组织金属蛋白酶抑制剂-1 和血管内皮生长因子在接受低剂量预防性重组因子 VIII 治疗的重度血友病 A 患儿中的作用：与亚临床关节病的关系。
Tissue-inhibitors of metalloproteinase-1 and vascular-endothelial growth-factor in severe haemophilia A children on low dose prophylactic recombinant factor VIII: Relation to subclinical arthropathy.
机构信息
Pediatric Department, Faculty of Medicine, Ain-Shams University, Cairo, Egypt.
Radiology Department, Faculty of Medicine, Ain-Shams University, Cairo, Egypt.
出版信息
Haemophilia. 2020 Jul;26(4):607-614. doi: 10.1111/hae.14041. Epub 2020 May 23.
BACKGROUND
Subclinical synovitis occur long before clinical haemophilic arthropathy (HA). New biomarkers are needed for early detection of HA.
AIM
To compare the levels of tissue inhibitors of metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF)in severe haemophilia A boys on prophylaxis and on-demand therapy to healthy boys and correlate them with the haemophilia joint health score (HJHS) & the Denver magnetic resonance imaging (MRI) scale; hence, determine their values in early detection of HA.
METHODS
Haemophilia joint health score, serum TIMP-1, VEGF and Denver MRI score were assessed in 50 boys with severe haemophilia A (31 on prophylactic factor VIII therapy (62%) with a dose of 15 IU/kg/twice weekly) and 50 age-matched healthy boys.
RESULTS
Boys with severe haemophilia A had significantly higher TIMP-1 240 ng/mL, SD200-350 (P < .001) and VEGF 600 pg/mL, SD400-1100 (P < .001). Their mean HJHS was 4.5 ± 3.0 (0-11) and their mean Denver MRI score was 5.55 ± 1.6 (2.00-8.00). A significant positive correlation was found between TIMP-1 and VEGF (P < .001), BMI Z-score (P = .029), HJHS (P = .041)and total MRI score (<.001). Significant correlations were found between VEGF and age (P < .001), HJHS (P = .003) and total MRI score (P < .001). Boys with severe haemophilia A on prophylaxis therapy had significantly lower HJHS (P = .021), VEGF (P < .001), TIMP-1 (P = .002) and total MRI score (P = .021) than those on on-demand therapy. Receiver operating characteristic curve, defined a cut-off value of 160 ng/mL for TIMP-1 with a sensitivity of 90% and specificity of 60% and that of 350 pg/mL for VEGF with a sensitivity of 78% and specificity of 88% for discrimination between severe haemophilia A and healthy boys.
CONCLUSION
Vascular endothelial growth factor and TIMP-1 can be used for early detection of HA. Further prospective studies should include larger study populations. In addition, studies should address the role of various anti-VEGFs as potential therapy for HA and their impact on prevention and treatment of HA.
背景
亚临床滑膜炎早在血友病性关节病（HA）的临床症状出现之前就已经存在。需要新的生物标志物来早期检测 HA。
目的
比较预防治疗和按需治疗的重度血友病 A 男孩与健康男孩的组织金属蛋白酶抑制剂-1（TIMP-1）和血管内皮生长因子（VEGF）水平，并与血友病关节健康评分（HJHS）和丹佛磁共振成像（MRI）评分相关联；从而确定它们在 HA 早期检测中的价值。
方法
评估 50 名重度血友病 A 男孩（31 名接受预防性因子 VIII 治疗（62%），剂量为 15 IU/kg/每周两次）和 50 名年龄匹配的健康男孩的 TIMP-1、VEGF 和丹佛 MRI 评分。
结果
重度血友病 A 男孩的 TIMP-1 为 240ng/mL，标准差 200-350（P <.001）和 VEGF 为 600pg/mL，标准差 400-1100（P <.001）。他们的平均 HJHS 为 4.5±3.0（0-11），平均丹佛 MRI 评分为 5.55±1.6（2.00-8.00）。TIMP-1 与 VEGF（P <.001）、BMI Z 分数（P=0.029）、HJHS（P=0.041）和总 MRI 评分（P <.001）之间存在显著正相关。VEGF 与年龄（P <.001）、HJHS（P=0.003）和总 MRI 评分（P <.001）之间存在显著相关性。接受预防治疗的重度血友病 A 男孩的 HJHS（P=0.021）、VEGF（P <.001）、TIMP-1（P=0.002）和总 MRI 评分（P=0.021）均明显低于按需治疗的男孩。受试者工作特征曲线定义了 TIMP-1 的截断值为 160ng/mL，灵敏度为 90%，特异性为 60%，VEGF 的截断值为 350pg/mL，灵敏度为 78%，特异性为 88%，用于区分重度血友病 A 和健康男孩。
结论
VEGF 和 TIMP-1 可用于 HA 的早期检测。进一步的前瞻性研究应包括更大的研究人群。此外，研究应探讨各种抗-VEGFs 作为 HA 潜在治疗方法的作用及其对 HA 的预防和治疗的影响。
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