CC BY-NC-ND 4.0 · TH Open 2023; 07(02): e155-e167
DOI: 10.1055/a-2087-0314
Original Article

Platelets and the Lectin Pathway of Complement Activation in Patients with Systemic Lupus Erythematosus or Antiphospholipid Syndrome

1   Department of Biomedicine, Aarhus University, Aarhus, Denmark
,
Anne Troldborg
1   Department of Biomedicine, Aarhus University, Aarhus, Denmark
2   Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
,
Anne-Mette Hvas
3   Faculty of Health, Aarhus University, Aarhus, Denmark
4   Thrombosis and Haemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
,
Steffen Thiel
1   Department of Biomedicine, Aarhus University, Aarhus, Denmark
› Author Affiliations
Funding This study was supported by grants from Grosserer LF Foghts, the A.P. Moller Foundation (19-L-0091), and the Danish Rheumatism Association (R184-A6401 and R172-A6101). A.T. was supported by grants from Lundbeck Fonden (R264-2017-3344) and the Danish Rheumatism Association (R172-A6101). Tests for pattern recognition molecules were supported by Danish National Research Foundation through the Center for Cellular Signal Patterns (CellPAT) (DNRF135).

Abstract

Background Patients with systemic lupus erythematosus (SLE) have an increased risk of thrombosis even when they do not have antiphospholipid syndrome (APS). Interactions between complement activation and activated platelets have been suggested in SLE and APS and could play a role in the increased thrombosis risk.

Objectives To explore factors potentially related to the prothrombotic pathophysiology in patients with SLE, primary APS, and healthy controls, by investigating lectin pathway proteins (LPPs), complement activation, platelet aggregation, and platelet activation.

Methods This cross-sectional cohort study included 20 SLE patients, 17 primary APS, and 39 healthy controls. Flow cytometry and light transmission aggregometry were used to assess platelet activation and aggregation. Using time-resolved immunofluorometric assays, the plasma concentrations of 11 LPPs and C3dg, reflecting complement activation, were measured.

Results H-ficolin plasma concentrations were higher in SLE and APS patients than in controls (p = 0.01 and p = 0.03). M-ficolin was lower in SLE than in APS (p = 0.01) and controls (p = 0.03). MAp19 was higher in APS patients than in SLE patients (p = 0.01) and controls (p < 0.001). In APS patients, MASP-2 and C3dg correlated negatively with platelet activation. Platelet-bound fibrinogen after agonist stimulation and C3dg concentrations correlated negatively with platelet activation.

Conclusion We observed significant differences between SLE and APS patients regarding complement proteins and platelet activation. Particularly the negative correlations between MASP-2 and C3dg with platelet activation only observed in APS patients suggest that interactions between complement activation and platelets differ in SLE and APS.

Supplementary Material



Publication History

Received: 28 October 2022

Accepted: 25 April 2023

Accepted Manuscript online:
05 May 2023

Article published online:
15 June 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid syndrome. N Engl J Med 2013; 368 (11) 1033-1044
  • 2 Pons-Estel GJ, Andreoli L, Scanzi F, Cervera R, Tincani A. The antiphospholipid syndrome in patients with systemic lupus erythematosus. J Autoimmun 2017; 76: 10-20
  • 3 Cervera R, Piette JC, Font J. et al; Euro-Phospholipid Project Group. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46 (04) 1019-1027
  • 4 D'Cruz DP, Khamashta MA, Hughes GR. Systemic lupus erythematosus. Lancet 2007; 369 (9561): 587-596
  • 5 Espinosa G, Cervera R. Antiphospholipid syndrome: frequency, main causes and risk factors of mortality. Nat Rev Rheumatol 2010; 6 (05) 296-300
  • 6 Fors Nieves CE, Izmirly PM. Mortality in systemic lupus erythematosus: an updated review. Curr Rheumatol Rep 2016; 18 (04) 21
  • 7 Ramirez GA, Efthymiou M, Isenberg DA, Cohen H. Under crossfire: thromboembolic risk in systemic lupus erythematosus. Rheumatology (Oxford) 2019; 58 (06) 940-952
  • 8 de Groot PG, de Laat B. Mechanisms of thrombosis in systemic lupus erythematosus and antiphospholipid syndrome. Best Pract Res Clin Rheumatol 2017; 31 (03) 334-341
  • 9 Negrini S, Pappalardo F, Murdaca G, Indiveri F, Puppo F. The antiphospholipid syndrome: from pathophysiology to treatment. Clin Exp Med 2017; 17 (03) 257-267
  • 10 Chaturvedi S, Brodsky RA, McCrae KR. Complement in the pathophysiology of the antiphospholipid syndrome. Front Immunol 2019; 10 (MAR): 449
  • 11 Baroni G, Banzato A, Bison E, Denas G, Zoppellaro G, Pengo V. The role of platelets in antiphospholipid syndrome. Platelets 2017; 28 (08) 762-766
  • 12 Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT. Complement system part I - molecular mechanisms of activation and regulation. Front Immunol 2015; 6 (JUN): 262
  • 13 Merle NS, Noe R, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, Roumenina LT. Complement system part II: role in immunity. Front Immunol 2015; 6 (MAY): 257
  • 14 Kjaer TR, Thiel S, Andersen GR. Toward a structure-based comprehension of the lectin pathway of complement. Mol Immunol 2013; 56 (03) 222-231
  • 15 Aringer M, Costenbader K, Daikh D. et al. 2019 EULAR/ACR classification criteria for systemic lupus erythematosus. Arthritis Rheumatol 2019; 71 (09) 1400
  • 16 Oku K, Atsumi T, Bohgaki M. et al. Complement activation in patients with primary antiphospholipid syndrome. Ann Rheum Dis 2009; 68 (06) 1030-1035
  • 17 Fischetti F, Durigutto P, Pellis V. et al. Thrombus formation induced by antibodies to beta2-glycoprotein I is complement dependent and requires a priming factor. Blood 2005; 106 (07) 2340-2346
  • 18 Linge P, Fortin PR, Lood C, Bengtsson AA, Boilard E. The non-haemostatic role of platelets in systemic lupus erythematosus. Nat Rev Rheumatol 2018; 14 (04) 195-213
  • 19 Urbanus RT, Pennings MTT, Derksen RHWM, de Groot PG. Platelet activation by dimeric beta2-glycoprotein I requires signaling via both glycoprotein Ibalpha and apolipoprotein E receptor 2′. J Thromb Haemost 2008; 6 (08) 1405-1412
  • 20 Eriksson O, Mohlin C, Nilsson B, Ekdahl KN. The human platelet as an innate immune cell: interactions between activated platelets and the complement system. Front Immunol 2019; 10 (JULY): 1590
  • 21 Subramaniam S, Jurk K, Hobohm L. et al. Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development. Blood 2017; 129 (16) 2291-2302
  • 22 Svenungsson E, Gustafsson JT, Grosso G. et al. Complement deposition, C4d, on platelets is associated with vascular events in systemic lupus erythematosus. Rheumatology (Oxford) 2020; 59 (11) 3264-3274
  • 23 Peerschke EIB, Yin W, Alpert DR, Roubey RAS, Salmon JE, Ghebrehiwet B. Serum complement activation on heterologous platelets is associated with arterial thrombosis in patients with systemic lupus erythematosus and antiphospholipid antibodies. Lupus 2009; 18 (06) 530-538
  • 24 Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40 (09) 1725
  • 25 Miyakis S, Lockshin MD, Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4 (02) 295-306
  • 26 Larsen JB, Hvas AM, Hojbjerg JA. Platelet function testing: update and future directions. Semin Thromb Hemost 2022; (e-pub ahead of print). DOI: 10.1055/S-0042-1757898.
  • 27 Rubak P, Nissen PH, Kristensen SD, Hvas AM. Investigation of platelet function and platelet disorders using flow cytometry. Platelets 2016; 27 (01) 66-74
  • 28 Lee JA, Spidlen J, Boyce K. et al; International Society for Advancement of Cytometry Data Standards Task Force. MIFlowCyt: the minimum information about a Flow Cytometry Experiment. Cytometry A 2008; 73 (10) 926-930
  • 29 Troldborg A, Thiel S, Trendelenburg M. et al. The lectin pathway of complement activation in patients with systemic lupus erythematosus. J Rheumatol 2018; 45 (08) 1136-1144
  • 30 Troldborg A, Halkjær L, Pedersen H. et al. Complement activation in human autoimmune diseases and mouse models; employing a sandwich immunoassay specific for C3dg. J Immunol Methods 2020; 486: 112866
  • 31 Pedersen OH, Nissen PH, Hvas AM. Platelet function investigation by flow cytometry: sample volume, needle size, and reference intervals. Platelets 2018; 29 (02) 199-202
  • 32 Troldborg A, Hansen A, Hansen SWK, Jensenius JC, Stengaard-Pedersen K, Thiel S. Lectin complement pathway proteins in healthy individuals. Clin Exp Immunol 2017; 188 (01) 138-147
  • 33 Breen KA, Kilpatrick DC, Swierzko AS, Cedzynski M, Hunt BJ. Lack of association of serum mannose/mannan binding lectin or ficolins with complement activation in patients with antiphospholipid antibodies. Blood Coagul Fibrinolysis 2014; 25 (06) 644-645
  • 34 Ekdahl KN, Persson B, Mohlin C, Sandholm K, Skattum L, Nilsson B. Interpretation of serological complement biomarkers in disease. Front Immunol 2018; 9 (OCT): 2237
  • 35 Hein E, Bay JT, Munthe-Fog L, Garred P. Ficolin-2 reveals different analytical and biological properties dependent on different sample handling procedures. Mol Immunol 2013; 56 (04) 406-412
  • 36 Degn SE, Thiel S, Nielsen O, Hansen AG, Steffensen R, Jensenius JC. MAp19, the alternative splice product of the MASP2 gene. J Immunol Methods 2011; 373 (1–2): 89-101
  • 37 Larsen JB, Laursen MA, Hvas CL, Larsen KM, Thiel S, Hvas AM. Reduced mannose-binding lectin-associated serine protease (MASP)-1 is associated with disturbed coagulation in septic shock. Thromb Haemost 2019; 119 (06) 952-961
  • 38 Bro-Jeppesen J, Jeppesen AN, Haugaard S. et al. The complement lectin pathway protein MAp19 and out-of-hospital cardiac arrest: Insights from two randomized clinical trials. Eur Heart J Acute Cardiovasc Care 2020; 9 (4_suppl): S145-S152
  • 39 Scherlinger M, Guillotin V, Truchetet ME. et al. Systemic lupus erythematosus and systemic sclerosis: all roads lead to platelets. Autoimmun Rev 2018; 17 (06) 625-635
  • 40 Cornwell MG, Luttrell-Williams ES, Golpanian M. et al. Hydroxychloroquine is associated with lower platelet activity and improved vascular health in systemic lupus erythematosus. Lupus Sci Med 2021; 8 (01) e000475
  • 41 Liverani E, Banerjee S, Roberts W, Naseem KM, Perretti M. Prednisolone exerts exquisite inhibitory properties on platelet functions. Biochem Pharmacol 2012; 83 (10) 1364-1373
  • 42 Hartmann LT, Alegretti AP, Machado ABMP. et al. Assessment of mean platelet volume in patients with systemic lupus erythematosus. Open Rheumatol J 2018; 12 (01) 129-138
  • 43 Connolly-Andersen AM, Sundberg E, Ahlm C. et al. Increased thrombopoiesis and platelet activation in hantavirus-infected patients. J Infect Dis 2015; 212 (07) 1061-1069
  • 44 Ekdahl KN, Bengtsson AA, Andersson J. et al. Thrombotic disease in systemic lupus erythematosus is associated with a maintained systemic platelet activation. Br J Haematol 2004; 125 (01) 74-78
  • 45 Štok U, Blokar E, Lenassi M. et al. Characterization of plasma-derived small extracellular vesicles indicates ongoing endothelial and platelet activation in patients with thrombotic antiphospholipid syndrome. Cells 2020; 9 (05) 1211
  • 46 Andrianova IA, Ponomareva AA, Mordakhanova ER. et al. In systemic lupus erythematosus anti-dsDNA antibodies can promote thrombosis through direct platelet activation. J Autoimmun 2020; 107: 102355
  • 47 Peerschke EI, Yin W, Ghebrehiwet B. Complement activation on platelets: implications for vascular inflammation and thrombosis. Mol Immunol 2010; 47 (13) 2170-2175
  • 48 Nunez D, Charriaut-Marlangue C, Barel M, Benveniste J, Frade R. Activation of human platelets through gp140, the C3d/EBV receptor (CR2). Eur J Immunol 1987; 17 (04) 515-520
  • 49 Lonati PA, Scavone M, Gerosa M. et al. Blood cell-bound C4d as a marker of complement activation in patients with the antiphospholipid syndrome. Front Immunol 2019; 10 (APR): 773
  • 50 Kozarcanin H, Lood C, Munthe-Fog L. et al. The lectin complement pathway serine proteases (MASPs) represent a possible crossroad between the coagulation and complement systems in thromboinflammation. J Thromb Haemost 2016; 14 (03) 531-545
  • 51 Gulla KC, Gupta K, Krarup A. et al. Activation of mannan-binding lectin-associated serine proteases leads to generation of a fibrin clot. Immunology 2010; 129 (04) 482-495
  • 52 Lood C, Tydén H, Gullstrand B. et al. Decreased platelet size is associated with platelet activation and anti-phospholipid syndrome in systemic lupus erythematosus. Rheumatology (Oxford) 2017; 56 (03) 408-416