Solid Phase Assays for Antiphospholipid Antibodies

Katrien M.J. Devreese

doi:10.1055/s-0042-1744364

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2022; 48(06): 661-671
DOI: 10.1055/s-0042-1744364

Review Article

Solid Phase Assays for Antiphospholipid Antibodies

Authors

Katrien M.J. Devreese

¹Department of Diagnostic Sciences, Coagulation Laboratory, Ghent University Hospital, Ghent University, Ghent, Belgium

Abstract

The diagnosis of antiphospholipid syndrome (APS) relies on the detection of circulating antiphospholipid antibodies (aPL). Currently, lupus anticoagulant (LA), anticardiolipin (aCL), and anti-β2-glycoprotein I antibodies (aβ2GPI) IgG or IgM are the laboratory criteria if persistently present over time. As aCL and aβ2GPI are two out of the three laboratory criteria, the detection of aPL by solid phase assays is an essential step in the diagnosis of APS. Advancement has been made to resolve some of the methodological challenges of aCL and aβ2GPI assays by providing guidelines how to measure aPL, as well as to gain a better understanding of their diagnostic role. However, solid phase assays for aCL and aβ2GPI still show substantive inter-assay differences, resulting in disagreement concerning positive/negative results, but also differences in titer of antibodies. This hampers the semiquantitative classification into low-medium-high positivity. The non-criteria aPL, such as antibodies against the domain one of β2GPI and anti-phosphatidylserine/prothrombin antibodies (aPS/PT) have roles in confirming the risk in APS, and can be useful, especially in patients with incomplete antibody profiles.

Keywords

antiphospholipid syndrome - anticardiolipin antibodies - anti-β2-glycoprotein I antibodies - prothrombin - β2-glycoprotein I - interference - classification

Full Text

References

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
2 Schreiber K, Sciascia S, de Groot PG. et al. Antiphospholipid syndrome. Nat Rev Dis Primers 2018; 4: 17103
3 Devreese KMJ, Ortel TL, Pengo V, de Laat B. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. Laboratory criteria for antiphospholipid syndrome: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (04) 809-813
4 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
5 Devreese KMJ, de Groot PG, de Laat B. et al. Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis: Update of the guidelines for lupus anticoagulant detection and interpretation. J Thromb Haemost 2020; 18 (11) 2828-2839
6 Barbhaiya M, Zuily S, Ahmadzadeh Y. et al; New APS Classification Criteria Collaborators. Development of a new international antiphospholipid syndrome classification criteria phase I/II report: generation and reduction of candidate criteria. Arthritis Care Res (Hoboken) 2021; 73 (10) 1490-1501
7 Devreese KM. Antiphospholipid antibodies: evaluation of the thrombotic risk. Thromb Res 2012; 130 (Suppl. 01) S37-S40
8 Garcia D, Erkan D. Diagnosis and management of the antiphospholipid syndrome. N Engl J Med 2018; 378 (21) 2010-2021
9 Pengo V, Ruffatti A, Legnani C. et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 2010; 8 (02) 237-242
10 Devreese KM. Antiphospholipid antibody testing and standardization. Int J Lab Hematol 2014; 36 (03) 352-363
11 Devreese KMJ. How to interpret antiphospholipid laboratory tests. Curr Rheumatol Rep 2020; 22 (08) 38
12 Devreese KMJ. Testing for antiphospholipid antibodies: advances and best practices. Int J Lab Hematol 2020; 42 (Suppl. 01) 49-58
13 Devreese K, Hoylaerts MF. Challenges in the diagnosis of the antiphospholipid syndrome. Clin Chem 2010; 56 (06) 930-940
14 Devreese KMJ, Ortel TL, Pengo V, de Laat B. Laboratory criteria for antiphospholipid syndrome: reply. J Thromb Haemost 2018; 16 (10) 2117-2119
15 Jiang D, Lim W, Crowther M, Garcia D. A systematic review of the association between anti-β-2 glycoprotein I antibodies and APS manifestations. Blood Adv 2021; 5 (20) 3931-3936
16 Persijn L, Decavele AS, Schouwers S, Devreese K. Evaluation of a new set of automated chemiluminescense assays for anticardiolipin and anti-beta2-glycoprotein I antibodies in the laboratory diagnosis of the antiphospholipid syndrome. Thromb Res 2011; 128 (06) 565-569
17 Van Hoecke F, Persijn L, Decavele AS, Devreese K. Performance of two new, automated chemiluminescence assay panels for anticardiolipin and anti-beta2-glycoprotein I antibodies in the laboratory diagnosis of the antiphospholipid syndrome. Int J Lab Hematol 2012; 34 (06) 630-640
18 Chayoua W, Kelchtermans H, Moore GW. et al. Detection of anti-cardiolipin and anti-β2glycoprotein I antibodies differs between platforms without influence on association with clinical symptoms. Thromb Haemost 2019; 119 (05) 797-806
19 Reynaud Q, Lega JC, Mismetti P. et al. Risk of venous and arterial thrombosis according to type of antiphospholipid antibodies in adults without systemic lupus erythematosus: a systematic review and meta-analysis. Autoimmun Rev 2014; 13 (06) 595-608
20 Durigutto P, Grossi C, Borghi MO. et al. New insight into antiphospholipid syndrome: antibodies to β2glycoprotein I-domain 5 fail to induce thrombi in rats. Haematologica 2019; 104 (04) 819-826
21 Andreoli L, Chighizola CB, Nalli C. et al. Clinical characterization of antiphospholipid syndrome by detection of IgG antibodies against β2 -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
22 Yin D, Chayoua W, Kelchtermans H. et al. Detection of anti-domain I antibodies by chemiluminescence enables the identification of high-risk antiphospholipid syndrome patients: A multicenter multiplatform study. J Thromb Haemost 2020; 18 (02) 463-478
23 Devreese KM, Poncet A, Lindhoff-Last E, Musial J, de Moerloose P, Fontana P. A multicenter study to assess the reproducibility of antiphospholipid antibody results produced by an automated system. J Thromb Haemost 2017; 15 (01) 91-95
24 Favaloro EJ, Wheatland L, Jovanovich S, Roberts-Thomson P, Wong RC. Internal quality control and external quality assurance in testing for antiphospholipid antibodies: Part I—Anticardiolipin and anti-β2-glycoprotein I antibodies. Semin Thromb Hemost 2012; 38 (04) 390-403
25 Tripodi A, Cohen H, Devreese KMJ. Lupus anticoagulant detection in anticoagulated patients. Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2020; 18 (07) 1569-1575
26 Zuily S, Cohen H, Isenberg D. et al. Use of direct oral anticoagulants in patients with thrombotic antiphospholipid syndrome: guidance from the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2020; 18 (09) 2126-2137
27 Wienholt LA, Richardson A, Wong RC, Chapman K, Lee FJ. A review of 10 years of data from an external quality assurance program for antiphospholipid antibodies: no evidence for improved aCL and β2GPI assay standardization. Ann Blood 2019; 4: 27
28 Montaruli B, De Luna E, Erroi L. et al. Analytical and clinical comparison of different immunoassay systems for the detection of antiphospholipid antibodies. Int J Lab Hematol 2016; 38 (02) 172-182
29 Monogioudi E, Martos G, Sheldon J, Meroni PL, Trapmann S, Zegers I. Development of a certified reference material for anti-β2-glycoprotein I IgG-commutability studies. Clin Chem Lab Med 2020; 59 (02) 325-332
30 Pengo V, Biasiolo A, Pegoraro C, Cucchini U, Noventa F, Iliceto S. Antibody profiles for the diagnosis of antiphospholipid syndrome. Thromb Haemost 2005; 93 (06) 1147-1152
31 Pregnolato F, Gerosa M, Raimondo MG. et al. EUREKA algorithm predicts obstetric risk and response to treatment in women with different subsets of anti-phospholipid antibodies. Rheumatology (Oxford) 2021; 60 (03) 1114-1124
32 Vanoverschelde L, Kelchtermans H, Musial J, de Laat B, Devreese KMJ. Influence of anticardiolipin and anti-β2 glycoprotein I antibody cutoff values on antiphospholipid syndrome classification. Res Pract Thromb Haemost 2019; 3 (03) 515-527
33 Clinical and Laboratory Standards Institute. Defining, establishing, and verifying reference intervals in the clinical laboratory C28–A3. Wayne, PA: Clinical and Laboratory Standards Institute; 2008
34 Bossuyt X, Rasmussen N, van Paassen P. et al. A multicentre study to improve clinical interpretation of proteinase-3 and myeloperoxidase anti-neutrophil cytoplasmic antibodies. Rheumatology (Oxford) 2017; 56 (09) 1533-1541
35 Vandevelde A, Chayoua W, de Laat B. et al. Semiquantitative interpretation of anticardiolipin and antiβ2glycoprotein I antibodies measured with various analytical platforms: communication from the ISTH SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. J Thromb Haemost 2022; 20 (02) 508-524
36 Lakos G, Bentow C, Mahler M. A clinical approach for defining the threshold between low and medium anti-cardiolipin antibody levels for QUANTA flash assays. Antibodies (Basel) 2016; 5 (02) E14
37 Chayoua W, Kelchtermans H, Gris JC. et al. The (non-)sense of detecting anti-cardiolipin and anti-β2glycoprotein I IgM antibodies in the antiphospholipid syndrome. J Thromb Haemost 2020; 18 (01) 169-179
38 Kelchtermans H, Pelkmans L, de Laat B, Devreese KM. IgG/IgM antiphospholipid antibodies present in the classification criteria for the antiphospholipid syndrome: a critical review of their association with thrombosis. J Thromb Haemost 2016; 14 (08) 1530-1548
39 Pastori D, Bucci T, Triggiani M. et al. Immunoglobulin G (IgG) anticardiolipin antibodies and recurrent cardiovascular events. A systematic review and Bayesian meta-regression analysis. Autoimmun Rev 2019; 18 (05) 519-525
40 Zuily S, Regnault V, Selton-Suty C. et al. Increased risk for heart valve disease associated with antiphospholipid antibodies in patients with systemic lupus erythematosus: meta-analysis of echocardiographic studies. Circulation 2011; 124 (02) 215-224
41 Zuily S, Domingues V, Suty-Selton C. et al. Antiphospholipid antibodies can identify lupus patients at risk of pulmonary hypertension: a systematic review and meta-analysis. Autoimmun Rev 2017; 16 (06) 576-586
42 Chock YP, Moulinet T, Dufrost V, Erkan D, Wahl D, Zuily S. Antiphospholipid antibodies and the risk of thrombocytopenia in patients with systemic lupus erythematosus: a systematic review and meta-analysis. Autoimmun Rev 2019; 18 (11) 102395
43 Chayoua W, Kelchtermans H, Moore GW. et al. Identification of high thrombotic risk triple-positive antiphospholipid syndrome patients is dependent on anti-cardiolipin and anti-β2glycoprotein I antibody detection assays. J Thromb Haemost 2018; 16 (10) 2016-2023
44 Pengo V, Banzato A, Bison E, Bracco A, Denas G, Ruffatti A. What have we learned about antiphospholipid syndrome from patients and antiphospholipid carrier cohorts?. Semin Thromb Hemost 2012; 38 (04) 322-327
45 Elkhalifa M, Orbai AM, Magder LS. et al. Anti-beta 2 glycoprotein I IgA in the SLICC classification criteria dataset. Lupus 2021; 30 (08) 1283-1288
46 Chayoua W, Yin D, Kelchtermans H. et al. Anti- cardiolipin and Anti- β2glycoprotein I IgA along with the current criteria does not have an added value in screening for clinical symptoms of the antiphospholipid syndrome. Res Pract Thromb Haemost 2019; 3 (S1): 687
47 Meijide H, Sciascia S, Sanna G, Khamashta MA, Bertolaccini ML. The clinical relevance of IgA anticardiolipin and IgA anti-β2 glycoprotein I antiphospholipid antibodies: a systematic review. Autoimmun Rev 2013; 12 (03) 421-425
48 Cousins L, Pericleous C, Khamashta M. et al. Antibodies to domain I of β-2-glycoprotein I and IgA antiphospholipid antibodies in patients with ‘seronegative’ antiphospholipid syndrome. Ann Rheum Dis 2015; 74 (01) 317-319
49 Aringer M, Costenbader K, Daikh D. et al. 2019 European League against rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis 2019; 78 (09) 1151-1159
50 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
51 Yin D, de Laat B, Devreese KMJ, Kelchtermans H. The clinical value of assays detecting antibodies against domain I of β2-glycoprotein I in the antiphospholipid syndrome. Autoimmun Rev 2018; 17 (12) 1210-1218
52 Iwaniec T, Kaczor MP, Celińska-Löwenhoff M, Polański S, Musiał J. Clinical significance of anti-domain 1 β2-glycoprotein I antibodies in antiphospholipid syndrome. Thromb Res 2017; 153: 90-94
53 Zuily S, de Laat B, Guillemin F. et al. Anti-domain I β2-glycoprotein I antibodies and activated protein C resistance predict thrombosis in antiphospholipid syndrome: TAC(I)T study. J Appl Lab Med 2020; 5 (06) 1242-1252
54 Chighizola CB, Pregnolato F, Andreoli L. et al. Beyond thrombosis: anti-β2GPI domain 1 antibodies identify late pregnancy morbidity in anti-phospholipid syndrome. J Autoimmun 2018; 90: 76-83
55 De Craemer AS, Musial J, Devreese KM. Role of anti-domain 1-β2 glycoprotein I antibodies in the diagnosis and risk stratification of antiphospholipid syndrome. J Thromb Haemost 2016; 14 (09) 1779-1787
56 Pengo V, Ruffatti A, Tonello M. et al. Antiphospholipid syndrome: antibodies to Domain 1 of β2-glycoprotein 1 correctly classify patients at risk. J Thromb Haemost 2015; 13 (05) 782-787
57 Bertolaccini ML, Amengual O, Andreoli L. et al. 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun Rev 2014; 13 (09) 917-930
58 Pengo V. Additional laboratory tests to improve on the diagnosis of antiphospholipid syndrome. J Thromb Haemost 2020; 18 (08) 1846-1848
59 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
60 Hoxha A, Mattia E, Tonello M, Grava C, Pengo V, Ruffatti A. Antiphosphatidylserine/prothrombin antibodies as biomarkers to identify severe primary antiphospholipid syndrome. Clin Chem Lab Med 2017; 55 (06) 890-898
61 Litvinova E, Darnige L, Kirilovsky A, Burnel Y, de Luna G, Dragon-Durey MA. Prevalence and significance of non-conventional antiphospholipid antibodies in patients with clinical APS criteria. Front Immunol 2018; 9: 2971
62 Tonello M, Mattia E, Favaro M. et al. IgG phosphatidylserine/prothrombin antibodies as a risk factor of thrombosis in antiphospholipid antibody carriers. Thromb Res 2019; 177: 157-160
63 Yin D, de Groot PG, Ninivaggi M, Devreese KMJ, de Laat B. Clinical Relevance of isolated lupus anticoagulant positivity in patients with thrombotic antiphospholipid syndrome. Thromb Haemost 2021; 121 (09) 1220-1227
64 Pengo V, Del Ross T, Ruffatti A. et al. Lupus anticoagulant identifies two distinct groups of patients with different antibody patterns. Thromb Res 2018; 172: 172-178
65 Tonello M, Bison E, Cattini MG. et al. Anti-phosphatidyl-serine/prothrombin antibodies (aPS/PT) in isolated lupus anticoagulant (LA): is their presence linked to dual test positivity?. Clin Chem Lab Med 2021; 59 (12) 1950-1953
66 Shi H, Zheng H, Yin YF. et al. Antiphosphatidylserine/prothrombin antibodies (aPS/PT) as potential diagnostic markers and risk predictors of venous thrombosis and obstetric complications in antiphospholipid syndrome. Clin Chem Lab Med 2018; 56 (04) 614-624
67 Tripodi A. Additional laboratory tests to improve on the diagnosis of antiphospholipid syndrome. J Thromb Haemost 2020; 18 (11) 3117-3118
68 Sciascia S, Sanna G, Murru V, Khamashta MA, Bertolaccini ML. Validation of a commercially available kit to detect anti-phosphatidylserine/prothrombin antibodies in a cohort of systemic lupus erythematosus patients. Thromb Res 2014; 133 (03) 451-454
69 Chinnaraj M, Pengo V, Pozzi N. A novel ELISA assay for the detection of anti-prothrombin antibodies in antiphospholipid syndrome patients at high risk of thrombosis. Front Immunol 2021; 12: 741589
70 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
71 Mustonen P, Lehtonen KV, Javela K, Puurunen M. Persistent antiphospholipid antibody (aPL) in asymptomatic carriers as a risk factor for future thrombotic events: a nationwide prospective study. Lupus 2014; 23 (14) 1468-1476
72 Yelnik CM, Urbanski G, Drumez E. et al. Persistent triple antiphospholipid antibody positivity as a strong risk factor of first thrombosis, in a long-term follow-up study of patients without history of thrombosis or obstetrical morbidity. Lupus 2017; 26 (02) 163-169
73 Pengo V, Ruffatti A, Del Ross T. et al. Confirmation of initial antiphospholipid antibody positivity depends on the antiphospholipid antibody profile. J Thromb Haemost 2013; 11 (08) 1527-1531
74 Devignes J, Smaïl-Tabbone M, Hervé A. et al. Extended persistence of antiphospholipid antibodies beyond the 12-week time interval: association with baseline antiphospholipid antibodies titres. Int J Lab Hematol 2019; 41 (06) 726-730
75 Pengo V, Bison E, Denas G, Jose SP, Zoppellaro G, Banzato A. Laboratory diagnostics of antiphospholipid syndrome. Semin Thromb Hemost 2018; 44 (05) 439-444
76 Uthman IW, Gharavi AE. Viral infections and antiphospholipid antibodies. Semin Arthritis Rheum 2002; 31 (04) 256-263
77 Devreese KMJ, Linskens EA, Benoit D, Peperstraete H. Antiphospholipid antibodies in patients with COVID-19: a relevant observation?. J Thromb Haemost 2020; 18 (09) 2191-2201
78 Foret T, Dufrost V, Salomon Du Mont L. et al. Systematic review of antiphospholipid antibodies in COVID-19 patients: culprits or bystanders?. Curr Rheumatol Rep 2021; 23 (08) 65
79 Nuri E, Taraborelli M, Andreoli L. et al. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res 2017; 65 (01) 17-24
80 Chatzidionysiou K, Samoli E, Sfikakis PP, Tektonidou MG. Effect of belimumab treatment on antiphospholipid antibody levels: post-hoc analysis based on two randomised placebo-controlled trials in systemic lupus erythematosus. Ann Rheum Dis 2020; 79 (02) 304-307