Microcirculatory disturbances are involved in the pathogenesis mostly of ALF. Activation of the inflammatory cascade may affect the coagulation system and the resulting intrahepatic coagulation may worsen sinusoidal blood flow, leading to massive liver necrosis; a histological feature of ALF. Activation of macrophages, as represented by the elevated serum levels of CD163 and osteopontin in ALF patients, seems to be a trigger for this inflammatory process. Following the onset of inflammation, disturbances in the intrahepatic coagulation system may enhance the destruction of liver cells. In patients with ALF, electron microscopy has revealed disorders in sinusoidal endothelial cells (SECs). Moreover, reduced mRNA expression of anticoagulants such as tissue factor pathway inhibitor and thrombomodulin are observed in SECs.
Following the activation of tissue factor, intrahepatic coagulation causes sinusoidal fibrin deposition and thus restricts blood circulation in the diseased liver[26-28]. Based on these observations, AT III treatment has been tested in animal models of ALF because of its anticoagulant activity. Systemic injection of AT III (500 U/kg body weight) prevented Con-A-induced liver injury by inhibiting macrophage inflammatory protein-2 release and endothelial cell production of prostacyclin. Meanwhile, a similar dose of AT III (400 U/kg body weight) reduced liver damage in an ALF model with coagulopathy induced by DMN, which was characterized by marked intrasinusoidal fibrin deposition and elevated serum fibrin monomer complexes.
However, large doses of AT III, which are unacceptable in clinical practice, were used to suppress liver injury in these experimental models. The effects of AT III for the treatment of ALF patients seem to be limited. Fujiwara et al treated 26 patients with fulminant hepatic failure with daily infusion of 3000 U AT III. Notably, survival time was longer in patients with plasma AT III levels within the normal range compared with levels beyond the normal range. However, the survival rates were not significantly different between patients treated with AT III and control patients. Another research group treated 13 ALF patients with 3000 U AT III, followed by a further 1000 U every AV-951 6 h. However, survival time was not improved by AT III and the extent of intravascular coagulation was similar between AT-III-treated and control patients. These different outcomes of clinical trials and animal experiments might be due to the insufficient concentration of AT III in the patients�� liver. Indeed, the relative doses of AT III per body weight used in patients were < 10% of those used in animals.