Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients

Abstract

Patients with cancer have an increased risk for venous thrombosis. Interestingly, different cancer types have different rates of thrombosis, with pancreatic cancer having one of the highest rates. However, the mechanisms responsible for the increase in venous thrombosis in patients with cancer are not understood. Tissue factor (TF) is a transmembrane receptor and primary initiator of blood coagulation. Tumor cells express TF and spontaneously release TF-positive microparticles (MPs) into the blood. MPs are small membrane vesicles that are highly procoagulant. It has been proposed that these circulating tumor-derived, TF-positive MPs may explain the increased rates of venous thrombosis seen in patients with cancer. In animal models, increased levels of tumor-derived, TF-positive MPs are associated with activation of coagulation. Moreover, these MPs bind to sites of vascular injury and enhance thrombosis. We and others have found that patients with cancer have elevated levels of circulating TF-positive MPs. These MPs are derived from tumors because they express tumor markers and are decreased by tumor resection. Importantly, several studies have shown that increased levels of TF-positive MPs correlate with venous thrombosis in patients with cancer. Taken together, these results suggest that TF-positive MPs may be a useful biomarker to identify patients with cancer who are at high risk for thrombosis.

Figure 1

TMP surface proteins and their functions. TMPs are constitutively released from tumors into the circulation. The procoagulant activity of TMPs is mediated by the expression of TF and the exposure of PS on the MP surface. Tumor markers such as MUC-1 can allow for the identification of TMPs in the circulation. Adhesion proteins including P-selectin ligand CD24 and E-selectin ligand CD43 have been proposed to be involved in the binding of TMPs to endothelium and thrombosis sites.^, Delivery of TMP TF to the site of thrombosis can then initiate thrombosis. This diagram is an example of proteins that can be expressed on the surface of TMPs. Protein expression on the surface of TMPs varies with each tumor. FVIIa, factor VIIa.