Circulating microparticles and the risk of thrombosis in inherited deficiencies of antithrombin, protein C and protein S

Elena Campello; Luca Spiezia; Claudia M. Radu; Cristiana Bulato; Sabrina Gavasso; Daniela Tormene; Barry Woodhams; Fabio Dalla Valle; Paolo Simioni

doi:10.1160/TH15-04-0286

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 115(01): 81-88
DOI: 10.1160/TH15-04-0286

Coagulation and Fibrinolysis

Schattauer GmbH Schattauer

Circulating microparticles and the risk of thrombosis in inherited deficiencies of antithrombin, protein C and protein S

Elena Campello

¹Department of Medicine, 5^th Chair of Internal Medicine, Thrombophilia and Hemophilia Center, University of Padua, Italy

,

Luca Spiezia

¹Department of Medicine, 5^th Chair of Internal Medicine, Thrombophilia and Hemophilia Center, University of Padua, Italy

,

Claudia M. Radu

¹Department of Medicine, 5^th Chair of Internal Medicine, Thrombophilia and Hemophilia Center, University of Padua, Italy

,

Cristiana Bulato

¹Department of Medicine, 5^th Chair of Internal Medicine, Thrombophilia and Hemophilia Center, University of Padua, Italy

,

Sabrina Gavasso

¹Department of Medicine, 5^th Chair of Internal Medicine, Thrombophilia and Hemophilia Center, University of Padua, Italy

,

Daniela Tormene

¹Department of Medicine, 5^th Chair of Internal Medicine, Thrombophilia and Hemophilia Center, University of Padua, Italy

,

Barry Woodhams

²HaemaCon Ltd, Bromley, UK

,

Fabio Dalla Valle

¹Department of Medicine, 5^th Chair of Internal Medicine, Thrombophilia and Hemophilia Center, University of Padua, Italy

,

Paolo Simioni

¹Department of Medicine, 5^th Chair of Internal Medicine, Thrombophilia and Hemophilia Center, University of Padua, Italy

› Author Affiliations

Abstract

Summary

Many subjects carrying inherited thrombophilic defects will never experience venous thromboembolism (VTE) while other individuals developed recurrent VTE with no known additional risk factors. High levels of circulating microparticles (MP) have been associated with increased risk of VTE in patients with factor V Leiden and prothrombin G20210A mutation, suggesting a possible contribution of MP in the hypercoagulability of mild genetic thrombophilia. The role of MP as additional risk factor of VTE in carriers of natural clotting inhibitors defects (severe thrombophilia) has never been assessed. Plasma levels of annexin V-MP, endothelial-derived MP (EMP), platelet-derived MP (PMP), tissue factor-bearing MP (TF+) and the MP procoagulant activity (PPL) were measured in 132 carriers of natural anticoagulant deficiencies (25 antithrombin, 63 protein C and 64 protein S defect) and in 132 age and gender-matched healthy controls. Carriers of natural anticoagulant deficiencies, overall and separately considered, presented with higher median levels of annexin V-MP, EMP, PMP, TF+MP and PPL activity than healthy controls (p< 0.001, < 0.001, < 0.01, 0.025 and 0.03, respectively). Symptomatic carriers with a previous episode of VTE had significantly higher median levels of annexin-V MP than those without VTE (p=0.027). Carriers with high levels of annexin V-MP, EMP and PMP had an adjusted OR for VTE of 3.36 (95 % CI, 1.59 to 7.11), 9.26 (95 % CI, 3.55 to 24.1) and 2.72 (95 %CI, 1.16 to 6.38), respectively. Elevated levels of circulating MP can play a role in carriers of mild and severe inherited thrombophilia. The clinical implications of this association remain to be defined.

Keywords

Coagulation inhibitors - hypercoagulability - microparticles - thrombophilia - venous thrombosis

Full Text

References

References
1 Martinelli I, De Stefano V, Mannucci PM. Inherited risk factors for venous thromboembolism. Nat Rev Cardiol 2014; 11: 140-156.
2 Cohn D, Vansenne F, de Borgie C. et al. Thrombophilia testing for prevention of recurrent venous thromboembolism. Cochrane Database Syst Rev 2009; 21 (01) CD007069.
3 Lijfering WM, Brouwer JL, Veeger NJ. et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood 2009; 113: 5314-5322.
4 Sanson BJ, Simioni P, Tormene D. et al. The incidence of venous thromboembolism in asymptomatic carriers of a deficiency of antithrombin, protein C, or protein S: a prospective cohort study. Blood 1999; 94: 3702-3706.
5 Vossen CY, Conard J, Fontcuberta J. et al. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect: the European Prospective Cohort on Thrombophilia (EPCOT). J ThrombHaemost 2005; 03: 459-464.
6 Simioni P, Sanson BJ, Prandoni P. et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999; 08: 198-202.
7 Mahmoodi BK, Brouwer JL, Ten Kate MK. et al. A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C or antithrombin. J Thromb Haemost 2010; 08: 1193-1200.
8 Bucciarelli P, Passamonti SM, Biguzzi E. et al. Low borderline plasma levels of antithrombin, protein C and protein S are risk factors for venous thromboembolism. J Thromb Haemost 2012; 10: 1783-1791.
9 Mannucci PM, Franchini M. The real value of thrombophilia markers in identifying patients at high risk of venous thromboembolism. Expert Rev Hematol 2014; 07: 757-765.
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 Ye R, Ye C, Huang Y. et al. Circulating tissue-factor positive microparticles in patients with acute recurrent deep vein thrombosis. Thromb Res 2012; 130: 253-258.
13 Boulanger CM, Dignat-George F. Microparticles: an introduction. Arterioscler Thromb Vasc Biol 2011; 31: 2-3.
14 Burger D, Schock S, Thompson CS. et al. Microparticles: biomarkers and beyond. Clin Sci 2013; 124: 423-441.
15 Morel O, Toti F, Hugel B. et al. Procoagulant microparticles: disrupting the vascular homeostasis equation?. Arterioscler Thromb Vasc Biol 2006; 26: 2594-2604.
16 Campello E, Spiezia L, Radu C. et al. Circulating microparticles in carriers of factor V Leiden with and without a history of venous thrombosis. Thromb Haemost 2012; 108: 633-639.
17 Campello E, Spiezia L, Radu CM. et al. Circulating microparticles in carriers of prothrombin G20210A mutation. Thromb Haemost 2014; 112: 432-418.
18 Bulato C, Tognin G, Spiezia L. et al. Identification of a novel frameshift mutation causing a premature stop codon in a young Nigerian man with type I antithrombin deficiency. Thromb Res 2013; 131: 463-465.
19 Castoldi E, Maurissen LF, Tormene D. et al. Similar hypercoagulable state and thrombosis risk in type I and type III protein S deficient individuals from families with mixed type I/III protein S deficiency. Haematologica 2010; 95: 1563-1571.
20 Michiels JJ, Hamulyak K. Laboratory diagnosis of hereditary thrombophilia. Semin Thromb Hemost 1998; 24: 309.
21 Campello E, Spiezia L, Radu CM. et al. Evaluation of a procoagulant phospholipid functional assay as a routine test for measuring circulating microparticle activity. Blood Coagul Fibrinolysis 2014; 25: 534-537.
22 Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia 2008; 14: 1229-1239.
23 Hackeng TM, Serè KM, Tans G. et al. Protein S stimulates inhibition of the tissue factor pathway inhibitor. Proc Natl Acad Sci USA 2006; 103: 3106-3111.
24 Tardy-Poncet B, Piot M, Brunet D. et al. TFPI resistance related to inherited or acquired protein S deficiency. Thromb Res 2012; 130: 925-928.
25 Lacroix R, Robert S, Poncelet P. et al. Standardisation of platelet-derived micro-particle 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.
26 Lacroix R, Judicone C, Mooberry M. et al. Standardisation of pre-analytical variables in plasma microparticle determination: results of the International Society on Thrombosis and Haemostasis SSC Collaborative workshop. J Thromb Haemost 2013; 11: 1190-1193.
27 Yuana Y, Bertina RM, Osanto S. Pre-analytical and analytical issues in the analysis of blood microparticles. Thromb Haemost 2011; 105: 396-408.
28 Arraud N, Gounou C, Turpin D. et al. Fluorescence triggering: a general strategy for enumerating and phenotyping extracellular vesicles by flow cytometry. Cytometry. 2015 Epub ahead of print.
29 Shantsila E, Montoro-García S, Gallego P. et al. Circulating microparticles: challenges and perspectives of flow cytometric assessment. Thromb Haemost 2014; 111: 1009-1014.
30 Lacroix R, Dubois C, Leroyer AS. et al. Revisited role of microparticles in arterial and venous thrombosis. J Thromb Haemost 2013; 11: 24-35.