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Circulating procoagulant microparticles in cancer patients

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Abstract

Accumulating evidence indicates that microparticles (MPs) are important mediators of the interaction between cancer and the hemostatic system. We conducted a large prospective cohort study to determine whether the number of circulating procoagulant MPs is elevated in cancer patients and whether the elevated MP levels are predictive of occurrence of venous thrombembolism (VTE). We analyzed plasma samples of 728 cancer patients from the ongoing prospective observational Vienna Cancer and Thrombosis Study. Study endpoint was the occurrence of symptomatic VTE. Sixty-five age- and sex-matched healthy controls were recruited for defining the cut-off point for elevated MPs (4.62 nanomolar phosphatidylserine [nM PS]), which was set at the 95th percentile of MP levels in healthy controls. The measurement of MPs was performed after capture onto immobilized annexin V, and determination of their procoagulant activity was quantified with a prothrombinase assay. During a median observation period of 710 days, 53 patients developed VTE. MP levels (nM PS) were significantly higher in cancer patients than in healthy controls (median [25th–75th percentile], 3.95 [1.74–7.96] vs. 1.19 [0.81–1.67], p < 0.001). Multivariate analysis including age, sex, surgery, chemo- and radiotherapy showed no statistically significant association of the hazard ratio of elevated MPs with VTE (0.95 [95% CI, 0.55–1.64], p = 0.856). In conclusion, MP levels were elevated in cancer patients compared to healthy individuals in this study. However, elevated MP levels were not predictive of VTE.

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Abbreviations

CATS:

Cancer and Thrombosis Study

CI:

Confidence interval

MPs:

Microparticles

HR:

Hazard ratio

PFP:

Platelet-free plasma

nM PS:

Nanomolar phosphatidylserine equivalent

PS:

Phosphatidylserine

PSGL-1:

P-selectin glycoprotein ligand

TF:

Tissue factor

VTE:

Venous thromboembolism

References

  1. Siljander P, Carpen O, Lassila R (1996) Platelet-derived microparticles associate with fibrin during thrombosis. Blood 87I:4651–4663

    Google Scholar 

  2. Willekens FL, Werre JM, Groenen-Dopp YA et al (2008) Erythrocyte vesiculation: a self-protective mechanism? Br J Haematol 141I:549–556

    Article  Google Scholar 

  3. Sabatier F, Roux V, Anfosso F et al (2002) Interaction of endothelial microparticles with monocytic cells in vitro induces tissue factor-dependent procoagulant activity. Blood 99I:3962–3970

    Article  Google Scholar 

  4. Diamant M, Tushuizen ME, Sturk A et al (2004) Cellular microparticles: new players in the field of vascular disease? Eur J Clin Invest 34I:392–401

    Article  Google Scholar 

  5. Satta N, Freyssinet JM, Toti F (1997) The significance of human monocyte thrombomodulin during membrane vesiculation and after stimulation by lipopolysaccharide. Br J Haematol 96I:534–542

    Article  Google Scholar 

  6. Schecter AD, Spirn B, Rossikhina M et al (2000) Release of active tissue factor by human arterial smooth muscle cells. Circ Res 87I:126–132

    Google Scholar 

  7. Hugel B, Martinez MC, Kunzelmann C et al (2005) Membrane microparticles: two sides of the coin. Physiology (Bethesda) 20I:22–27

    Google Scholar 

  8. Falati S, Liu Q, Gross P et al (2003) Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle p-selectin glycoprotein ligand 1 and platelet p-selectin. J Exp Med 197I:1585–1598

    Article  Google Scholar 

  9. Del Conde I, Bharwani LD, Dietzen DJ et al (2007) Microvesicle-associated tissue factor and Trousseau’s syndrome. J Thromb Haemost 5I:70–74

    Article  Google Scholar 

  10. Zwicker JI, Liebman HA, Neuberg D et al (2009) Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res 15I:6830–6840

    Article  Google Scholar 

  11. Morel O, Toti F, Hugel B et al (2006) Procoagulant microparticles: disrupting the vascular homeostasis equation? Arterioscler Thromb Vasc Biol 26I:2594–2604

    Article  Google Scholar 

  12. Polgar J, Matuskova J, Wagner DD (2005) The p-selectin, tissue factor, coagulation triad. J Thromb Haemost 3I:1590–1596

    Article  Google Scholar 

  13. Tesselaar ME, Romijn FP, Van Der Linden IK et al (2007) Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J Thromb Haemost 5I:520–527

    Article  Google Scholar 

  14. Chirinos JA, Heresi GA, Velasquez H et al (2005) Elevation of endothelial microparticles, platelets, and leukocyte activation in patients with venous thromboembolism. J Am Coll Cardiol 45I:1467–1471

    Article  Google Scholar 

  15. Ay C, Freyssinet JM, Sailer T et al (2009) Circulating procoagulant microparticles in patients with venous thromboembolism. Thromb Res 123I:724–726

    Article  Google Scholar 

  16. Heit JA, Silverstein MD, Mohr DN et al (2000) Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 160I:809–815

    Article  Google Scholar 

  17. Blom JW, Doggen CJ, Osanto S et al (2005) Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 293I:715–722

    Article  Google Scholar 

  18. Sousou T, Khorana A (2009) Identifying cancer patients at risk for venous thromboembolism. Hamostaseologie 29I:121–124

    Google Scholar 

  19. Toth B, Liebhardt S, Steinig K et al (2008) Platelet-derived microparticles and coagulation activation in breast cancer patients. Thromb Haemost 100I:663–669

    Google Scholar 

  20. Kim HK, Song KS, Park YS et al (2003) Elevated levels of circulating platelet microparticles, VEGF, IL-6 and RANTES in patients with gastric cancer: possible role of a metastasis predictor. Eur J Cancer 39I:184–191

    Article  Google Scholar 

  21. Sud R, Khorana AA (2009) Cancer-associated thrombosis: risk factors, candidate biomarkers and a risk model. Thromb Res 123(Suppl 4I):S18–S21

    Article  PubMed  CAS  Google Scholar 

  22. Langer F, Spath B, Haubold K, Holstein K, Marx G, Wierecky J, Brümmendorf TH, Dierlamm J, Bokemeyer C, Eifrig B (2008) Tissue factor procoagulant activity of plasma microparticles in patients with cancer-associated disseminated intravascular coagulation. Ann Hematol 87I:451–457

    Article  Google Scholar 

  23. Ay C, Simanek R, Vormittag R et al (2008) High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS). Blood 112I:2703–2708

    Article  Google Scholar 

  24. Vormittag R, Simanek R, Ay C et al (2009) High factor VIII levels independently predict venous thromboembolism in cancer patients: the cancer and thrombosis study. Arterioscler Thromb Vasc Biol 29I:2176–2181

    Article  Google Scholar 

  25. Ay C, Vormittag R, Dunkler D et al (2009) D-dimer and prothrombin fragment 1 + 2 predict venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 27I:4124–4129

    Article  Google Scholar 

  26. Aupeix K, Hugel B, Martin T et al (1997) The significance of shed membrane particles during programmed cell death in vitro, and in vivo, in HIV-1 infection. J Clin Invest 99I:1546–1554

    Article  Google Scholar 

  27. Pigault C, Follenius-Wund A, Schmutz M et al (1994) Formation of two-dimensional arrays of annexin V on phosphatidylserine-containing liposomes. J Mol Biol 236I:199–208

    Article  Google Scholar 

  28. Stewart JC (1980) Colorimetric determination of phospholipids with ammonium ferrothiocyanate. Anal Biochem 104I:10–14

    Article  Google Scholar 

  29. Hron G, Kollars M, Weber H et al (2007) Tissue factor-positive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer. Thromb Haemost 97I:119–123

    Google Scholar 

  30. Kakkar AK, Levine M, Pinedo HM et al (2003) Venous thrombosis in cancer patients: insights from the frontline survey. Oncologist 8I:381–388

    Article  Google Scholar 

  31. Jenkins EO, Schiff D, Mackman N et al (2010) Venous thromboembolism in malignant gliomas. J Thromb Haemost 8:221–227

    Article  PubMed  CAS  Google Scholar 

  32. Simanek R, Vormittag R, Hassler M et al (2007) Venous thromboembolism and survival in patients with high-grade glioma. Neuro Oncol 9I:89–95

    Article  Google Scholar 

  33. Semrad TJ, O’Donnell R, Wun T et al (2007) Epidemiology of venous thromboembolism in 9489 patients with malignant glioma. J Neurosurg 106I:601–608

    Google Scholar 

  34. Rong Y, Post DE, Pieper RO et al (2005) PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma. Cancer Res 65:1406–1413

    Article  PubMed  CAS  Google Scholar 

  35. Jy W, Horstman LL, Jimenez JJ et al (2004) Measuring circulating cell-derived microparticles. J Thromb Haemost 2I:1842–1851

    Article  Google Scholar 

  36. Abid Hussein MN, Boing AN, Biro E et al (2008) Phospholipid composition of in vitro endothelial microparticles and their in vivo thrombogenic properties. Thromb Res 121I:865–871

    Article  Google Scholar 

  37. Biro E, Akkerman JW, Hoek FJ et al (2005) The phospholipid composition and cholesterol content of platelet-derived microparticles: a comparison with platelet membrane fractions. J Thromb Haemost 3I:2754–2763

    Article  Google Scholar 

  38. Weerheim AM, Kolb AM, Sturk A et al (2002) Phospholipid composition of cell-derived microparticles determined by one-dimensional high-performance thin-layer chromatography. Anal Biochem 302I:191–198

    Article  Google Scholar 

  39. Nieuwland R, Berckmans RJ, McGregor S et al (2000) Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood 95I:930–935

    Google Scholar 

  40. Sabatier F, Darmon P, Hugel B et al (2002) Type 1 and type 2 diabetic patients display different patterns of cellular microparticles. Diabetes 51I:2840–2845

    Article  Google Scholar 

  41. Mallat Z, Benamer H, Hugel B et al (2000) Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation 101I:841–843

    Google Scholar 

  42. Manly DA, Wang J, Glover SL et al (2009) Increased microparticle tissue factor activity in cancer patients with venous thromboembolism. Thromb Res 125I:511–512

    Google Scholar 

  43. Gonzalez-Quintero VH, Jimenez JJ, Jy W et al (2003) Elevated plasma endothelial microparticles in preeclampsia. Am J Obstet Gynecol 189I:589–593

    Article  Google Scholar 

  44. Valeri CR, Ragno G, Khuri S (2005) Freezing human platelets with 6 percent dimethyl sulfoxide with removal of the supernatant solution before freezing and storage at −80 degrees C without postthaw processing. Transfusion 45I:1890–1898

    Article  Google Scholar 

Download references

Acknowledgements

We thank all persons that supported us in patient recruitment for the Vienna Cancer and Thrombosis Study (CATS), Silvia Koder for skillful technical assistance, and Tanja Altreiter for proof-reading of the manuscript.

Financial support

This study was supported by grants from the “Jubiläumsfonds” of the Austrian National Bank, by an unrestricted grant from Pfizer Austria, and the “Fellinger Krebsforschung”.

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Authors and Affiliations

  1. Department of Medicine I, Clinical Division of Haematology and Haemostaseology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria

    Johannes Thaler, Cihan Ay, Harald Weinstabl, Ralph Simanek, Rainer Vormittag & Ingrid Pabinger

  2. Center for Medical Statistics, Informatics and Intelligent Systems, Section for Clinical Biometrics, Medical University of Vienna, Vienna, Austria

    Daniela Dunkler

  3. Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria

    Christoph Zielinski

  4. Faculté de Médecine, Institut d’Hématologie & Immunologie, U. 770 INSERM Hôpital de Bicêtre, Université Paris-Sud, Le Kremlin-Bicêtre, Université Louis Pasteur, Strasbourg, France

    Jean-Marie Freyssinet

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  1. Johannes Thaler
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  2. Cihan Ay
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Correspondence to Ingrid Pabinger.

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Thaler, J., Ay, C., Weinstabl, H. et al. Circulating procoagulant microparticles in cancer patients. Ann Hematol 90, 447–453 (2011). https://doi.org/10.1007/s00277-010-1111-1

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  • DOI: https://doi.org/10.1007/s00277-010-1111-1

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