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Semin Thromb Hemost 2018; 44(05): 453-457
DOI: 10.1055/s-0037-1601328
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA

The Clinical Relevance of Noncriteria Antiphospholipid Antibodies

Maria Laura Bertolaccini
1   Academic Department of Vascular Surgery, Cardiovascular Division, King's College London, United Kingdom
,
Giovanni Sanna
2   Louise Coote Lupus Unit, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
› Author Affiliations
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Publication History

Publication Date:
03 May 2017 (online)

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Abstract

While lupus anticoagulant (LA), anticardiolipin antibodies (aCL), anti-β2 glycoprotein I (anti-β2GPI) antibodies represent the best available and the most widely used tests in the investigation for antiphospholipid syndrome (APS), evidence gathered in recent years indicates that other antiphospholipid antibodies (aPL) specificities may also play a role in the syndrome. Several autoantibodies have been shown to be complexed with phospholipids other than cardiolipin, or to some domains of β2GPI, or else directed to other proteins of the coagulation cascade, and these have also been proposed to be of relevance to APS, and their diagnostic value and clinical utility are the focus of current research.

Keywords

prothrombin - coagulation - phosphatidylserine - lupus - thrombotic risk - β2GPI
 

  • References

  • 1 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
    CrossrefPubMedGoogle Scholar
  • 2 Forastiero R, Papalardo E, Watkins M. , et al. Evaluation of different immunoassays for the detection of antiphospholipid antibodies: report of a wet workshop during the 13th International Congress on Antiphospholipid Antibodies. Clin Chim Acta 2014; 428: 99-105
    CrossrefPubMedGoogle Scholar
  • 3 Pierangeli SS, Harris EN. A protocol for determination of anticardiolipin antibodies by ELISA. Nat Protoc 2008; 3 (05) 840-848
    CrossrefPubMedGoogle Scholar
  • 4 Pengo V, Tripodi A, Reber G. , et al; Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost 2009; 7 (10) 1737-1740
    CrossrefPubMedGoogle Scholar
  • 5 Lakos G, Favaloro EJ, Harris EN. , et al. International consensus guidelines on anticardiolipin and anti-b2-glycoprotein I testing: report from the 13th International Congress on Antiphospholipid Antibodies. Arthritis Rheum 2012; 64 (01) 1-10
    CrossrefPubMedGoogle Scholar
  • 6 Devreese KM, Pierangeli SS, de Laat B, Tripodi A, Atsumi T, Ortel TL. ; Subcommittee on Lupus Anticoagulant/Phospholipid/Dependent Antibodies. Testing for antiphospholipid antibodies with solid phase assays: guidance from the SSC of the ISTH. J Thromb Haemost 2014; 12 (05) 792-795
    CrossrefPubMedGoogle Scholar
  • 7 Moore GW. Recent guidelines and recommendations for laboratory detection of lupus anticoagulants. Semin Thromb Hemost 2014; 40 (02) 163-171
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Hughes GR, Khamashta MA. Seronegative antiphospholipid syndrome. Ann Rheum Dis 2003; 62 (12) 1127
    CrossrefPubMedGoogle Scholar
  • 9 Bertolaccini ML, Hughes GR, Khamashta MA. Revisiting antiphospholipid antibodies: from targeting phospholipids to phospholipid binding proteins. Clin Lab 2004; 50 (11-12): 653-665
    PubMedGoogle Scholar
  • 10 Bertolaccini ML, Atsumi T, Koike T, Hughes GR, Khamashta MA. Antiprothrombin antibodies detected in two different assay systems. Prevalence and clinical significance in systemic lupus erythematosus. Thromb Haemost 2005; 93 (02) 289-297
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Galli M, Luciani D, Bertolini G, Barbui T. Anti-beta 2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood 2003; 102 (08) 2717-2723
    CrossrefPubMedGoogle Scholar
  • 12 Funke A, Bertolaccini ML, Atsumi T, Amengual O, Khamashta MA, Hughes GRV. Autoantibodies to prothrombin-phosphatidylserine complex: clinical significance in systemic lupus erythematosus. (abstract) Arthritis Rheum 1998; 41: S240
    PubMedGoogle Scholar
  • 13 Atsumi T, Ieko M, Bertolaccini ML. , et al. Association of autoantibodies against the phosphatidylserine-prothrombin complex with manifestations of the antiphospholipid syndrome and with the presence of lupus anticoagulant. Arthritis Rheum 2000; 43 (09) 1982-1993
    CrossrefPubMedGoogle Scholar
  • 14 Bertolaccini ML, Gomez S, Pareja JF. , et al. Antiphospholipid antibody tests: spreading the net. Ann Rheum Dis 2005; 64 (11) 1639-1643
    CrossrefPubMedGoogle Scholar
  • 15 Sciascia S, Murru V, Sanna G, Roccatello D, Khamashta MA, Bertolaccini ML. Clinical accuracy for diagnosis of antiphospholipid syndrome in systemic lupus erythematosus: evaluation of 23 possible combinations of antiphospholipid antibody specificities. J Thromb Haemost 2012; 10 (12) 2512-2518
    CrossrefPubMedGoogle Scholar
  • 16 Sciascia S, Sanna G, Murru V, Roccatello D, Khamashta MA, Bertolaccini ML. Anti-prothrombin (aPT) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies and the risk of thrombosis in the antiphospholipid syndrome. A systematic review. Thromb Haemost 2014; 111 (02) 354-364
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Pregnolato F, Chighizola CB, Encabo S. , et al. Anti-phosphatidylserine/prothrombin antibodies: an additional diagnostic marker for APS?. Immunol Res 2013; 56 (2-3): 432-438
    CrossrefPubMedGoogle Scholar
  • 18 Bertolaccini ML, Sciascia S, Murru V, Garcia-Fernandez C, Sanna G, Khamashta MA. Prevalence of antibodies to prothrombin in solid phase (aPT) and to phosphatidylserine-prothrombin complex (aPS/PT) in patients with and without lupus anticoagulant. Thromb Haemost 2013; 109 (02) 207-213
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Iverson GM, Reddel S, Victoria EJ. , et al. Use of single point mutations in domain I of beta 2-glycoprotein I to determine fine antigenic specificity of antiphospholipid autoantibodies. J Immunol 2002; 169 (12) 7097-7103
    CrossrefPubMedGoogle Scholar
  • 20 de Laat B, de Groot PG. Autoantibodies directed against domain I of beta2-glycoprotein I. Curr Rheumatol Rep 2011; 13 (01) 70-76
    CrossrefPubMedGoogle Scholar
  • 21 Iverson GM, Victoria EJ, Marquis DM. Anti-beta2 glycoprotein I (beta2GPI) autoantibodies recognize an epitope on the first domain of beta2GPI. Proc Natl Acad Sci U S A 1998; 95 (26) 15542-15546
    CrossrefPubMedGoogle Scholar
  • 22 Reddel SW, Wang YX, Sheng YH, Krilis SA. Epitope studies with anti-beta 2-glycoprotein I antibodies from autoantibody and immunized sources. J Autoimmun 2000; 15 (02) 91-96
    CrossrefPubMedGoogle Scholar
  • 23 de Laat B, Derksen RH, Urbanus RT, de Groot PG. IgG antibodies that recognize epitope Gly40-Arg43 in domain I of beta 2-glycoprotein I cause LAC, and their presence correlates strongly with thrombosis. Blood 2005; 105 (04) 1540-1545
    CrossrefPubMedGoogle Scholar
  • 24 de Laat B, Pengo V, Pabinger I. , et al. The association between circulating antibodies against domain I of beta2-glycoprotein I and thrombosis: an international multicenter study. J Thromb Haemost 2009; 7 (11) 1767-1773
    CrossrefPubMedGoogle Scholar
  • 25 Banzato A, Pozzi N, Frasson R. , et al. Antibodies to domain I of b(2)glycoprotein I are in close relation to patients risk categories in antiphospholipid syndrome (APS). Thromb Res 2011; 128 (06) 583-586
    CrossrefPubMedGoogle Scholar
  • 26 Pericleous C, Ferreira I, Borghi O. , et al. Measuring IgA anti-b2-glycoprotein I and IgG/IgA anti-domain I antibodies adds value to current serological assays for the antiphospholipid syndrome. PLoS One 2016; 11 (06) e0156407
    CrossrefPubMedGoogle Scholar
  • 27 Mahler M, Albesa R, Zohoury N. , et al. Autoantibodies to domain 1 of beta 2 glycoprotein I determined using a novel chemiluminescence immunoassay demonstrate association with thrombosis in patients with antiphospholipid syndrome. Lupus 2016; 25 (08) 911-916
    CrossrefPubMedGoogle Scholar
  • 28 Andreoli L, Nalli C, Motta M. , et al. Anti-b2-glycoprotein I IgG antibodies from 1-year-old healthy children born to mothers with systemic autoimmune diseases preferentially target domain 4/5: might it be the reason for their ‘innocent’ profile?. Ann Rheum Dis 2011; 70 (02) 380-383
    CrossrefPubMedGoogle Scholar
  • 29 Arvieux J, Renaudineau Y, Mane I, Perraut R, Krilis SA, Youinou P. Distinguishing features of anti-beta2 glycoprotein I antibodies between patients with leprosy and the antiphospholipid syndrome. Thromb Haemost 2002; 87 (04) 599-605
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Avcin T, Ambrozic A, Kuhar M, Kveder T, Rozman B. Anticardiolipin and anti-beta(2) glycoprotein I antibodies in sera of 61 apparently healthy children at regular preventive visits. Rheumatology (Oxford) 2001; 40 (05) 565-573
    CrossrefPubMedGoogle Scholar
  • 31 Ambrozic A, Avicin T, Ichikawa K. , et al. Anti-beta(2)-glycoprotein I antibodies in children with atopic dermatitis. Int Immunol 2002; 14 (07) 823-830
    CrossrefPubMedGoogle Scholar
  • 32 Andreoli L, Chighizola CB, Nalli C. , et al. Clinical characterization of antiphospholipid syndrome by detection of IgG antibodies against b2 -glycoprotein i domain 1 and domain 4/5: ratio of anti-domain 1 to anti-domain 4/5 as a useful new biomarker for antiphospholipid syndrome. Arthritis Rheumatol 2015; 67 (08) 2196-2204
    CrossrefPubMedGoogle Scholar
  • 33 Sanmarco M, Gayet S, Alessi MC. , et al. Antiphosphatidylethanolamine antibodies are associated with an increased odds ratio for thrombosis. A multicenter study with the participation of the European Forum on antiphospholipid antibodies. Thromb Haemost 2007; 97 (06) 949-954
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Bertolaccini ML, Murru V, Sciascia S, Sanna G, Khamashta MA. The clinical value of testing for antibodies to phosphatidylethanolamine (aPE) in patients with systemic lupus erythematosus (SLE). Thromb Res 2012; 130 (06) 914-918
    CrossrefPubMedGoogle Scholar
  • 35 Staub HL, Bertolaccini ML, Khamashta MA. Anti-phosphatidylethanolamine antibody, thromboembolic events and the antiphospholipid syndrome. Autoimmun Rev 2012; 12 (02) 230-234
    CrossrefPubMedGoogle Scholar
  • 36 Kaburaki J, Kuwana M, Yamamoto M, Kawai S, Ikeda Y. Clinical significance of anti-annexin V antibodies in patients with systemic lupus erythematosus. Am J Hematol 1997; 54 (03) 209-213
    CrossrefPubMedGoogle Scholar
  • 37 Rand JH, Wu XX, Andree HAM. , et al. Pregnancy loss in the antiphospholipid-antibody syndrome--a possible thrombogenic mechanism. N Engl J Med 1997; 337 (03) 154-160
    CrossrefPubMedGoogle Scholar
  • 38 Sugi T, McIntyre JA. Autoantibodies to phosphatidylethanolamine (PE) recognize a kininogen-PE complex. Blood 1995; 86 (08) 3083-3089
    PubMedGoogle Scholar
  • 39 Sugi T, McIntyre JA. Certain autoantibodies to phosphatidylethanolamine (aPE) recognize factor XI and prekallikrein independently or in addition to the kininogens. J Autoimmun 2001; 17 (03) 207-214
    CrossrefPubMedGoogle Scholar
  • 40 Shibata S, Sasaki T, Harpel P, Fillit H. Autoantibodies to vascular heparan sulfate proteoglycan in systemic lupus erythematosus react with endothelial cells and inhibit the formation of thrombin-antithrombin III complexes. Clin Immunol Immunopathol 1994; 70 (02) 114-123
    CrossrefPubMedGoogle Scholar
  • 41 Shibata S, Harpel PC, Gharavi A, Rand J, Fillit H. Autoantibodies to heparin from patients with antiphospholipid antibody syndrome inhibit formation of antithrombin III-thrombin complexes. Blood 1994; 83 (09) 2532-2540
    Google Scholar
  • 42 Jones DW, Gallimore MJ, Harris SL, Winter M. Antibodies to factor XII associated with lupus anticoagulant. Thromb Haemost 1999; 81 (03) 387-390
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Jones DW, Gallimore MJ, MacKie IJ, Harris SL, Winter M. Reduced factor XII levels in patients with the antiphospholipid syndrome are associated with antibodies to factor XII. Br J Haematol 2000; 110 (03) 721-726
    CrossrefPubMedGoogle Scholar
  • 44 Jones DW, MacKie IJ, Gallimore MJ, Winter M. Antibodies to factor XII and recurrent fetal loss in patients with the anti-phospholipid syndrome. Br J Haematol 2001; 113 (02) 550-552
    CrossrefPubMedGoogle Scholar
  • 45 Hwang KK, Grossman JM, Visvanathan S. , et al. Identification of anti-thrombin antibodies in the antiphospholipid syndrome that interfere with the inactivation of thrombin by antithrombin. J Immunol 2001; 167 (12) 7192-7198
    CrossrefPubMedGoogle Scholar
  • 46 Oosting JD, Derksen RH, Bobbink IW, Hackeng TM, Bouma BN, de Groot PG. 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
    PubMedGoogle Scholar
  • 47 Atsumi T, Khamashta MA, Amengual O. , et al. Binding of anticardiolipin antibodies to protein C via beta2-glycoprotein I (beta2-GPI): a possible mechanism in the inhibitory effect of antiphospholipid antibodies on the protein C system. Clin Exp Immunol 1998; 112 (02) 325-333
    CrossrefPubMedGoogle Scholar
  • 48 Erkan D, Zhang HW, Shriky RC, Merrill JT. Dual antibody reactivity to beta2-glycoprotein I and protein S: increased association with thrombotic events in the antiphospholipid syndrome. Lupus 2002; 11 (04) 215-220
    CrossrefPubMedGoogle Scholar
  • 49 Bertolaccini ML, Sanna G, Ralhan S. , et al. Antibodies directed to protein S in patients with systemic lupus erythematosus: prevalence and clinical significance. Thromb Haemost 2003; 90 (04) 636-641
    Article in Thieme ConnectPubMedGoogle Scholar
  • 50 Carson CW, Comp PC, Esmon NL, Rezaie AR, Esmon CT. Thrombomodulin antibodies inhibit protein C activation and are found in patients with lupus anticoagulant and unexplained thrombosis. (abstract) Arthritis Rheum 1994; 37: S296
    PubMedGoogle Scholar
  • 51 Molina JF, Gutierrez-Ureña S, Molina J. , et al. Variability of anticardiolipin antibody isotype distribution in 3 geographic populations of patients with systemic lupus erythematosus. J Rheumatol 1997; 24 (02) 291-296
    PubMedGoogle Scholar
  • 52 Diri E, Cucurull E, Gharavi AE. , et al. Antiphospholipid (Hughes') syndrome in African-Americans: IgA aCL and abeta2 glycoprotein-I is the most frequent isotype. Lupus 1999; 8 (04) 263-268
    CrossrefPubMedGoogle Scholar
  • 53 Bertolaccini ML, Atsumi T, Escudero Contreras A, Khamashta MA, Hughes GRV. The value of IgA antiphospholipid testing for diagnosis of antiphospholipid (Hughes) syndrome in systemic lupus erythematosus. J Rheumatol 2001; 28 (12) 2637-2643
    PubMedGoogle Scholar
  • 54 Meijide H, Sciascia S, Sanna G, Khamashta MA, Bertolaccini ML. The clinical relevance of IgA anticardiolipin and IgA anti-b2 glycoprotein I antiphospholipid antibodies: a systematic review. Autoimmun Rev 2013; 12 (03) 421-425
    CrossrefPubMedGoogle Scholar
  • 55 Fanopoulos D, Teodorescu MR, Varga J, Teodorescu M. High frequency of abnormal levels of IgA anti-beta2-glycoprotein I antibodies in patients with systemic lupus erythematosus: relationship with antiphospholipid syndrome. J Rheumatol 1998; 25 (04) 675-680
    PubMedGoogle Scholar
  • 56 Lee RM, Branch DW, Silver RM. Immunoglobulin A anti-beta2-glycoprotein antibodies in women who experience unexplained recurrent spontaneous abortion and unexplained fetal death. Am J Obstet Gynecol 2001; 185 (03) 748-753
    CrossrefPubMedGoogle Scholar
  • 57 Kumar S, Papalardo E, Sunkureddi P, Najam S, González EB, Pierangeli SS. Isolated elevation of IgA anti-beta2glycoprotein I antibodies with manifestations of antiphospholipid syndrome: a case series of five patients. Lupus 2009; 18 (11) 1011-1014
    CrossrefPubMedGoogle Scholar
  • 58 Morales JM, Serrano M, Martínez-Flores JA. , et al. The presence of pretransplant antiphospholipid antibodies IgA anti-b-2-glycoprotein I as a predictor of graft thrombosis after renal transplantation. Transplantation 2017; 101 (03) 597-607
    CrossrefPubMedGoogle Scholar