Semin Thromb Hemost 2009; 35(7): 621-629
DOI: 10.1055/s-0029-1242716
© Thieme Medical Publishers

Thrombosis in Systemic Lupus Erythematosus

Anita Palatinus1 , Murray Adams1
  • 1School of Human Life Sciences, University of Tasmania, Tasmania, Australia
Further Information

Publication History

Publication Date:
09 December 2009 (online)

ABSTRACT

Systemic lupus erythematosus (SLE) is a potentially fatal multiorgan inflammatory disease that primarily affects females. Due to the heterogeneity of clinical manifestations and lack of laboratory tests that are both specific and sensitive for the disease, diagnosis of SLE can often be difficult. Although the precise etiology remains to be fully elucidated, it is probable that various environmental, genetic, and hormonal factors contribute to the development of the disease. Patients with SLE have an increased risk for premature thrombosis and/or atherosclerosis, with up to half experiencing a thrombotic event. Furthermore, antiphospholipid antibodies probably play a key role in the development of thrombosis by affecting various hemostatic protein interactions with phospholipids and cell surfaces as well as platelet function. Despite recent advances in knowledge related to the factors that contribute to the pathophysiology of SLE, numerous challenges related to earlier diagnosis as well as the prediction and prevention of thrombotic events remain to be fully addressed.

REFERENCES

  • 1 Swigris J J, Fischer A, Gillis J, Meehan R T, Brown K K. Pulmonary and thrombotic manifestations of systemic lupus erythematosus.  Chest. 2008;  133(1) 271-280
  • 2 Cervera R, Khamashta M A, Font J European Working Party on Systemic Lupus Erythematosus et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients.  Medicine (Baltimore). 2003;  82(5) 299-308
  • 3 Cervera R, Khamashta M A, Font J European Working Party on Systemic Lupus Erythematosus et al. Morbidity and mortality in systemic lupus erythematosus during a 5-year period. A multicenter prospective study of 1,000 patients.  Medicine (Baltimore). 1999;  78(3) 167-175
  • 4 McClain M T, Arbuckle M R, Heinlen L D et al.. The prevalence, onset, and clinical significance of antiphospholipid antibodies prior to diagnosis of systemic lupus erythematosus.  Arthritis Rheum. 2004;  50(4) 1226-1232
  • 5 Asherson R A. The primary, secondary, catastrophic, and seronegative variants of the antiphospholipid syndrome: a personal history long in the making.  Semin Thromb Hemost. 2008;  34(3) 227-235
  • 6 Danchenko N, Satia J A, Anthony M S. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden.  Lupus. 2006;  15(5) 308-318
  • 7 D'Cruz D P. Systemic lupus erythematosus.  BMJ. 2006;  332(7546) 890-894
  • 8 Petri M. Sex hormones and systemic lupus erythematosus.  Lupus. 2008;  17(5) 412-415
  • 9 Rahman A, Isenberg D. Systemic lupus erythematosus.  N Engl J Med. 2008;  358 929-939
  • 10 Mills J A. Systemic lupus erythematosus.  N Engl J Med. 1994;  330(26) 1871-1879
  • 11 Panjwani S. Early diagnosis and treatment of discoid lupus erythematosus.  J Am Board Fam Med. 2009;  22(2) 206-213
  • 12 van Vugt R M, Derksen R H, Kater L, Bijlsma J W. Deforming arthropathy or lupus and rhupus hands in systemic lupus erythematosus.  Ann Rheum Dis. 1998;  57(9) 540-544
  • 13 Wang Z, Tang Z, Zhang H T, Hu W X, Liu Z H, Li L S. Clinicopathological characteristics of familial SLE patients with lupus nephritis.  Lupus. 2009;  18(3) 243-248
  • 14 Mosley K, Tam F W, Edwards R J, Crozier J, Pusey C D, Lightstone L. Urinary proteomic profiles distinguish between active and inactive lupus nephritis.  Rheumatology (Oxford). 2006;  45(12) 1497-1504
  • 15 Cervera R, Font J, Paré C et al.. Cardiac disease in systemic lupus erythematosus: prospective study of 70 patients.  Ann Rheum Dis. 1992;  51(2) 156-159
  • 16 Frostegård J. Systemic lupus erythematosus and cardiovascular disease.  Lupus. 2008;  17(5) 364-367
  • 17 Hahn B H. Systemic lupus erythematosus and accelerated atherosclerosis.  N Engl J Med. 2003;  349(25) 2379-2380
  • 18 Salmon J E, de Groot P G. Pathogenic role of antiphospholipid antibodies.  Lupus. 2008;  17(5) 405-411
  • 19 Kim S Y, Lee J H. Prognosis of neonates in pregnant women with systemic lupus erythematosus.  Yonsei Med J. 2008;  49(4) 515-520
  • 20 Yan Yuen S, Krizova A, Ouimet J M, Pope J E. Pregnancy outcome in systemic lupus erythematosus (SLE) is improving: results from a case control study and literature review.  Open Rheumatol J. 2008;  2 89-98
  • 21 Doria A, Tincani A, Lockshin M. Challenges of lupus pregnancies.  Rheumatology (Oxford). 2008;  47(Suppl 3) iii9-iii12
  • 22 Ginsberg J S, Brill-Edwards P, Johnston M et al.. Relationship of antiphospholipid antibodies to pregnancy loss in patients with systemic lupus erythematosus: a cross-sectional study.  Blood. 1992;  80(4) 975-980
  • 23 Giannouli S, Voulgarelis M, Ziakas P D, Tzioufas A G. Anaemia in systemic lupus erythematosus: from pathophysiology to clinical assessment.  Ann Rheum Dis. 2006;  65(2) 144-148
  • 24 Voulgarelis M, Kokori S I, Ioannidis J P, Tzioufas A G, Kyriaki D, Moutsopoulos H M. Anaemia in systemic lupus erythematosus: aetiological profile and the role of erythropoietin.  Ann Rheum Dis. 2000;  59(3) 217-222
  • 25 Kuwana M, Kaburaki J, Okazaki Y, Miyazaki H, Ikeda Y. Two types of autoantibody-mediated thrombocytopenia in patients with systemic lupus erythematosus.  Rheumatology (Oxford). 2006;  45(7) 851-854
  • 26 Criswell L A. The genetic contribution to systemic lupus erythematosus.  Bull NYU Hosp Jt Dis. 2008;  66(3) 176-183
  • 27 Cooper G S, Gilbert K M, Greidinger E L et al.. Recent advances and opportunities in research on lupus: environmental influences and mechanisms of disease.  Environ Health Perspect. 2008;  116(6) 695-702
  • 28 Cross L S, Aslam A, Misbah S A. Antinuclear antibody-negative lupus as a distinct diagnostic entity—does it no longer exist?.  QJM. 2004;  97(5) 303-308
  • 29 Reichlin M. ANA negative systemic lupus erythematosus sera revisited serologically.  Lupus. 2000;  9(2) 116-119
  • 30 Witte T, Hartung K, Sachse C SLE Study Group et al. IgM anti-dsDNA antibodies in systemic lupus erythematosus: negative association with nephritis.  Rheumatol Int. 1998;  18(3) 85-91
  • 31 Koffler D, Agnello V, Kimkel H G. Polynucleotide immune complexes in serum and glomeruli of patients with systemic lupus erythematosus.  Am J Pathol. 1974;  74(1) 109-124
  • 32 Tsao B P, Ebling F M, Roman C, Panosian-Sahakian N, Calame K, Hahn B H. Structural characteristics of the variable regions of immunoglobulin genes encoding a pathogenic autoantibody in murine lupus.  J Clin Invest. 1990;  85(2) 530-540
  • 33 Satoh M, Kumar A, Kanwar Y S, Reeves W H. Anti-nuclear antibody production and immune-complex glomerulonephritis in BALB/c mice treated with pristane.  Proc Natl Acad Sci U S A. 1995;  92(24) 10934-10938
  • 34 Ruiz-Irastorza G, Egurbide M V, Martinez-Berriotxoa A, Ugalde J, Aguirre C. Antiphospholipid antibodies predict early damage in patients with systemic lupus erythematosus.  Lupus. 2004;  13(12) 900-905
  • 35 Miyakis S, Lockshin M D, Atsumi T et al.. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).  J Thromb Haemost. 2006;  4(2) 295-306
  • 36 Swadzba J, De Clerck L S, Stevens W J et al.. Anticardiolipin, anti-beta(2)-glycoprotein I, antiprothrombin antibodies, and lupus anticoagulant in patients with systemic lupus erythematosus with a history of thrombosis.  J Rheumatol. 1997;  24(9) 1710-1715
  • 37 Oosting J D, Derksen R H, Bobbink I W, Hackeng T M, Bouma B N, de Groot P G. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism?.  Blood. 1993;  81(10) 2618-2625
  • 38 Favaloro E J, Wong R C. Laboratory testing and identification of antiphospholipid antibodies and the antiphospholipid syndrome: a potpourri of problems, a compilation of possible solutions.  Semin Thromb Hemost. 2008;  34(4) 389-410
  • 39 Feinbloom D, Bauer K A. Assessment of hemostatic risk factors in predicting arterial thrombotic events.  Arterioscler Thromb Vasc Biol. 2005;  25(10) 2043-2053
  • 40 Toloza S M, Uribe A G, McGwin Jr G LUMINA Study Group et al. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXIII. Baseline predictors of vascular events.  Arthritis Rheum. 2004;  50(12) 3947-3957
  • 41 Manzi S, Meilahn E N, Rairie J E 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
  • 42 Ho K T, Ahn C W, Alarcón G S et al.. Systemic lupus erythematosus in a multiethnic cohort (LUMINA): XXVIII. Factors predictive of thrombotic events.  Rheumatology (Oxford). 2005;  44(10) 1303-1307
  • 43 Love P E, Santoro S A. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance.  Ann Intern Med. 1990;  112(9) 682-698
  • 44 Kaiser R, Cleveland C M, Criswell L A. Risk and protective factors for thrombosis in systemic lupus erythematosus: results from a large, multi-ethnic cohort.  Ann Rheum Dis. 2009;  68(2) 238-241
  • 45 Arnout J, Vermylen J. Current status and implications of autoimmune antiphospholipid antibodies in relation to thrombotic disease.  J Thromb Haemost. 2003;  1(5) 931-942
  • 46 Sallai K K, Nagy E, Bodó I, Mohl A, Gergely P. Thrombosis risk in systemic lupus erythematosus: the role of thrombophilic risk factors.  Scand J Rheumatol. 2007;  36(3) 198-205
  • 47 Kinev A V, Roubey R A. Tissue factor in the antiphospholipid syndrome.  Lupus. 2008;  17(10) 952-958
  • 48 Tektonidou M G, Laskari K, Panagiotakos D B, Moutsopoulos H M. Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies.  Arthritis Rheum. 2009;  61(1) 29-36
  • 49 Khamashta M A, Cuadrado M J, Mujic F, Taub N A, Hunt B J, Hughes G R. The management of thrombosis in the antiphospholipid-antibody syndrome.  N Engl J Med. 1995;  332(15) 993-997
  • 50 Rosove M H, Brewer P M. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients.  Ann Intern Med. 1992;  117(4) 303-308
  • 51 Anders H J. Predicting thrombosis in systemic lupus erythematosus.  Nat Clin Pract Nephrol. 2009;  5(2) 68-69
  • 52 Wu H, Birmingham D J, Rovin B et al.. D-dimer level and the risk for thrombosis in systemic lupus erythematosus.  Clin J Am Soc Nephrol. 2008;  3(6) 1628-1636
  • 53 Forastiero R R, Martinuzzo M E, de Larrañaga G F. Circulating levels of tissue factor and proinflammatory cytokines in patients with primary antiphospholipid syndrome or leprosy related antiphospholipid antibodies.  Lupus. 2005;  14(2) 129-136
  • 54 Nemerson Y. Tissue factor and hemostasis.  Blood. 1988;  71(1) 1-8
  • 55 de Prost D, Ollivier V, Ternisien C, Chollet-Martin S. Increased monocyte procoagulant activity independent of the lupus anticoagulant in patients with systemic lupus erythematosus.  Thromb Haemost. 1990;  64(2) 216-221
  • 56 Zhou H, Wolberg A S, Roubey R A. Characterization of monocyte tissue factor activity induced by IgG antiphospholipid antibodies and inhibition by dilazep.  Blood. 2004;  104(8) 2353-2358
  • 57 Martini F, Farsi A, Gori A M et al.. Antiphospholipid antibodies (aPL) increase the potential monocyte procoagulant activity in patients with systemic lupus erythematosus.  Lupus. 1996;  5(3) 206-211
  • 58 Forastiero R R, Martinuzzo M E, Broze G J. High titers of autoantibodies to tissue factor pathway inhibitor are associated with the antiphospholipid syndrome.  J Thromb Haemost. 2003;  1(4) 718-724
  • 59 Adams M, Breckler L, Stevens P, Thom J, Baker R, Oostryck R. Anti-tissue factor pathway inhibitor activity in subjects with antiphospholipid syndrome is associated with increased thrombin generation.  Haematologica. 2004;  89(8) 985-990
  • 60 Lean S Y, Ellery P, Ivey L et al.. The effects of tissue factor pathway inhibitor and anti-beta-2-glycoprotein-I IgG on thrombin generation.  Haematologica. 2006;  91(10) 1360-1366
  • 61 Roubey R A. Mechanisms of autoantibody-mediated thrombosis.  Lupus. 1998;  7(Suppl 2) S114-S119
  • 62 Galli M, Ruggeri L, Barbui T. Differential effects of anti-beta2-glycoprotein I and antiprothrombin antibodies on the anticoagulant activity of activated protein C.  Blood. 1998;  91(6) 1999-2004
  • 63 Pierangeli S, Mariano E, Vega-Ostertag M et al.. New targeted therapies for treatment of thrombosis in antiphospholipid syndrome.  Expert Rev Mol Med. 2007;  9 1-15
  • 64 Roubey R A. Autoantibodies to phospholipid-binding plasma proteins: a new view of lupus anticoagulants and other “antiphospholipid” autoantibodies.  Blood. 1994;  84(9) 2854-2867
  • 65 Nojima J, Kuratsune H, Suehisa E, Iwatani Y, Kanakura Y. Acquired activated protein C resistance associated with IgG antibodies against beta2-glycoprotein I and prothrombin as a strong risk factor for venous thromboembolism.  Clin Chem. 2005;  51(3) 545-552
  • 66 Ekdahl K N, Bengtsson A A, Andersson J et al.. Thrombotic disease in systemic lupus erythematosus is associated with a maintained systemic platelet activation.  Br J Haematol. 2004;  125(1) 74-78
  • 67 Lutters B C, Derksen R H, Tekelenburg W L, Lenting P J, Arnout J, de Groot P G. Dimers of beta 2-glycoprotein I increase platelet deposition to collagen via interaction with phospholipids and the apolipoprotein E receptor 2′.  J Biol Chem. 2003;  278(36) 33831-33838
  • 68 Urbanus R T, Derksen R H, de Groot P G. Platelets and the antiphospholipid syndrome.  Lupus. 2008;  17(10) 888-894
  • 69 Dhar J P, Andersen J, Essenmacher L, Ager J, Bentley G, Sokol R J. Thrombophilic patterns of coagulation factors in lupus.  Lupus. 2009;  18(5) 400-406
  • 70 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
  • 71 Danese S, de la Motte C, Reyes B M, Sans M, Levine A D, Fiocchi C. Cutting edge: T cells trigger CD40-dependent platelet activation and granular RANTES release: a novel pathway for immune response amplification.  J Immunol. 2004;  172(4) 2011-2015
  • 72 Joseph J E, Harrison P, Mackie I J, Isenberg D A, Machin S J. Increased circulating platelet-leucocyte complexes and platelet activation in patients with antiphospholipid syndrome, systemic lupus erythematosus and rheumatoid arthritis.  Br J Haematol. 2001;  115(2) 451-459
  • 73 Nojima J, Kuratsune H, Suehisa E, Kitani T, Iwatani Y, Kanakura Y. Strong correlation between the prevalence of cerebral infarction and the presence of anti-cardiolipin/beta2-glycoprotein I and anti-phosphatidylserine/prothrombin antibodies—co-existence of these antibodies enhances ADP-induced platelet activation in vitro.  Thromb Haemost. 2004;  91(5) 967-976
  • 74 Jankowski M, Vreys I, Wittevrongel C et al.. Thrombogenicity of beta 2-glycoprotein I-dependent antiphospholipid antibodies in a photochemically induced thrombosis model in the hamster.  Blood. 2003;  101(1) 157-162
  • 75 Dorsch C, Meyerhoff J. Elevated plasma beta-thromboglobulin levels in systemic lupus erythematosus.  Thromb Res. 1980;  20(5-6) 617-622
  • 76 Ekdahl K N, Rönnblom L, Sturfelt G, Nilsson B. 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(12) 2178-2186
  • 77 Lockshin M D. Update on antiphospholipid syndrome.  Bull NYU Hosp Jt Dis. 2008;  66(3) 195-197
  • 78 Afeltra A, Vadacca M, Conti L et al.. Thrombosis in systemic lupus erythematosus: congenital and acquired risk factors.  Arthritis Rheum. 2005;  53(3) 452-459
  • 79 Lincz L F, Adams M J, Scorgie F E, Thom J, Baker R I, Seldon M. Polymorphisms of the tissue factor pathway inhibitor gene are associated with venous thromboembolism in the antiphospholipid syndrome and carriers of factor V Leiden.  Blood Coagul Fibrinolysis. 2007;  18(6) 559-564
  • 80 Tan E M, Cohen A S, Fries J F et al.. The 1982 revised criteria for the classification of systemic lupus erythematosus.  Arthritis Rheum. 1982;  25(11) 1271-1277
  • 81 Gill J M, Quisel A M, Rocca P V, Walters D T. Diagnosis of systemic lupus erythematosus.  Am Fam Physician. 2003;  68(11) 2179-2186
  • 82 Hochberg M C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.  Arthritis Rheum. 1997;  40(9) 1725
  • 83 Fernando M M, Stevens C R, Sabeti P C et al.. Identification of two independent risk factors for lupus within the MHC in United Kingdom families.  PLoS Genet. 2007;  3(11) e192
  • 84 Graham R R, Ortmann W, Rodine P et al.. Specific combinations of HLA-DR2 and DR3 class II haplotypes contribute graded risk for disease susceptibility and autoantibodies in human SLE.  Eur J Hum Genet. 2007;  15(8) 823-830
  • 85 Graham R R, Ortmann W A, Langefeld C D et al.. Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus.  Am J Hum Genet. 2002;  71(3) 543-553
  • 86 Walport M J. Complement and systemic lupus erythematosus.  Arthritis Res. 2002;  4(Suppl 3) S279-S293
  • 87 Prokunina L, Castillejo-López C, Oberg F et al.. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans.  Nat Genet. 2002;  32(4) 666-669
  • 88 Chung S A, Criswell L A. PTPN22: its role in SLE and autoimmunity.  Autoimmunity. 2007;  40(8) 582-590
  • 89 Kyogoku C, Langefeld C D, Ortmann W A et al.. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE.  Am J Hum Genet. 2004;  75(3) 504-507
  • 90 Graham R R, Kozyrev S V, Baechler E C Argentine and Spanish Collaborative Groups et al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus.  Nat Genet. 2006;  38(5) 550-555
  • 91 Graham R R, Kyogoku C, Sigurdsson S et al.. Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus.  Proc Natl Acad Sci U S A. 2007;  104(16) 6758-6763
  • 92 Sigurdsson S, Nordmark G, Göring H H et al.. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus.  Am J Hum Genet. 2005;  76(3) 528-537
  • 93 Karassa F B, Trikalinos T A, Ioannidis J P. FcgammaRIIa-SLE Meta-Analysis Investigators . Role of the Fcgamma receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis.  Arthritis Rheum. 2002;  46(6) 1563-1571
  • 94 Karassa F B, Trikalinos T A, Ioannidis J P. Fc gamma RIIIA-SLE meta-analysis investigators . The Fc gamma RIIIA-F158 allele is a risk factor for the development of lupus nephritis: a meta-analysis.  Kidney Int. 2003;  63(4) 1475-1482
  • 95 Russell A I, Cunninghame Graham D S, Shepherd C et al.. Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus.  Hum Mol Genet. 2004;  13(1) 137-147
  • 96 Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz H G, Möröy T. Features of systemic lupus erythematosus in Dnase1-deficient mice.  Nat Genet. 2000;  25(2) 177-181
  • 97 Yasutomo K, Horiuchi T, Kagami S et al.. Mutation of DNASE1 in people with systemic lupus erythematosus.  Nat Genet. 2001;  28(4) 313-314
  • 98 Remmers E F, Plenge R M, Lee A T et al.. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus.  N Engl J Med. 2007;  357(10) 977-986

Murray AdamsPh.D. M.A.I.M.S. 

Senior Lecturer, School of Human Life Sciences

University of Tasmania, Tasmania, Australia

Email: Murray.Adams@utas.edu.au

    >