Background & Aims

Hypercoagulability and hypofibrinolysis in acutely decompensated cirrhosis (AD) may be implicated in disease progression and haemostatic complications. We conducted a prospective study to: (1) characterise haemostatic alterations in AD; (2) evaluate whether such alterations can predict acute-on-chronic liver failure (ACLF) and bleeding/thrombosis.

Methods

Hospitalised individuals with AD were prospectively recruited and underwent an extensive haemostatic profiling including coagulation factors, thrombomodulin-modified thrombin generation assay with evaluation of endogenous thrombin potential (ETP; marker for plasmatic hypercoagulability), fibrinolytic factors, and plasmin–antiplasmin complex (fibrinolysis activation marker). Inflammation severity was assessed by C-reactive protein (CRP). In part 1 of the study, we compared haemostasis in AD vs. controls (stable decompensated and compensated cirrhosis). In part 2 of the study, we prospectively followed individuals with AD for 1 year and investigated predictors of ACLF and bleeding/thrombosis.

Results

A total of 169 individuals with AD were recruited (median model for end-stage liver disease score 20; CLIF-C AD 54). Compared with controls, AD was associated with more pronounced hypercoagulability (ETP: 871 vs. 750 vs. 605 nmol/L per min; p <0.0001), without differences in fibrinolysis activation. During follow-up, 55 individuals developed ACLF. CLIF-C AD, CRP, and Child-Pugh were independently associated with ACLF. A predictive model combining these variables (Padua model) accurately identified individuals at higher risk of ACLF (AUROC 0.857; 95% CI 0.798–0.915; sensitivity 74.5%, specificity 83.3%). Notably, CRP and progression to ACLF, but not baseline coagulopathy, were associated with bleeding (n = 11); CRP and antifibrinolytic factor PAI-1 >50 ng/ml were associated with thrombosis (n = 14). The prognostic value of the Padua model was validated in an independent, bicentric European cohort (N = 301).

Conclusions

Inflammation severity, and not coagulopathy, is the most important predictor of ACLF and bleeding in AD. The Padua model can be used to identify individuals with AD at risk of ACLF.

Impact and implications

A better understanding of haemostasis in individuals with acutely decompensated cirrhosis may help to identify those at higher risk of progression and complications. In this prospective study, we found no significant association between alterations of haemostasis and cirrhosis progression, indicating that the assessment of haemostatic alterations is not useful to identify those at risk. However, we found that C-reactive protein (a simple blood test that reflects severity of inflammation) and severity of chronic liver disease itself (as assessed by specific scores) were associated with cirrhosis progression and development of bleeding complications. Therefore, we developed a simple predictive model – based on C-reactive protein and liver disease scores – that, if validated by independent studies, could be used in clinical practice to assist physicians in identifying individuals with decompensated cirrhosis at higher risk of disease progression and death (i.e. in whom to consider an expedited evaluation for liver transplantation).

中文翻译：

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全身炎症的严重程度是急性失代偿性肝硬化患者 ACLF 和出血的主要预测因子

背景与目标

急性失代偿性肝硬化(AD) 中的高凝状态和低纤维蛋白溶解可能与疾病进展和止血并发症有关。我们进行了一项前瞻性研究，以：(1) 表征 AD 中的止血改变；(2) 评估这种改变是否可以预测慢加急性肝衰竭 (ACLF) 和出血/血栓形成。

方法

前瞻性招募患有 AD 的住院患者并进行广泛的止血分析，包括凝血因子、血栓调节蛋白修饰的凝血酶生成试验以及内源性凝血酶潜能评估（ETP；血浆高凝状态标志物）、纤维蛋白溶解因子和纤溶酶-抗纤溶酶复合物（纤维蛋白溶解激活标志物） ). 通过 C 反应蛋白 (CRP) 评估炎症严重程度。在研究的第 1 部分中，我们比较了 AD与对照组（稳定的失代偿性和代偿性肝硬化）的止血情况。在研究的第 2 部分中，我们对 AD 患者进行了为期 1 年的前瞻性随访，并调查了 ACLF 和出血/血栓形成的预测因素。

结果

总共招募了 169 名患有 AD 的个体（终末期肝病评分模型的中值 20；CLIF-C AD 54）。与对照组相比，AD 与更明显的高凝状态相关（ETP：每分钟871 vs. 750 vs. 605 nmol/L； p <0.0001），在纤维蛋白溶解激活方面没有差异。在随访期间，55 人发生了 ACLF。CLIF-C AD、CRP 和 Child-Pugh 与 ACLF 独立相关。结合这些变量的预测模型（Padua 模型）准确识别出 ACLF 风险较高的个体（AUROC 0.857；95% CI 0.798–0.915；敏感性 74.5%，特异性 83.3%）。值得注意的是，CRP 和进展为 ACLF，但与基线凝血病无关，与出血相关（n = 11）；C反应蛋白和抗纤维蛋白溶解因子 PAI-1 >50 ng/ml 与血栓形成相关 (n = 14)。Padua 模型的预后价值在独立的双中心欧洲队列 (N = 301) 中得到验证。

结论

炎症严重程度而非凝血病是 ACLF 和 AD 出血的最重要预测因素。Padua 模型可用于识别患有 ACLF 风险的 AD 患者。

影响和启示

更好地了解急性失代偿性肝硬化患者的止血可能有助于识别进展和并发症风险较高的患者。在这项前瞻性研究中，我们发现止血改变与肝硬化进展之间没有显着关联，这表明止血改变的评估对于识别处于危险中的人没有用。然而，我们发现 C 反应蛋白（一种反映炎症严重程度的简单血液测试）和炎症的严重程度慢性肝病本身（通过特定评分评估）与肝硬化进展和出血并发症的发生有关。因此，我们开发了一个简单的预测模型——基于 C 反应蛋白和肝病评分——如果通过独立研究验证，该模型可用于临床实践，以帮助医生识别具有更高疾病进展风险的失代偿性肝硬化患者和死亡（即考虑对谁进行肝移植的快速评估）。