Tissue factor, factor VIII and IX in microvesicle-induced thrombosis and tumor growth of pancreatic cancer.

Background: Tissue factor (TF)-rich cancer microvesicles are correlated with thrombosis risk. Intrinsic coagulation factors are also associated with the risk of thrombosis in cancer patients. This study explored the roles of pancreatic cancer-derived microvesicles and intrinsic factors in thrombogenesis.

Methods: Human pancreatic cancer cell lines rich in TF (AsPC-1-TF^high, MIAPaCa-2-TF^high) or poor in TF [AsPC-1-TF^KO(knockout) and MIAPaCa-2-TF^low] were generated for microvesicle preparation and injected into coagulation-defective mice. Inferior vena cava (IVC) clots and lung thrombosis were evaluated. Immunodeficient hemophilia A (NSG-HA) mice were orthotopically injected with the cells mentioned above, and the tumor and IVC clot weights were analyzed.

Results: With the injection of TF^high microvesicles, IVC clots were rarely found in hemophilic mice. The TF^low and TF^KO microvesicles resulted in few IVC clots in any mouse. Lung thrombosis was substantially reduced in the hemophilic mice infused with any microvesicle type. In orthotopic tumor models, TF^high cells grew faster than did TF^low cells. TF^high tumor-bearing NSG-WT mice had the most enormous IVC clots, whereas NSG-HA mice had no IVC clots.

Conclusion: Pancreatic cancer thrombosis induced by TF-expressing microvesicles strongly depended on FVIII and FIX, while VWF played a minor role. Moreover, TF, but not FVIII, was significantly related to tumor growth.