Clinical Rheumatology

, Volume 37, Issue 8, pp 2087–2093 | Cite as

Influence of autoimmunity and inflammation on endothelial function and thrombosis in systemic lupus erythematosus patients

  • Kamil BugałaEmail author
  • Adam Mazurek
  • Krzysztof Gryga
  • Monika Komar
  • Grzegorz Kopeć
  • Jacek Musiał
  • Piotr Podolec
  • Carlo Perricone
  • Wojciech Płazak
Original Article


The aim of this study is to assess the relationship between autoimmunity and endothelial activation/damage (ICAM-1 and vWF serum levels) and the degree of prothrombotic activity (thrombin–antithrombin complexes—TAT serum levels) in SLE. In 60 clinically stable SLE patients, levels of the following parameters were estimated in their serum: lupus anticoagulant (LA), anticardiolipin antibodies in both IgG and IgM classes (aCL-IgG and aCL-IgM, respectively), antiβ2GPI antibodies in both IgG and IgM classes (antiβ2GPI-IgG and antiβ2GPI-IgM, respectively), ICAM, von Willebrand factor (vWF), TAT, CRP, C3c, C4, and IL-6. ICAM-1 values exceeded the upper reference limit in 9 (15%) patients. vWF levels were increased in 21 (35%) patients. In all patients with elevated ICAM-1 values, vWF were also increased. TAT concentrations were elevated in 12 (20%) people. ICAM-1 were significantly higher in patients with elevated aCL-IgM (> 30 MPL vs ≤ 30 MPL; p < 0.05). Similarly, ICAM-1 were significantly higher in patients with elevated antiβ2-GPI-IgM (> 20 SMU vs ≤ 20 SMU; p < 0.05). There was no significant difference in ICAM-1 levels in relation to LA-positivity. vWF were not significantly different in relation to antiphospholipid antibodies nor the inflammation marker levels. TAT were significantly higher in patients with elevated aCL-IgM (> 30 MPL vs ≤ 30 MPL; p < 0.05). In one third of young patients with stable SLE, signs of endothelial activation/damage were found, as shown by elevated plasma ICAM-1 or vWF. Increased prothrombotic tendency manifested by elevated TAT was found in one fifth of the patients. Elevated anticardiolipin (IgM) and anti-β2-glycoprotein I (IgM) antibodies influence endothelial dysfunction and enhance prothrombotic state.


Atherosclerosis Autoimmune diseases Endothelial dysfunction Systemic lupus erythematosus 


Compliance with ethical standards

Before entering the study, each patient was informed about its aims and gave informed consent to participate. The study protocol was in line with the guidelines of the 1975 Declaration of Helsinki. The study obtained a positive opinion and approval from the Ethical Committee of the Jagiellonian University in Krakow.




  1. 1.
    Esdaile JM, Abrahamowicz M, Grodzicky T, Li Y, Panaritis C, Berger RD, Côte R, Grover SA, Fortin PR, Clarke AE, Senécal JL (2001) Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum 44:2331–2337CrossRefPubMedGoogle Scholar
  2. 2.
    O’Neill SG, Pego-Reigosa JM, Hingorani AD et al (2009) Use of a strategy based on calculated risk scores in managing cardiovascular risk factors in a large British cohort of patients with systemic lupus erythematosus. Rheumatology (Oxford) 48:573–575. CrossRefGoogle Scholar
  3. 3.
    Petri M, Spence D, Bone LR, Hochberg MC (1992) Coronary artery disease risk factors in the Johns Hopkins lupus cohort: prevalence, recognition by patients, and preventive practices. Medicine (Baltimore) 71:291–302CrossRefGoogle Scholar
  4. 4.
    Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA, Jansen-McWilliams L, D’Agostino RB, Kuller LH (1997) Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham study. Am J Epidemiol 145:408–415CrossRefPubMedGoogle Scholar
  5. 5.
    Bulkley BH, Roberts WC (1975) The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy. A study of 36 necropsy patients. Am J Med 58:243–264CrossRefPubMedGoogle Scholar
  6. 6.
    Haider YS, Roberts WC (1981) Coronary arterial disease in systemic lupus erythematosus; quantification of degrees of narrowing in 22 necropsy patients (21 women) aged 16 to 37 years. Am J Med 70:775–781CrossRefPubMedGoogle Scholar
  7. 7.
    Gustafsson JT, Simard JF, Gunnarsson I, Elvin K, Lundberg IE, Hansson LO, Larsson A, Svenungsson E (2012) Risk factors for cardiovascular mortality in patients with systemic lupus erythematosus, a prospective cohort study. Arthritis Res Ther 14:R46. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ballocca F, D’Ascenzo F, Moretti C, Omedè P, Cerrato E, Barbero U, Abbate A, Bertero MT, Zoccai GB, Gaita F (2015) Predictors of cardiovascular events in patients with systemic lupus erythematosus (SLE): a systematic review and meta-analysis. Eur J Prev Cardiol 22:1435–1441. CrossRefPubMedGoogle Scholar
  9. 9.
    Bruce IN (2005) “Not only … but also”: factors that contribute to accelerated atherosclerosis and premature coronary heart disease in systemic lupus erythematosus. Rheumatology (Oxford) 44:1492–1502. CrossRefGoogle Scholar
  10. 10.
    Hamsten A (1993) The hemostatic system and coronary heart disease. Thromb Res 70:1–38CrossRefPubMedGoogle Scholar
  11. 11.
    Haq I, Isenberg DA (2002) How does one assess and monitor patients with systemic lupus erythematosus in daily clinical practice? Best Pract Res Clin Rheumatol 16:181–194. CrossRefPubMedGoogle Scholar
  12. 12.
    Merrill JT (2002) Measuring disease activity in systemic lupus: progress and problems. J Rheumatol 29:2256–2257PubMedGoogle Scholar
  13. 13.
    Yee C-S, Farewell V, Isenberg DA, Rahman A, Teh LS, Griffiths B, Bruce IN, Ahmad Y, Prabu A, Akil M, McHugh N, D'Cruz D, Khamashta MA, Maddison P, Gordon C (2007) British isles lupus assessment group 2004 index is valid for assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 56:4113–4119. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Yee C-S, McElhone K, Teh L-S, Gordon C (2009) Assessment of disease activity and quality of life in systemic lupus erythematosus—new aspects. Best Pract Res Clin Rheumatol 23:457–467. CrossRefPubMedGoogle Scholar
  15. 15.
    Swadzba J, De Clerck LS, Stevens WJ et al (1997) Anticardiolipin, anti-beta(2)-glycoprotein I, antiprothrombin antibodies, and lupus anticoagulant in patients with systemic lupus erythematosus with a history of thrombosis. J Rheumatol 24:1710–1715PubMedGoogle Scholar
  16. 16.
    Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, de Groot PG, Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis (2009) Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost 7:1737–1740. CrossRefPubMedGoogle Scholar
  17. 17.
    Miyakis S, Lockshin MD, Atsumi T et al (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4:295–306. CrossRefPubMedGoogle Scholar
  18. 18.
    Steiner S, Speidl WS, Pleiner J, Seidinger D, Zorn G, Kaun C, Wojta J, Huber K, Minar E, Wolzt M, Kopp CW (2005) Simvastatin blunts endotoxin-induced tissue factor in vivo. Circulation 111:1841–1846. CrossRefPubMedGoogle Scholar
  19. 19.
    Kälsch T, Nguyen XD, Elmas E, Grebert N, Süselbeck T, Klüter H, Borggrefe M, Dempfle CE (2006) Coagulation activation and expression of CD40 ligand on platelets upon in vitro lipopolysaccharide-challenge in patients with unstable angina. Int J Cardiol 111:217–223. CrossRefPubMedGoogle Scholar
  20. 20.
    Kälsch T, Elmas E, Nguyen XD et al (2005) Enhanced coagulation activation by in vitro lipopolysaccharide challenge in patients with ventricular fibrillation complicating acute myocardial infarction. J Cardiovasc Electrophysiol 16:858–863. CrossRefPubMedGoogle Scholar
  21. 21.
    Götz AK, Zahler S, Stumpf P, Welsch U, Becker BF (2005) Intracoronary formation and retention of micro aggregates of leukocytes and platelets contribute to postischemic myocardial dysfunction. Basic Res Cardiol 100:413–421. CrossRefPubMedGoogle Scholar
  22. 22.
    Davies MJ, Gordon JL, Gearing AJH, Pigott R, Woolf N, Katz D, Kyriakopoulos A (1993) The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis. J Pathol 171:223–229. CrossRefPubMedGoogle Scholar
  23. 23.
    Kim I, Moon S-O, Hoon Kim S, Jin Kim H, Soon Koh Y, Young Koh G (2001) Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-κB activation in endothelial cells. J Biol Chem 276:7614–7620. CrossRefPubMedGoogle Scholar
  24. 24.
    Kim K-J, Baek I-W, Yoon C-H et al (2017) Elevated levels of soluble CD40 ligand are associated with antiphospholipid antibodies in patients with systemic lupus erythematosus. Clin Exp RheumatolGoogle Scholar
  25. 25.
    Hwang SJ, Ballantyne CM, Sharrett AR, Smith LC, Davis CE, Gotto AM, Boerwinkle E (1997) Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study. Circulation 96:4219–4225CrossRefPubMedGoogle Scholar
  26. 26.
    Printseva OY, Peclo MM, Gown AM (1992) Various cell types in human atherosclerotic lesions express ICAM-1. Further immunocytochemical and immunochemical studies employing monoclonal antibody 10F3. Am J Pathol 140:889–896PubMedPubMedCentralGoogle Scholar
  27. 27.
    Miwa K, Igawa A, Inoue H (1997) Soluble E-selectin, ICAM-1 and VCAM-1 levels in systemic and coronary circulation in patients with variant angina. Cardiovasc Res 36:37–44CrossRefPubMedGoogle Scholar
  28. 28.
    Bowie EJ, Solberg LA, Fass DN et al (1986) Transplantation of normal bone marrow into a pig with severe von Willebrand’s disease. J Clin Invest 78:26–30. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Vischer UM (2006) von Willebrand factor, endothelial dysfunction, and cardiovascular disease. J Thromb Haemost 4:1186–1193. CrossRefPubMedGoogle Scholar
  30. 30.
    Methia N, André P, Denis CV, Economopoulos M, Wagner DD (2001) Localized reduction of atherosclerosis in von Willebrand factor-deficient mice. Blood 98:1424–1428CrossRefPubMedGoogle Scholar
  31. 31.
    Fuster V, Lie JT, Badimon L et al (1985) Spontaneous and diet-induced coronary atherosclerosis in normal swine and swine with von Willebrand disease. Arteriosclerosis 5:67–73CrossRefPubMedGoogle Scholar
  32. 32.
    Montoro-García S, Shantsila E, Lip GYH (2014) Potential value of targeting von Willebrand factor in atherosclerotic cardiovascular disease. Expert Opin Ther Targets 18:43–53. CrossRefPubMedGoogle Scholar
  33. 33.
    Sonneveld MAH, de Maat MPM, Leebeek FWG (2014) Von Willebrand factor and ADAMTS13 in arterial thrombosis: a systematic review and meta-analysis. Blood Rev 28:167–178. CrossRefPubMedGoogle Scholar
  34. 34.
    Spiel AO, Gilbert JC, Jilma B (2008) Von Willebrand factor in cardiovascular disease: focus on acute coronary syndromes. Circulation 117:1449–1459. CrossRefPubMedGoogle Scholar
  35. 35.
    Domingues V, Magder LS, Petri M (2016) Assessment of the independent associations of IgG, IgM and IgA isotypes of anticardiolipin with thrombosis in SLE. Lupus Sci Med 3:e000107. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    van Aken BE, den Heijer M, Bos GM, van Deventer S, Reitsma P (2000) Recurrent venous thrombosis and markers of inflammation. Thromb Haemost 83:536–539CrossRefPubMedGoogle Scholar
  37. 37.
    Devreese K, Peerlinck K, Hoylaerts MF (2010) Thrombotic risk assessment in the antiphospholipid syndrome requires more than the quantification of lupus anticoagulants. Blood 115:870–878. CrossRefPubMedGoogle Scholar
  38. 38.
    Cabral AR, Cabiedes J, Alarcón-Segovia D (1995) Antibodies to phospholipid-free beta 2-glycoprotein-I in patients with primary antiphospholipid syndrome. J Rheumatol 22:1894–1898PubMedGoogle Scholar
  39. 39.
    Cabiedes J, Cabral AR, Alarcón-Segovia D (1995) Clinical manifestations of the antiphospholipid syndrome in patients with systemic lupus erythematosus associate more strongly with anti-beta 2-glycoprotein-I than with antiphospholipid antibodies. J Rheumatol 22:1899–1906PubMedGoogle Scholar
  40. 40.
    Cabral AR, Amigo MC, Cabiedes J, Alarcon-Segovia D (1996) The antiphospholipid/cofactor syndromes: a primary variant with antibodies to beta 2-glycoprotein-I but no antibodies detectable in standard antiphospholipid assays. Am J Med 101:472–481CrossRefPubMedGoogle Scholar
  41. 41.
    Del Ross T, Ruffatti A, Cuffaro S et al (2015) The clinical relevance of the IgM isotype of antiphospholipid antibodies in the vascular antiphospholipid syndrome. Thromb Res 136:883–886. CrossRefPubMedGoogle Scholar
  42. 42.
    Lindner G, Funk G-C, Pfortmueller CA, Leichtle AB, Fiedler GM, Schwarz C, Exadaktylos AK, Puig S (2014) D-dimer to rule out pulmonary embolism in renal insufficiency. Am J Med 127:343–347. CrossRefPubMedGoogle Scholar
  43. 43.
    Thachil J, Fitzmaurice DA, Toh CH (2010) Appropriate use of D-dimer in hospital patients. Am J Med 123:17–19. CrossRefPubMedGoogle Scholar
  44. 44.
    Aguilar C, del Villar V (2005) Diagnostic performance of D-dimer is lower in elderly outpatients with suspected deep venous thrombosis. Br J Haematol 130:803–804; author reply 805. CrossRefPubMedGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  • Kamil Bugała
    • 1
    Email author
  • Adam Mazurek
    • 3
  • Krzysztof Gryga
    • 4
  • Monika Komar
    • 2
    • 3
  • Grzegorz Kopeć
    • 2
    • 3
  • Jacek Musiał
    • 2
    • 4
  • Piotr Podolec
    • 2
    • 3
  • Carlo Perricone
    • 5
  • Wojciech Płazak
    • 2
    • 3
  1. 1.Department for DiagnosisJohn Paul II HospitalKrakowPoland
  2. 2.Jagiellonian University Medical CollegeKrakowPoland
  3. 3.Department of Cardiac and Vascular DiseasesJohn Paul II HospitalKrakowPoland
  4. 4.Department of Internal MedicineJagiellonian University Medical CollegeKrakowPoland
  5. 5.Rheumatology Unit, Department of Internal MedicineSapienza University of RomeRomeItaly

Personalised recommendations