Microparticle-Associated Tissue Factor Activity: A Link between Cancer and Thrombosis?.

Abstract

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.

Emerging roles for vascular smooth muscle cell exosomes in calcification and coagulation

“…), and recently the levels of circulating EVs associated with tissue factor (TF), an important activator of extrinsic coagulation pathways, was linked to the increased risk of venous thromboembolism in cancer patients (Tesselaar et al . ). Vascular thrombosis due to atherosclerotic plaque rupture is the main cause of vascular occlusion events including myocardial infarction, unstable angina, stroke and sudden cardiac death.…”

Apheresis platelet concentrates contain platelet‐derived and endothelial cell‐derived microparticles

“…The release of MP occurs upon cell activation and during apoptosis [2]. Elevated concentrations of MP have been associated with clinical conditions, including vascular diseases, diabetes, severe trauma and several types of cancers [3–9].…”

Progesterone utilizes distinct membrane pools of tissue factor to increase coagulation and invasion and these effects are inhibited by TFPI

“…Furthermore, levels of TF are associated with the aggressiveness of cancer and thus poor patient prognosis (Kato et al, 2005). Reports have indicated that cancer patients present high rates of thrombosis due to elevated levels of TF microparticles, presumably originating from cancer cells that circulate in their plasma (Tesselaar et al, 2007; Kasthuri et al, 2009; Krikun et al, 2010). The first interesting observation to stem from this study was the demonstration that progesterone increases the levels of TF in heavy membrane fractions, whereas the coagulant activity of TF was by and large restricted to the cholesterol‐rich lipid rafts where TF protein was extremely low.…”