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门静脉血栓(PVT)指在血栓形成于门静脉主干,肝内分支伴或不伴(脾静脉、肠系膜上静脉等)受累,是肝硬化的常见并发症之一,发病率为0.6%~26.0%[1-2]。研究[3-4]发现,PVT可导致门静脉闭塞或海绵样变性,加重门静脉高压,不仅导致顽固性腹水,增加食管静脉曲张破裂出血风险,还严重影响肝硬化食管静脉曲张病人的预后。因此,早期评估肝硬化食管胃静脉曲张破裂出血后门静脉系统血栓栓塞的发生风险,能够及早干预和调整治疗方案以改善肝硬化病人的预后。对于食管胃静脉曲张临床上需进行定期的镜下治疗,然而频繁的影像学检查不仅浪费医疗资源,还会加重病人的经济负担。因而,寻找一种能够预测肝硬化病人食管静脉曲张PVT发生风险的方法,对早期选择干预方案及判断病人预后具有重要意义。目前临床上针对肝硬化病人食管胃静脉曲张破裂出血后PVT形成相关因素的研究大多是从发病原因、影响因素等研究,且以单个因素评估高危病人,忽略了PVT的发生受多种因素的影响。因此,联合多个维度指标建立更客观的预测系统具有重要作用。本研究拟基于多因素分析筛选的风险因素以构建肝硬化病人食管胃静脉曲张破裂出血后PVT发生风险的列线图预测模型。
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研究队列与检验队列病人性别、年龄、BMI、肝硬化类型、肝功能Child-Pugh分级、食管静脉曲张分级等临床资料差异均无统计学意义(P>0.05)(见表 1)。
因素 研究队列
(n=336)检验队列
(n=112)t P 男性 189(56.25) 65(58.04) 0.11△ >0.05 年龄/岁 45.88±10.05 46.94±9.52 0.99 >0.05 BMI/(kg/m2) 23.67±2.96 23.81±3.11 0.43 >0.05 吸烟史 66(19.64) 20(17.86) 0.48△ >0.05 高血压 98(29.17) 36(32.14) 0.36△ >0.05 糖尿病 51(15.17) 19(16.96) 0.20△ >0.05 冠心病 8(2.38) 6(5.36) 2.46△ >0.05 NSBB治疗史 108(32.14) 30(26.79) 1.13△ >0.05 外科手术 103(30.65) 28(25.00) 1.30△ >0.05 肝硬化类型 病毒性 198(58.93) 74(66.07) 酒精性 103(30.65) 28(25.00) 1.81△ >0.05 其他 35(10.42) 10(8.93) 肝功能Child-Pugh分级 A级
B+C级121(36.01)
215(63.99)30(26.78)
82(73.21)3.20△ >0.05 食管静脉曲张分级 轻度 36(10.71) 15(13.39) 中度 40(11.91) 18(16.07) 2.18△ >0.05 重度 260(77.38) 79(70.53) 腹水 169(50.30) 70(62.50) 0.86△ >0.05 消化道溃疡 103(30.65) 31(27.69) 0.36△ >0.05 内镜止血 161(47.92) 58(51.79) 0.50△ >0.05 门静脉内径/mm 15.52±3.73 15.23±3.36 0.72 >0.05 脾静脉内径/mm 9.06±2.85 9.15±2.92 0.29 >0.05 脾脏厚度/mm 44.56±7.58 43.96±7.62 0.73 >0.05 WBC/(×109/L) 7.23±2.38 7.35±2.46 0.46 >0.05 PLT/(×109/L) 95.72±20.13 96.46±18.94 0.34 >0.05 RBC/(×1012/L) 2.90±0.77 3.01±0.82 1.29 >0.05 Hb/(g/L) 92.16±11.60 92.87±11.92 0.56 >0.05 Alb/(g/L) 26.91±6.02 27.25±5.90 0.52 >0.05 FIB/(g/L) 2.79±0.81 2.68±0.76 1.26 >0.05 TBIL/(mol/L) 72.56±18.42 71.89±19.01 0.33 >0.05 PT/s 16.97±3.95 16.70±3.79 0.88 >0.05 APTT/s 38.46±8.46 39.02±8.20 0.61 >0.05 TT/s 12.82±3.95 13.52±4.03 1.62 >0.05 D-D/(μg/L) 2.87±0.43 2.78±0.40 1.59 >0.05 UN/(mmol/L) 7.11±2.29 7.01±2.23 0.40 >0.05 Cr/(μmol/L) 72.16±5.80 72.43±6.21 0.42 >0.05 P-选择素/(ng/mL) 70.17±8.09 69.89±7.92 0.27 >0.05 ALT/(U/L) 86.97±22.70 85.83±23.34 0.46 >0.05 AST/(U/L) 56.79±17.42 55.99±17.50 0.68 >0.05 TG/(mmol/L) 1.46±0.31 1.41±0.37 1.08 >0.05 TC/(mmol/L) 4.98±1.22 5.01±1.34 0.18 >0.05 INR 2.78±0.80 3.03±0.78 2.88 < 0.01 △示χ2值 表 1 研究队列与检验队列的临床资料比较(x±s)
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研究队列中77例(22.92%)发生PVT,其中出血后最快形成PVT者用时2周,49.35%(38/77)在1年内发生PVT,79.22%(61/77)在2年内合并PVT。检验队列中26例(23.21%)发生PVT,出血后最快形成PVT者用时12 d,50.00%(13/26)在1年内发生PVT,80.77%(21/26)在2年内合并PVT。单因素分析结果显示,研究队列PVT组与无PVT组肝功能Child-Pugh分级、门静脉内径、PLT、D-D、P-选择素、TG差异均有统计学意义(P < 0.05~P < 0.01)(见表 2)。
因素 PVT组
(n=77)无PVT组
(n=259)t P 男性 46(59.74) 143(55.21) 0.11△ >0.05 年龄/岁 46.47±10.13 47.22±9.86 0.58 >0.05 BMI/(kg/m2) 23.20±3.01 22.85±3.10 0.88 >0.05 吸烟史 18(23.38) 48(18.53) 2.29△ >0.05 高血压 29(37.66) 69(26.64) 3.49△ >0.05 糖尿病 17(22.08) 34(13.13) 3.69△ >0.05 冠心病 3(3.90) 4(1.54) 1.61△ >0.05 NSBB治疗史 30(38.96) 78(30.12) 2.13△ >0.05 外科手术 29(37.66) 74(28.57) 2.31△ >0.05 肝硬化类型 病毒性 49(63.63) 149(66.07) 酒精性 21(27.27) 82(31.66) 0.92△ >0.05 其他 7(9.09) 28(10.81) Child-Pugh分级 A级
B+C级19(24.68)
58(75.32)102(39.38)
157(60.62)5.57△ < 0.05 食管静脉曲张分级 轻度 8(10.39) 28(10.81) 中度 15(19.48) 25(9.65) 5.50△ >0.05 重度 54(70.13) 206(79.54) 腹水 40(50.30) 129(62.50) 0.11△ >0.05 消化道溃疡 27(30.65) 76(27.69) 0.91△ >0.05 内镜止血 42(47.92) 119(51.79) 1.76△ >0.05 门静脉内径/mm 18.16±4.50 13.04±3.22 11.11 < 0.01 脾静脉内径/mm 9.52±3.07 8.97±2.91 1.44 >0.05 脾脏厚度/mm 44.56±9.18 43.99±8.74 0.50 >0.05 WBC/(×109/L) 7.19±2.27 7.41±2.40 0.72 >0.05 PLT/(×109/L) 124.64±28.44 95.87±20.20 9.92 < 0.01 RBC/(×1012/L) 2.97±0.81 2.82±0.75 1.51 >0.05 Hb/(g/L) 92.71±13.52 92.08±12.89 0.37 >0.05 Alb/(g/L) 27.36±6.63 26.85±6.27 0.62 >0.05 FIB/(g/L) 2.80±0.83 2.72±0.79 0.77 >0.05 TBIL/(mol/L) 72.56±18.42 71.89±19.01 0.27 >0.05 PT/s 16.53±3.74 16.47±3.64 0.13 >0.05 APTT/s 38.96±8.33 40.11±8.51 1.05 >0.05 TT/s 12.82±3.95 13.52±4.03 1.34 >0.05 D-D/(μg/L) 2.93±0.43 2.26±0.39 12.92 < 0.01 UN/(mmol/L) 7.45±2.26 6.98±2.30 1.58 >0.05 Cr/(μmol/L) 72.55±5.78 73.46±6.33 1.13 >0.05 P-选择素/(ng/mL) 75.77±10.09 68.77±7.87 6.40 < 0.01 ALT/(U/L) 87.64±22.66 85.50±26.34 0.65 >0.05 AST/(U/L) 57.11±17.97 56.23±17.76 0.38 >0.05 TG/(mmol/L) 1.11±0.29 1.50±0.41 7.78 < 0.01 TC/(mmol/L) 5.14±1.33 5.05±1.13 0.59 >0.05 INR 2.89±0.81 3.08±0.76 1.90 >0.05 △示χ2值 表 2 研究队列肝硬化病人食管胃静脉曲张破裂出血后发生PVT的单因素分析(x±s)
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将研究队列单因素分析中PVT组与无PVT组差异有统计学意义的因素作为自变量,将病人发生PVT作为因变量,纳入多因素logistic回归分析,分类变量肝功能Child-Pugh分级赋值:A级=0,B+C级=1,其余定量资料以实际值录入。多因素分析结果显示,肝功能Child-Pugh分级、门静脉内径、PLT、D-D、P-选择素、TG均为肝硬化病人食管胃静脉曲张破裂出血后PVT的风险因素(P < 0.01)(见表 3)。
变量 B SE Waldχ2 P OR 95%CI Child-Pugh分级 1.872 0.548 11.666 < 0.01 6.505 2.221~19.049 门静脉内径 0.394 0.707 32.099 < 0.01 1.484 1.294~1.700 PLT 0.038 0.010 14.791 < 0.01 1.039 1.019~1.059 D-D 0.999 0.258 14.937 < 0.01 2.716 1.636~4.507 P-选择素 0.078 0.025 9.342 < 0.01 1.081 1.028~1.136 TG -2.212 0.670 22.962 < 0.01 0.040 0.011~0.150 表 3 研究队列肝硬化病人食管胃静脉曲张破裂出血后发生PVT的多因素logistic回归分析
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将多因素分析结果进行可视化处理,构建了列线图模型,该列线图由肝功能Child-Pugh分级、门静脉内径、PLT、D-D、P-选择素及TG 6个指标及其对应的线段组成(见图 1)。
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在RStudio软件中对所构建模型进行研究队列与检验队列双重验证,ROC曲线分析结果显示,模型在研究队列的曲线下面积(AUC)为0.953(95%CI:0.931~0.976),灵敏度为81.8%,特异度为94.2%;检验队列的AUC为0.944(95%CI:0.904~0.984),灵敏度为98.9%,特异度为81.4%。
基于多维度指标构建肝硬化病人食管胃静脉曲张破裂出血后门静脉血栓风险列线图模型及验证
Construction and validation of a nomogram model for portal vein thrombosis risk after esophagogastric variceal rupture and bleeding in patients with cirrhosis based on multi-dimensional indicators
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摘要:
目的基于多维度指标构建肝硬化病人食管胃静脉曲张破裂出血后门静脉血栓(PVT)风险的列线图模型,并进行验证。 方法选取肝硬化伴食管胃底静脉曲张破裂出血病人448例,按照3∶1的比例分为研究队列336例和检验队列112例,2队列再根据是否发生PVT分为血栓组和无血栓组,采用单因素分析和多因素回归分析筛选研究队列肝硬化病人食管胃静脉曲张破裂出血后发生PVT主要风险因素,采用RStudio软件中的rms程序包构建列线图并进行验证。 结果研究队列中77例(22.92%)发生PVT,其中出血后最快形成PVT者用时2周,49.35%(38/77)在1年内发生PVT,79.22%(61/77)在2年内合并PVT。检验队列中26例(23.21%)发生PVT,出血后最快形成PVT者用时12 d,50%(13/26)在1年内发生PVT,80.77%(21/26)在2年内合并PVT。单因素分析结果显示,研究队列PVT组与无PVT组肝功能Child-Pugh分级、门静脉内径、血小板计数、D-二聚体、P-选择素、三酰甘油差异均有统计学意义(P < 0.05~P < 0.01)。多因素logistic回归分析结果显示,肝功能Child-Pugh分级、门静脉内径、血小板计数、D-二聚体、P-选择素、三酰甘油均为肝硬化病人食管胃静脉曲张破裂出血后PVT的风险因素(P < 0.01)。ROC曲线分析结果显示,风险列线图预测模型在研究队列的曲线下面积(AUC)为0.953(95%CI:0.931~0.976),灵敏度为81.8%,特异度为94.2%;风险列线图预测模型在检验队列的AUC为0.944(95%CI:0.904~0.984),灵敏度为98.9%,特异度为81.4%。 结论肝功能Child-Pugh分级、门静脉内径、血小板计数、D-二聚体、P-选择素、三酰甘油均为肝硬化病人食管胃静脉曲张破裂出血PVT的风险因素。基于上述指标建立的列线图预测模型具有良好的诊断效能,可为临床制定针对性治疗方案提供参考。 Abstract:ObjectiveTo construct and validate a nomograph model for portal vein thrombosis(PVT) risk after esophagogastric variceal rupture and bleeding in patients with cirrhosis based on multi-dimensional indicators. MethodsA total of 448 patients with liver cirrhosis complicated with esophagogastric variceal rupture and bleeding were selected and divided into the study cohort(n=336) and test cohort(n=112) at the ratio of 3:1.The two cohorts were subdivided into the thrombus group and non-thrombus group according to whether PVT occurrence.The main risk factors of PVT in the study cohort after esophagogastric variceal rupture and bleeding in patients with cirrhosis were screened by univariate analysis and multivariate regression analysis, and a nomograph model was constructed using rms package in RStudio software and verified. ResultsIn the study cohort, 77 cases(22.92%) developed PVT, in which the fastest PVT formation after bleeding took two weeks, 49.35%(38/77) developed PVT within one year, and 79.22%(61/77) combined with PVT within two years.In the test cohort, 26 cases(23.21%) developed PVT, in which the fastest PVT formation after bleeding took 12 days, 50%(13/26) developed PVT within 1 year, and 80.77%(21/26)combined PVT within 2 years.Univariate analysis showed that there were significant differences in Child-Pugh liver function grade, portal vein diameter, platelet count, D-dimer, P-selectin and triacylglycerol between PVT group and non-PVT group(P < 0.05 to P < 0.01).Multivariate logistic regression analysis showed that Child-Pugh liver function grade, portal vein diameter, platelet count, D-dimer, P-selectin and triacylglycerol were the risk factors for PVT after esophagogastric variceal rupture and bleeding in patients with cirrhosis(P < 0.01).ROC curve analysis showed that the area under the curve(AUC) of the risk nomogram prediction model in the study cohort was 0.953(95%CI: 0.931-0.976), the sensitivity was 81.8%, and the specificity was 94.2%.ROC curve analysis showed that the AUC of the risk nomogram prediction model in the test cohort was 0.944(95%CI: 0.904-0.984), the sensitivity was 98.9%, and the specificity was 81.4%. ConclusionsChild-Pugh liver function grade, portal vein diameter, platelet count, D-dimer, P-selectin and triacylglycerol are the risk factors of PVT in patients with liver cirrhosis complicated with esophagogastric variceal rupture and bleeding.The nomogram prediction model based on the above indicators has good diagnostic performance, and can provide a reference for development of targeted treatment plans in clinic. -
表 1 研究队列与检验队列的临床资料比较(x±s)
因素 研究队列
(n=336)检验队列
(n=112)t P 男性 189(56.25) 65(58.04) 0.11△ >0.05 年龄/岁 45.88±10.05 46.94±9.52 0.99 >0.05 BMI/(kg/m2) 23.67±2.96 23.81±3.11 0.43 >0.05 吸烟史 66(19.64) 20(17.86) 0.48△ >0.05 高血压 98(29.17) 36(32.14) 0.36△ >0.05 糖尿病 51(15.17) 19(16.96) 0.20△ >0.05 冠心病 8(2.38) 6(5.36) 2.46△ >0.05 NSBB治疗史 108(32.14) 30(26.79) 1.13△ >0.05 外科手术 103(30.65) 28(25.00) 1.30△ >0.05 肝硬化类型 病毒性 198(58.93) 74(66.07) 酒精性 103(30.65) 28(25.00) 1.81△ >0.05 其他 35(10.42) 10(8.93) 肝功能Child-Pugh分级 A级
B+C级121(36.01)
215(63.99)30(26.78)
82(73.21)3.20△ >0.05 食管静脉曲张分级 轻度 36(10.71) 15(13.39) 中度 40(11.91) 18(16.07) 2.18△ >0.05 重度 260(77.38) 79(70.53) 腹水 169(50.30) 70(62.50) 0.86△ >0.05 消化道溃疡 103(30.65) 31(27.69) 0.36△ >0.05 内镜止血 161(47.92) 58(51.79) 0.50△ >0.05 门静脉内径/mm 15.52±3.73 15.23±3.36 0.72 >0.05 脾静脉内径/mm 9.06±2.85 9.15±2.92 0.29 >0.05 脾脏厚度/mm 44.56±7.58 43.96±7.62 0.73 >0.05 WBC/(×109/L) 7.23±2.38 7.35±2.46 0.46 >0.05 PLT/(×109/L) 95.72±20.13 96.46±18.94 0.34 >0.05 RBC/(×1012/L) 2.90±0.77 3.01±0.82 1.29 >0.05 Hb/(g/L) 92.16±11.60 92.87±11.92 0.56 >0.05 Alb/(g/L) 26.91±6.02 27.25±5.90 0.52 >0.05 FIB/(g/L) 2.79±0.81 2.68±0.76 1.26 >0.05 TBIL/(mol/L) 72.56±18.42 71.89±19.01 0.33 >0.05 PT/s 16.97±3.95 16.70±3.79 0.88 >0.05 APTT/s 38.46±8.46 39.02±8.20 0.61 >0.05 TT/s 12.82±3.95 13.52±4.03 1.62 >0.05 D-D/(μg/L) 2.87±0.43 2.78±0.40 1.59 >0.05 UN/(mmol/L) 7.11±2.29 7.01±2.23 0.40 >0.05 Cr/(μmol/L) 72.16±5.80 72.43±6.21 0.42 >0.05 P-选择素/(ng/mL) 70.17±8.09 69.89±7.92 0.27 >0.05 ALT/(U/L) 86.97±22.70 85.83±23.34 0.46 >0.05 AST/(U/L) 56.79±17.42 55.99±17.50 0.68 >0.05 TG/(mmol/L) 1.46±0.31 1.41±0.37 1.08 >0.05 TC/(mmol/L) 4.98±1.22 5.01±1.34 0.18 >0.05 INR 2.78±0.80 3.03±0.78 2.88 < 0.01 △示χ2值 表 2 研究队列肝硬化病人食管胃静脉曲张破裂出血后发生PVT的单因素分析(x±s)
因素 PVT组
(n=77)无PVT组
(n=259)t P 男性 46(59.74) 143(55.21) 0.11△ >0.05 年龄/岁 46.47±10.13 47.22±9.86 0.58 >0.05 BMI/(kg/m2) 23.20±3.01 22.85±3.10 0.88 >0.05 吸烟史 18(23.38) 48(18.53) 2.29△ >0.05 高血压 29(37.66) 69(26.64) 3.49△ >0.05 糖尿病 17(22.08) 34(13.13) 3.69△ >0.05 冠心病 3(3.90) 4(1.54) 1.61△ >0.05 NSBB治疗史 30(38.96) 78(30.12) 2.13△ >0.05 外科手术 29(37.66) 74(28.57) 2.31△ >0.05 肝硬化类型 病毒性 49(63.63) 149(66.07) 酒精性 21(27.27) 82(31.66) 0.92△ >0.05 其他 7(9.09) 28(10.81) Child-Pugh分级 A级
B+C级19(24.68)
58(75.32)102(39.38)
157(60.62)5.57△ < 0.05 食管静脉曲张分级 轻度 8(10.39) 28(10.81) 中度 15(19.48) 25(9.65) 5.50△ >0.05 重度 54(70.13) 206(79.54) 腹水 40(50.30) 129(62.50) 0.11△ >0.05 消化道溃疡 27(30.65) 76(27.69) 0.91△ >0.05 内镜止血 42(47.92) 119(51.79) 1.76△ >0.05 门静脉内径/mm 18.16±4.50 13.04±3.22 11.11 < 0.01 脾静脉内径/mm 9.52±3.07 8.97±2.91 1.44 >0.05 脾脏厚度/mm 44.56±9.18 43.99±8.74 0.50 >0.05 WBC/(×109/L) 7.19±2.27 7.41±2.40 0.72 >0.05 PLT/(×109/L) 124.64±28.44 95.87±20.20 9.92 < 0.01 RBC/(×1012/L) 2.97±0.81 2.82±0.75 1.51 >0.05 Hb/(g/L) 92.71±13.52 92.08±12.89 0.37 >0.05 Alb/(g/L) 27.36±6.63 26.85±6.27 0.62 >0.05 FIB/(g/L) 2.80±0.83 2.72±0.79 0.77 >0.05 TBIL/(mol/L) 72.56±18.42 71.89±19.01 0.27 >0.05 PT/s 16.53±3.74 16.47±3.64 0.13 >0.05 APTT/s 38.96±8.33 40.11±8.51 1.05 >0.05 TT/s 12.82±3.95 13.52±4.03 1.34 >0.05 D-D/(μg/L) 2.93±0.43 2.26±0.39 12.92 < 0.01 UN/(mmol/L) 7.45±2.26 6.98±2.30 1.58 >0.05 Cr/(μmol/L) 72.55±5.78 73.46±6.33 1.13 >0.05 P-选择素/(ng/mL) 75.77±10.09 68.77±7.87 6.40 < 0.01 ALT/(U/L) 87.64±22.66 85.50±26.34 0.65 >0.05 AST/(U/L) 57.11±17.97 56.23±17.76 0.38 >0.05 TG/(mmol/L) 1.11±0.29 1.50±0.41 7.78 < 0.01 TC/(mmol/L) 5.14±1.33 5.05±1.13 0.59 >0.05 INR 2.89±0.81 3.08±0.76 1.90 >0.05 △示χ2值 表 3 研究队列肝硬化病人食管胃静脉曲张破裂出血后发生PVT的多因素logistic回归分析
变量 B SE Waldχ2 P OR 95%CI Child-Pugh分级 1.872 0.548 11.666 < 0.01 6.505 2.221~19.049 门静脉内径 0.394 0.707 32.099 < 0.01 1.484 1.294~1.700 PLT 0.038 0.010 14.791 < 0.01 1.039 1.019~1.059 D-D 0.999 0.258 14.937 < 0.01 2.716 1.636~4.507 P-选择素 0.078 0.025 9.342 < 0.01 1.081 1.028~1.136 TG -2.212 0.670 22.962 < 0.01 0.040 0.011~0.150 -
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