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.