Skip to main content
Log in

Systemic Antiphospholipid Syndrome and Atherosclerosis

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

Atherosclerosis (AT) is a metabolic, systemic inflammatory/immune disease characterized by lipoproteins metabolism alteration that leads to immune/inflammatory system activation with the consequent proliferation of smooth-muscle cells, narrowing arteries and atheroma formation. Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombophilic state and circulating antiphospholipid antibodies (aPL) including anti β2-GPI. Experimental studies and human observations suggest that APS is associated with AT. In fact, innate and adaptive immune responses participate in the pathogenesis of both diseases. Anti-oxLDL, anti-aPL, anti β2GPI, anti-HSP antibodies, among others, has been found in patients with APS and AT. Endothelial dysfunctions, oxidative stress, increase of cell adhesion molecules, active platelets, are common findings in both diseases. Macrophages, dendritic cells, T-cell activation, CD40–CD40 ligand interaction, are considered as pathogenic mechanism of AT and APS. Premature AT may be the first symptom of APS. Thrombophilia, aPL antibodies, and APS may be present in patients with premature AT. An association between AT and venous thrombosis (a clinical hallmark of APS) has been proposed in unselected patients with deep venous thrombosis of the legs without symptomatic AT. Asymptomatic AT, defined in terms of carotid intima media thickness and lumen diameter decrease, was observed in patients with APS. Premenopausal female patients with PAPS have a higher prevalence of cerebrovascular disease in comparison with male patients. Accelerated AT and hormones could be the explanation of these findings. High levels of aCLs, significantly predict the risk of future ischemic stroke in women but not in men. AT is one of the main features of systemic APS and offer opportunities for new treatment strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Ross R (1999) Atherosclerosis: an inflammatory disease. N Engl J Med 340:115–126

    Article  PubMed  CAS  Google Scholar 

  2. Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685–1695

    Article  PubMed  CAS  Google Scholar 

  3. Jara LJ, Medina G, Vera-Lastra O, Amigo MC (2006) Accelerated atherosclerosis, immune response and autoimmune rheumatic diseases. Autoimmun Rev 5:195–201

    Article  PubMed  Google Scholar 

  4. Shoenfeld Y, Gerli R, Doria A, Matsuura E, Cerinic MM, Ronda N et al (2005) Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation 112:3337–3347

    Article  PubMed  Google Scholar 

  5. Sherer Y, Shoenfeld Y (2002) Atherosclerosis. Ann Rheum Dis 61:97–99

    Article  PubMed  CAS  Google Scholar 

  6. Vlachoyiannopoulos PG, Samarkos M (2004) Peripheral vascular disease in antiphospholipid syndrome. Thromb Res 114:509–519

    Article  PubMed  CAS  Google Scholar 

  7. Vaarala O (1996) Antiphospholipid antibodies and atherosclerosis. Lupus 5:442–447

    PubMed  CAS  Google Scholar 

  8. Vaarala O, Puurunen M, Lukka M, Alfthan G, Leirisalo-Repo M, Aho K et al (1996) Affinity-purified cardiolipin-binding antibodies show heterogeneity in their binding to oxidized low-density lipoprotein. Clin Exp Immunol 104:269–274

    Article  PubMed  CAS  Google Scholar 

  9. Horkko S, Miller E, Dudl E, Reaven P, Curtiss LK, Zvaifler NJ et al (1996) Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein. J Clin Invest 98:815–825

    PubMed  CAS  Google Scholar 

  10. George J, Afek A, Gilburd B, Levy Y, Blank M, Kopolovic J et al (1997) Atherosclerosis in LDL-receptor knockout mice is accelerated by immunization with anticardiolipin antibodies. Lupus 6:723–729

    PubMed  CAS  Google Scholar 

  11. Hasunuma Y, Matsuura E, Makita Z, Katahira T, Nishi S, Koike T (1997) Involvement of beta 2-glycoprotein I and anticardiolipin antibodies in oxidatively modified low-density lipoprotein uptake by macrophages. Clin Exp Immunol 107:569–573

    Article  PubMed  CAS  Google Scholar 

  12. George J, Haratz D, Shoenfeld Y (2001) Accelerated atheroma, antiphospholipid antibodies, and the antiphospholipid syndrome. Rheum Dis Clin North Am 27:603–610

    Article  PubMed  CAS  Google Scholar 

  13. George J, Shoenfeld Y, Harats D (1999) The involvement of beta2-glycoprotein I (beta2-GPI) in human and murine atherosclerosis. J Autoimmun 13:57–60

    Article  PubMed  CAS  Google Scholar 

  14. George J, Yacov N, Breitbart E, Bangio L, Shaish A, Gilburd B et al (2004) Suppression of early atherosclerosis in LDL-receptor deficient mice by oral tolerance with beta 2-glycoprotein I. Cardiovasc Res 62:603–609

    Article  PubMed  CAS  Google Scholar 

  15. Groyer E, Caligiuri G, Laschet-Khallou J, Nicoletti A (2006) Immunological aspects of atherosclerosis. Presse Med 35:475–486

    PubMed  Google Scholar 

  16. George J, Harats D, Gilburd B, Afek A, Shaish A, Kopolovic J et al (2000) Adoptive transfer of beta(2)-glycoprotein I-reactive lymphocytes enhances early atherosclerosis in LDL receptor-deficient mice. Circulation 102:1822–1827

    PubMed  CAS  Google Scholar 

  17. Blank M, Krause I, Lanir N, Vardi P, Gilburd B, Tincani A et al (1995) Transfer of experimental antiphospholipid syndrome by bone marrow cell transplantation. The importance of the T cell. Arthritis Rheum 38:115–122

    Article  PubMed  CAS  Google Scholar 

  18. Visvanathan S, McNeil HP (1999) Cellular immunity to beta 2-glycoprotein-1 in patients with the antiphospholipid syndrome. J Immunol 162:6919–6925

    PubMed  CAS  Google Scholar 

  19. Hattori N, Kuwana M, Kaburaki J, Mimori T, Ikeda Y, Kawakami Y (2000) T cells that are autoreactive to beta2-glycoprotein I in patients with antiphospholipid syndrome and healthy individuals. Arthritis Rheum 43:65–75

    Article  PubMed  CAS  Google Scholar 

  20. Ito H, Matsushita S, Tokano Y, Nishimura H, Tanaka Y, Fujisao S et al (2000) Analysis of T cell responses to the beta 2-glycoprotein I-derived peptide library in patients with anti-beta 2-glycoprotein I antibody-associated autoimmunity. Hum Immunol 61:366–377

    Article  PubMed  CAS  Google Scholar 

  21. Karakantza M, Theodorou GL, Meimaris N, Mouzaki A, John E, Andonopoulos AP et al (2004) Type 1 and type 2 cytokine-producing CD4+ and CD8+ T cells in primary antiphospholipid syndrome. Ann Hematol 83:704–711

    Article  PubMed  CAS  Google Scholar 

  22. Arai T, Yoshida K, Kaburaki J, Inoko H, Ikeda Y, Kawakami Y et al (2001) Autoreactive CD4(+) T-cell clones to beta2-glycoprotein I in patients with antiphospholipid syndrome: preferential recognition of the major phospholipid-binding site. Blood 98:1889–1896

    Article  PubMed  CAS  Google Scholar 

  23. Kuwana M (2004) Beta2-glycoprotein I: antiphospholipid syndrome and T-cell reactivity. Thromb Res 114:347–355

    Article  PubMed  CAS  Google Scholar 

  24. Yoshida K, Arai T, Kaburaki J, Ikeda Y, Kawakami Y, Kuwana M (2002) Restricted T-cell receptor beta-chain usage by T cells autoreactive to beta(2)-glycoprotein I in patients with antiphospholipid syndrome. Blood 99:2499–2504

    Article  PubMed  CAS  Google Scholar 

  25. Fischer K, Collins H, Taniguchi M, Kaufmann SH, Schaible UE (2002) IL-4 and T cells are required for the generation of IgG1 isotype antibodies against cardiolipin. J Immunol 168:2689–2694

    PubMed  CAS  Google Scholar 

  26. Ames PR, Tommasino C, Fossati G, Matsuura E, Margarita A, Saulino A et al (2005) Lymphocyte subpopulations and intima media thickness in primary antiphospholipid syndrome. Lupus 14:809–813

    Article  PubMed  CAS  Google Scholar 

  27. Shortell CK, Ouriel K, Green RM, Condemi JJ, DeWeese JA (1992) Vascular disease in the antiphospholipid syndrome: a comparison with the patient population with atherosclerosis. J Vasc Surg 15:158–165

    Article  PubMed  CAS  Google Scholar 

  28. Levy PJ, Cooper CF, Gonzalez MF (1995) Massive lower extremity arterial thrombosis and acute hepatic insufficiency in a young adult with premature atherosclerosis associated with hyperlipoprotein(a)emia and antiphospholipid syndrome. A case report. Angiology 46:853–858

    Article  PubMed  CAS  Google Scholar 

  29. Spronk PE, Overbosch EH, Scut NH (2001) Severe atherosclerotic changes including aortic occlusion , associated with hyperhomocysteinaemia and antiphospholipid antibodies. Ann Rheum Dis 60:699–701

    Article  PubMed  CAS  Google Scholar 

  30. Evans SM, Brittenden J, Adam DJ, Ludlam C, Bradbury AW (1999) Vascular surgical society of Great Britain and Ireland: prevalence and significance of thrombophilia in patients with intermittent claudication. Br J Surg 86:702–703

    Article  PubMed  Google Scholar 

  31. Rosove MH, Brewer PM (1992) Antiphospholipid thrombosis. Clinical course after the first thrombotic event in 70 patients. Annals Int Med 117:303–308

    CAS  Google Scholar 

  32. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR (1995) The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 332(15):993–997

    Article  PubMed  CAS  Google Scholar 

  33. Gomez-Puerta JA, Martin H, Amigo MC, Aguirre MA, Camps MT, Cuadrado MJ et al (2005) Long-term follow-up in 128 patients with primary antiphospholipid syndrome: do they develop lupus? Medicine (Baltimore) 84:225–230

    Article  Google Scholar 

  34. Medina G, Vera-Lastra O, Angeles U, Jara LJ (2005) Mono-organic versus multi-organic involvement in primary antiphospholipid syndrome. Ann N Y Acad Sci 1051:304–312

    Article  PubMed  CAS  Google Scholar 

  35. Lopez LR, Dier KJ, Lopez D, Merrill JT, Fink CA (2004) Anti-beta 2-glycoprotein I and antiphosphatidylserine antibodies are predictors of arterial thrombosis in patients with antiphospholipid syndrome. Am J Clin Pathol 121:142–149

    Article  PubMed  CAS  Google Scholar 

  36. Lopez D, Kobayashi K, Merrill JT, Matsuura E, Lopez LR (2003) IgG autoantibodies against beta2-glycoprotein I complexed with a lipid ligand derived from oxidized low-density lipoprotein are associated with arterial thrombosis in antiphospholipid syndrome. Clin Dev Immunol 10:203–211

    Article  PubMed  CAS  Google Scholar 

  37. Ames PR, Delgado Alves J, Lopez LR, Gentile F, Margarita A, Pizzella L et al (2006) Antibodies against beta2-glycoprotein I complexed with an oxidised lipoprotein relate to intima thickening of carotid arteries in primary antiphospholipid syndrome. Clin Dev Immunol 13:1–9

    Article  PubMed  CAS  Google Scholar 

  38. Prandoni P, Bilora F, Marchiori A, Bernardi E, Petrobelli F, Lensing AW et al (2003) An association between atherosclerosis and venous thrombosis. N Engl J Med 348:1435–1441

    Article  PubMed  Google Scholar 

  39. Sueishi K, Ichikawa K, Kato K, Nakagawa K, Chen YX (1998) Atherosclerosis: coagulation and fibrinolysis. Semin Thromb Hemost 24:255–260

    Article  PubMed  CAS  Google Scholar 

  40. Sailer T, Vormittag R, Pabinger I, Vukovich T, Lehr S, Quehenberger P et al (2005) Inflammation in patients with lupus anticoagulant and implications for thrombosis. J Rheumatol 32:397–399

    Google Scholar 

  41. Wakefield TW, Henke PK (2005) The role of inflammation in early and late venous thrombosis: are there clinical implications? Semin Vasc Surg 18:118–129

    Article  PubMed  Google Scholar 

  42. Fox EA, Kahn SR (2005) The relationship between inflammation and venous thrombosis. A systematic review of clinical studies. Thromb Haemost 94:362–365

    PubMed  CAS  Google Scholar 

  43. Vlachoyiannopoulus PG, Kanellopoulus PG, Ioannidis JP, Tektonidou MG, Mastorakou I, Moutsopoulos HM (2003) Atherosclerosis in premenopausal women with antiphospholipid syndrome and systemic lupus erythematosus: a controlled study. Rheumatology 42:645–651

    Article  CAS  Google Scholar 

  44. Medina G, Casaos D, Jara LJ, Vera-Lastra O, Fuentes M, Barile L et al (2003) Increased carotid artery intima-media thickness may be associated with stroke in primary antiphospholipid syndrome. Ann Rheum Dis 62:607–610

    Article  PubMed  CAS  Google Scholar 

  45. Ames PR, Margarita A, Delgado Alves J, Tommasino C, Iannaccone L, Brancaccio V (2002) Anticardiolipin antibody titre and plasma homocysteine level independently predict intima media thickness of carotid arteries in subjects with idiopathic antiphospholipid antibodies. Lupus 11:208–214

    Article  PubMed  CAS  Google Scholar 

  46. Ames PRJ, Margarita A, Sokoll KB, Weston M, Brancaccio V (2005) Premature atherosclerosis in primary antiphospholipid syndrome: preliminary data. Ann Rheum Dis 64:315–317

    Article  PubMed  CAS  Google Scholar 

  47. Jara LJ, Medina G, Vera-Lastra O, Barile L (2005) The impact of gender on clinical manifestations of primary antiphospholipid syndrome. Lupus 14:607–612

    Article  PubMed  CAS  Google Scholar 

  48. Janardhan V, Wolf PA, Kase CS, Massaro JM, D’Agostino RB, Franzblau C et al (2004) Anticardiolipin antibodies and risk of ischemic stroke and transient ischemic attack: the Framingham cohort and offspring study. Stroke 35:736–741

    Article  PubMed  Google Scholar 

  49. Jimenez S, Garcia-Criado MA, Tassies D, Reverter JC, Cervera R, Gilabert MR et al (2005) Preclinical vascular disease in systemic lupus erythematosus and primary antiphospholipid syndrome. Rheumatology (Oxford) 44:756–761

    Article  Google Scholar 

  50. Baron MA, Khamashta MA, Hughes GR, D’Cruz DP (2005) Prevalence of an abnormal ankle-brachial index in patients with primary antiphospholipid syndrome: preliminary data. Ann Rheum Dis 64:144–146

    Article  PubMed  CAS  Google Scholar 

  51. Stalc M, Poredos P, Peternel P, Tomsic M, Sebestjen M, Kveder T (2006) Endothelial function is impaired in patients with primary antiphospholipid syndrome. Thromb Res 118(4):455–461

    Article  PubMed  CAS  Google Scholar 

  52. Vargas A, Ricalde A, Meave A, Vera-Lastra O, Vargas AR, Medina G et al (2004) Endothelial dysfunction in patients with primary antiphospholipid syndrome (APS) demonstrated with positron emission tomography. Arthritis Rheum 50(Suppl):S74

    Google Scholar 

  53. Espinola-Zavaleta N, Alexanderson-Rosas E, Granados N, Elena Soto M, Amigo MC (2006) Myocardial perfusion defects in patients with autoimmune diseases: a prospective study. Analysis of two diagnostic tests. Lupus 15:38–43

    Article  PubMed  CAS  Google Scholar 

  54. Medina-García G, Molina-Carrión LE, Angeles-Garay U, Vera-Lastra O, Jara-Quezada LJ (2006) Cerebral flow abnormalities in primary antiphospholipid syndrome patients demonstrated by transcranial doppler. A controlled study. J Rheumatol 33:424 (Abstract 73)

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Luis J. Jara.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jara, L.J., Medina, G. & Vera-Lastra, O. Systemic Antiphospholipid Syndrome and Atherosclerosis. Clinic Rev Allerg Immunol 32, 172–177 (2007). https://doi.org/10.1007/s12016-007-0008-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-007-0008-9

Keywords

Navigation