Premium
Tissue factor–positive tumor microvesicles activate platelets and enhance thrombosis in mice
Author(s) -
Geddings J. E.,
Hisada Y.,
Boulaftali Y.,
Getz T. M.,
Whelihan M.,
Fuentes R.,
Dee R.,
Cooley B. C.,
Key N. S.,
Wolberg A. S.,
Bergmeier W.,
Mackman N.
Publication year - 2016
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13181
Subject(s) - microvesicles , tissue factor , platelet , medicine , cancer research , pancreatic cancer , cancer , platelet activation , thrombosis , venous thrombosis , population , immunology , pathology , coagulation , chemistry , microrna , biochemistry , environmental health , gene
Essentials Cancer patients have a high rate of venous thrombosis (VT) but the underlying mechanisms are unknown. Tumor‐derived, tissue factor‐positive microvesicles in platelet activation in vitro and in vivo were studied. Tumor‐derived, tissue factor‐positive microvesicles enhanced VT in mice. Platelets may contribute to VT in some cancer patients, and this could be prevented with antiplatelet drugs.Summary Background Cancer patients have an approximately 4‐fold increased risk of venous thromboembolism ( VTE ) compared with the general population, and cancer patients with VTE have reduced survival. Tumor cells constitutively release small membrane vesicles called microvesicles ( MV s) that may contribute to thrombosis in cancer patients. Clinical studies have shown that levels of circulating tumor–derived, tissue factor–positive ( TF + ) MV s in pancreatic cancer patients are associated with VTE . Objectives We tested the hypothesis that TF + tumor–derived MV s ( TMV s) activate platelets in vitro and in mice. Materials and methods We selected two human pancreatic adenocarcinoma cell lines expressing high (BxPc‐3) and low (L3.6pl) levels of TF as models to study the effect of TF + TMV s on platelets and thrombosis. Results and conclusions We found that both types of TF + TMV s activated human platelets and induced aggregation in vitro in a TF and thrombin‐dependent manner. Further, injection of BxPc‐3 TF + TMV s triggered platelet activation in vivo and enhanced thrombosis in two mouse models of venous thrombosis in a TF ‐dependent manner. Importantly, BxPc‐3 TF + TMV ‐enhanced thrombosis was reduced in Par4‐deficient mice and in wild‐type mice treated with clopidogrel, suggesting that platelet activation was required for enhanced thrombosis. These studies suggest that TF + TMV ‐induced platelet activation contributes to thrombosis in cancer patients.