Endothelial, platelet, and tissue factor-bearing microparticles in cancer patients with and without venous thromboembolism

doi:10.1016/j.thromres.2011.01.002

Thrombosis Research

Volume 127, Issue 5, May 2011, Pages 473-477

https://doi.org/10.1016/j.thromres.2011.01.002 Get rights and content

Abstract

Background

Cancer is a prothrombotic state, with an increased prevalence of venous thromboembolism (VTE). Microparticles (MPs) are sub-micron-sized vesicles derived from activated or apoptotic cells that may play a role in VTE, although evidence of this association is still limited.

Objectives

To evaluate the hypothesis that elevated numbers of endothelial (EMPs), platelets (PMPs), and Tissue Factor-bearing MPs (TF⁺MPs) in plasma may contribute to cancer-associated thrombosis.

Patients/Methods

EMPs, PMPs and TF⁺MPs plasma levels were measured in 90 consecutive patients (cases) referred to our Department (30 with a first episode of unprovoked VTE; 30 with active cancer; 30 with a diagnosis of acute VTE associated with active cancer), and in a group of 90 healthy subjects (controls). MPs analyses were performed by flow-cytometry (Cytomics FC500).

Results

Cases showed statistically significant higher (mean ± SD) circulating EMPs and PMPs plasma levels (920 ± 341 and 1221 ± 413 MP/μL, respectively) than controls (299 ± 102 and 495 ± 241 MP/μL; p < 0.005). Moreover cancer patients (with and without VTE) showed higher (mean ± SD) TF⁺MPs (927 ± 415 MPs/μL) than controls (204 ± 112 MPs/μL; p < 0.001). The subgroup of cancer patients plus VTE showed statistically significant higher TF⁺MPs plasma levels (1019 ± 656 MPs/μL) than cancer patients without VTE (755 ± 391 MPs/μL, p = 0.002). Multivariate analysis failed to show a significant association between elevated TF⁺MPs and VTE in cancer patients.

Conclusions

Our results suggest that MPs might be an important intermediate in the cascade of cellular injury and vascular dysfunctions underlying the process of thrombosis, particularly in cancer. Further clinical investigations are needed to confirm the precise role of MPs in predicting hypercoagulable state in patients with cancer.

Introduction

Microparticles (MPs) are phospholipid vesicles, smaller than 1 μm in diameter, derived mainly from blood and endothelial cells, in response to activation or apoptosis. MPs release is an integral part of the membrane-remodelling process in which the asymmetric distribution of constitutive phospholipids between the two leaflets is lost [1]. MPs are detected and characterized on the basis of antigens characteristic of their respective parental cells [2]. Found at the electronic microscopy since 1967 by Wolf and coll. [3], MPs were considered “cellular dust” without any biological function. Recently it has been hypothesized that MPs play a role in inflammation, coagulation and vascular function [4], and it was demonstrated that these elements could induce cell signalling [5] and regulate many pathophysiological processes [6] including neoangiogenesis [7]. Moreover, a procoagulant function has been attributed to MPs, due to the presence phospholipids on their outer surface, in particular phosphatidilserine (PS), which could induce the activation of the coagulation cascade. This procoagulant role is amplified by the capability of PS to activate tissue factor (TF) [8]. Elevated MPs of different phenotypes have been documented in the blood of patients with venous thromboembolism (VTE) [9], [10], [11] and with various diseases characterized by arterial and venous thrombotic complications (i.e. heparin induced thrombocytopenia [12], cardiovascular diseases [13], [14], thrombotic thrombocytopenic purpura [15], sickle cells diseases [16], uraemia [17], diabetes [18] and anti-phospholipid antibody syndrome [19]). Thromboembolic disease is a well recognized complication of cancer. Clinical studies reported that approximately 5–15% of all cancer patients develop thrombotic events [20], [21]. However, despite this strong association between VTE and malignant diseases, the molecular and cellular bases of this relationship remain uncertain. Recent studies have shown that cancer patients with VTE have higher MPs levels than cancer patients without thrombosis [22], [23], [24], [25]. In this case-control study we evaluated the role of endothelial (E-), platelet (P-) and TF⁺MPs in the development of cancer-associated thrombosis.

Section snippets

Material and Methods

Out of 145 patients consecutively admitted from January 2007 to June 2008 to the Thrombotic Unit and Oncology Department at the Padua University Hospital, 90 patients (M/F 42/48; age range 40-92 yrs) were enrolled in the study: thirty patients (M/F 12/18; age range 43-79 yrs) with a first episode of objectively confirmed acute unprovoked VTE [at diagnosis, and before anticoagulant therapy was started]; 30 (M/F 15/15; age range 45-89 yrs) with active cancer [diagnosis less than six months before

MPs in patients and controls

Enrolment of study patients is reported in Fig. 1. The total study population, consisted of 90 patients, showed higher (mean ± SD) circulating EMPs and PMPs plasma levels (920 ± 341 and 1221 ± 413 MPs/μL, respectively) than controls (299 ± 102 and 495 ± 241 MPs/μL). The difference was statistically significant (p = 0.005 and 0.001, respectively). The analysis of sex-specific differences showed a statistically significant higher PMPs level (mean ± SD) in female (1324 ± 712 MPs/μL) than in male (1089 ± 821 MPs/μL;

Discussion

In this study we investigated quantitative and “qualitative” characteristics of circulating MPs in a group of cancer patients, with and without VTE, and in a group with acute unprovoked VTE compared to a healthy control population. EMPs, PMPs, and TF⁺MPs plasma levels were significantly higher in both groups of patients than in healthy subjects.

The pathogenesis of VTE in cancer is multifactorial and rather unclear. Recently, increasing evidence link MPs to cancer associated thrombosis. In

Conflict of interest

None.

Acknowledgements

We thank Laura Salmaso for her kind support in statistical analysis.

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Regular ArticleEndothelial, platelet, and tissue factor-bearing microparticles in cancer patients with and without venous thromboembolism

Abstract

Background

Objectives

Patients/Methods

Results

Conclusions

Introduction

Section snippets

Material and Methods

MPs in patients and controls

Discussion

Conflict of interest

Acknowledgements

J Thromb Haemost

Ann Fr Anesth Rèanim

J Thromb Haemost

J Am Coll Cardiol

Thromb Res

Thromb Res

Kidney Int

J Thromb Heamost

J Thromb Haemost

Thromb Res

Thromb Res

Cell-derived microparticles: “Miniature envoys with many faces”

J Thromb Haemost

The nature and significance of platelet products in human plasma

Br J Haematol

Microparticles in cardiovascular diseases

Cardiovasc Res

Cellular microparticles: a disseminated storage pool of bioactive vascular effectors

Curr Opin Haematology

Regular Article
Endothelial, platelet, and tissue factor-bearing microparticles in cancer patients with and without venous thromboembolism