Background: The fibrinogen-like protein 2 (FGL2) acts in the axis of coagulation and immunity. It is a membrane associated prothrombinase capable of acting independent of the canonical coagulation pathway (mFGL2), as well as a secreted protein exhibiting potent immune-suppressive activity (sFGL2). FGL2 is expressed in the blood and cancer cells and was shown to be actively involved in assortment of physiological and pathological processes. Recent studies have linked FGL2 activity with thrombosis and tumorigenesis. Yet, very little is known about its origin, mechanism of action or functional significance.
Methods: Peripheral blood samples were collected from healthy controls and patients suffering from colon cancer or prostate cancer. Prothrombinase activity was determined in plasma-free cells. Blotting immunoassays, immunoprecipitation, flow cytometry and immuno-inhibition methodologies were implemented to identify the blood entities exerting FGL2 activity, expression and functional localization.
Results: We found that platelets can exert prothrombinase activity by FGL2 independent of factor X. While FGL2 was detected in both peripheral blood mononuclear cells (PBMC) and platelets, the PBMC derived FGL2 displayed no coagulative activity. FGL2 was not detected in megakaryoblasts. Platelet comprised both a membrane FGL2 form (mFGL2) and a cytosolic soluble form (sFGL2). Platelets activation led to the secretion of both forms accompanied by significant prothrombinase activity. Furthermore, FGL2 activity in the platelets of colon or prostate cancer patients was enhanced comparison to healthy controls.
Conclusion: We provide evidence for a new immune-coagulant factor presented by platelets. While factor X is absent in platelets, FGL2 may directly initiate thrombin generation upon platelets activation. Accordingly, platelets may utilize FGL2 to promote coagulation independent of the classical coagulation pathway. FGL2 activity is enhanced in platelets from of colon or prostate cancer patients. Therefore, in view of the tumorigenic and thrombotic capabilities of FGL2, this study suggests a new mechanistic understanding of platelets- tumorigenesis-thrombosis relationships. In summary, this study lays new foundation for understanding of physiological and pathophysiological mechanisms mediated by platelets.