Tissue factor‐bearing microparticles derived from tumor cells: impact on coagulation activation

Abstract

Summary. Background: Tissue factor (TF)-bearing microparticles (MP) from different origins are thought to be involved in the pathogenesis of cancer-associated thrombosis. However, the role of circulating tumor cell-derived TF is not well understood. Methods: TF antigen and activity were measured in MP generated in vitro from human TF-expressing cancer cells by ELISA and clotting or thrombin generation assays, respectively. TF antigen and activity were also measured in vivo in cell-free plasmas from mice previously injected with in vitrogenerated MP or in cell-free plasmas from nude mice bearing orthotopically injected human cancer cells. Results: Tumor cellderived MP (TMP) exhibited strong TF-dependent procoagulant activity (PCA) in vitro and in vivo. Injection of TMP into mice was associated with acute thrombocytopenia and signs of shock, which were prevented by prior heparinization. Human TF antigen and activity could be detected in mouse cell-free plasmas up to 30 min after TMP injections. Human TF was detected in the spleen of injected mice and its clearance from circulation was delayed in splenectomized mice, suggesting the involvement of the spleen in the rapid clearance of circulating MP in vivo. Detectable levels of TF-dependent PCA and thrombin-antithrombin complex were found in cell-free plasmas from mice growing pancreatic human tumors, suggesting that circulating tumor-derived TF causes coagulation activation in vivo. Conclusions: MP derived from certain cancer cells exhibit TF-dependent PCA both in vitro and in vivo. These results provide new information about the specific contribution of tumor-derived MP to the hypercoagulable state observed in cancer.

Circulating tumour cells are associated with increased risk of venous thromboembolism in metastatic breast cancer patients

“…It is supposed that the direct toxic effect of anticancer treatment on cancer cells may lead to an increase in CTC fragments or microparticles with procoagulant activity (Dvorak et al, 1983). Circulating tumour cells could be involved in the activation of coagulation through the expression and release of tissue factors (TFs) (Davila et al, 2008). It was shown that TFs are overexpressed in cells with cancer stem cell phenotype (Milsom et al, 2007).…”

Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer

“…22 Further, plasma from these tumor-bearing mice was found to enhance thrombin generation in vitro in a human TF-dependent manner. 22 Another study found that human (SOJ-4) and mouse (PANC02) pancreatic cell lines expressed TF, and the investigators observed an accumulation of tumor-derived MPs at the site of thrombosis and increased thrombosis in a microvascular model. 18 The objective of the present study was to determine the role of tumor-derived TF in the activation of coagulation and thrombosis in a xenograft mouse model of human pancreatic tumors.…”

“…21 In nude mice bearing orthotopic human pancreatic tumors (L3.6pl) plasma levels of human TF protein were correlated with the levels of thrombin-antithrombin (TAT) complex, a marker of the activation of coagulation. 22 Further, plasma from these tumor-bearing mice was found to enhance thrombin generation in vitro in a human TF-dependent manner. 22 Another study found that human (SOJ-4) and mouse (PANC02) pancreatic cell lines expressed TF, and the investigators observed an accumulation of tumor-derived MPs at the site of thrombosis and increased thrombosis in a microvascular model.…”

“…Both subcutaneous and orthotopic tumor mouse models have been used to study the release of tumor-derived TF protein and TF-positive MPs into the circulation. 21,22 We chose to use HPAF-II cells in the present study because they expressed the highest levels of TF. Similarly sized orthotopic and subcutaneous HPAF-II tumors were grown in nude mice (orthotopic tumors 0.97 Ϯ 0.33 g, n ϭ 7; subcutaneous tumors 0.98 Ϯ 0.13 g, n ϭ 6) and TF protein in the plasma and activation of coagulation were measured.…”

Circulating Microparticles Decrease After Cardiac Stress in Patients With Significant Coronary Artery Stenosis

“…26 Clearance of tumorderived human TF + MPs was examined in control and splenectomized mice. 27 In control mice, peak levels of TF + MPs were observed at 30 minutes, and none were detected at 120 minutes; whereas in the splenectomized mice, significant levels of TF + MPs were observed at 120 minutes. These results support the conclusion that the spleen is the major site for the clearance of PS + MPs with or without TF.…”