Circulating hepatocyte growth factor as an independent prognostic factor of disseminated intravascular coagulation

Abstract 

Background

Hepatocyte growth factor (HGF), a pleiotropic factor regulating development and wound healing, is secreted as inactive pro-HGF and is converted into active HGF by coagulation serine proteases. HGF receptor overexpression can cause massive venous thrombi, and factor Xa is reported to release soluble HGF from granulocytes. We hypothesized that a hypercoagulable condition, such as disseminated intravascular coagulation (DIC), may increase circulating HGF through active cleavage by coagulation serine proteases.

Methods

In 172 DIC-suspected patients, plasma levels of total and active HGF, thrombin-antithrombin complex (TAT), plasmin-antiplasmin complex (PAP), and interleukin (IL)-6 were measured by ELISA. Active HGF release in granulocytes was examined in patients with and without overt-DIC. HGF-induced tissue factor expression in peripheral monocytes was measured by flow cytometry.

Results

Circulating levels of total and active HGF correlated well with coagulopathy severity, including DIC score, D-dimer, TAT and PAP levels. HGF positively correlated with IL-6 and absolute neutrophil count. In contrast to the cancer group, HGF levels were significantly increased in accordance with increased DIC scores in non-cancer group. Elevated circulating HGF was an independent prognostic marker in the non-cancer group, while HGF level failed to predict mortality in the cancer group. Amounts of HGF released from stimulated granulocytes were not significantly different between overt-DIC and no overt-DIC patients. HGF potentiated endotoxin-induced tissue factor expression of monocytes in vitro.

Conclusion

These findings suggest that circulating HGF is a potential laboratory marker reflecting coagulation activity and DIC prognosis in non-cancer patients and that HGF may play a role in a vicious cycle of hypercoagulability.