Changes in hemostasis and clinical significance of coagulation function test in patients with liver cirrhosis

Shiqi CHAI; Jinjun CHEN; Tingting QI

doi:10.3969/j.issn.1001-5256.2021.12.040

Volume 37 Issue 12

Dec. 2021

Turn off MathJax

Article Contents

Abstract

References

Article Navigation > Journal of Clinical Hepatology > 2021 > 37(12): 2928-2931

PDF( 1884 KB)

Changes in hemostasis and clinical significance of coagulation function test in patients with liver cirrhosis

DOI: 10.3969/j.issn.1001-5256.2021.12.040

Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

Research funding:

The National Science and Technology Major Project (2018ZX10723203);

The National Science and Technology Major Project (2018ZX10302206);

National Natural Science Foundation of China (82070650);

National Key Research and Development Program of China (2017YFC0908100);

Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01S131);

Department of Science and Technology of Guangdong Province (2014B020228003);

Department of Science and Technology of Guangdong Province (2015B020226004);

Clinical Research Program of Nanfang Hospital, Southern Medical University (2020CR026);

Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education (LC2019ZD006);

President Foundation of Nanfang Hospital, Southern Medical University (2019Z003)

Received Date: 2021-07-07
Accepted Date: 2021-08-06
Published Date: 2021-12-20

Abstract

Abstract

The liver plays an important role in procoagulant and anticoagulant mechanisms in human body. There are complex changes in hemostasis in patients with liver cirrhosis, with the presence of interaction between the portal venous system and the peripheral system and differences in etiology, and such patients have a dual trend of hemorrhage and thrombosis. At present, there are certain limitations in coagulation function tests commonly used in clinical practice. The primary etiology and results of various coagulation tests should be considered before initiation of anticoagulant therapy for patients with liver cirrhosis, so as to make the best clinical decisions for patients.
- Liver Cirrhosis,
- Hemorrhage,
- Blood Coagulation Factors,
- Blood Coagulation Tests

FullText(HTML)

原发性肝癌(primary liver cancer，PLC)是癌症相关死亡的最主要因素之一，2018最新的GLOBOCAN统计显示其占所有癌症死亡8.2%^[1]。其中，肝细胞癌(HCC)占90%以上，因起病隐匿，发现较晚，预后欠佳^[2]。根据BCLC分期诊疗指南，0/A期肝癌优先考虑手术切除治疗，而稍晚期的则推荐其考虑经肝动脉化疗栓塞(TACE)治疗，但疗效差异较大^[3]。因此，早期发现并行根治性切除是HCC患者获得较长总体生存最重要的治疗方法。然而，术后复发转移却极大影响疗效，研究^[4]表明术后5年复发率高达70%，而且目前尚无针对复发后治疗优良方案，导致长期存活率低。因此，如何预测术后患者复发风险，建立相关的预警系统来指导患者术后复查及治疗显得尤其重要。根据预测系统为患者拟定个体化复诊方案，以达到早期治疗、分类干预、降低复发率从而提高生存率的目的。以期为根治性切除BCLC 0/A期肝癌患者获得更好的术后生存提供参考。

1. 资料与方法

1.1 研究对象

回顾性分析2009年1月—2015年1月在川北医学院附属医院接受根治性外科切除术治疗的BCLC 0/A期HCC患者相关资料。纳入标准：(1)根据美国肝病学会(AASLD)和欧洲肝病学会(EASL)肝癌治疗指南诊断为BCLC 0/A期的HCC患者，并在第一次诊断后即接受手术切除; (2) Child-Pugh A~B级、ECOG-PS 0分; (3)影像学检查明确未见远处转移。排除标准：(1)BCLC分期更晚者; (2)既往有微波及射频消融、放化疗、靶向药物等相关治疗史者; (3) 伴有严重的心、肺、肾功能不全或其他系统恶性肿瘤者; (4)临床资料不全及失访者。

1.2 治疗方式

开腹手术与腹腔镜下手术的选择，在以能更好地达到根治性切除的前提下，根据临床主刀医师的经验及习惯进行选择。所纳入病例的手术均由经验丰富的教授主刀完成(主刀台次＞100例同类手术)。本研究中根治性外科切除术定义：完全切除肿瘤结节，主要采取解剖性切除，不能行解剖性切除的要求至少达到无肉眼可见肿瘤切缘。根据Couinaud的分类，解剖性切除是指对肝功能储备满意的患者进行至少一个节段(即节段切除、扇形切除或半肝切除)的完全切除。非R0切除患者术后予以口服中成药(半年至一年)：十味蒂达胶囊0.9 g(2粒)每天3次、复方斑蝥胶囊750 mg(3粒)每天2次; 术前HBsAg阳性患者且病毒滴度高的患者，术前行抗病毒治疗待病毒滴度下降后行手术治疗; 所有术前HBsAg阳性患者术后长期予以抗病毒治疗(恩替卡韦0.5 mg每天1次)。复发前，余未行其他方式治疗，门诊定期复查随访。

1.3 数据收集

收集入组患者的一般人口学资料(年龄、性别、体质量等)，血液化验结果(肝肾功能、血常规等)，影像学检查结果(肿瘤数目、血管包膜侵犯、肿瘤最大直径等)。入组患者均在术后通过住院资料及电话咨询等方式进行回顾性随访统计，咨询和统计内容包括临床查体，血液学检查(肿瘤标志物、血常规、肝肾功能及凝血功能等)，影像学检查(胸部、腹部平扫及增强扫描CT或磁共振等)。总生存期(overall survival，OS)定义为：从患者接受治疗之日开始到患者死亡或最后一次临床随访的时间为止。最后一次临床回顾性随访(＜5年)无复发则默认该患者5年时间内未复发。

1.4 伦理学审查

本研究方案经由川北医学院附属医院伦理委员会审批，符合医学伦理学规定。

1.5 统计学方法

采用SPSS 26.0软件对研究数据进行统计学分析。符合正态分布的计量资料以x±s表示，两组间比较采用t检验; 非正态分布的计量资料以M(P₂₅~P₇₅)表示，两组间比较采用Mann-Whitney U检验。计数资料两组间比较采用χ²检验或Fisher精确法检验。将差异具有统计学意义的指标纳入二元logistic回归分析。采用受试者工作特征(ROC)曲线下面积(AUC)评估其诊断效能。P＜0.05为差异有统计学意义。

2. 结果

2.1 一般资料

共纳入232例BCLC 0/A期HCC患者，依据5年内复发状态分为复发组(103例)和非复发组(129例)。在所有纳入研究的根治性切除的BCLC 0/A期HCC患者中，复发部位绝大部分(83.4%)为肝内复发，其次为肺、腹腔，也包括骨、脑、淋巴结等。两组比较，BCLC 0/A分期差异无统计学意义(P＞0.05)。其中性别、年龄、体质量、术前RBC、WBC、PLT、TBil、DBil、肿瘤数、分化程度、并发症、住院时间差异均无统计学意义(P值均＞0.05);而术前AST、ALT复发组明显高于非复发组，术前Alb复发组明显低于非复发组(P值均＜0.05);复发组HBsAg阳性、包膜侵犯、微血管侵犯(MVI)、肿瘤直径≥5 cm、肝硬化(中重度)、非R0切除、5年死亡数所占比例显著高于非复发组(P值均＜0.05);复发组的OS明显低于非复发组(P＜0.05)(表 1)。

表 1 术后5年内复发组与非复发组相关基线资料、并发症及结局的比较

项目	复发组(n=103)	非复发组(n=129)	统计值	P值
住院时间(d)	9.84±3.98	10.23±4.72	t=-0.666	0.506
年龄(岁)	50.36±12.05	52.28±12.99	t=-1.155	0.249
体质量(kg)	56.94±4.85	56.68±6.70	t=0.337	0.745
OS(月)	18.0(8.0~31.0)	25.0(15.5~40.5)	Z=-2.880	0.004
术前RBC(10⁹/L)	4.63±0.68	4.53±0.59	t=1.166	0.245
术前WBC(10⁹/L)	5.57±1.63	5.60±2.02	t=-0.438	0.662
术前PLT(10⁹/L)	144(101~203)	138(92~200)	Z=0.445	0.656
术前TBil(μmol/L)	14.7(11.7~19.3)	13.6(10.1~18.0)	Z=1.666	0.096
术前DBil(μmol/L)	4.8(3.5~6.4)	4.5(3.6~5.8)	Z=0.975	0.330
术前ALT(U/L)	51(39~63)	39(30~52)	Z=4.587	＜0.001
术前AST(U/L)	44(33~65)	34(25~51)	Z=3.864	＜0.001
术前Alb(g/L)	39.08±4.19	42.34±4.53	t=-5.628	＜0.001
男性[例(%)]	84(81.6)	102(79.1)	χ²=0.222	0.637
HBsAg阳性[例(%)]	87(84.5)	60(46.5)	χ²=35.539	＜0.001
包膜侵犯[例(%)]	48(46.6)	23(17.8)	χ²=22.325	＜0.001
肿瘤直径≥5 cm[例(%)]	86(83.5)	88(68.2)	χ²=7.130	0.008
MVI[例(%)]	32(31.1)	15(11.6)	χ²=13.398	＜0.001
R0切除[例(%)]	79(76.7)	112(86.8)	χ²=4.034	0.045
低分化程度[例(%)]	40(38.8)	53(41.1)	χ²=0.121	0.728
肿瘤数≥2个[例(%)]	11(10.7)	15(11.6)	χ²=0.052	0.820
5年死亡数[例(%)]	51(49.5)	29(22.5)	χ²=18.527	＜0.001
肝硬化(中重度)[例(%)]	34(33.0)	27(20.9)	χ²=4.312	0.038
BCLC分期[例(%)]
0期	9(8.7)	8(6.2)	χ²=0.543	0.461
A期	94(91.3)	121(93.8)
并发症[例(%)]
肺部感染	8(7.8)	8(6.2)	χ²=0.219	0.640
腹腔感染	3(2.9)	2(1.6)		0.841
腹腔出血	2(1.9)	7(5.4)		0.172
腹腔积液	81(78.6)	88(68.2)	χ²=3.146	0.076
胸腔积液	9(8.7)	5(3.9)	χ²=2.387	0.122
复发部位[例(%)]
肝	86(83.5)
肺	5(4.9)
肝肺	3(2.9)
肝脑	1(1.0)
腹腔	5(4.9)
骨	1(1.0)
淋巴结	2(1.9)

下载: 导出CSV

| 显示表格

2.2 影响BCLC 0/A期HCC患者术后5年复发的危险因素

以入组患者的基线资料及术前部分化验指标为自变量，术后5年内复发状态为因变量，进行二元logistic回归分析。单因素分析结果显示，术前Alb＜40 g/L、术前ALT≥40 U/L、MVI、HBsAg阳性、包膜侵犯、肿瘤直径≥5 cm、肝硬化(中重度)、非R0切除均是根治性切除的BCLC 0/A期HCC患者术后5年复发的影响因素(P值均＜0.05)(表 2)。

表 2 BCLC 0/A期HCC患者行根治性切除术5年复发的logistic单因素分析

项目	B值	SE	Wald	P值	OR(95%CI)
术前Alb(＜40 g/L)	1.563	0.286	29.804	＜0.001	4.774(2.724~8.368)
术前ALT(≥40 U/L)	1.045	0.278	14.093	＜0.001	2.843(1.648~4.906)
MVI	1.231	0.348	12.551	＜0.001	3.425(1.733~6.769)
HBsAg阳性	1.833	0.324	31.955	＜0.001	6.253(3.312~11.806)
肿瘤直径(≥5 cm)	0.857	0.326	6.921	0.009	2.357(1.244~4.464)
包膜侵犯	1.392	0.303	21.073	＜0.001	4.022(2.220~7.287)
肝硬化(中重度)	0.621	0.301	4.255	0.039	1.862(1.031~3.360)
非R0切除	0.694	0.349	3.944	0.047	2.001(1.009~3.970)

下载: 导出CSV

| 显示表格

将单因素分析有统计学意义的影响因素纳入多因素分析，结果显示，术前Alb＜40 g/L(OR=5.796，P＜0.001)、术前ALT≥40 U/L(OR=3.029，P=0.002)、MVI(OR=3.981，P=0.003)、HBsAg阳性(OR=7.829，P＜0.001)、包膜侵犯(OR=5.357，P＜0.001)、非R0切除(OR=3.048，P=0.018)均为根治性切除的BCLC 0/A期HCC患者术后5年复发的独立危险因素(表 3)。因此，对肝功能异常患者，术前应积极保肝、纠正低蛋白血症等对症治疗，对于HBsAg阳性、包膜侵犯、MVI、肿瘤直径≥5 cm、中重度肝硬化、非R0切除的患者告知复发风险，规律按时复诊十分关键。因此，本研究希望通过对危险因素进行联合分析，建立患者术后复发的预警系统。

表 3 BCLC 0/A期HCC患者行根治性切除术5年复发的logistic多因素分析

项目	B值	SE	Wald	P值	OR(95%CI)
常量	-4.598	0.661	48.371	＜0.001	0.010
术前Alb(＜40 g/L)	1.757	0.376	21.826	＜0.001	5.796(2.773~12.113)
术前ALT(≥40 U/L)	1.108	0.366	9.175	0.002	3.029(1.479~6.204)
MVI	1.382	0.463	8.922	0.003	3.981(1.608~9.856)
HBsAg阳性	2.058	0.413	24.884	＜0.001	7.829(3.488~17.574)
肿瘤直径(≥5 cm)	0.606	0.410	2.187	0.139	1.833(0.821~4.091)
包膜侵犯	1.678	0.411	16.668	＜0.001	5.357(2.393~11.992)
肝硬化(中重度)	0.406	0.406	1.001	0.317	1.502(0.677~3.329)
非R0切除	1.115	0.473	5.552	0.018	3.048(1.206~7.704)

下载: 导出CSV

| 显示表格

2.3 肝癌根治性切除术后复发评分预警系统(PLC-EWSPRS)评分分布及差异

根据危险因素建立PLC-EWSPRS评分系统，其中独立危险因素赋值为2分，危险因素赋值为1分，该评分系统的阈值为0~14分，统计分析结果显示复发组最低分2分，最高分14分，平均(8.39±2.58)分; 非复发组最低分0分，最高分11分，平均(4.33±2.35)分; 即复发组的最低分与最高分均高于非复发组。将其分为0~5、6~10、11~14低中高3个分数段。复发组病例主要分布在中、高分数段，非复发组病例主要分布在低、中分数段，复发组中高分数段所占比例远高于非复发组，即中高分数段的复发率显著高于低分段(P＜0.05)(表 4)。

表 4 两组患者PLC-EWSPRS评分的分布及复发差异分析

分值分段(复发率)	分值	各分值病例分布[例(%)]		分值段病例分布[例(%)]		χ²值	P值
分值分段(复发率)	分值	复发组(n=103)	非复发组(n=129)	复发组(n=103)	非复发组(n=129)	χ²值	P值
低分段(0~5)	0	0	5(3.9)			91.502	＜0.001
(9.8%)	1	0	15(11.6)
	2	2(1.9)	8(6.2)
	3	2(1.9)	18(14.0)
	4	2(1.9)	18(14.0)
	5	4(3.9)	28(21.7)	10(9.7)	92(71.3)
中分段(6~10)	6	14(13.6)	16(12.4)
(68.2%)	7	10(9.7)	14(10.9)
	8	25(24.3)	1(0.8)
	9	12(11.7)	2(1.6)
	10	14(14.6)	2(1.6)	75(72.8)	35(27.1)
高分段(11~14)	11	2(1.9)	2(1.6)
(90.0%)	12	8(7.8)	0
	13	6(5.8)	0
	14	2(1.9)	0	18(17.5)	2(1.6)

下载: 导出CSV

| 显示表格

2.4 诊断预测效能

为了进一步证实PLC-EWSPRS评分系统评分越高，复发风险越大，具有复发风险预测价值，同时评估其对根治性切除的BCLC 0/A期HCC患者术后5年生存状态是否具有预测价值，本研究对该系统评分进行诊断效能分析。ROC曲线分析结果显示，预测根治性切除的BCLC 0/A期HCC患者术后5年死亡的AUC(95%CI)为0.672(0.599~0.744)，P＜0.001; 亚组预测低、中、高分数段术后5年死亡的AUC(95%CI)分别为：0.478(0.338~0.619), P=0.595;0.544(0.436~0.652), P=0.425;0.571(0.315~0.826), P=0.770。预测根治性切除的BCLC 0/A期HCC患者术后5年内复发的AUC(95%CI)为0.918(0.883~0.953), P＜0.001;亚组预测低、中、高分数段术后5年内复发的AUC(95%CI)分别为：0.796(0.695~0.896), P=0.002;0.859(0.791~0.927), P＜0.001;0.944(0.839~1.000), P=0.044。因此，PLC-EWSPRS系统对根治性切除的BCLC 0/A期HCC患者术后5年内生存状态预测价值有限，各亚组预测无意义(P＞0.05);而对术后5年复发具有良好的预测价值，各亚组预测价值仍较高(P＜0.05)(图 1、2)。

图 1 PLC-EWSPRS预测术后5年复发的ROC曲线

下载: 全尺寸图片幻灯片

图 2 PLC-EWSPRS预测术后5年死亡的ROC曲线

下载: 全尺寸图片幻灯片

3. 讨论

PLC严重威胁着人类的健康，是全球癌症相关死亡的第三大主要原因^[5]，根治性外科切除是HCC极其重要的治疗方式^[6]。HCC治疗方式的选择当前主要以BCLC分期为主要参考标准，其中BCLC 0/A期主要首选根治性手术^[3]。虽然已经有研究预扩大BCLC肝癌切除标准，即对BCLC-B甚至BCLC-C期HCC患者也行手术切除治疗^[7]。已经有部分回顾性分析提出肝切除术能够使部分BCLC B/C期患者取得可接受的结果^[7-8]，但还需要大量前瞻性临床研究加以证实。因此，本研究选择以BCLC 0/A期HCC患者为研究对象，探究术后复发的相关问题。早期HCC往往具有更大的手术治疗机会，掌握手术时机及积极术前准备均十分关键^[9]。尽管BCLC 0/A期HCC多数具有良好的手术治疗指征，本应取得良好的手术效果，然而肝癌切除术后5年肿瘤复发转移率高达40%~70%^[10]，本研究术后5年复发率为44.40%，亦在此高发范围内。并且在本研究中复发组的5年病死率为49.5%，非复发组的5年病死率为22.5%，由此可见术后复发严重制约着肝癌患者术后生存。因此，建立一个全面系统的肝癌术后复发预警系统十分关键，通过预警系统为患者拟定个性化的治疗及复诊方案，以达到预防或减少复发、提高OS的目的。

HBV可促进中国人群肝癌的侵袭性^[11]。抗病毒治疗应贯穿乙型肝炎相关HCC的外科手术前、术后及非手术治疗的全过程^[12]。既往研究提出术前HBV DNA高负荷是肝癌术后复发的独立危险因素，术后复发预示着更低的复发后生存率^[7]，这与本研究证实HBsAg阳性为术后复发独立危险因素结果一致。Wu等^[13]通过多因素分析表明HBV DNA水平＞10⁶拷贝/ml与远期复发(＞2年)显著相关，因此术前降低病毒滴度和术后抗病毒及抗炎治疗对降低复发至关重要。有研究^[14-15]表明肿瘤直径与早期复发及MVI发生也显著相关，而MVI与肝癌预后不良及早期复发亦密切相关^{[11, 16-17]}。对肿瘤肌肉壁及距包膜1 cm外的血管被侵润的患者，术后更加容易复发^[18]。但MVI目前只能通过术后病理获得，具有局限性，迫切需要新的指标和方法来预测MVI的发生^[19]。也有更早的研究^[20]提出肿瘤直径≥5 cm为肝切除术后1年内进展导致早期死亡的独立危险因素。以上都表明肿瘤直径及MVI与预后不良密切相关。对于肝功能异常的患者，如：低蛋白血症、转氨酶升高、高胆红素血症等，需要积极纠正后再行手术治疗。有学者^[21]总结肝内胆管癌及HCC行手术治疗时，提出切缘阴性(R0切除)可显著降低复发、提高生存率，并且如果能够保留足够的功能性肝残余，建议对HCC和肝内胆管癌进行宽切缘的解剖切除，与本研究结果相同，也体现了行R0切除的必要性。要求术者经验丰富，做到精准解剖十分关键。包膜侵犯与HCC患者的总体生存及术后复发密切相关，对于HCC术后化疗患者，包膜浸润为OS的独立危险因素^[22]。以上研究结果均与本研究确立的危险因素吻合，因此将这些危险因素纳入预测系统。

面对目前尚无针对术后复发有效预测系统的现状，PLC-EWSPRS评分系统的建立具有重要意义。并且该系统通过危险因素进行赋值评分加以汇总，综合临床指标更加全面具体，比单一因素具有更强的客观预测价值。在本研究中发现，复发组中高分数段所占比例远高于非复发组，提示该系统评分越高，复发风险越大，应该引起临床医师及患者的注意。根据总体及分层分析的ROC曲线的AUC值可知，PLC-EWSPRS系统对根治性切除的BCLC 0/A期HCC患者术后5年内生存状态预测价值有限，而对术后5年复发具有良好的预测价值。

本研究为单中心、小样本的回顾性研究，研究中两组患者肿瘤数和肿瘤分化程度无显著差异，与目前共识存在差异，未能纳入进行分析，这可能与研究样本量及病例纳入标准不同有关。另外，因目前肝癌术后复发相关预警系统罕见，未能进行预测价值的对比分析。后续还可以扩大纳入对象范围，以BCLC分期进行亚组分析，评估该系统对不同分期患者是否均具有术后复发预测价值。最后，因纳入对象的无瘤生存时间不明确病例较多，故未能行时间相关性的Cox回归分析，在后续验证中可以进行探究。因此，该系统还需要大样本、多中心、前瞻性的研究加以完善。但不能否认其在预测术后复发中所表现出的潜在价值。

综上，PLC-EWSPRS对BCLC 0/A期HCC患者术后5年复发具有良好的预测价值，对根治性切除的BCLC 0/A期HCC患者术后复查及治疗策略的制订具有重要的指导意义。

References(50)

References

[1]	O'LEARY JG, GREENBERG CS, PATTON HM, et al. AGA clinical practice update: Coagulation in cirrhosis[J]. Gastroenterology, 2019, 157(1): 34-43. e1. DOI: 10.1053/j.gastro.2019.03.070.
[2]	LATORRE R, VAQUERO J, RINCÓN D, et al. Determinants of platelet count are different in patients with compensated and decompensated cirrhosis[J]. Liver Int, 2016, 36(2): 232-239. DOI: 10.1111/liv.12908.
[3]	AREF S, SLEEM T, EL MENSHAWY N, et al. Antiplatelet antibodies contribute to thrombocytopenia associated with chronic hepatitis C virus infection[J]. Hematology, 2009, 14(5): 277-281. DOI: 10.1179/102453309X439818.
[4]	MITCHELL O, FELDMAN DM, DIAKOW M, et al. The pathophysiology of thrombocytopenia in chronic liver disease[J]. Hepat Med, 2016, 8: 39-50. DOI: 10.2147/HMER.S74612.
[5]	VINHOLT PJ, HVAS AM, NIELSEN C, et al. Reduced platelet activation and platelet aggregation in patients with alcoholic liver cirrhosis[J]. Platelets, 2018, 29(5): 520-527. DOI: 10.1080/09537104.2017.1349308.
[6]	ZHANG H, ZHANG S, ZHANG J, et al. Improvement of human platelet aggregation post-splenectomy with paraesophagogastric devascularization in chronic hepatitis B patients with cirrhotic hypersplenism[J]. Platelets, 2020, 31(8): 1019-1027. DOI: 10.1080/09537104.2019.1704715.
[7]	LISMAN T, BONGERS TN, ADELMEIJER J, et al. Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity[J]. Hepatology, 2006, 44(1): 53-61. DOI: 10.1002/hep.21231.
[8]	LISMAN T, ADELMEIJER J, de GROOT PG, et al. No evidence for an intrinsic platelet defect in patients with liver cirrhosis--studies under flow conditions[J]. J Thromb Haemost, 2006, 4(9): 2070-2072. DOI: 10.1111/j.1538-7836.2006.02122.x.
[9]	GROENEVELD DJ, POOLE LG, LUYENDYK JP. Targeting von Willebrand factor in liver diseases: A novel therapeutic strategy?[J]. J Thromb Haemost, 2021, 19(6): 1390-1408. DOI: 10.1111/jth.15312.
[10]	BACCOUCHE H, LABIDI A, FEKIH M, et al. Haemostatic balance in cirrhosis[J]. Blood Coagul Fibrinolysis, 2017, 28(2): 139-144. DOI: 10.1097/MBC.0000000000000561.
[11]	PRADHAN-SUNDD T, GUDAPATI S, KAMINSKI TW, et al. Exploring the complex role of coagulation factor Ⅷ in chronic liver disease[J]. Cell Mol Gastroenterol Hepatol, 2021, 12(3): 1061-1072. DOI: 10.1016/j.jcmgh.2021.02.014.
[12]	LEBRETON A, SINEGRE T, PEREIRA B, et al. Plasma hypercoagulability in the presence of thrombomodulin but not of activated protein C in patients with cirrhosis[J]. J Gastroenterol Hepatol, 2017, 32(4): 916-924. DOI: 10.1111/jgh.13493.
[13]	PATIL AG, BIHARI C, SHEWADE HD, et al. Decreased protein C function predicts mortality in patients with cirrhosis[J]. Int J Lab Hematol, 2018, 40(4): 466-472. DOI: 10.1111/ijlh.12836.
[14]	STEIN SF, HARKER LA. Kinetic and functional studies of platelets, fibrinogen, and plasminogen in patients with hepatic cirrhosis[J]. J Lab Clin Med, 1982, 99(2): 217-230.
[15]	HUGENHOLTZ GC, MACRAE F, ADELMEIJER J, et al. Procoagulant changes in fibrin clot structure in patients with cirrhosis are associated with oxidative modifications of fibrinogen[J]. J Thromb Haemost, 2016, 14(5): 1054-1066. DOI: 10.1111/jth.13278.
[16]	GREEN G, POLLER L, THOMSON JM, et al. Association of abnormal fibrin polymerisation with severe liver disease[J]. Gut, 1977, 18(11): 909-912. DOI: 10.1136/gut.18.11.909.
[17]	COLUCCI M, BINETTI BM, BRANCA MG, et al. Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis[J]. Hepatology, 2003, 38(1): 230-237. DOI: 10.1053/jhep.2003.50277.
[18]	RAUTOU PE, BRESSON J, SAINTE-MARIE Y, et al. Abnormal plasma microparticles impair vasoconstrictor responses in patients with cirrhosis[J]. Gastroenterology, 2012, 143(1): 166-176. e6. DOI: 10.1053/j.gastro.2012.03.040.
[19]	RAUTOU PE, VION AC, LUYENDYK JP, et al. Circulating microparticle tissue factor activity is increased in patients with cirrhosis[J]. Hepatology, 2014, 60(5): 1793-1795. DOI: 10.1002/hep.27033.
[20]	OWENS AP 3rd, MACKMAN N. Microparticles in hemostasis and thrombosis[J]. Circ Res, 2011, 108(10): 1284-1297. DOI: 10.1161/CIRCRESAHA.110.233056.
[21]	GOULD TJ, VU TT, SWYSTUN LL, et al. Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms[J]. Arterioscler Thromb Vasc Biol, 2014, 34(9): 1977-1984. DOI: 10.1161/ATVBAHA.114.304114.
[22]	AGRAZ-CIBRIAN JM, SEGURA-ORTEGA JE, DELGADO-RIZO V, et al. Alterations in neutrophil extracellular traps is associated with the degree of decompensation of liver cirrhosis[J]. J Infect Dev Ctries, 2016, 10(5): 512-517. DOI: 10.3855/jidc.7165.
[23]	BLASI A, PATEL VC, ADELMEIJER J, et al. Plasma levels of circulating DNA are associated with outcome, but not with activation of coagulation in decompensated cirrhosis and ACLF[J]. JHEP Rep, 2019, 1(3): 179-187. DOI: 10.1016/j.jhepr.2019.06.002.
[24]	STINE JG, WANG J, SHAH PM, et al. Decreased portal vein velocity is predictive of the development of portal vein thrombosis: A matched case-control study[J]. Liver Int, 2018, 38(1): 94-101. DOI: 10.1111/liv.13500.
[25]	QUECK A, CARNEVALE R, USCHNER FE, et al. Role of portal venous platelet activation in patients with decompensated cirrhosis and TIPS[J]. Gut, 2020, 69(8): 1535-1536. DOI: 10.1136/gutjnl-2019-319044.
[26]	DELAHOUSSE B, LABAT-DEBELLEIX V, DECALONNE L, et al. Comparative study of coagulation and thrombin generation in the portal and jugular plasma of patients with cirrhosis[J]. Thromb Haemost, 2010, 104(4): 741-749. DOI: 10.1160/TH10-01-0040.
[27]	SHOJAEI S, TAFAZZOLI-SHADPOUR M, SHOKRGOZAR MA, et al. Stress phase angle regulates differentiation of human adipose-derived stem cells toward endothelial phenotype[J]. Prog Biomater, 2018, 7(2): 121-131. DOI: 10.1007/s40204-018-0090-5.
[28]	CARNEVALE R, RAPARELLI V, NOCELLA C, et al. Gut-derived endotoxin stimulates factor Ⅷ secretion from endothelial cells. Implications for hypercoagulability in cirrhosis[J]. J Hepatol, 2017, 67(5): 950-956. DOI: 10.1016/j.jhep.2017.07.002.
[29]	SHALABY S, SIMIONI P, CAMPELLO E, et al. Endothelial damage of the portal vein is associated with heparin-like effect in advanced stages of cirrhosis[J]. Thromb Haemost, 2020, 120(8): 1173-1181. DOI: 10.1055/s-0040-1713169.
[30]	TRIPODI A, MANNUCCI PM. The coagulopathy of chronic liver disease[J]. N Engl J Med, 2011, 365(2): 147-156. DOI: 10.1056/NEJMra1011170.
[31]	ALI M, ANANTHAKRISHNAN AN, MCGINLEY EL, et al. Deep vein thrombosis and pulmonary embolism in hospitalized patients with cirrhosis: A nationwide analysis[J]. Dig Dis Sci, 2011, 56(7): 2152-2159. DOI: 10.1007/s10620-011-1582-5.
[32]	QI X, REN W, GUO X, et al. Epidemiology of venous thromboembolism in patients with liver diseases: A systematic review and meta-analysis[J]. Intern Emerg Med, 2015, 10(2): 205-217. DOI: 10.1007/s11739-014-1163-7.
[33]	INTAGLIATA NM, CALDWELL SH, TRIPODI A. Diagnosis, development, and treatment of portal vein thrombosis in patients with and without cirrhosis[J]. Gastroenterology, 2019, 156(6): 1582-1599. e1. DOI: 10.1053/j.gastro.2019.01.265.
[34]	UNGPRASERT P, WIJARNPREECHA K, THONGPRAYOON C. Risk of cerebrovascular accident in patients with primary biliary cirrhosis: A systematic review and meta-analysis[J]. Eur J Gastroenterol Hepatol, 2016, 28(1): 90-94. DOI: 10.1097/MEG.0000000000000493.
[35]	ZHENG K, YOSHIDA EM, TACKE F, et al. Risk of stroke in liver cirrhosis: A systematic review and meta-analysis[J]. J Clin Gastroenterol, 2020, 54(1): 96-105. DOI: 10.1097/MCG.0000000000001201.
[36]	XIONG J, XU W, HUANG H, et al. Cirrhosis and risk of stroke: A systematic review and meta-analysis[J]. Atherosclerosis, 2018, 275: 296-303. DOI: 10.1016/j.atherosclerosis.2018.06.876.
[37]	STINE JG, SHAH PM, CORNELLA SL, et al. Portal vein thrombosis, mortality and hepatic decompensation in patients with cirrhosis: A meta-analysis[J]. World J Hepatol, 2015, 7(27): 2774-2780. DOI: 10.4254/wjh.v7.i27.2774.
[38]	Hepatobiliary Disease Study Group, Chinese Society of Gastroenterology, Chinese Medical Association. Consensus for management of portal vein thrombosis in liver cirrhosis(2020, Shanghai)[J]. J Clin Hepatol, 2020, 36(12): 2667-2674. DOI: 10.3969/j.issn.1001-5256.2020.12.007. 中华医学会消化病学分会肝胆疾病学组. 肝硬化门静脉血栓管理专家共识(2020年, 上海)[J]. 临床肝胆病杂志, 2020, 36(12): 2667-2674. DOI: 10.3969/j.issn.1001-5256.2020.12.007.
[39]	BOS S, van DEN BOOM B, KAMPHUISEN PW, et al. Haemostatic profiles are similar across all aetiologies of cirrhosis[J]. Thromb Haemost, 2019, 119(2): 246-253. DOI: 10.1055/s-0038-1676954.
[40]	OZER B, SERIN E, SEZGIN N, et al. Thrombopoietin or interleukin-6 has no effect on thrombocytopenia of cirrhosis[J]. Hepatogastroenterology, 2007, 54(76): 1187-1191. http://europepmc.org/abstract/MED/17629067
[41]	MANGIA A, MARGAGLIONE M, CASCAVILLA I, et al. Anticardiolipin antibodies in patients with liver disease[J]. Am J Gastroenterol, 1999, 94(10): 2983-2987. DOI: 10.1111/j.1572-0241.1999.01447.x.
[42]	LI SJ, WANG L, CHEN Z, et al. Association of genotype with cellular immunity and coagulation function in chronic hepatitis B virus infection patients with different disease spectrums in Sichuan, China[J]. J Clin Hepatol, 2020, 36(5): 1014-1018. DOI: 10.3969/j.issn.1001-5256.2020.05.013. 李守娟, 王丽, 陈竹, 等. 四川地区不同疾病谱慢性HBV感染者病毒基因分型与细胞免疫及凝血功能的关系[J]. 临床肝胆病杂志, 2020, 36(5): 1014-1018. DOI: 10.3969/j.issn.1001-5256.2020.05.013.
[43]	XU Y, HUANG XP, CHEN L, et al. Role of coagulation abnormalities in thrombosis in patients with hepatitis B virus-associated acute-on-chronic liver failure[J]. J Clin Hepatol, 2021, 37(3): 560-564. DOI: 10.3969/j.issn.1001-5256.2021.03.012. 徐英, 黄小平, 陈丽, 等. 凝血异常在HBV相关慢加急性肝衰竭患者血栓形成中的作用[J]. 临床肝胆病杂志, 2021, 37(3): 560-564. DOI: 10.3969/j.issn.1001-5256.2021.03.012.
[44]	GIANNINI EG, STRAVITZ RT, CALDWELL SH. Correction of hemostatic abnormalities and portal pressure variations in patients with cirrhosis[J]. Hepatology, 2014, 60(4): 1442. DOI: 10.1002/hep.27029.
[45]	TRIPODI A, SALERNO F, CHANTARANGKUL V, et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests[J]. Hepatology, 2005, 41(3): 553-558. DOI: 10.1002/hep.20569.
[46]	TALON L, SINEGRE T, LECOMPTE T, et al. Hypercoagulability (thrombin generation) in patients with cirrhosis is detected with ST-Genesia[J]. J Thromb Haemost, 2020, 18(9): 2177-2190. DOI: 10.1111/jth.14963.
[47]	CAI TT, LI TX, ZENG W, et al. Study on emergency blood transfusion strategy for traumatic hemorrhagic shock[J]. Trauma Crit Med, 2021, 9(2): 128-131. DOI: 10.16048/j.issn.2095-5561.2021.02.11 蔡婷婷, 李天星, 曾文, 等. 血栓弹力图指导创伤失血性休克急诊输血策略研究[J]. 创伤与急危重病医学, 2021, 9(2): 128-131. DOI: 10.16048/j.issn.2095-5561.2021.02.11.
[48]	COPPELL JA, THALHEIMER U, ZAMBRUNI A, et al. The effects of unfractionated heparin, low molecular weight heparin and danaparoid on the thromboelastogram (TEG): An in-vitro comparison of standard and heparinase-modified TEGs with conventional coagulation assays[J]. Blood Coagul Fibrinolysis, 2006, 17(2): 97-104. DOI: 10.1097/01.mbc.0000203859.62739.25.
[49]	DE PIETRI L, BIANCHINI M, MONTALTI R, et al. Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: A randomized, controlled trial[J]. Hepatology, 2016, 63(2): 566-573. DOI: 10.1002/hep.28148.
[50]	KUMAR M, AHMAD J, MAIWALL R, et al. Thromboelastography-guided blood component use in patients with cirrhosis with nonvariceal bleeding: A randomized controlled trial[J]. Hepatology, 2020, 71(1): 235-246. DOI: 10.1002/hep.30794.

Relative Articles

[1]	Haijian DONG, Hui LI, Yujing TAO, Jialing GUO, Yuru ZHONG, Zijian ZENG. Role of A-kinase anchor protein 12 in chronic liver diseases[J]. Journal of Clinical Hepatology, 2023, 39(3): 718-722. doi: 10.3969/j.issn.1001-5256.2023.03.037
[2]	Ming WANG, Jianhu XU, Li MA. Mechanism of action of Dange Jiecheng decoction in a rat model of alcoholic liver disease based on the Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 signaling pathway[J]. Journal of Clinical Hepatology, 2023, 39(5): 1119-1125. doi: 10.3969/j.issn.1001-5256.2023.05.018
[3]	Yanhong BAO, Qiang WANG, Wenlong ZHANG, Na GE, Nan LI, Jun SU, Kexin LI. Ursolic acid in Hippophae rhamnoides L. inhibits hepatocyte apoptosis in rats with alcoholic liver disease by regulating mitochondria-cytochrome c[J]. Journal of Clinical Hepatology, 2023, 39(7): 1617-1626. doi: 10.3969/j.issn.1001-5256.2023.07.016
[4]	Cheng MA, Hui YANG. Role of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway in alcoholic liver disease[J]. Journal of Clinical Hepatology, 2023, 39(7): 1708-1713. doi: 10.3969/j.issn.1001-5256.2023.07.028
[5]	Boyuan GU, Shengyou XIAO, Chen LIU, Yonglang CHENG, Wenguang FU. Research advances in the role of Enterococcus faecalis in alcoholic liver disease[J]. Journal of Clinical Hepatology, 2023, 39(7): 1696-1702. doi: 10.3969/j.issn.1001-5256.2023.07.026
[6]	Qun ZHOU, Hua ZHANG, Ping LIU, Jiamei CHEN. Role of Takeda G protein-coupled receptor-5 in non-viral liver diseases[J]. Journal of Clinical Hepatology, 2022, 38(9): 2172-2176. doi: 10.3969/j.issn.1001-5256.2022.09.043
[7]	Rui ZHANG, Xiujuan CHANG, Jiamin CHENG, Zhiqin ZHAO, Yinyin LI, Yinying LU, Zhen ZENG. Influence of high-density lipoprotein cholesterol on the prognosis of patients with alcohol-related hepatocellular carcinoma after radical treatment[J]. Journal of Clinical Hepatology, 2021, 37(3): 621-626. doi: 10.3969/j.issn.1001-5256.2021.03.023
[8]	Qian WANG, Chunyan CHANG, Song YANG. Research advances in alcoholic liver disease with sarcopenia[J]. Journal of Clinical Hepatology, 2021, 37(8): 1943-1947. doi: 10.3969/j.issn.1001-5256.2021.08.043
[9]	Hui QUAN, Yuyong JIANG. Role of interleukin-1β in the pathogenesis of alcoholic liver disease[J]. Journal of Clinical Hepatology, 2021, 37(5): 1226-1228. doi: 10.3969/j.issn.1001-5256.2021.05.053
[10]	Chinese Medical Association, Chinese Medical Journals Publishing House, Chinese Society of Gastroenterology, Chinese Medical Association, Chinese Society of General Practice, Chinese Medical Association, Editorial Board of Chinese Journal of General Practitioners of Chinese Medical Association, Expert Group of Guidelines for Primary Care of Gastrointestinal Disease. Guideline for primary care of alcoholic liver disease(2019)[J]. Journal of Clinical Hepatology, 2021, 37(1): 36-40. doi: 10.3969/j.issn.1001-5256.2021.01.008
[11]	Niu ChunYan, Liu Qin, Luo XiaoChun. Reexamination of the diagnosis of fatty liver disease under the background of disease spectrum progression[J]. Journal of Clinical Hepatology, 2020, 36(10): 2356-2359. doi: 10.3969/j.issn.1001-5256.2020.10.043
[12]	NIU ChunYan, ZHANG Qiang, ZHAO XiangYang. Influence of drinking on nonalcoholic fatty liver disease[J]. Journal of Clinical Hepatology, 2020, 36(11): 2593-2596. doi: 10.3969/j.issn.1001-5256.2020.11.044
[14]	Liu Chen, Xing HuiChun, Cheng Jun, Yang Song. Influence of drinking on progression of chronic hepatitis B and outcome of antiviral therapy[J]. Journal of Clinical Hepatology, 2019, 35(3): 472-475. doi: 10.3969/j.issn.1001-5256.2019.03.003
[15]	Ma JiaLi, He LingLing, Li Ping, Jiang Yu, Hu JuLong, Zhou YuLing, Liang XiuXia, Wei HongShan. Influence of alcohol consumption on liver function and rebleeding in alcoholic cirrhotic patients with esophageal and gastric varices[J]. Journal of Clinical Hepatology, 2019, 35(11): 2478-2482. doi: 10.3969/j.issn.1001-5256.2019.11.018
[18]	Li QianNan, Chang JianBo, Bai YanXia, Wan Yan, Bi JianHong, Dai GuangRong. An epidemiological survey of alcoholic liver disease among staff of Yanchang Oilfield[J]. Journal of Clinical Hepatology, 2017, 33(9): 1769-1773. doi: 10.3969/j.issn.1001-5256.2017.09.029
[19]	Shen Wei. Alcohol consumption, metabolic syndrome and liver cancer [J]. Journal of Clinical Hepatology, 2010, 26(3): 255-256.

Supplements(0)

Cited By

Cited by
Periodical cited type(1)
1. 王叮叮. MEWS联合qSOFA评分在肿瘤危重症患者中应用价值. 中国城乡企业卫生. 2022(09): 112-114 .
Other cited types(1)

Proportional views

Proportional views

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

Get Citation

PDF

XML

Article Metrics

Article views (1000) PDF downloads(117)

Changes in hemostasis and clinical significance of coagulation function test in patients with liver cirrhosis

DOI: 10.3969/j.issn.1001-5256.2021.12.040