Increased Concentrations of Tumor Necrosis Factor and lnterleukin-6 Contribute to the Hemostatic Abnormalities in Advanced Liver Disease

Abstract

Abnormal cytokine levels have been described in patients with chronic liver disease, but studies correlating cytokine homeostasis with abnormalities in coagulation and fibrinolysis are lacking. In order to establish a link between cytokines and the hemostatic changes the following parameters were determined in 44 patients with cirrhosis (alcoholic =15, postnecrotic = 22, others = 7): TNF-α, IL·6, thrombin-antithrombin (TAT) complexes, prothrombin fragment 1 + 2 (F1 + 2) and t-PA by using enzyme-linked immunosorbent assays, and PAI-1, plasminogen and α₂-antiplasmin (α₂-AP) by using chromogenic substrates. All patients were at stages B and C of Child’s classification when entering the study. Mean cytokine concentrations were significantly higher in cirrhotic patients as compared to age- and sex-matched controls (p < 0.009). There was a significant increase of TAT (p < 0.02) and F1 + 2 (p < 0.001) in the patients groups, suggesting a grade of intravascular coagulation. A hyperfibrinolytic state as demonstrated by an increase of t-PA and decrease of plasminogen and α₂-AP was also observed (p < 0.001). We could define a subgroup of patients with cytokine values higher than 20 pg/ml. Interestingly, in this group there was a significant increase of TAT (p < 0.04) and t-PA (p < 0.02) levels and a decrease of plasminogen and α₂-AP (p < 0.02) as compared to values observed in patients with cytokines lower than 20 pg/ml. We conclude that high levels of TNF-α and IL-6 may contribute to hyperfibrinolysis and intravascular coagulation in patients with liver cirrhosis, as assessed by the increase of TAT and t-PA levels and the reduction of plasminogen and α₂-AP.

Thrombin generation measured as thrombin–antithrombin complexes predicts clinical outcomes in patients with cirrhosis

“…Furthermore, TAT and AT were the only coagulation parameters to be independently associated with liver function impairment. Our findings are similar to that reported by other groups 7,8,19–21 reinforcing the existence of a hypercoagulable profile in patients with cirrhosis.…”

“…18 The TAT assay has been frequently employed in the published work as a laboratory index to excessive TG in patients with cirrhosis. [19][20][21][22] A marked increase in TG together with a depressed anticoagulant activity was noted in patients with cirrhosis compared with normal subjects. Interestingly, TAT levels were elevated even in Child-Pugh A patients compared with controls in this study.…”

“…A question that may arise is what triggers TG in advanced cirrhosis perturbing the unstable hemostatic balance towards a thrombotic state. Although endotoxin levels were not measured in our study, cirrhosis-related endotoxemia may represent an underlying mechanism because it can stimulate TG 21,28 and increases in proportion to the progression of liver disease. 29 Notably, 25% of deaths in our study were due to infection, suggesting that a further increase in endotoxemia may more adversely affect prognosis through deterioration of hypercoagulability in patients with a higher baseline thrombotic tendency.…”

Cytokines and Liver Diseases

“…It has been suggested that bacterial infections and endotoxemia may be important triggers of variceal bleeding in cirrhosis (21). Endotoxemia has been proven to be a powerful activator of clotting and fibrinolysis in liver cirrhosis (19,22).…”

Markers of Thrombogenesis and Fibrinolysis and Their Relation to Inflammation and Endothelial Activation in Patients with Idiopathic Pulmonary Arterial Hypertension

“…In observational studies in various patient populations including healthy individuals, patients at high cardiovascular risk as well as in patients with advanced liver disease [36-39] IL-6 levels have been shown to correlate with tPA, which supports IL-6 induced endothelial cell activation and subsequent release of tPA as one of the potential underlying pathways [40]. In experimental models IL-6 also induced the expression of plasminogen, which is a substrate for plasmin [41].…”