The role of microparticles in VTE

 

Cancer-associated venous thromboembolism (VTE) causes significant morbidity and mortality in patients and constitutes the second most common of death, after the progression of the cancer itself.
Cancer-associated VTE was firstly described in 1823 by Jean-Baptiste Bouillard. Defined as deep vein thrombosis and/or pulmonary embolism, VTE occurs more frequently in case of pancreatic (5.3%-26%) or brain (1.6-26%) cancers. Patients with metastatic cancer have higher rates of VTE than patients with localized cancer. Platelets are small (2-4 µm), anucleate, hematopoietic cells released by bone marrow megakaryocytes in the bloodstream.
In healthy humans, the concentration of circulating platelets is approximately 150 to 350 X 109/L. For a long time, platelets were described as the major effectors of hemostasis and thrombosis. In 1865, Armand Trousseau demonstrated a close relation between DVT, platelets and cancer. Subsequently, much clinical and experimental evidence supports the idea that platelets play several roles in the progression of malignancies and in cancer-associated thrombosis. A real cross-talk exists between platelets and cancer. Indeed, cancer itself can influence platelet count and activation state, which is critical for cancer progression. Inhibition of thrombocytosis or induction of thrombocytopenia are related to a decrease in tumor growth and metastasis, indicating that the ability of cancer cells to enhance platelet count is not harmless. Based on both the results of numerous experimental models addressing the involvement of platelets in cancer progression and the results of epidemiologic studies on the use of anti-platelet drugs to prevent cancer, platelets have been proposed as a potential target to reduce the short-term risk of cancer, cancer dissemination and cancer mortality. However, the prothrombotic state associated with tumor progression and the risk of bleeding due to anti-platelet drugs are not given enough consideration, particularly in experimental models. Therefore, the interesting contribution of platelets to cancer and cancer-associated thrombosis requires the clarification as well as the standardization of preclinical and clinical models.
 

Many risk factors for cancer-associated VTE have been identified, such as patient characteristics (history of VTE, obesity, immobilization), tumor characteristics (location, metastatic), anti-cancer treatments, blood cells (platelet, leukocyte, neutrophil extracellular traps), hypercoagulable state (thrombin-antithrombin complexes, prothrombin fragment, factor VIII, D dimer, soluble P-selectin, Tissue Factor (TF) and microparticles (MPs)).

Microparticles (MPs), are mainly represented by platelet MPs (70-90%) in the bloodstream. In case of cancer, MPs have been described to be associated with thrombotic state. MPs are heterogeneous vesicles 0.1-1.0 mm, produced by the plasma membrane and express on their surface anionic phospholipids (mainly phosphatidylserine) and cellular origin antigens as well as different glycoproteins. MPs may content cytokines, intracellular enzymes, DNA, mRNA and microRNA. Based on their composition it is now accepted that MPs could act as a biovector to transfer proteins and RNA/DNA from their parental cell to their target. In case of cancer, we have described the microparticulosome signature, which is a specific signature of MPs in colorectal and pancreatic cancer, compared to inflammatory bowel or pancreatic diseases and healthy subjects (Mege 2015). Circulating fibrin-bearing microparticles were more frequently observed in the presence of cancer-associated thrombo-embolic events than D-dimer. High levels of fibrin-bearing microparticles were associated with poor survival. We thus suggest that circulating microparticles, particularly fibrin-bearing microparticles, could be used as a new biomarker to predict cancer-associated thromboembolic events and poor survival. To date, however, further larger studies are required to confirm these results.

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