More Pronounced Hypercoagulable State and Hypofibrinolysis in Patients With Cirrhosis With Versus Without HCC

Abstract

In patients with cirrhosis, particularly those with hepatocellular carcinoma (HCC), hypercoagulability may be associated with purported increased risks of portal vein thrombosis and cirrhosis progression. In this study, we extensively investigated hemostatic alterations potentially responsible for the thrombotic tendency in HCC, and evaluated whether such alterations were predictive of hepatic decompensation. Patients with cirrhosis at all stages were prospectively recruited and underwent an extensive hemostatic assessment, including all procoagulant factors and inhibitors, thrombin generation with and without thrombomodulin (TG), profibrinolytic and antifibrinolytic factors, and plasmin-antiplasmin complex. In study part 1 (case control), we compared alterations of coagulation and fibrinolysis in patients with cirrhosis with versus without HCC. In study part 2 (prospective), the subgroup of patients with decompensated cirrhosis was followed for development of further decompensation, and predictors of outcome were assessed by multivariate analysis. One-hundred patients were recruited (50 each with and without HCC). Severity of cirrhosis was comparable between groups. Median HCC volume was 9 cm 3 (range: 5-16). Compared with controls, patients with HCC demonstrated a significantly more prothrombotic hemostatic profile due to increased TG and reduced activation of fibrinolysis, independent of cirrhosis stage. During a median follow-up of 175 days, 20 patients with decompensated cirrhosis developed further episodes of decompensation that were predicted by low FVII and high plasminogen activator inhibitor-1 levels, independent of Model for End-Stage Liver Disease score. Conclusion: Patients with cirrhosis with HCC have profound hyper-coagulable changes that can account for their increased thrombotic tendency. In contrast, hypercoagulability in patients with decompensated cirrhosis is more likely a consequence of chronic liver disease rather than a driver for cirrhosis progression. (Hepatology Communications 2021;0:1-14). P atients with cirrhosis have complex alterations of hemostasis that include low platelet count and increased levels of von Willebrand factor, reduced hepatic synthesis of both procoagulant factors and inhibitors, and altered fibrinolysis. (1) Current theory posits that these alterations result in a rebalanced but precarious hemostatic system that may easily tilt toward either hypocoagulability (increased bleeding tendency) or hypercoagulability (increased clotting tendency).

Hepatocellular Carcinoma in Chronic Viral Hepatitis: Where Do We Stand?

“…Chronic inflammation due to viral infection leads to a progressive alteration of immune cells, which causes an increased release ROS and proinflammatory cytokines within the liver niche and finally determines the remodeling of liver microenvironment [ 34 ]. Recently, it has also been suggested that alterations of hemostasis, particularly of platelets, could have a role in hepatocarcinogenesis [ 35 , 36 ]. Additional mechanisms that promote the induction of HCC in patients with HBV, HCV, and HBV-HDV infection are discussed below ( Table 1 ) [ 37 , 38 , 39 , 40 , 41 , 42 , 43 ].…”

Global hemostatic profiling in patients with decompensated cirrhosis and bacterial infections

“…These exclusion criteria were chosen to mitigate the effects of potential confounders on the assessment of hemostasis. [23] , [24] , [25] , [26] , [27] , [28] …”

“…Secondary hemostasis (coagulation) was assessed by measuring fibrinogen, procoagulant factors II (FII), V (FV), VII (FVII), VIII (FVIII), IX (FIX), X (FX), XI (FXI), XII (FXII), fibrin-stabilizing factor XIII (FXIII), natural anticoagulants (protein C [PC] chromogenic and coagulometric, protein S [PS], and antithrombin [AT]), as well as thrombin generation with and without thrombomodulin (TM). 27 , 31 Thrombin-antithrombin complex was determined as a marker of coagulation activation.…”

Haemostatic alterations in patients with cirrhosis and hepatocellular carcinoma: laboratory evidence and clinical implications

“…26 One study thoroughly investigated alterations in coagulation and fibrinolysis in cirrhosis with HCC and demonstrated that HCC was associated with a significantly increased thrombin generation, indicating increased clotting capacity and reduced activation of fibrinolysis. 24 In clinical practice, the evaluation of haemostatic alterations in cirrhosis with HCC may help identify patients at higher risk for thrombosis and perhaps guide thromboprophylaxis. However, prior to considering primary prophylaxis in these patients (currently not recommended), further prospective studies that correlate laboratory findings with development of thrombosis in patients with cirrhosis and HCC are required (Table 1).…”

“…It is not yet fully understood whether and how HCC destabilizes the rebalanced haemostatic state in patients with cirrhosis 20 . However, there is growing evidence that patients with cirrhosis and HCC present a more hypercoagulable phenotype than controls with cirrhosis without HCC 21‐26 …”