Are Microparticles the Missing Link between Thrombosis and Autoimmune Diseases? Involvement in Selected Rheumatologic Diseases

Abstract

Microparticles (MPs) are membrane-bound vesicles with important physiologic effects. MPs exchange information intercellularly, with each kind of MP carrying antigens and receptors of the cells from which they originated. They are biologic effectors in inflammation, angiogenesis, vascular injury, and thrombosis. Thrombosis is generally caused by abnormalities in blood flow, blood composition, and/or properties of the vessel wall. Thrombosis is a well-described feature of cardiovascular disease and cerebrovascular disease. Accumulating evidence suggests that increased risk of thrombosis is also characteristic of autoimmune disorders and immune-mediated diseases affecting all age groups, although the older adults are most vulnerable. Current research has also implicated MPs as a source of autoantigenic nuclear material that can form immune complexes, activate the innate immune system, and may lead to autoimmunity. This review focuses on the contribution of MPs to both the pathogenesis of autoimmune diseases and, as the immune and coagulation systems are tightly linked, their role in hypercoagulability in the setting of autoimmunity in an aging population.

Keywords

microparticles - thrombosis - rheumatoid arthritis - systemic sclerosis - systemic - lupus erythematosus

• References

• 1 Zöller B, Li X, Sundquist J, Sundquist K. Autoimmune diseases and venous thromboembolism: a review of the literature. Am J Cardiovasc Dis 2012; 2 (3) 171-183
• 2 Rosendaal FR. Thrombosis in the young: epidemiology and risk factors. A focus on venous thrombosis. Thromb Haemost 1997; 78 (1) 1-6
• 3 Favaloro EJ, Franchini M, Lippi G. Aging hemostasis: changes to laboratory markers of hemostasis as we age—a narrative review. Semin Thromb Hemost 2014; 40 (6) 621-633
• 4 Tracy RP, Bovill EG. Thrombosis and cardiovascular risk in the elderly. Arch Pathol Lab Med 1992; 16: 1307-1312
• 5 Celermajer DS, Sorensen KE, Bull C, Robinson J, Deanfield JE. Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. J Am Coll Cardiol 1994; 24 (6) 1468-1474
• 6 Ershler WB. Interleukin-6: a cytokine for gerontologists. J Am Geriatr Soc 1993; 41 (2) 176-181
• 7 Bonfigli AR, Sirolla C, Cenerelli S , et al. Plasminogen activator inhibitor-1 plasma level increases with age in subjects with the 4G allele at position -675 in the promoter region. Thromb Haemost 2004; 92 (5) 1164-1165
• 8 Markiewicz M, Richard E, Marks N, Ludwicka-Bradley A. Impact of endothelial microparticles on coagulation, inflammation, and angiogenesis in age-related vascular diseases. J Aging Res 2013; 2013: 734509
• 9 Brandes RP, Fleming I, Busse R. Endothelial aging. Cardiovasc Res 2005; 66 (2) 286-294
• 10 Loscalzo J. Nitric oxide insufficiency, platelet activation, and arterial thrombosis. Circ Res 2001; 88 (8) 756-762
• 11 Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989; 83 (5) 1774-1777
• 12 Linton P, Thoman ML. T cell senescence. Front Biosci 2001; 6: D248-D261
• 13 Prelog M. Aging of the immune system: a risk factor for autoimmunity?. Autoimmun Rev 2006; 5 (2) 136-139
• 14 Antonaci S, Jirillo E, Bonomo L. Immunoregulation in aging. Diagn Clin Immunol 1987; 5 (2) 55-61
• 15 Kendall MD, Johnson HR, Singh J. The weight of the human thymus gland at necropsy. J Anat 1980; 131 (Pt 3) 483-497
• 16 Subbarao B, Morris J, Kryscio RJ. Phenotypic and functional properties of B lymphocytes from aged mice. Mech Ageing Dev 1990; 51 (3) 223-241
• 17 Utsuyama M, Hirokawa K, Kurashima C , et al. Differential age-change in the numbers of CD4+CD45RA+ and CD4+CD29+ T cell subsets in human peripheral blood. Mech Ageing Dev 1992; 63 (1) 57-68
• 18 Ginaldi L, De Martinis M, D'Ostilio A, Marini L, Loreto MF, Quaglino D. Immunological changes in the elderly. Aging (Milano) 1999; 11 (5) 281-286
• 19 Goronzy JJ, Fujii H, Weyand CM. Telomeres, immune aging and autoimmunity. Exp Gerontol 2006; 41 (3) 246-251
• 20 Costenbader KH, Prescott J, Zee RY, De Vivo I. Immunosenescence and rheumatoid arthritis: does telomere shortening predict impending disease?. Autoimmun Rev 2011; 10 (9) 569-573
• 21 Distler JH, Huber LC, Gay S, Distler O, Pisetsky DS. Microparticles as mediators of cellular cross-talk in inflammatory disease. Autoimmunity 2006; 39 (8) 683-690
• 22 Roos MA, Gennero L, Denysenko T , et al. Microparticles in physiological and in pathological conditions. Cell Biochem Funct 2010; 28 (7) 539-548
• 23 Puddu P, Puddu GM, Cravero E, Muscari S, Muscari A. The involvement of circulating microparticles in inflammation, coagulation and cardiovascular diseases. Can J Cardiol 2010; 26 (4) 140-145
• 24 Burger D, Montezano AC, Nishigaki N, He Y, Carter A, Touyz RM. Endothelial microparticle formation by angiotensin II is mediated via Ang II receptor type I/NADPH oxidase/ Rho kinase pathways targeted to lipid rafts. Arterioscler Thromb Vasc Biol 2011; 31 (8) 1898-1907
• 25 Leroyer AS, Anfosso F, Lacroix R , et al. Endothelial-derived microparticles: Biological conveyors at the crossroad of inflammation, thrombosis and angiogenesis. Thromb Haemost 2010; 104 (3) 456-463
• 26 Owens III AP, Mackman N. Microparticles in hemostasis and thrombosis. Circ Res 2011; 108 (10) 1284-1297
• 27 Burnier L, Fontana P, Kwak BR, Angelillo-Scherrer A. Cell-derived microparticles in haemostasis and vascular medicine. Thromb Haemost 2009; 101 (3) 439-451
• 28 Horstman LL, Ahn YS. Platelet microparticles: a wide-angle perspective. Crit Rev Oncol Hematol 1999; 30 (2) 111-142
• 29 Flaumenhaft R, Dilks JR, Richardson J , et al. Megakaryocyte-derived microparticles: direct visualization and distinction from platelet-derived microparticles. Blood 2009; 113 (5) 1112-1121
• 30 Rozmyslowicz T, Majka M, Kijowski J , et al. Platelet- and megakaryocyte-derived microparticles transfer CXCR4 receptor to CXCR4-null cells and make them susceptible to infection by X4-HIV. AIDS 2003; 17 (1) 33-42
• 31 Chirinos JA, Heresi GA, Velasquez H , et al. Elevation of endothelial microparticles, platelets, and leukocyte activation in patients with venous thromboembolism. J Am Coll Cardiol 2005; 45 (9) 1467-1471
• 32 Preston RA, Jy W, Jimenez JJ , et al. Effects of severe hypertension on endothelial and platelet microparticles. Hypertension 2003; 41 (2) 211-217
• 33 Tans G, Rosing J, Thomassen MC, Heeb MJ, Zwaal RF, Griffin JH. Comparison of anticoagulant and procoagulant activities of stimulated platelets and platelet-derived microparticles. Blood 1991; 77 (12) 2641-2648
• 34 Knijff-Dutmer EA, Koerts J, Nieuwland R, Kalsbeek-Batenburg EM, van de Laar MA. Elevated levels of platelet microparticles are associated with disease activity in rheumatoid arthritis. Arthritis Rheum 2002; 46 (6) 1498-1503
• 35 Pereira J, Alfaro G, Goycoolea M , et al. Circulating platelet-derived microparticles in systemic lupus erythematosus. Association with increased thrombin generation and procoagulant state. Thromb Haemost 2006; 95 (1) 94-99
• 36 Nielsen CT, Østergaard O, Stener L , et al. Increased IgG on cell-derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation. Arthritis Rheum 2012; 64 (4) 1227-1236
• 37 Angelillo-Scherrer A. Leukocyte-derived microparticles in vascular homeostasis. Circ Res 2012; 110 (2) 356-369
• 38 Lacy P. Mechanisms of degranulation in neutrophils. Allergy Asthma Clin Immunol 2006; 2 (3) 98-108
• 39 Gasser O, Hess C, Miot S, Deon C, Sanchez JC, Schifferli JA. Characterisation and properties of ectosomes released by human polymorphonuclear neutrophils. Exp Cell Res 2003; 285 (2) 243-257
• 40 Hess C, Sadallah S, Hefti A, Landmann R, Schifferli JA. Ectosomes released by human neutrophils are specialized functional units. J Immunol 1999; 163 (8) 4564-4573
• 41 Gasser O, Schifferli JA. Microparticles released by human neutrophils adhere to erythrocytes in the presence of complement. Exp Cell Res 2005; 307 (2) 381-387
• 42 Mesri M, Altieri DC. Endothelial cell activation by leukocyte microparticles. J Immunol 1998; 161 (8) 4382-4387
• 43 Mesri M, Altieri DC. Leukocyte microparticles stimulate endothelial cell cytokine release and tissue factor induction in a JNK1 signaling pathway. J Biol Chem 1999; 274 (33) 23111-23118
• 44 Gasser O, Schifferli JA. Activated polymorphonuclear neutrophils disseminate anti-inflammatory microparticles by ectocytosis. Blood 2004; 104 (8) 2543-2548
• 45 Brodsky SV, Zhang F, Nasjletti A, Goligorsky MS. Endothelium-derived microparticles impair endothelial function in vitro. Am J Physiol Heart Circ Physiol 2004; 286 (5) H1910-H1915
• 46 Dalli J, Norling LV, Renshaw D, Cooper D, Leung KY, Perretti M. Annexin 1 mediates the rapid anti-inflammatory effects of neutrophil-derived microparticles. Blood 2008; 112 (6) 2512-2519
• 47 Pluskota E, Woody NM, Szpak D , et al. Expression, activation, and function of integrin alphaMbeta2 (Mac-1) on neutrophil-derived microparticles. Blood 2008; 112 (6) 2327-2335
• 48 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 (3) 534-542
• 49 Aharon A, Tamari T, Brenner B. Monocyte-derived microparticles and exosomes induce procoagulant and apoptotic effects on endothelial cells. Thromb Haemost 2008; 100 (5) 878-885
• 50 Egorina EM, Sovershaev MA, Olsen JO, Østerud B. Granulocytes do not express but acquire monocyte-derived tissue factor in whole blood: evidence for a direct transfer. Blood 2008; 111 (3) 1208-1216
• 51 Baka Z, Senolt L, Vencovsky J , et al. Increased serum concentration of immune cell derived microparticles in polymyositis/dermatomyositis. Immunol Lett 2010; 128 (2) 124-130
• 52 Shah MD, Bergeron AL, Dong JF, López JA. Flow cytometric measurement of microparticles: pitfalls and protocol modifications. Platelets 2008; 19 (5) 365-372
• 53 Canellini G, Rubin O, Delobel J, Crettaz D, Lion N, Tissot JD. Red blood cell microparticles and blood group antigens: an analysis by flow cytometry. Blood Transfus 2012; 10 (Suppl. 02) s39-s45
• 54 Rubin O, Canellini G, Delobel J, Lion N, Tissot JD. Red blood cell microparticles: clinical relevance. Transfus Med Hemother 2012; 39 (5) 342-347
• 55 Rosse WF, Gallagher D, Kinney TR , et al; The Cooperative Study of Sickle Cell Disease. Transfusion and alloimmunization in sickle cell disease. Blood 1990; 76 (7) 1431-1437
• 56 Cox JV, Steane E, Cunningham G, Frenkel EP. Risk of alloimmunization and delayed hemolytic transfusion reactions in patients with sickle cell disease. Arch Intern Med 1988; 148 (11) 2485-2489
• 57 Bosman GJ. Erythrocyte aging in sickle cell disease. Cell Mol Biol (Noisy-le-grand) 2004; 50 (1) 81-86
• 58 Westerman M, Pizzey A, Hirschman J , et al. Microvesicles in haemoglobinopathies offer insights into mechanisms of hypercoagulability, haemolysis and the effects of therapy. Br J Haematol 2008; 142 (1) 126-135
• 59 van Beers EJ, Schaap MC, Berckmans RJ , et al; CURAMA study group. Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease. Haematologica 2009; 94 (11) 1513-1519
• 60 Sadallah S, Eken C, Schifferli JA. Erythrocyte-derived ectosomes have immunosuppressive properties. J Leukoc Biol 2008; 84 (5) 1316-1325
• 61 Sadallah S, Eken C, Schifferli JA. Ectosomes as modulators of inflammation and immunity. Clin Exp Immunol 2011; 163 (1) 26-32
• 62 Morel O, Toti F, Freyssinet JM. Markers of thrombotic disease: procoagulant microparticles [in French]. Ann Pharm Fr 2007; 65 (2) 75-84
• 63 Ueba T, Haze T, Sugiyama M , et al. Level, distribution and correlates of platelet-derived microparticles in healthy individuals with special reference to the metabolic syndrome. Thromb Haemost 2008; 100 (2) 280-285
• 64 Lacroix R, Dignat-George F. Microparticles as a circulating source of procoagulant and fibrinolytic activities in the circulation. Thromb Res 2012; 129 (Suppl. 02) S27-S29
• 65 Forest A, Pautas E, Ray P , et al. Circulating microparticles and procoagulant activity in elderly patients. J Gerontol A Biol Sci Med Sci 2010; 65: 414-420
• 66 Jodo S, Xiao S, Hohlbaum A, Strehlow D, Marshak-Rothstein A, Ju ST. Apoptosis-inducing membrane vesicles. A novel agent with unique properties. J Biol Chem 2001; 276 (43) 39938-39944
• 67 Dye JR, Ullal AJ, Pisetsky DS. The role of microparticles in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus. Scand J Immunol 2013; 78 (2) 140-148
• 68 Pamuk GE, Vural O, Turgut B, Demir M, Pamuk ON, Cakir N. Increased platelet activation markers in rheumatoid arthritis: are they related with subclinical atherosclerosis?. Platelets 2008; 19 (2) 146-154
• 69 Sellam J, Proulle V, Jüngel A , et al. Increased levels of circulating microparticles in primary Sjögren's syndrome, systemic lupus erythematosus and rheumatoid arthritis and relation with disease activity. Arthritis Res Ther 2009; 11 (5) R156
• 70 van Eijk IC, Tushuizen ME, Sturk A , et al. Circulating microparticles remain associated with complement activation despite intensive anti-inflammatory therapy in early rheumatoid arthritis. Ann Rheum Dis 2010; 69 (7) 1378-1382
• 71 Biró E, Nieuwland R, Tak PP , et al. Activated complement components and complement activator molecules on the surface of cell-derived microparticles in patients with rheumatoid arthritis and healthy individuals. Ann Rheum Dis 2007; 66 (8) 1085-1092
• 72 Boilard E, Nigrovic PA, Larabee K , et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010; 327 (5965) 580-583
• 73 Berckmans RJ, Nieuwland R, Böing AN, Romijn FP, Hack CE, Sturk A. Cell-derived microparticles circulate in healthy humans and support low grade thrombin generation. Thromb Haemost 2001; 85 (4) 639-646
• 74 Turesson C, Jarenros A, Jacobsson L. Increased incidence of cardiovascular disease in patients with rheumatoid arthritis: results from a community based study. Ann Rheum Dis 2004; 63 (8) 952-955
• 75 Maradit-Kremers H, Crowson CS, Nicola PJ , et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum 2005; 52 (2) 402-411
• 76 Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE. Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum 2005; 52 (3) 722-732
• 77 Solomon DH, Goodson NJ, Katz JN , et al. Patterns of cardiovascular risk in rheumatoid arthritis. Ann Rheum Dis 2006; 65 (12) 1608-1612
• 78 Bucciarelli P, Martinelli I, Artoni A , et al. Circulating microparticles and risk of venous thromboembolism. Thromb Res 2012; 129 (5) 591-597
• 79 Holmqvist ME, Neovius M, Eriksson J , et al. Risk of venous thromboembolism in patients with rheumatoid arthritis and association with disease duration and hospitalization. JAMA 2012; 308 (13) 1350-1356
• 80 Choi HK, Rho YH, Zhu Y, Cea-Soriano L, Aviña-Zubieta JA, Zhang Y. The risk of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a UK population-based outpatient cohort study. Ann Rheum Dis 2013; 72 (7) 1182-1187
• 81 Chung WS, Peng CL, Lin CL , et al. Rheumatoid arthritis increases the risk of deep vein thrombosis and pulmonary thromboembolism: a nationwide cohort study. Ann Rheum Dis 2013;
• 82 Beyer C, Pisetsky DS. The role of microparticles in the pathogenesis of rheumatic diseases. Nat Rev Rheumatol 2010; 6 (1) 21-29
• 83 Iversen LV, Østergaard O, Ullman S , et al. Circulating microparticles and plasma levels of soluble E- and P-selectins in patients with systemic sclerosis. Scand J Rheumatol 2013; 42 (6) 473-482
• 84 Guiducci S, Distler JH, Jüngel A , et al. The relationship between plasma microparticles and disease manifestations in patients with systemic sclerosis. Arthritis Rheum 2008; 58 (9) 2845-2853
• 85 Diehl P, Aleker M, Helbing T , et al. Increased platelet, leukocyte and endothelial microparticles predict enhanced coagulation and vascular inflammation in pulmonary hypertension. J Thromb Thrombolysis 2011; 31 (2) 173-179
• 86 Maugeri N, Rovere-Querini P, Baldini M , et al. Oxidative stress elicits platelet/leukocyte inflammatory interactions via HMGB1: a candidate for microvessel injury in sytemic sclerosis. Antioxid Redox Signal 2014; 20 (7) 1060-1074
• 87 Ullal AJ, Reich III CF, Clowse M , et al. Microparticles as antigenic targets of antibodies to DNA and nucleosomes in systemic lupus erythematosus. J Autoimmun 2011; 36 (3-4) 173-180
• 88 Ullal AJ, Pisetsky DS. The role of microparticles in the generation of immune complexes in murine lupus. Clin Immunol 2013; 146 (1) 1-9
• 89 Wloch MK, Alexander AL, Pippen AM, Pisetsky DS, Gilkeson GS. Differences in V kappa gene utilization and VH CDR3 sequence among anti-DNA from C3H-lpr mice and lupus mice with nephritis. Eur J Immunol 1996; 26 (9) 2225-2233
• 90 Nielsen CT, Østergaard O, Johnsen C, Jacobsen S, Heegaard NH. Distinct features of circulating microparticles and their relationship to clinical manifestations in systemic lupus erythematosus. Arthritis Rheum 2011; 63 (10) 3067-3077
• 91 Østergaard O, Nielsen CT, Iversen LV , et al. Unique protein signature of circulating microparticles in systemic lupus erythematosus. Arthritis Rheum 2013; 65 (10) 2680-2690
• 92 Manzi S, Meilahn EN, Rairie JE , et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997; 145 (5) 408-415
• 93 Bruce IN, Urowitz MB, Gladman DD, Ibañez D, Steiner G. Risk factors for coronary heart disease in women with systemic lupus erythematosus: the Toronto Risk Factor Study. Arthritis Rheum 2003; 48 (11) 3159-3167
• 94 Esdaile JM, Abrahamowicz M, Grodzicky T , et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum 2001; 44 (10) 2331-2337
• 95 Parker B, Al-Husain A, Pemberton P , et al. Suppression of inflammation reduces endothelial microparticles in active systemic lupus erythematosus. Ann Rheum Dis 2013;
• 96 Chironi GN, Boulanger CM, Simon A, Dignat-George F, Freyssinet JM, Tedgui A. Endothelial microparticles in diseases. Cell Tissue Res 2009; 335 (1) 143-151
• 97 Mayr M, Grainger D, Mayr U , et al. Proteomics, metabolomics, and immunomics on microparticles derived from human atherosclerotic plaques. Circ Cardiovasc Genet 2009; 2 (4) 379-388