The relationship between cytokine concentrations and hemostatic abnormalities in patients with liver cirrhosis of postviral or cryptogenic origin

Background: Elevated thrombin/antithrombin III (TAT) complex and elevated D-dimer levels have been reported in liver cirrhosis, indicating that cirrhotics have both increased thrombin generation and increased plasmin formation. A number of factors that are elevated in various inflammatory and vascular diseases, including the cytokines tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), endotoxin (LPS), transforming growth factor-β (TGF-β), and thrombin, can stimulate plasminogen activator inhibitor (PAI-1) production by endothelial cells in vitro. Moreover, both in vitro and in vivo investigations have suggested that TNF is an important mediator of the activation of coagulation. However, the relationship between cytokines and hemostatic abnormalities in liver cirrhosis is unknown.

Methods: Plasma concentrations of TNF-α, IL-6, TAT, and PAI-1 were determined, by using enzyme linked immunosorbent assay, in 50 patients with cirrhosis (alcoholic=1, postviral=35, cryptogenic=14) who were at different stages (A=3, B=21, C=26) of Child classification and results were compared to those obtained in 24 healthy subjects.

Results: The IL-6 and TNF-α levels in patients with cirrhosis were significantly increased compared with those in healthy subjects (median [interquantile ranges]: 15.96 [8.69–49.79] vs 0.73 [0.37–1.52] pg/ml, P<0.0001; 5.30 [3.60–10.85] vs 1.10 [0.77–2.67] pg/ml, P<0.05, respectively). The TAT and PAI-1 levels in patients with cirrhosis were also significantly increased compared with those in healthy subjects (3.95 [3.2–9.15] vs 2.35 [2.20–2.65] μg/l, P<0.001; 32.45 [17.5–49.8] vs 12.25 [4.7–24.9] ng/ml, P<0.001, respectively). The TNF-α level was positively correlated with TAT (r=0.5979, P<0.001). The IL-6 level was also positively correlated with those of TNF-α (r=0.3436, P<0.05) and TAT (r=0.3982, P<0.05). However, the PAI-1 level did not show any correlation with cytokines or TAT.

There was significant difference of IL-6 levels between postviral group (22.69 [1.52–101.48] pg/ml) and cryptogenic group (64.89 [7.73–209.67] pg/ml) (P=0.006).

Conclusion: We conclude from this study that TNF-α could play an important part in the activation of hemostatic mechanism in liver cirrhosis, a condition commonly associated with intravascular coagulation. Our results suggest that the presence of increased plasma levels of TNF-α and IL-6 in these patients probably reflects chronic secretion which could be induced or perpetuated by endotoxins or other factors associated with host-defense immune mechanisms.