Clinical significance of circulating microparticles for venous thrombo - embolism in cancer patients

Summary

Cancer patients have a four-to seven-fold increased risk to develop a venous thromboembolic event. Accumulating evidence from experimental and clinical studies indicates that microparticles (MPs), small procoagulant membrane vesicles that are defined by size and a negatively charged phosphatidylserine rich surface, play an important role in the pathogenesis of cancer-related venous thromboembolism (VTE). However, the clinical significance of MPs as a predictive biomarker for VTE in cancer patients has not been fully elucidated yet. This might be due to unresolved methodological problems and a lack of data from large prospective clinical studies that investigate the role of MPs in cancer-related VTE.

It is the aim of this review to give an overview on the most important characteristics of MPs and studies dealing with the role of MPs in cancer-related VTE. Also recent progresses, unresolved problems and future perspectives in this research field will be discussed. In the conclusion we will assess the clinical significance of MPs in cancer-related VTE.

Zusammenfassung

Krebspatienten weisen ein vier-bis siebenfach erhöhtes Risiko auf, eine venöse Thromboembolie (VTE) zu entwickeln. Daten klinischer und experimenteller Studien deuten darauf hin, dass Mikropartikel (MPs), kleine negativ geladene und Phosphatidylserinreiche Membranvesikel, eine wichtige Rolle in der Pathogenese der tumorassoziierten Thrombose spielen. Allerdings ist die klinische Bedeutung von MPs als prädiktiver Biomarker für das Auftreten von VTE bei Krebspatienten noch nicht völlig geklärt. Dies liegt wahrscheinlich an ungelösten methodischen Problemen und einem Mangel an Daten von großen prospektiven Studien, die die Rolle von MPs in der Entstehung der tumor-assoziierten Thrombose untersuchen.

Es ist das Ziel dieser Übersichtsarbeit die wichtigsten Charakteristika von MPs zu beschreiben und von neuen Studien zu berichten. Auch jüngste Fortschritte, ungelöste Probleme und Zukunftsaussichten aus diesem Forschungsgebiet werden besprochen. In der Schlussfolgerung werden wir die klinische Signifikanz von Mikropartikeln in der tumor-assoziierten Thrombose beurteilen.

Keywords

Microparticles - cancer - venous thromboembolism - tissue factor

Schlüsselwörter

Mikropartikel - Krebserkrankungen - venöse Thromboembolie - Tissue Faktor

• References

• 1 Castellana D, Kunzelmann C, Freyssinet JM. Pathophysiologic significance of procoagulant microvesicles in cancer disease and progression. Hämostaseologie 2009; 29: 51-57.
• 2 Siljander P, Carpen O, Lassila R. Platelet-derived microparticles associate with fibrin during thrombosis. Blood 1996; 87: 4651-4663.
• 3 Willekens FL, Werre JM, Groenen-Dopp YA. et al. Erythrocyte vesiculation: a self-protective mechanism?. Br J Haematol 2008; 141: 549-556.
• 4 Sabatier F, Roux V. Anfosso et al. Interaction of endothelial microparticles with monocytic cells in vitro induces tissue factor-dependent procoagulant activity. Blood 2002; 99: 3962-3970.
• 5 Diamant M, Tushuizen ME, Sturk A, Nieuwland R. Cellular microparticles. Eur J Clin Invest 2004; 34: 392-401.
• 6 Satta N, Freyssinet JM, Toti F. The significance of human monocyte thrombomodulin during membrane vesiculation and after stimulation by lipopolysaccharide. Br J Haematol 1997; 96: 534-542.
• 7 Schecter AD, Spirn B, Rossikhina M. et al. Release of active tissue factor by human arterial smooth muscle cells. Circ Res 2000; 87: 126-132.
• 8 Horstman LL, Ahn YS. Platelet microparticles: a wide-angle perspective. Crit Rev Oncol Hematol 1999; 30: 111-142.
• 9 Freyssinet JM. Cellular microparticles: what are they bad or good for?. J Thromb Haemost 2003; 01: 1655-1662.
• 10 Aharon A, Brenner B. Microparticles, thrombosis and cancer. Best Pract Res Clin Haematol 2009; 22: 61-69.
• 11 Dvorak HF, Van DeWater L, Bitzer AM. et al. Procoagulant activity associated with plasma membrane vesicles shed by cultured tumor cells. Cancer Res 1983; 43: 4434-4442.
• 12 Harris NL, Dvorak AM, Smith J, Dvorak HF. Fibrin deposits in Hodgkin’s disease. Am J Pathol 1982; 108: 119-129.
• 13 Rak J. Microparticles in cancer. Semin Thromb Hemost 2010; 36: 888-906.
• 14 Sims PJ, Faioni EM, Wiedmer T, Shattil SJ. Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity. J Biol Chem 1988; 263: 18205-18212.
• 15 Andreola G, Rivoltini L, Castelli C. et al. Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J Exp Med 2002; 195: 1303-1316.
• 16 Castellana D, Zobairi F, Martinez MC. et al. Membrane microvesicles as actors in the establishment of a favorable prostatic tumoral niche. Cancer Res 2009; 69: 785-793.
• 17 Yu JL, May L, Lhotak V. et al. Oncogenic events regulate tissue factor expression in colorectal cancer cells. Blood 2005; 105: 1734-1741.
• 18 Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol 1967; 13: 269-288.
• 19 Sinauridze EI, Kireev DA, Popenko NY. et al. Platelet microparticle membranes have 50-to 100-fold higher specific procoagulant activity than activated platelets. Thromb Haemost 2007; 97: 425-434.
• 20 Tans G, Rosing J, Thomassen MC. et al. Comparison of anticoagulant and procoagulant activities of stimulated platelets and platelet-derived microparticles. Blood 1991; 77: 2641-26418.
• 21 Del Conde I, Shrimpton CN, Thiagarajan P, Lopez JA. Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 2005; 106: 1604-1611.
• 22 Nieuwland R, Berckmans RJ, McGregor S. et al. Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood 2000; 95: 930-935.
• 23 Shet AS, Aras O, Gupta K. et al. Sickle blood contains tissue factor-positive microparticles derived from endothelial cells and monocytes. Blood 2003; 102: 2678-2683.
• 24 Osterud B. The role of platelets in decrypting monocyte tissue factor. Dis Mon 2003; 49: 7-13.
• 25 Hron G, Kollars M, Weber H. et al. Tissue factorpositive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer. Thromb Haemost 2007; 97: 119-123.
• 26 Yu JL, Rak JW. Shedding of tissue factor (TF)-containing microparticles rather than alternatively spliced TF is the main source of TF activity released from human cancer cells. J Thromb Haemost 2004; 02: 2065-2067.
• 27 Diamant M, Nieuwland R, Pablo RF. et al. Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus. Circulation 2002; 106: 2442-2447.
• 28 Tesselaar ME, Romijn FP, Van Der Linden IK. et al. Microparticle-associated tissue factor activity: a link between cancer and thrombosis?. J Thromb Haemost 2007; 05: 520-527.
• 29 Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359: 938-949.
• 30 Versteeg HH, Ruf W. Tissue factor coagulant function is enhanced by protein-disulfide isomerase independent of oxidoreductase activity. J Biol Chem 2007; 282: 25416-25424.
• 31 Orozco AF, Lewis DE. Flow cytometric analysis of circulating microparticles in plasma. Cytometry A 2010; 77: 502-514.
• 32 Jy W, Horstman LL, Jimenez JJ. et al. Measuring circulating cell-derived microparticles. J Thromb Haemost 2004; 02: 1842-1851.
• 33 Shah MD, Bergeron AL, Dong JF, Lopez JA. Flow cytometric measurement of microparticles. Platelets 2008; 19: 365-372.
• 34 Robert S, Poncelet P, Lacroix R. et al. Standardization of platelet-derived microparticle counting using calibrated beads and a Cytomics FC500 routine flow cytometer. J Thromb Haemost 2009; 07: 190-197.
• 35 Key NS. Analysis of tissue factor positive microparticles. Thromb Res 2010; 125 (Suppl. 01) 42-45.
• 36 Key NS, Chantrathammachart P, Moody PW, Chang JY. Membrane microparticles in VTE and cancer. Thromb Res 2010; 125 (Suppl. 02) 80-83.
• 37 Lawrie AS, Albanyan A, Cardigan RA. et al. Microparticle sizing by dynamic light scattering in freshfrozen plasma. Vox Sang 2009; 96: 206-212.
• 38 Aupeix K, Hugel B, Martin T. et al. The significance of shed membrane particles during programmed cell death in vitro, and in vivo, in HIV-1 infection. J Clin Invest 1997; 99: 1546-1554.
• 39 Yuana Y, Oosterkamp TH, Bahatyrova S. et al. Atomic force microscopy: a novel approach to the detection of nanosized blood microparticles. J Thromb Haemost 2010; 08: 315-323.
• 40 Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 343: 1846-1850.
• 41 Lip GY, Chin BS, Blann AD. Cancer and the prothrombotic state. Lancet Oncol 2002; 03: 27-34.
• 42 Manly DA, Wang J, Glover SL. et al. Increased microparticle tissue factor activity in cancer patients with venous thromboembolism. Thromb Res 2010; 125: 511-512.
• 43 Campello E, Spiezia L, Radu CM. et al. Endothelial, platelet, and tissue factor-bearing microparticles in cancer patients with and without venous thromboembolism. Thromb Res 2011; 127: 473-477.
• 44 Khorana AA, Francis CW, Menzies KE. et al. Plasma tissue factor may be predictive of venous thromboembolism in pancreatic cancer. J Thromb Haemost 2008; 06: 1983-1985.
• 45 Zwicker JI. Tissue factor-bearing microparticles and cancer. Semin Thromb Hemost 2008; 34: 195-198.
• 46 Zwicker JI. Predictive value of tissue factor bearing microparticles in cancer associated thrombosis. Thromb Res 2010; 125 (Suppl. 02) 89-91.
• 47 Auwerda JJ, Yuana Y, Osanto S. et al. Microparticle-associated tissue factor activity and venous thrombosis in multiple myeloma. Thromb Haemost 2011; 105: 14-20.
• 48 Thaler J, Ay C, Weinstabl H. et al. Circulating procoagulant microparticles in cancer patients. Ann Hematol 2011; 90: 447-453.