Circulating microparticles in carriers of factor V Leiden with and without a history of venous thrombosis

Elena Campello; Luca Spiezia; Claudia M. Radu; Maria Bon; Sabrina Gavasso; Patrizia Zerbinati; Barry Woodhams; Daniela Tormene; Paolo Prandoni; Paolo Simioni

doi:10.1160/TH12-05-0280

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 108(04): 633-639
DOI: 10.1160/TH12-05-0280

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Circulating microparticles in carriers of factor V Leiden with and without a history of venous thrombosis

Elena Campello

¹Department of Cardiologic, Thoracic, and Vascular Sciences, 2nd Chair of Internal Medicine, University of Padua Medical School, Padua, Italy

,

Luca Spiezia

¹Department of Cardiologic, Thoracic, and Vascular Sciences, 2nd Chair of Internal Medicine, University of Padua Medical School, Padua, Italy

,

Claudia M. Radu

¹Department of Cardiologic, Thoracic, and Vascular Sciences, 2nd Chair of Internal Medicine, University of Padua Medical School, Padua, Italy

,

Maria Bon

¹Department of Cardiologic, Thoracic, and Vascular Sciences, 2nd Chair of Internal Medicine, University of Padua Medical School, Padua, Italy

,

Sabrina Gavasso

¹Department of Cardiologic, Thoracic, and Vascular Sciences, 2nd Chair of Internal Medicine, University of Padua Medical School, Padua, Italy

,

Patrizia Zerbinati

¹Department of Cardiologic, Thoracic, and Vascular Sciences, 2nd Chair of Internal Medicine, University of Padua Medical School, Padua, Italy

,

Barry Woodhams

²Diagnostica Stago, Gennevilliers, France

,

Daniela Tormene

¹Department of Cardiologic, Thoracic, and Vascular Sciences, 2nd Chair of Internal Medicine, University of Padua Medical School, Padua, Italy

,

Paolo Prandoni

¹Department of Cardiologic, Thoracic, and Vascular Sciences, 2nd Chair of Internal Medicine, University of Padua Medical School, Padua, Italy

,

Paolo Simioni

¹Department of Cardiologic, Thoracic, and Vascular Sciences, 2nd Chair of Internal Medicine, University of Padua Medical School, Padua, Italy

› Author Affiliations

Abstract

Summary

Although factor V Leiden (FVL) is a major determinant of thrombotic risk, the reason why less than 10% of carriers eventually develop venous thromboembolic (VTE) events is unknown. Recent observations suggest that circulating levels of microparticles (MP) may contribute to the thrombogenic profile of FVL carriers. We measured the plasma level of annexin V-MP (AMP) platelet-MP (PMP), endothelial-MP (EMP), leukocyte-MP (LMP) and tissue factor-bearing MP (TF⁺MP), and the MP procoagulant activity (PPL) in 142 carriers of FVL (of these 30 homozygous and 49 with prior VTE), and in 142 age and gender-matched healthy individuals. The mean (± SD) level of AMP was 2,802 ± 853 MP/ μl in carriers and 1,682 ± 897 in controls (p<0.0001). A statistically significant difference between homozygous and heterozygous carriers of FVL was seen in the level of PMP, EMP and LMP, but not in that of the remaining parameters. When the analysis was confined to carriers with and without a VTE history, the mean level of AMP was 3,110 ± 791 MP/ μl in the former, and 2,615 ± 839 MP/μl in the latter (p<0.005). The mean level of all subtypes of circulating MP showed a similar pattern. The PPL clotting time was 39 ± 9 seconds (sec) in carriers, and 52 ± 15 sec in controls (p=0.003); and was 35 ± 8 sec in carriers with prior thrombosis, and 41 ± 10 sec in thrombosis-free carriers (p<0.005). Our study results suggest that circulating MP may contribute to the development of thrombosis in carriers of FVL mutation.

Keywords

Microparticles - factor V Leiden - tissue factor-bearing microparticles - venous thromboembolism

Full Text

References

References
1 Bertina RM, Koeleman BP, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
2 Rosendaal FR, Koster T, Vandenbroucke JP. et al. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85: 1504-1508.
3 Simioni P, Sanson BJ, Prandoni P. et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999; 81: 198-202.
4 Lensen RP, Bertina RM, de Ronde H. et al. Venous thrombotic risk in family members of unselected individuals with factor V Leiden. Thromb Haemost 2000; 83: 817-821.
5 Juul K, Tybjaerg-Hansen A, Schnohr P. et al. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med 2004; 140: 330-337.
6 Segers O, Simioni P, Tormene D. et al. Genetic Modulation of the FV(Leiden) /normal FV Ratio and Risk of Venous Thrombosis in FV Leiden Heterozygotes. J Thromb Haemost 2012; 10: 73-80.
7 Rosendaal FR. Risk factors for venous thrombotic disease. Thromb Haemost 1999; 82: 610-619.
8 Heit JA, Sobell JL, Li H. et al. The incidence of venous thromboembolism among Factor V Leiden carriers: a community-based cohort study. J Thromb Haemost 2005; 03: 305-311.
9 Chirinos JA, Heresi GA, Velasquez H. et al. Elevation of endothelial microparticles, platelets, and leucocyte activation in patients with venous thromboemoblism. J Am Coll Cardiol 2005; 45: 1467-1471.
10 Ay C, Freyssinet JM, Sailer T. et al. Circulating procoagulant microparticles in patients with venous thromboembolism. Thromb Res 2009; 123: 724-726.
11 Owens III AP, Mackman N. Microparticles in Hemostasis and Thrombosis. Circ Res 2011; 108: 1284-1297.
12 Garcia Rodriguez P, Eikenboom HCJ, Tesselaar MET. et al. Plasma levels of microparticles-associated tissue factor activity in patients with clinically suspected pulmonary embolism. Thromb Res 2010; 126: 345-349.
13 Tesselaar ME, Romijn FP, Van der Linden IK. et al. Microparticle-associated tissue factor activity in cancer patients with and without thrombosis. J Thromb Haemost 2009; 07: 1421-1423.
14 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.
15 Furie B, Furie BC. Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation. Trends Mol Med 2004; 10: 171-178.
16 Morel O, Toti F, Hugel B. et al. Procoagulant microparticles disrupting the vascular homeostasis equation?. Arterioscler Thromb Vasc Biol 2006; 26: 2594-2604.
17 Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteomics 2010; 73: 1907-1920.
18 Perez-Casal M, Downey C, Fukudome K. et al. Activated protein C induces the release of microparticle-associated endothelial protein C receptor. Blood 2005; 105: 1515-1522.
19 Enjeti AK, Lincz LF, Scorgie FE. et al. Circulating microparticles are elevated in carriers of Factor V Leiden. Thromb Res 2010; 126: 250-253.
20 Wagner C, Fibrinogen Dati F. In: Clinical Laboratory Diagnostics. Frankfurt TH: Books Verlagsgesellschaft; 1998: 609-612.
21 Fickenscher K. Analysis of individual coagulation factors. In: Clinical Laboratory Diagnostics. Frankfurt TH: Books Verlagsgesellschaft; 1998: 607-609.
22 Simioni P, Scudeller A, Radossi P. et al. Pseudo-homozygous activated protein C resistance due to double heterozygous factor V defects (factor V Leiden mutation and type I quantitative factor V defect) associated with thrombosis: report of two cases belonging to two unrelated kindreds. Thromb Haemost 1996; 75: 422-426.
23 Simioni P, Prandoni P, Lensing AWA. et al. The risk of recurrent venous thromboembolism in patients with an Arg506 --- Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med 1997; 336: 399-403.
24 Campello E, Spiezia L, Radu CM. et al. Endothelial, platelet and tissue facrot-bearing microparticles in cancer patients with and without venous thrombembolism. Thromb Res 2011; 127: 473-477.
25 Robert S, Poncelet P, Lacroix R. et al. Standardization of platelet-derived microparticle counting using calibrated beads and a Cytomics FC500 routine cytometer: a first step towards multicenter studies?. J Throm Haemost 2008; 07: 190-197.
26 van Dreden P, Rousseau A, Fontaine S. et al. Monitoring patient plasma platelet-derived procoagulant microparticles (PMP) with a new factor Xa-based clotting test (XaCT). Blood Coag Fibrinolysis 2009; 20: 494-502.
27 Noubouossie DC, Lê PQ, Rozen L. et al. Evaluation of the procoagulant activity of endogenous phospholipids in the platelet-free plasma of children with sickle cell disease using functional assays. Thromb Res. 2011 epub ahead of print.
28 Simioni P, Tormene D, Prandoni P. et al. Incidence of venous thromboembolism in asymptomatic family members who are carriers of factor V Leiden: a prospective cohort study. Blood 2002; 99: 1938-1942.
29 Lincz LF, Lonergan A, Scorgie FE. et al. Endogenous thrombin potential for predicting risk of venous thromboembolism in carriers of factor V Leiden. Pathophysiol Haemost Thromb 2006; 35: 435-439.
30 Curvers J, Thomassen MC, Rimmer J. et al. Effects of hereditary and acquired risk factors of venous thrombosis on a thrombin generation-based APC resistance test. Thromb Haemost 2002; 88: 5-11.
31 Tans G, van Hylckama Vlieg A, Thomassen MC. et al. Activated protein C resistance determined with a thrombin generation- based test predicts for venous thrombosis in men and women. Br J Haematol 2003; 122: 465-470.
32 Couturaud F, Duchemin J, Leroyer C. et al. Thrombin generation in first-degree relatives of patients with venous thromboembolism who have factor V Leiden. A pilot study. Thromb Haemost 2008; 99: 223-228.
33 Lawrie AS, Albanyan A, Cardigan RA. et al. Microparticles sizing by dynamic light scattering in fresh-frozen plasma. Vox Sang 2009; 96: 206-212.
34 Chandler WL, Yeung W, Tait JF. A new microparticle size calibration standard for use in measuring smaller microparticles using a new flow cytometer. J Thromb Haemost 2011; 09: 1216-1224.
35 Ayers L, Kohler M, Harrison P. et al. Measurement of circulating cell derived microparticles by flow cytometry: sources of variability within the assay. Thromb Res 2011; 127: 370-377.
36 Lacroix R, Robert S, Poncelet P. et al. Standardization of platelet-derived microparticle enumeration by flow cytometry with calibrated beads: results of the International Society on Thrombosis and Haemostasis SSC Collaborative workshop. J Thromb Haemost 2010; 08: 2571-2574.
37 Rautou PE, Vion AC, Amabile N. et al. Microparticles, Vascular Function, and Atherothrombosis. Circ Res 2011; 109: 593-606.
38 Puddu P, Puddu GM, Cravero E. et al. The involvement of circulating microparticles in inflammation, coagulation and cardiovascular diseases. Can J Cardiol 2010; 26: 140-145.
39 Marchiori A, Mosena L, Prins MH. et al. The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies. Haematologica 2007; 92: 1107-1114.
40 Segal JB, Brotman DJ, Necochea AJ. et al. Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. J Am Med Assoc 2009; 301: 2472-2485.