Semin Thromb Hemost 2012; 38(04): 360-374
DOI: 10.1055/s-0032-1313564
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Current International Initiatives in Antiphospholipid Antibody Testing

Rohan Willis
1   Antiphospholipid Standardization Laboratory, Division of Rheumatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas
2   Department of Microbiology, University of the West Indies, Kingston, Jamaica
,
E. Nigel Harris
3   Office of the Vice Chancellor, University of the West Indies, Kingston, Jamaica
,
Silvia S. Pierangeli
1   Antiphospholipid Standardization Laboratory, Division of Rheumatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas
› Author Affiliations
Further Information

Publication History

Publication Date:
10 May 2012 (online)

Abstract

Positive results in the anticardiolipin antibody (aCL), anti-β2-glycoprotein I antibody (aβ2GPI), and/or lupus anticoagulant (LA) assays constitute the laboratory criteria for the definite diagnosis of the antiphospholipid syndrome (APS). These tests became available from as early as the1980s, and since then several novel assays have become available that have varied usefulness in the diagnosis and prognosis of APS patients. For almost three decades there has been an ongoing effort to standardize the aCL, aβ2GPI, and LA assays, but there are still reports of significant intra- and interlaboratory variation in the results of all three assays. There have also been numerous issues with the implementation of novel (noncriteria) antiphospholipid antibody (aPL) tests in standard testing panels, due to either lack of standardized testing methods or limited evidence of their clinical utility in APS patients. At the recent 13th International Congress on Antiphospholipid Antibodies (APLA 2010, 13–16 April 2010, Galveston, TX), two task forces were set up to address these problems. This review gives a general description of current problems hindering the standardization of aPL tests and the implementation of novel assays as standard components of aPL testing panels. It also highlights the approach used by APLA 2010 Task Forces to address these problems and presents their recommendations.

 
  • References

  • 1 Wilson WA, Gharavi AE, Koike T , et al. International consensus statement on preliminary classification for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999; 42: 1309-1311
  • 2 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 (2) 295-306
  • 3 Reber G, Schousboe I, Tincani A , et al. Inter-laboratory variability of anti-beta2-glycoprotein I measurement. A collaborative study in the frame of the European Forum on Antiphospholipid Antibodies Standardization Group. Thromb Haemost 2002; 88 (1) 66-73
  • 4 Harris EN, Gharavi AE, Patel SP, Hughes GRC. Evaluation of the anti-cardiolipin antibody test: report of an international workshop held 4 April 1986. Clin Exp Immunol 1987; 68 (1) 215-222
  • 5 Harris EN. The second international anticardiolipin standardization workshop: the Kingston Anticardiolipin Antibody Study (KAPS) group. Am J Clin Pathol 1990; 94 (4) 476-484
  • 6 Harris EN, Pierangeli S, Birch D. Anticardiolipin wet workshop report. Fifth International Symposium on antiphospholipid antibodies. Am J Clin Pathol 1994; 101 (5) 616-624
  • 7 Pierangeli SS, Stewart M, Silva LK, Harris EN. Report of an anticardiolipin wet workshop during the VIIth International Symposium on antiphospholipid antibodies. J Rheumatol 1998; 25: 156-162
  • 8 Wong RCW, Wilson RJ, Pollock W, Steele R, Gillis D. Anti-cardiolipin antibody testing and reporting practices among laboratories participating in a large external Quality Assurance Program. Pathology 2004; 36 (2) 174-181
  • 9 Tincani A, Allegri F, Sanmarco M , et al. Anticardiolipin antibody assay: a methodological analysis for a better consensus in routine determinations—a cooperative project of the European Antiphospholipid Forum. Thromb Haemost 2001; 86 (2) 575-583
  • 10 Wong RCW, Wilson RJ, Pollock W, Steele RH, Gillis D. Anti-cardiolipin antibody testing and reporting practices among laboratories participating in a large external Quality Assurance Program. Pathology 2004; 36 (2) 174-181
  • 11 Goudemand J, Caron C, De Prost D , et al. Evaluation of sensitivity and specificity of a standardized procedure using different reagents for the detection of lupus anticoagulants. The Working Group on Hemostasis of the Société Française de Biologie Clinique and for the Groupe d'Etudes sur I'Hémostase et la Thrombose. Thromb Haemost 1997; 77 (2) 336-342
  • 12 Exner T, Triplett DA, Taberner DA, Howard MA, Harris EN. Comparison of test methods for the lupus anticoagulant: international survey on lupus anticoagulants-I (ISLA-1). Thromb Haemost 1990; 64 (3) 478-484
  • 13 Hemostasis Committee of the Societe Francaise de Biologie Clinique. Laboratory heterogeneity of the lupus anticoagulant: a multicentre study using different clotting assays on a panel of 78 samples. Hemostasis Committee of the “Société Française de Biologie Clinique”. Thromb Res 1992; 66 (4) 349-364
  • 14 Jennings I, Kitchen S, Woods TA, Preston FE, Greaves M. Potentially clinically important inaccuracies in testing for the lupus anticoagulant: an analysis of results from three surveys of the UK National External Quality Assessment Scheme (NEQAS) for Blood Coagulation. Thromb Haemost 1997; 77 (5) 934-937
  • 15 Arnout J, Meijer P, Vermylen J. Lupus anticoagulant testing in Europe: an analysis of results from the first European Concerted Action on Thrombophilia (ECAT) survey using plasmas spiked with monoclonal antibodies against human β2-glycoprotein I. Thromb Haemost 1999; 81 (6) 929-934
  • 16 Reber G, Tincani A, Sanmarco M, de Moerloose P, Boffa MC ; Standardization group of the European Forum on Antiphospholipid Antibodies. Proposals for the measurement of anti-β2-glycoprotein I antibodies. Standardization group of the European Forum on Antiphospholipid Antibodies. J Thromb Haemost 2004; 2 (10) 1860-1862
  • 17 Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost 1995; 74 (4) 1185-1190
  • 18 Exner T, Triplett DA, Taberner D, Machin SJ ; SSC Subcommittee for the Standardization of Lupus Anticoagulants. Guidelines for testing and revised criteria for lupus anticoagulants. Thromb Haemost 1991; 65 (3) 320-322
  • 19 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
  • 20 Guidelines on testing for the lupus anticoagulant. Lupus Anticoagulant Working Party on behalf of the BCSH Haemostasis and Thrombosis Task Force. J Clin Pathol 1991; 44: 885-889
  • 21 Favaloro EJ, Silvestrini R, Mohammed A. Clinical utility of anticardiolipin antibody assays: high inter-laboratory variation and limited consensus by participants of external quality assurance programs signals a cautious approach. Pathology 1999; 31 (2) 142-147
  • 22 Bertolaccini ML, Hughes GR, Khamashta MA. Revisiting antiphospholipid antibodies: from targeting phospholipids to phospholipid binding proteins. Clin Lab 2004; 50 (11–12) 653-665
  • 23 Rand JH, Wu XX, Andree HA , et al. Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipids: a “lupus procoagulant” phenomenon. Blood 1998; 92 (5) 1652-1660
  • 24 Harris EN, Gharavi AE, Boey ML , et al. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983; 2 (8361) 1211-1214
  • 25 Gharavi AE, Harris EN, Asherson RA, Hughes GR. Anticardiolipin antibodies: isotype distribution and phospholipid specificity. Ann Rheum Dis 1987; 46 (1) 1-6
  • 26 Mouritsen S, Høier-Madsen M, Wiik A, Orum O, Strandberg Pedersen N. The specificity of anti-cardiolipin antibodies from syphilis patients and from patients with systemic lupus erythematosus. Clin Exp Immunol 1989; 76 (2) 178-183
  • 27 Harris EN, Gharavi AE, Wasley GD, Hughes GR. Use of an enzyme-linked immunosorbent assay and of inhibition studies to distinguish between antibodies to cardiolipin from patients with syphilis or autoimmune disorders. J Infect Dis 1988; 157 (1) 23-31
  • 28 Harris EN. Antiphospholipid antibodies. Br J Haematol 1990; 74 (1) 1-9
  • 29 Galli M, Comfurius P, Maassen C , et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335 (8705) 1544-1547
  • 30 McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A 1990; 87 (11) 4120-4124
  • 31 Reber G, Arvieux J, Comby E , et al. Multicenter evaluation of nine commercial kits for the quantitation of anticardiolipin antibodies. The Working Group on Methodologies in Haemostasis from the GEHT (Groupe d'Etudes sur l'Hémostase et la Thrombose). Thromb Haemost 1995; 73 (3) 444-452
  • 32 Erkan D, Derksen W, Kaplan V , et al. Real world experience with antiphospholipid antibodies (APL): how stable are APL over time?. Arthritis Rheum 2004; 50 (9) S67 Suppl [abstract 1]
  • 33 De Moerloose P, Reber G, Vogel JJ. Anticardiolipin antibody determination: comparison of three ELISA assays. Clin Exp Rheumatol 1990; 8 (6) 575-577
  • 34 Favaloro EJ, Silvestrini R. Assessing the usefulness of anticardiolipin antibody assays: a cautious approach is suggested by high variation and limited consensus in multilaboratory testing. Am J Clin Pathol 2002; 118 (4) 548-557
  • 35 Pierangeli SS, Gharavi AE, Harris EN. Testing for antiphospholipid antibodies: problems and solutions. Clin Obstet Gynecol 2001; 44 (1) 48-57 , quiz 58–59
  • 36 Kutteh WH, Franklin RD. Assessing the variation in antiphospholipid antibody (APA) assays: comparison of results from 10 centers. Am J Obstet Gynecol 2004; 191 (2) 440-448
  • 37 Harris EN, Pierangeli SS. Revisiting the anticardiolipin test and its standardization. Lupus 2002; 11 (5) 269-275
  • 38 Pierangeli SS, de Groot PG, Dlott J , et al. 'Criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, Texas, April 2010. Lupus 2011; 20 (2) 182-190
  • 39 Iverson GM, Matsuura E, Victoria EJ, Cockerill KA, Linnik MD. The orientation of beta2GPI on the plate is important for the binding of anti-beta2GPI autoantibodies by ELISA. J Autoimmun 2002; 18 (4) 289-297
  • 40 Kaplan V, Erkan D, Derksen W , et al. Real world experience with antiphospholipid antibodies (APL): how useful is anti-β2glycoprotein (β2GPI) test?. Arthritis Rheum 2004; 50 (9) S67 Suppl [abstract 2]
  • 41 Triplett DA, Brandt JT. Lupus anticoagulants: misnomer, paradox, riddle, epiphenomenon. Hematol Pathol 1988; 2 (3) 121-143
  • 42 Brandt JT, Triplett DA, Musgrave K, Orr C. The sensitivity of different coagulation reagents to the presence of lupus anticoagulants. Arch Pathol Lab Med 1987; 111 (2) 120-124
  • 43 Brandt JT, Triplett DA, Rock WA, Bovill EG, Arkin CF. Effect of lupus anticoagulants on the activated partial thromboplastin time. Results of the College of American Pathologists survey program. Arch Pathol Lab Med 1991; 115 (2) 109-114
  • 44 Denis-Magdelaine A, Flahault A, Verdy E. Sensitivity of sixteen APTT reagents for the presence of lupus anticoagulants. Haemostasis 1995; 25 (3) 98-105
  • 45 Jacobsen EM, Barna-Cler L, Taylor JM, Triplett DA, Wisløff F. The Lupus Ratio test—an interlaboratory study on the detection of Lupus anticoagulants by an APTT-based, integrated, and semi-quantitative test. Fifth International Survey of Lupus Anticoagulants—ISLA 5. Thromb Haemost 2000; 83 (5) 704-708
  • 46 Brandt JT, Barna LK, Triplett DA. Laboratory identification of lupus anticoagulants: results of the Second International Workshop for Identification of Lupus Anticoagulants. On behalf of the Subcommittee on Lupus Anticoagulants/Antiphospholipid Antibodies of the ISTH. Thromb Haemost 1995; 74 (6) 1597-1603
  • 47 Tripodi A, Biasiolo A, Chantarangkul V, Pengo V. Lupus anticoagulant (LA) testing: performance of clinical laboratories assessed by a national survey using lyophilized affinity-purified immunoglobulin with LA activity. Clin Chem 2003; 49 (10) 1608-1614
  • 48 Jennings I, Greaves M, Mackie IJ, Kitchen S, Woods TA, Preston FE ; UK National External Quality Assessment Scheme for Blood Coagulation. Lupus anticoagulant testing: improvements in performance in a UK NEQAS proficiency testing exercise after dissemination of national guidelines on laboratory methods. Br J Haematol 2002; 119 (2) 364-369
  • 49 Budd R, Harley E, Quarshie A , et al. A re-appraisal of the normal cut-off assignment for anticardiolipin IgM tests. J Thromb Haemost 2006; 4: 2210-2214
  • 50 Ruffatti A, Olivieri S, Tonello M , et al. Influence of different IgG anticardiolipin antibody cut-off values on antiphospholipid syndrome classification. J Thromb Haemost 2008; 6 (10) 1693-1696
  • 51 Forastiero R, Papalardo E, Morin K , et al. Comparative evaluation of different immunoassays for the detection of antiphospholipid antibodies: report of a wet workshop during the 13th International Congress on Antiphospholipid Antibodies. Arthritis Rheum 2010; 62 (Suppl. 10) 2252 DOI: 10.1002/art.30015. [abstract]
  • 52 Forastiero R, Papalardo E, Watkins M , et al. Evaluation of the performance of monoclonal and polyclonal antibody standards in different assays for the detection of antiphospholipid (aPL) antibodies: report of a wet workshop at the 13th International Congress on Antiphospholipid Antibodies. Arthritis Rheum 2010; 62 (Suppl. 10) 2251 DOI: 10.1002/art.30014 . [abstract]
  • 53 Lakos G, Favaloro EJ, Harris EN , et al. International consensus guidelines on anticardiolipin and anti-β2-glycoprotein I testing: report from the 13th International Congress on Antiphospholipid Antibodies. Arthritis Rheum 2012; 64 (1) 1-10
  • 54 Pierangeli SS, Favaloro EJ, Lakos G , et al. Standards and reference materials for the anticardiolipin and anti-β2glycoprotein I assays: a report of recommendations from the APL Task Force at the 13th International Congress on Antiphospholipid Antibodies. Clin Chim Acta 2012; 413 (1–2) 358-360
  • 55 Adcock DM, Hoefner DM, Kottke-Marchant K, Marlar RA, Szamosi DI, Warunek DJ. Collection, transport, and processing of blood specimens for testing plasma-based coagulation assays and molecular hemostasis assays; approved guideline—fifth edition. CLSI document H21–A5. Wayne (PA): Clinical and Laboratory Standards Institute; 2008
  • 56 Lewis DA, Pound ML, Ortel TL. The reactivity of paired plasma and serum samples are comparable in the anticardiolipin and anti-β2-glycoprotein-1 ELISAs. J Thromb Haemost 2006; 4 (1) 265-267
  • 57 Hasselaar P, Triplett DA, LaRue A , et al. Heat treatment of serum and plasma induces false positive results in the antiphospholipid antibody ELISA. J Rheumatol 1990; 17 (2) 186-191
  • 58 Brey RL, Cote SA, McGlasson DL, Triplett DA, Barna LK. Effects of repeated freeze-thaw cycles on anticardiolipin antibody immunoreactivity. Am J Clin Pathol 1994; 102 (5) 586-588
  • 59 Bertolaccini ML, Amengual O, Atsumi T , et al. 'Non-criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, TX, USA, April 2010. Lupus 2011; 20 (2) 191-205
  • 60 Sammaritano LR, Lockshin MD, Gharavi AE. Antiphospholipid antibodies differ in aPL cofactor requirement. Lupus 1992; 1 (2) 83-90
  • 61 Chamley LW, Pattison NS, McKay EJ. Anomalous anticardiolipin antibody results may be due to cofactor variability. Am J Hematol 1991; 37 (4) 289
  • 62 Schlame M, Haller I, Sammaritano LR, Blanck TJ. Effect of cardiolipin oxidation on solid-phase immunoassay for antiphospholipid antibodies. Thromb Haemost 2001; 86 (6) 1475-1482
  • 63 Matsuura E, Igarashi Y, Yasuda T, Triplett DA, Koike T. Anticardiolipin antibodies recognize β 2-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med 1994; 179 (2) 457-462
  • 64 Roubey RA, Eisenberg RA, Harper MF, Winfield JB. “Anticardiolipin” autoantibodies recognize β 2-glycoprotein I in the absence of phospholipid. Importance of Ag density and bivalent binding. J Immunol 1995; 154 (2) 954-960
  • 65 DE Moerloose P, Reber G, Musial J, Arnout J. Analytical and clinical performance of a new, automated assay panel for the diagnosis of antiphospholipid syndrome. J Thromb Haemost 2010; 8 (7) 1540-1546
  • 66 Findlay JW, Dillard RF. Appropriate calibration curve fitting in ligand binding assays. AAPS J 2007; 9 (2) E260-E267
  • 67 Vesper HW, Thienpont LM. Traceability in laboratory medicine. Clin Chem 2009; 55 (6) 1067-1075
  • 68 Westgard JO. Use and interpretation of common statistical tests in method comparison studies. Clin Chem 2008; 54 (3) 612
  • 69 Pierangeli SS, Harris EN. A protocol for determination of anticardiolipin antibodies by ELISA. Nat Protoc 2008; 3 (5) 840-848
  • 70 Tholen DW, Kroll M, Astles JR , et al. Evaluation of the linearity of quantitative measurement procedures: a statistical approach; approved guideline. CLSI/NCCLS document EP6-A. Wayne (PA): Clinical and Laboratory Standards Institute; 2003
  • 71 Carey RN, Anderson FP, George H , et al. User verification of performance for precision and trueness; approved guideline—second edition. CLSI document EP15–A2. Wayne (PA): Clinical and Laboratory Standards Institute; 2005
  • 72 Wong RC, Gillis D, Adelstein S , et al. Consensus guidelines on anti-cardiolipin antibody testing and reporting. Pathology 2004; 36 (1) 63-68
  • 73 Wong RC, Favaloro EJ, Adelstein S , et al. Consensus guidelines on anti-β 2 glycoprotein I testing and reporting. Pathology 2008; 40 (1) 58-63
  • 74 Tincani A, Allegri F, Balestrieri G , et al. Minimal requirements for antiphospholipid antibodies ELISAs proposed by the European Forum on antiphospholipid antibodies. Thromb Res 2004; 114 (5–6) 553-558
  • 75 Horowitz GL, Altaie S, Boyd JC , et al. Defining, establishing, and verifying reference intervals in the clinical laboratory; approved guideline—third edition. CLSI document C28–A3. Wayne (PA): Clinical and Laboratory Standard Institute; 2008
  • 76 Lakos G, Teodorescu M. IgM, but not IgA rheumatoid factor interferes with anti-cardiolipin and antiβ2 glycoprotein I measurements: a quantitative analysis. Lupus 2011; 20 (6) 614-619
  • 77 Hlatky MA, Greenland P, Arnett DK , et al; American Heart Association Expert Panel on Subclinical Atherosclerotic Diseases and Emerging Risk Factors and the Stroke Council. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation 2009; 119 (17) 2408-2416
  • 78 Otomo K, Atsumi T, Amengual O , et al. Efficacy of the antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis Rheum 2012;64(2):504–512.
  • 79 Pengo V, Biasiolo A, Pegoraro C, Cucchini U, Noventa F, Iliceto S. Antibody profiles for the diagnosis of antiphospholipid syndrome. Thromb Haemost 2005; 93 (6) 1147-1152
  • 80 Pengo V, Biasiolo A, Gresele P , et al. A comparison of lupus anticoagulant-positive patients with clinical picture of antiphospholipid syndrome and those without. Arterioscler Thromb Vasc Biol 2007; 27 (12) e309-e310
  • 81 de Groot PG, Lutters B, Derksen RH, Lisman T, Meijers JC, Rosendaal FR. Lupus anticoagulants and the risk of a first episode of deep venous thrombosis. J Thromb Haemost 2005; 3 (9) 1993-1997
  • 82 Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003; 101 (5) 1827-1832
  • 83 Pengo V, Ruffatti A, Legnani C , et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 2010; 8 (2) 237-242
  • 84 Pengo V, Ruffatti A, Legnani C , et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study. Blood 2011; 118 (17) 4714-4718
  • 85 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
  • 86 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
  • 87 Ioannou Y, Pericleous C, Giles I, Latchman DS, Isenberg DA, Rahman A. Binding of antiphospholipid antibodies to discontinuous epitopes on domain I of human beta(2)-glycoprotein I: mutation studies including residues R39 to R43. Arthritis Rheum 2007; 56 (1) 280-290
  • 88 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 (4) 1540-1545
  • 89 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
  • 90 Ioannou Y, Romay-Penabad Z, Pericleous C , et al. In vivo inhibition of antiphospholipid antibody-induced pathogenicity utilizing the antigenic target peptide domain I of beta2-glycoprotein I: proof of concept. J Thromb Haemost 2009; 7 (5) 833-842
  • 91 Arvieux J, Darnige L, Caron C, Reber G, Bensa JC, Colomb MG. Development of an ELISA for autoantibodies to prothrombin showing their prevalence in patients with lupus anticoagulants. Thromb Haemost 1995; 74 (4) 1120-1125
  • 92 Pengo V, Biasiolo A, Brocco T, Tonetto S, Ruffatti A. Autoantibodies to phospholipid-binding plasma proteins in patients with thrombosis and phospholipid-reactive antibodies. Thromb Haemost 1996; 75 (5) 721-724
  • 93 Forastiero RR, Martinuzzo ME, Cerrato GS, Kordich LC, Carreras LO. Relationship of anti beta2-glycoprotein I and anti prothrombin antibodies to thrombosis and pregnancy loss in patients with antiphospholipid antibodies. Thromb Haemost 1997; 78 (3) 1008-1014
  • 94 Tincani A, Morozzi G, Afeltra A , et al; Forum Interdisciplinare per la Ricerca nelle Malattie Autoimmuni (FIRMA). Antiprothrombin antibodies: a comparative analysis of homemade and commercial methods. A collaborative study by the Forum Interdisciplinare per la Ricerca nelle Malattie Autoimmuni (FIRMA). Clin Exp Rheumatol 2007; 25 (2) 268-274
  • 95 Vaarala O, Puurunen M, Mänttäri M, Manninen V, Aho K, Palosuo T. Antibodies to prothrombin imply a risk of myocardial infarction in middle-aged men. Thromb Haemost 1996; 75 (3) 456-459
  • 96 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 (2) 289-297
  • 97 Forastiero R, Martinuzzo M, Pombo G , et al. A prospective study of antibodies to beta2-glycoprotein I and prothrombin, and risk of thrombosis. J Thromb Haemost 2005; 3 (6) 1231-1238
  • 98 Bizzaro N, Ghirardello A, Zampieri S , et al. Anti-prothrombin antibodies predict thrombosis in patients with systemic lupus erythematosus: a 15-year longitudinal study. J Thromb Haemost 2007; 5 (6) 1158-1164
  • 99 Forastiero R, Martinuzzo M, Iglesias Varela ML, Cerrato G. Multiple (triple or quadruple) aPL positivity is much more prevalent in patients with definite antiphospholipid syndrome. Lupus 2010; 19: C109 (abstract)
  • 100 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 (9) 1982-1993
  • 101 Binder W, Lewis S, Shums Z. Clinical significance of IgG and IgM autoantibodies that target the complex of phosphatidylserine and prothrombin. Lupus 2010; 19: C134 (abstract)
  • 102 Branch DW, Silver R, Pierangeli S, van Leeuwen I, Harris EN. Antiphospholipid antibodies other than lupus anticoagulant and anticardiolipin antibodies in women with recurrent pregnancy loss, fertile controls, and antiphospholipid syndrome. Obstet Gynecol 1997; 89 (4) 549-555
  • 103 Bertolaccini ML, Roch B, Amengual O, Atsumi T, Khamashta MA, Hughes GRV. Multiple antiphospholipid tests do not increase the diagnostic yield in antiphospholipid syndrome. Br J Rheumatol 1998; 37 (11) 1229-1232
  • 104 Fialová L, Mikulíková L, Matous-Malbohan I, Benesová O, Zwinger A. Prevalence of various antiphospholipid antibodies in pregnant women. Physiol Res 2000; 49 (3) 299-305
  • 105 Amoroso A, Mitterhofer AP, Del Porto F , et al. Antibodies to anionic phospholipids and anti-beta2-GPI: association with thrombosis and thrombocytopenia in systemic lupus erythematosus. Hum Immunol 2003; 64 (2) 265-273
  • 106 Matzner W, Chong P, Xu G, Ching W. Characterization of antiphospholipid antibodies in women with recurrent spontaneous abortions. J Reprod Med 1994; 39 (1) 27-30
  • 107 Gilman-Sachs A, Lubinski J, Beer AE, Brend S, Beaman KD. Patterns of anti-phospholipid antibody specificities. J Clin Lab Immunol 1991; 35 (2) 83-88
  • 108 Yetman DL, Kutteh WH. Antiphospholipid antibody panels and recurrent pregnancy loss: prevalence of anticardiolipin antibodies compared with other antiphospholipid antibodies. Fertil Steril 1996; 66 (4) 540-546
  • 109 Katsuragawa H, Kanzaki H, Inoue T, Hirano T, Mori T, Rote NS. Monoclonal antibody against phosphatidylserine inhibits in vitro human trophoblastic hormone production and invasion. Biol Reprod 1997; 56 (1) 50-58
  • 110 Branch DW, Khamashta MA. Antiphospholipid syndrome: obstetric diagnosis, management, and controversies. Obstet Gynecol 2003; 101 (6) 1333-1344
  • 111 Rand JH, Wu XX, Quinn AS , et al. Human monoclonal antiphospholipid antibodies disrupt the annexin A5 anticoagulant crystal shield on phospholipid bilayers: evidence from atomic force microscopy and functional assay. Am J Pathol 2003; 163 (3) 1193-1200
  • 112 Hanly JG, Smith SA. Anti-beta2-glycoprotein I (GPI) autoantibodies, annexin V binding and the anti-phospholipid syndrome. Clin Exp Immunol 2000; 120 (3) 537-543
  • 113 Gaspersic N, Ambrozic A, Bozic B, Majhenc J, Svetina S, Rozman B. Annexin A5 binding to giant phospholipid vesicles is differentially affected by anti-beta2-glycoprotein I and anti-annexin A5 antibodies. Rheumatology (Oxford) 2007; 46 (1) 81-86
  • 114 Tomer A, Bar-Lev S, Fleisher S, Shenkman B, Friger M, Abu-Shakra M. Antiphospholipid antibody syndrome: the flow cytometric annexin A5 competition assay as a diagnostic tool. Br J Haematol 2007; 139 (1) 113-120
  • 115 Rand JH, Wu XX, Lapinski R , et al. Detection of antibody-mediated reduction of annexin A5 anticoagulant activity in plasmas of patients with the antiphospholipid syndrome. Blood 2004; 104 (9) 2783-2790
  • 116 de Laat B, Wu XX, van Lummel M, Derksen RH, de Groot PG, Rand JH. Correlation between antiphospholipid antibodies that recognize domain I of beta2-glycoprotein I and a reduction in the anticoagulant activity of annexin A5. Blood 2007; 109 (4) 1490-1494
  • 117 Rand JH, Arslan AA, Wu XX , et al. Reduction of circulating annexin A5 levels and resistance to annexin A5 anticoagulant activity in women with recurrent spontaneous pregnancy losses. Am J Obstet Gynecol 2006; 194 (1) 182-188
  • 118 Gris JC, Quéré I, Sanmarco M , et al; The Nimes Obstetricians and Haematologists Study – NOHA. Antiphospholipid and antiprotein syndromes in non-thrombotic, non-autoimmune women with unexplained recurrent primary early foetal loss. The Nîmes Obstetricians and Haematologists Study—NOHA. Thromb Haemost 2000; 84 (2) 228-236
  • 119 Sugi T, Matsubayashi H, Inomo A, Dan L, Makino T. Antiphosphatidylethanolamine antibodies in recurrent early pregnancy loss and mid-to-late pregnancy loss. J Obstet Gynaecol Res 2004; 30 (4) 326-332
  • 120 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 (6) 949-954
  • 121 Sanmarco M. ELISA for antiphosphatidylethanolamine antibody detection: high impact of assay buffer on results. J Immunol Methods 2010; 358 (1–2) 9-16