Thromb Haemost 2006; 95(01): 94-99
DOI: 10.1160/TH05-05-0310
Platelets and Blood Cells
Schattauer GmbH

Circulating platelet-derived microparticles in systemic lupus erythematosus

Association with increased thrombin generation and procoagulant state
Jaime Pereira
1   Departments of Hematology-Oncology, Clinical Laboratory and Rheumatology, School of Medicine, Catholic University of Chile, Santiago, Chile
,
Gino Alfaro
1   Departments of Hematology-Oncology, Clinical Laboratory and Rheumatology, School of Medicine, Catholic University of Chile, Santiago, Chile
,
Manuela Goycoolea
1   Departments of Hematology-Oncology, Clinical Laboratory and Rheumatology, School of Medicine, Catholic University of Chile, Santiago, Chile
,
Teresa Quiroga
1   Departments of Hematology-Oncology, Clinical Laboratory and Rheumatology, School of Medicine, Catholic University of Chile, Santiago, Chile
,
Mauricio Ocqueteau
1   Departments of Hematology-Oncology, Clinical Laboratory and Rheumatology, School of Medicine, Catholic University of Chile, Santiago, Chile
,
Loreto Massardo
1   Departments of Hematology-Oncology, Clinical Laboratory and Rheumatology, School of Medicine, Catholic University of Chile, Santiago, Chile
,
Carol Pérez
1   Departments of Hematology-Oncology, Clinical Laboratory and Rheumatology, School of Medicine, Catholic University of Chile, Santiago, Chile
,
Claudia Sáez
1   Departments of Hematology-Oncology, Clinical Laboratory and Rheumatology, School of Medicine, Catholic University of Chile, Santiago, Chile
,
Olga Panes
1   Departments of Hematology-Oncology, Clinical Laboratory and Rheumatology, School of Medicine, Catholic University of Chile, Santiago, Chile
,
Valeria Matus
1   Departments of Hematology-Oncology, Clinical Laboratory and Rheumatology, School of Medicine, Catholic University of Chile, Santiago, Chile
,
Diego Mezzano
1   Departments of Hematology-Oncology, Clinical Laboratory and Rheumatology, School of Medicine, Catholic University of Chile, Santiago, Chile
› Institutsangaben
Financial support: This work was supported by grant 8010002 (Líneas Complementarias) from FONDECYT (Fondo Nacional de Cienciay Tecnología, Chile).
Weitere Informationen

Publikationsverlauf

Received 05. Mai 2005

Accepted after resubmission 21. Oktober 2005

Publikationsdatum:
28. November 2017 (online)

Summary

The risk for thrombosis is significantly increased in systemic lupus erythematosus (SLE), affecting both venous and arterial vessels. Activated platelets are known to participate in thrombus formation and growth. A general feature of activated cells is the shedding of microparticles (MP) which support coagulation by exposure of negatively charged phospholipids and possibly tissue factor (TF). In this work we characterized circulating MP in patients with SLE and their relationship with a procoagulant state. Thirty patients with SLE (aged 15–72 years, mean age 38 years) and 20 healthy controls (aged 22–54 years, mean age 34 years) were studied; patients fulfilled 4 revised criteria for SLE. The number and cellular source of circulating MP were determined by flow cytometry using double labeling with specific monoclonal antibodies and annexin V. Thrombin generation was measured as the endogenous thrombin potential (ETP) without the addition of exogenous phospholipids and TF; under these conditions the generation of thrombin depended directly on the number of MP present in plasma. Thrombin anti-thrombin (TAT) and plasmin-antiplasmin (PAP) complexes were measured by ELISA. Compared to the controls, circulating MP were significantly elevated in the patient group (1218 ± 136 vs 653 ± 74 x103/ml plasma, p: 0.0007). In both groups, most of these MP were of platelet origin (927± 131 vs 517 ± 72 x103/ml plasma, p:0.009 ). ETP was higher among patients as compared to the controls (804± 64 vs 631 ± 37 nM thrombin, p: 0.025). Plasma levels of TAT in patients and controls were 3.4 ± 0.8 and 1.4 ± 0.5 µg/L, respectively (p:0.04), and of PAP complexes were 62.5 ± 14 and 24.05± 2.5 µg/ml, respectively (p: 0.014).The number of platelet-derived MP correlated significantly with thrombin generation (r: 0.42; p: 0.038) and TAT levels (r: 0.40; p: 0.035).We did not find an association of circulating MP with disease activity nor with the presence of antiphospholipid antibodies. The increased number of circulating platelet-derived microparticles and their association with high ETP and activation of the coagulation system suggest that these microparticles play an important role in the pathogenesis of the prothrombotic state in SLE patients.

 
  • References

  • 1 Ruiz-Irastorza G. et al. Systemic lupus erythematosus. Lancet 2001; 357: 1027-32.
  • 2 Salmon JE, Roman MJ. Accelerated atherosclerosis in systemic lupus erythematosus: implication for patient management. Curr Opin Rheumatol 2001; 13: 341-4.
  • 3 Manzi S. 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: 408-15.
  • 4 Esdaile JM. et al. Traditional Framingham risk factors fails to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum 2001; 44: 2331-7.
  • 5 Fitzgerald DJ. et al. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315: 983-9.
  • 6 Furman MI. et al. Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol 1998; 31: 352-8.
  • 7 Huo Y. et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2003; 09: 61-7.
  • 8 Pasquet JM. et al. Procoagulant activity and active calpain in platelet-derived microparticles. Blood 1996; 82: 509-22.
  • 9 Zwaal RFA, Schroit AJ. Pathophysiologic implications of membrane phopholipid asymmetry in blood cells. Blood 1997; 89: 1121-32.
  • 10 Müller I. et al. Intravascular tissue factor initiates coagulation via circulating microvesicles and platelets. FASEB J 2003; 17: 476-8.
  • 11 Biró E. et al. Human cell-derived microparticles promote thrombus formation in vivo in a tissue factordependent manner. J Thromb Haemost 2003; 01: 2561-8.
  • 12 VanWijk MJ. et al. Microparticles in cardiovascular diseases. Cardiovasc Res 2003; 59: 277-87.
  • 13 Warkentin TE. et al. Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparininduced thrombocytopenia. Blood 1994; 84: 3691-9.
  • 14 Combes V. et al. In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant. J Clin Invest 1999; 104: 93-102.
  • 15 Mallat Z. et al. Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation 2000; 101: 841-3.
  • 16 Bretelle F. et al. Circulating microparticles: a marker of procoagulant state in normal pregnancy and pregnancy complicated by preeclampsia or intrauterine growth restriction. Thromb Haemost 2003; 89: 486-92.
  • 17 Nagahama M. et al. Platelet activation markers and soluble adhesion molecules in patients with systemic lupus erythematosus. Autoimmunity 2001; 33: 85-94.
  • 18 Joseph JE. et al. Increased circulating platelet-leukocyte complexes and platelet activation in patients with antiphospholipid syndrome, systemic lupus erythematosus and rheumatoid arthritis. BrJ Haematol 2001; 115: 451-9.
  • 19 Knijff-Dutmar EAJ. et al. Elevated levels of platelet microparticles are associated with disease activity in rheumatoid arthritis. Arthritis Rheum 2002; 46: 1498-503.
  • 20 Abid MNHussein. et al. Antigenic characterization of endothelial cell-derived microparticles and their detection ex vivo. J Thromb Haemost 2003; 01: 2434-43.
  • 21 Ekdahl KN. et al. Thrombotic disease in systemic lupus erythematosus is associated with maintained systemic platelet activation. Br J Haematol 2004; 125: 74-8.
  • 22 Tan EM. et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271-7.
  • 23 Guzmán J. et al. Measurement of disease activity in systemic lupus erythematosus. Prospective validation of 3 clinical indices. J Rheumatol 1992; 19: 1551-8.
  • 24 Shet AS. et al. Sickle blood contains tissue factorpositive microparticles dereived from endothelial cells and monocytes. Blood 2003; 102: 2678-83.
  • 25 Quiroga T. et al. Thrombin generation in plateletpoor plasma is normal in patients with hereditary mucocutaneous haemorrhages. Pathophysiol Haemost Thromb 2003; 33: 30-5.
  • 26 Hemker HC. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33: 4-15.
  • 27 Brandt JT. et al. Laboratory identification of lupus anticoagulants: results of the Second International Workshop for the identification of Lupus Anticoagulants. On behalf of the Subcommittee on Lupus Anticoagulants/Antiphospholipids Antibodies of the ISTH. Thromb Haemost 1995; 74: 1597-603.
  • 28 Sims PJ. et al. Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. J Biol Chem 1989; 264: 17049-57.
  • 29 Zwaal RFA. et al. Platelet procoagulant activity and microvesicle formation: its putative role in hemostasis and thrombosis. Biochim Biophys Acta 1992; 1180: 1-8.
  • 30 Dorsch C, Meyerhoff J. Elevated plasma betathromboglobulin levels in systemic lupus erythematosus. Thromb Res 1980; 20: 617-22.
  • 31 Ekdahl KN. et al. Increased phosphate content in complement component C3, fibrinogen, vitronectin, and other plasma proteins in systemic lupus erythematosus: covariation with platelet activation and possible association with thrombosis. Arthritis Rheum 1997; 40: 2178-86.
  • 32 Desai-Mehta A. et al. Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest 1996; 97: 2063-73.
  • 33 Koshy M. et al. Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. J Clin Invest 1996; 98: 826-37.
  • 34 Inwald DP. et al. CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation. Cir Res 2003; 92: 1041-8.
  • 35 Danese S. et al. Cutting edge: T cells trigger CD40-dependent platelet activation and granular RANTES release : a novel pathway for immune response amplification. J Immunol 2004; 172: 2010-15.
  • 36 Vanags DM. et al. Alterations in Bcl-2/Bax protein levels in platelets form part of an ionomycin-induced process that resembles apoptosis. Br J Haematol 1997; 99: 824-31.
  • 37 Wolf BB. et al. Calpain functions in a caspase-independent manner to promote apoptosis- like events during platelet activation. Blood 1999; 94: 1683-92.
  • 38 Brown SB. et al. Constitutive death of platelets leading to scavenger receptor-mediated phagocytosis. A caspase-independent cell clearance program. J Biol Chem 2000; 275: 5987-96.
  • 39 Li J. et al. The mechanism of apoptosis in human platelets during storage. Transfusion 2000; 40: 1320-9.
  • 40 Klint C, Truedsson L, Andreasson A. et al. Toxic effects of SLE serum on normal monocytes in vitro: cell death induced by apoptosis related to complement dysfunction. Lupus 2000; 09: 278-87.
  • 41 Bengtsson AA. et al. Induction of apoptosis in monocytes and lymphocytes by serum from patients with systemic lupus erythematosus- an additional mechanism to increased autoantigen load?. Clin Exp Immunol 2004; 135: 535-43.
  • 42 Rajagopalan S. et al. Endothelial cell apoptosis in systemic lupus erythematosus:a common pathway for abnormal vascular function and thrombosis propensity. Blood 2004; 103: 3677-83.
  • 43 Gilbert GE. et al. Platelet-derived microparticles express high affinity receptors for factor VIII. J Biol Chem 1991; 266: 17261-8.
  • 44 Wiedmer T. et al. Role of calcium and calpain in complement-induced vesiculation of the platelet plasma membrane and in the exposure of the platelet factor Va receptor. Biochemistry 1990; 29: 623-32.
  • 45 Joop K. et al. Microparticles from patients with multiple organ dysfunction syndrome and sepsis support coagulation through multiple mechanisms. Thromb Haemost 2001; 85: 810-20.
  • 46 Sturk-Maquelin KN. et al. Pro- and non-coagulant forms of non-cell-bound tissue factor in vivo . J Thromb Haemost 2003; 01: 1920-6.
  • 47 Hemker HC. et al. Thrombin generation assays: accruing clinical relevance. Curr Opin Hematol 2004; 11: 170-5.
  • 48 Dignat-George F. et al. Endothelial microparticles: a potential contribution to the thrombotic complications of antiphospholipid syndrome. Thromb Haemost 2004; 91: 667-73.
  • 49 De Prost D. et al. Increased monocyte procoagulant activity independent of the lupus anticoagulant in patients with systemic lupus erythematosus. Thromb Haemost 1990; 64: 216-21.