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肝硬化门静脉高压症患者脾切除后早期血栓形成与Janus激酶-信号转导和转录激活因子信号通路的关系
DOI: 10.3969/j.issn.1001-5256.2022.10.012
伦理学声明：本研究方案于2017年12月23日经由贵州医科大学附属医院伦理委员会审批，批号：伦(审)2017-12-89。所纳入患者均签署知情同意书。
利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明：王欢负责课题设计，资料分析，撰写论文；申晓旭参与收集数据，修改论文；陈良琪、龚天兰负责拟定写作思路，指导撰写文章并最后定稿。
Association of JAK/STAT signaling pathway with portal vein thrombosis after splenectomy in cirrhotic patients with portal hypertension
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摘要:
目的 探讨肝硬化门静脉高压症患者脾切除后早期血栓形成因素，及其与Janus激酶(JAK)-信号转导和转录激活因子(STAT)信号通路的关系。 方法 选择2018年3月—2020年4月在贵州医科大学附属医院因肝硬化门静脉高压行脾切除断流术患者198例，根据患者术后3个月内是否发生门静脉血栓将其分为血栓组(n=41)和非血栓组(n=157)。检测两组患者术后外周血单个核细胞中JAK2 mRNA及STAT3 mRNA表达情况。计量资料组间比较采用t检验，计数资料组间比较采用χ2检验，对可能影响患者术后门静脉血栓形成的各因素进行单因素及多因素Logistic回归分析；采用受试者工作曲线(ROC曲线)分析术后JAK2mRNA、STAT3 mRNA相对表达量对门静脉血栓的预测价值。 结果 单因素结果显示，血栓组患者术前门静脉直径、术后门静脉直径、门静脉流速差、脾容积均显著高于非血栓组(t值分别为4.718、3.945、8.671、2.006，P值均＜0.05)。术后两组患者外周血单个核细胞JAK2 mRNA及STAT3 mRNA相对表达量较术前均显著升高(t值分别为12.933、15.442、14.386、10.896，P值均＜0.05)，同时血栓组患者JAK2 mRNA及STAT3 mRNA相对表达量升高程度均明显高于非血栓组(P值均＜0.05)。多因素logistic回归分析结果显示，门静脉流速差、术后JAK2 mNRA、术后STAT3 mRNA及术前门静脉直径为影响患者术后门静脉血栓发生的重要因素(P值均＜0.05)。患者术后JAK2 mRNA、STAT3 mRNA相对表达量预测门静脉血栓的ROC曲线下面积分别为0.850、0.787。 结论 JAK/STAT信号通路激活参与了肝硬化门静脉高压患者脾切除后血栓形成过程，可能是患者术后门静脉血栓形成的重要机制之一，有望成为患者术后门静脉血栓预防和治疗的潜在生物学途径。 Abstract:Objective To investigate the role of the Janus tyrosine kinase (JAK)- signal transducer and activators of transcription (STAT) signaling pathway in thrombosis formation after splenectomy in cirrhotic patients with portal hypertension. Methods A total of 198 liver cirrhosis patients with portal hypertension who underwent splenectomy and devascularization were recruited from March 2018 to April 2020 and then divided into thrombosis (n=41) and non-thrombosis groups (n=157) according to whether portal vein thrombosis occurred 3 months after surgery. mRNA levels of JAK2 and STAT3 in peripheral blood mononuclear cells (PBMCs) were assessed. Comparison of continuous data between groups was performed using t test, while comparison of categorial data between group was performed using chi square test. Clinicopathological data from patients were collected and analyzed for the potential risk factors of portal vein thrombosis by using univariate and multivariate Logistic regression analyses. The prediction values of JAK2 and STAT3 mRNA for portal vein thrombosis were evaluated by area under the receiver operating curve (AUC). Results The diameter of portal vein, the diameter of portal vein, the velocity difference of portal vein and the volume of spleen in the thrombus group were significantly higher than those in the non-thrombus group (t=4.718, 3.945, 8.671, and 2.006 respectively; P < 0.05).The relative mRNA levels of JAK2 and STAT3 in PBMCs of the two groups were significantly increased after surgery (t=12.933, 15.442, 14.386, 10.896; P < 0.05), and their levels were also much higher in the thrombosis group than in the non-thrombosis group of patients (P < 0.05). Multivariate Logistic regression analytic data showed that the portal vein diameter, the velocity difference of portal vein and mRNA level of JAK2 and STAT3 were all predictors for thrombosis in these patients (P < 0.05). The AUC of JAK2 and STAT3 mRNAs was 0.850 and 0.787, respectively in diagnosis of thrombosis in these patients. Conclusion The JAK / STAT signaling was activated in the process of thrombosis after splenectomy in cirrhotic patients with portal hypertension, which may be one of the important mechanisms of postoperative portal vein thrombosis, and may become a potential target for the prevention and treatment of postoperative portal vein thrombosis. -
Key words:
- Liver Cirrhosis /
- Hypertension /
- Portal /
- Splenectomy
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图 1 ROC曲线分析术后JAK2 mRNA、STAT3 mRNA对门静脉血栓的预测价值
Figure 1. The predictive value of JAK2 mRNA and STAT3 mRNA for portal vein thrombosis was analyzed by ROC curve
表 1 单因素分析
Table 1. Single factor analysis
因素 血栓组(n=41) 非血栓组(n=157) 统计值 P值 性别(例) χ2=2.896 0.089 男 29 88 女 12 69 年龄(例) χ2=0.265 0.607 ≥50岁 23 81 ＜50岁 18 76 Child-Pugh分级(例) χ2=0.245 0.621 A级 25 89 B级 16 68 门静脉高压性胃病(例) χ2=0.469 0.493 是 36 131 否 5 26 病毒性肝炎(例) χ2=0.582 0.446 是 33 134 否 8 23 静脉曲张类型(例) χ2=0.037 0.848 GOV1 15 60 GOV2 26 97 术前门静脉直径(mm) 12.97±1.03 12.17±0.95 t=4.718 ＜0.001 术后门静脉直径(mm) 12.18±0.92 11.56±0.89 t=3.945 ＜0.001 门静脉流速差(cm/s) 8.95±2.02 6.27±1.69 t=8.671 ＜0.001 门静脉压力差(cmH2O) 9.37±1.98 8.96±2.31 t=1.041 0.299 脾容积(cm3) 1 382.48±560.28 1 202.83±497.03 t=2.006 0.046 腹水量(mL) 69.38±15.20 71.22±17.39 t=0.618 0.537 手术时间(min) 259.30±45.28 254.29±51.27 t=0.570 0.569 术中出血量(mL) 368.49±126.42 330.85±150.63 t=1.470 0.143 BMI(kg/m2) 23.26±3.04 22.37±3.79 t=1.391 0.166 术后7 d CRP 18.27±2.63 18.96±3.41 t=1.205 0.230 术后7 d VAS 1.30±0.31 1.21±0.40 t=1.339 0.182 
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表 2 两组患者手术前后JAK-STAT通路表达
Table 2. Expression of JAK-STAT pathway before and after operation in two groups
组别 例数 JAK2 mRNA STAT3 mRNA 血栓组 41 术前 0.793±0.167 0.842±0.188 术后 1.372±0.233 1.564±0.279 t值 12.933 15.442 P值 ＜0.001 ＜0.001 非血栓组 157 术前 0.762±0.179 0.860±0.205 术后 1.093±0.2261) 1.189±0.3181) t值 14.386 10.896 P值 ＜0.001 ＜0.001 注：与血栓组术后比较，1)P＜0.05。
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表 3 影响患者术后门静脉血栓发生的多因素Logistic回归分析
Table 3. Multivariate Logistic regression analysis on the incidence of postoperative portal vein thrombosis
因素 回归系数 标准误 Wald值 P值 OR(95%CI) 门静脉流速差 0.279 0.188 0.602 0.002 2.183(1.382~2.974) 术后JAK2 mRNA 0.318 0.173 0.583 0.013 1.795(1.028~3.118) 术后STAT3 mRNA 0.337 0.193 0.398 0.035 1.603(1.221~3.472) 术前门静脉直径 0.418 0.220 0.527 0.044 1.493(1.093~2.791)
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表 4 术后JAK2 mRNA、STAT3 mRNA对门静脉血栓预测价值ROC曲线分析
Table 4. ROC curve analysis of the predictive value of JAK2 mRNA and STAT3 mRNA in postoperative portal vein thrombosis
指标 最佳截断值 标准误 P值 曲线下面积 95%CI JAK2 mRNA 1.228 0.033 ＜0.001 0.850 0.785~0.914 STAT3 mRNA 1.402 0.099 ＜0.001 0.787 0.710~0.864
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