To cite this article: Tesselaar MET, Romijn FPHTM, van der Linden IK, Prins FA, Bertina RM, Osanto S. Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J Thromb Haemost 2007; 5: 520-7.Summary. Background: Cancer, in particular mucinous adenocarcinoma, is associated with venous thromboembolism (VTE). Tissue factor (TF), initiator of coagulation, plays a central role in the paradigm that clotting and tumor growth form a vicious circle, in which hypercoagulability facilitates the aggressive biology of cancer and vice versa. Expression of TF in tumors is associated with poor differentiation and poor prognosis. Patient/methods: We investigated the association between clinically manifest VTE and procoagulant properties of circulating microparticles (MP) isolated from blood of unselected pancreatic and breast adenocarcinoma patients' consecutive subjects, who presented with ultrasound or CT-scan confirmed VTE, and healthy subjects. Results: Patients with disseminated breast and pancreatic cancer had significantly increased levels of MP-associated TF activity compared with healthy controls, subjects with idiopathic acute VTE and non-metastatic cancer patients. Patients with both high MP-associated TF-activity and MP-associated epithelial mucin (MUC1) had a lower survival rate at 3-9 months follow-up than those with low TFactivity and no MUC1 expression: the likelihood of survival was 0.42 (95% CI: 0.19-0.94) for an individual with these two predictor variables present, after adjustment for other factors (age cohort, type of cancer, VTE) in the Cox proportional hazards model. Conclusions: Our results suggest an important role for MP-associated TF and MUC1 in the pathogenesis of thrombosis in disseminated mucinous adenocarcinoma patients. Future studies should reveal the mechanism underlying the observed associations.

Background: Cancer, in particular mucinous adenocarcinomas, is associated with an increased risk of venous thromboembolism (VTE). Tissue factor (TF), a transmembrane-receptor protein and initiator of coagulation, plays a central role in the paradigm that clotting and tumor growth form a vicious circle, in which hypercoagulability facilitates the aggressive biology of cancer and vice versa. Expression of TF is associated with poor differentiation of tumors and poor prognosis. We initiated a study in cancer patients, to find out whether microparticles (MP) derived from malignant epithelial cells, may directly initiate blood coagulation locally or at distant sites via TF expressed on these MP and play a critical role in the development of the hypercoagulability Patients & Methods: MP were isolated from peripheral blood samples obtained from healthy subjects, and unselected cancer patients, i.e. patients with primary breast carcinoma (before and after surgery), with metastatic breast carcinoma and with pancreatic carcinoma. Tissue factor procoagulant activity associated with isolated MP was studied by factor VIIa dependent generation of factor Xa. MP were examined by flow cytrometric phenotyping, and electron and confocal immunofluorescence laser scanning microscopical examination. Results: Compared to 37 healthy sujects, significantly increased levels of MP-associated TF activity were found in patients with disseminated breast and pancreatic cancer. Pancreatic (n=5) and breast cancer patients (n=2) who presented with clinically manifest venous thrombosis had a 18-fold increase in MP-associated TF activity as compared to healthy subjects or 6 subjects with idiopathic VTE (P<0.003). In all individuals most of the circulating MP expressed the platelet antigen CD61. MP expressing the epithelial antigen MUC1 -most likely derived from malignant cells- were found in 65% of metastatic breast and 59% of advanced c.q. metastatic pancreatic patients. Co-expression of CD61 and MUC1 on MPs was shown by flow cytometry and confocal immunofluorescence microscopy. Conclusion: Highly elevated MP-associated TF activity significantly correlated with development of VTE and with the presence of circulating MUC1-positive MP, suggesting a decisive role in the pathogenesis of the prothrombotic state in cancer patients with disseminated mucinous carcinomas. Patients with a low level of TF-activity on MP that also lacked expression of mucin had a higher survival rate at 3–9 months follow-up than those with a high TF-activity and mucin present: the estimated risk of dying was about 0.42 (95% CI 0.19–0.94) for an individual with these 2 predictor variables present, adjusting for the other factors (age cohort, type of cancer, VTE) in the Cox proportional hazards model.

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