的相关性
Correlation between ATJBR and changes of HJHS score.
3. 讨论
已有数据证实足剂量预防治疗较按需治疗明显有效的控制出血，保护关节功能状况甚至达到正常的状态，为世界血友病联盟（WFH）推荐的《血友病防治指南》和欧美重型血友病A的标准治疗方式提供了依据[11]。然而对于资源有限的发展中国家，难以承受足剂量预防治疗的因子消耗及费用，只能以低剂量和中剂量预防治疗甚至按需治疗作为主要的治疗方案。近年来已有多项研究证明在资源有限条件下，低剂量和中剂量预防治疗在改善临床出血表型、提高生活质量方面效果明显优于按需治疗。Fischer等[13]比较了应用中剂量和足剂量预防治疗方案，Fischer等[14]回顾1974至1979年期间荷兰中剂量预防治疗的情况，表明中剂量预防治疗可以有效控制出血，在某种程度上减少关节病变。本中心参与的中国多中心中重型血友病A患儿短期低剂量预防治疗前瞻性研究[23]及吴润晖报道的单中心中重型血友病A患儿低剂量预防治疗研究[24]证实低剂量预防治疗可减少出血事件，提高日常活动能力。本课题组的重型血友病A儿童和成人低中剂量预防治疗研究[16, 25]也有类似结论。
既往研究低中剂量预防治疗疗效主要是以ABR和AJBR等临床出血表型为观察指标，旨在减少出血次数。但是，预防治疗不仅是控制或减少出血事件，更重要的是防止或延缓关节病变发生及进展，从而保护关节结构功能，维持正常活动能力。本次研究基于ABR、AJBR、ATJBR等临床出血表型传统指标上，利用目前国际新进的敏感性更高的HJHS评分、彩超、FISH评分进行评估，评估手段更为全面。结果表明了低中剂量预防治疗均较按需治疗明显改善临床出血表型，与此前结论及国内外研究相同。在关节影像结构及功能综合评估方面，HJHS总分变化、FISH总分变化，最严重单个靶关节彩超和最严重单个靶关节HJHS评分变化四个指标，低中剂量预防治疗的变化值有明显小于按需治疗的优势，而且中剂量有可能有优于低剂量预防治疗的趋势。
有关临床出血表型与关节结构、关节功能、活动能力的相关性研究，目前国内未见报道。近年来发现有些患者临床出血次数与关节病变呈弱相关性，有数据表明，AJBR与核磁共振（MRI）结果不一定相关，有些患者既往未发现关节出血事件，MRI检查显示关节损害，而且有些患者即使出现多次关节出血，MRI检查并未发现关节损伤，这除了亚临床出血情况存在外，也说明个体关节出血对骨和软骨造成损害敏感性有关[11, 26-27]。从本研究的初步数据可见：重型血友病A患儿，ATJBR与其彩超评分变化、ATJBR与其HJHS变化、AJBR与FISH总分变化均无相关性或可能有弱相关性，与国外在足量预防治疗研究中的发现类似。说明临床出血表型并不能有效评价重型血友病A患儿低中剂量预防治疗的病情变化。研究在资源有限条件下重型血友病A患儿低中剂量预防治疗的疗效时，不仅需要ABR、ATJBR、AJBR等临床出血表型传统指标，更应利用新进敏感性更高的HJHS、彩超、FISH等指标才能更全面、准确地评估患儿关节结构、功能及活动能力等病情变化。本研究进一步证实低中剂量预防治疗能改善临床出血表型，但效果不如足量预防治疗，只能一定程度延缓关节结构、功能及活动能力病情进展，中剂量预防治疗有优于低剂量预防治疗的趋势，短期内却未见明显差异性。今后需要有更长期的重型血友病A患儿低中剂量预防治疗的疗效研究，弥补目前国际上有关资源有限条件下重型血友病A患儿关节功能状况变化规律等相关数据的空白，为我国等资源有限国家血友病诊疗指南的修订提供依据。
从本研究和既往本课题组与国内有关低中剂量预防治疗的研究数据可见，低中剂量预防治疗与国外足剂量预防治疗均较按需治疗明显改善临床出血表型，均明显改善活动能力，但足剂量预防治疗多可实现零出血，而低中剂量预防治疗无法实现零出血，甚至无法达到2017年中国儿童血友病专家指导意见[10]建议血友病患儿AJBR应控制在3次以下从而达到保护肌肉关节功能状况的目标。从本研究的关节结构、关节功能和活动能力指标判断，180 d随访低中剂量预防治疗组最严重单个靶关节彩超影像及HJHS评分均有一定程度增加，且HJHS总分和FISH总分均有进展的趋势。这说明低中剂量预防治疗可以明显改善临床出血表型及活动能力，亦可以较按需治疗改善关节影像及功能和活动能力的变化，即延缓关节损伤的进展，但可能仍无法完全阻止或逆转血友病关节病情进展。
Biography
庄金木，硕士研究生，E-mail: 15915709806@163.com
Funding Statement
南方医科大学临床重点研究项目（LC2016ZD016）
Contributor Information
庄 金木 (Jinmu ZHUANG), Email: 15915709806@163.com.
孙 竞 (Jing SUN), Email: jsun_cn@hotmail.com.
References
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