Abstract
The international classification criteria for definite antiphospholipid syndrome (APS) include three laboratory measurements: lupus anticoagulant (LA), IgG and IgM isotypes of anti-cardiolipin (aCL) and anti-β2glycoprotein I antibodies (anti-β2GPI). When persistently elevated, they are specific for APS; however, many patients that fulfil clinical criteria may exhibit negative serological results. These “seronegative” APS (SN-APS) are exposed to an increased thrombotic risk. The aims of our cross-sectional, retrospective study of consecutive autoimmune patients’ samples were to evaluate the association of non-criteria antiphospholipid antibodies (aPL) with thrombosis and obstetric events, to calculate the risk score for adverse events and to assess the specific contribution of single aPL positivity in SN-APS. LA, aCL, anti-β2GPI and anti-phosphatidylserine/prothrombin antibodies (aPS/PT) of IgG, IgM, and IgA isotypes were determined in sera of 323 patients with autoimmune disorders. Medical records of all patients were carefully analyzed. aCL, anti-β2GPI and aPS/PT of IgG and IgA isotypes were significantly associated with thrombosis while none of the IgM aPL showed such association. aPS/PT of all isotypes, aCL and anti-β2GPI of IgG and IgA isotype showed significant correlation to obstetric events. When considering results of aPS/PT ELISA, we could additionally identify 3% of thrombotic patients and 2% of obstetric patients. Thrombotic and obstetric risk scores were calculated showing significantly higher association to clinical events, as compared to evaluating individual risk factors. aPS/PT could represent an additional biomarker in SN-APS patients. IgA aPL are associated with thrombosis and obstetric complications. Risk scores accounting different aPL and conventional risk factors, better assesses risk for adverse event, as compared to evaluating individual factors alone.
Similar content being viewed by others
References
Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, De Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). JThrombHaemost 4(2):295–306
Hughes GR, Khamashta MA (2003) Seronegative antiphospholipid syndrome. Ann Rheum Dis 62(12):1127
Bertolaccini ML, Amengual O, Atsumi T, Binder WL, de LB FR, Kutteh WH, Lambert M, Matsubayashi H, Murthy V, Petri M, Rand JH, Sanmarco M, Tebo AE, Pierangeli SS (2011) ‘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 20(2):191–205
Zohoury N, Bertolaccini ML, Rodriguez-Garcia JL, Shums Z, Ateka-Barrutia O, Sorice M, Norman GL, Khamashta M (2017) Closing the serological gap in the antiphospholipid syndrome: the value of “non-criteria” antiphospholipid antibodies. J Rheumatol 44(11):1597–1602. https://doi.org/10.3899/jrheum.170044
Zigon P, Ambrozic A, Cucnik S, Kveder T, Rozman B, Bozic B (2011) Modified phosphatidylserine-dependent antithrombin ELISA enables identification of patients negative for other antiphospholipid antibodies and also detects low avidity antibodies. Clin Chem Lab Med 49(6):1011–1018
Zigon P, Cucnik S, Ambrozic A, Kveder T, Semrl SS, Rozman B, Bozic B (2013) Detection of antiphosphatidylserine/prothrombin antibodies and their potential diagnostic value. Clin Dev Immunol 2013:8–8. https://doi.org/10.1155/2013/724592
Zigon P, Cucnik S, Ambrozic A, Sodin Semrl S, Kveder T, Bozic B (2012) Antibodies to phosphatidylserine/prothrombin complex as an additional diagnostic marker of APS? Lupus 21(7):790–792. https://doi.org/10.1177/0961203312444173
Zigon P, Perdan Pirkmajer K, Tomsic M, Kveder T, Bozic B, Sodin Semrl S, Cucnik S, Ambrozic A (2015) Anti-phosphatidylserine/prothrombin antibodies are associated with adverse pregnancy outcomes. J Immunol Res 2015:975704–975708. https://doi.org/10.1155/2015/975704
Ciesla M, Wypasek E, Undas A (2014) IgA antiphospholipid antibodies and anti-domain 1 of Beta 2 glycoprotein 1 antibodies are associated with livedo reticularis and heart valve disease in antiphospholipid syndrome. Adv Clin Exp Med 23(5):729–733
Hood DB, Snyder KR, Buckner TR, Hurley BL, Pitts KR, Lopez LR (2015) Differential assay reactivity of immunglobulin a anti-beta(2) glycoprotein I antibodies: implications for the clinical interpretation of antiphospholipid antibody testing. Eur J Rheumatol 2(4):135–138. https://doi.org/10.5152/eurjrheum.2015.0012
Mavropoulos A, Sully G, Cope AP, Clark AR (2005) Stabilization of IFN-gamma mRNA by MAPK p38 in IL-12- and IL-18-stimulated human NK cells. Blood 105(1):282–288. https://doi.org/10.1182/blood-2004-07-2782
Meijide H, Sciascia S, Sanna G, Khamashta MA, Bertolaccini ML (2013) The clinical relevance of IgA anticardiolipin and IgA anti-beta2 glycoprotein I antiphospholipid antibodies: a systematic review. Autoimmun Rev 12(3):421–425. https://doi.org/10.1016/j.autrev.2012.08.002
Despierres L, Beziane A, Kaplanski G, Granel B, Serratrice J, Cohen W, Bretelle F, Rossi P, Morange PE, Weiller PJ, Robert Harle J, Bongrand P, Bardin N (2014) Contribution of anti-beta2glycoprotein I IgA antibodies to the diagnosis of anti-phospholipid syndrome: potential interest of target domains to discriminate thrombotic and non-thrombotic patients. Rheumatology (Oxford) 53(7):1215–1218. https://doi.org/10.1093/rheumatology/keu003
Paulmyer-Lacroix O, Despierres L, Courbiere B, Bardin N (2014) Antiphospholipid antibodies in women undergoing in vitro fertilization treatment: clinical value of IgA anti-beta2glycoprotein I antibodies determination. Biomed Res Int 2014:314704–314705. https://doi.org/10.1155/2014/314704
Andreoli L, Fredi M, Nalli C, Piantoni S, Reggia R, Dall'Ara F, Franceschini F, Tincani A (2013) Clinical significance of IgA anti-cardiolipin and IgA anti-beta2glycoprotein I antibodies. Curr Rheumatol Rep 15(7):343. https://doi.org/10.1007/s11926-013-0343-1
Otomo K, Atsumi T, Amengual O, Fujieda Y, Kato M, Oku K, Horita T, Yasuda S, Koike T (2012) Efficacy of the antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis Rheum 64(2):504–512. https://doi.org/10.1002/art.33340
Sciascia S, Sanna G, Murru V, Roccatello D, Khamashta MA, Bertolaccini ML (2013) GAPSS: the global anti-phospholipid syndrome score. Rheumatology (Oxford) 52(8):1397–1403. https://doi.org/10.1093/rheumatology/kes388
Oku K, Amengual O, Bohgaki T, Horita T, Yasuda S, Atsumi T (2015) An independent validation of the global anti-phospholipid syndrome score in a Japanese cohort of patients with autoimmune diseases. Lupus 24(7):774–775. https://doi.org/10.1177/0961203314561284
Zuily S, de Laat B, Mohamed S, Kelchtermans H, Shums Z, Albesa R, Norman GL, Lamboux-Matthieu C, Rat AC, Ninet J, Magy-Bertrand N, Pasquali JL, Lambert M, Lorcerie B, Kaminsky P, Guillemin F, Regnault V, Wahl D (2015) Validity of the global anti-phospholipid syndrome score to predict thrombosis: a prospective multicentre cohort study. Rheumatology (Oxford) 54(11):2071–2075. https://doi.org/10.1093/rheumatology/kev238
Zigon P, Ambrozic A, Cucnik S, Kveder T, Rozman B, Bozic B (2011) Modified phosphatidylserine-dependent antiprothrombin ELISA enables identification of patients negative for other antiphospholipid antibodies and also detects low avidity antibodies. Clin Chem Lab Med 49(9):1573
Bozic B, Kveder T, Stegnar M, Morosini-Berus E, Kos-Golja M, Peternel P, Rozman B (1997) Influence of degraded phosphatidylserine on binding of antiphospholipid antibodies. IntArchAllergy Immunol 112(1):19–26
Čučnik S, Krizaj I, Rozman B, Kveder T, Božič B (2004) Concomitant isolation of protein C inhibitor and unnicked beta2-glycoprotein I. ClinChemLab Med 42(2):171–174
Reber G, Schousboe I, Tincani A, Sanmarco M, Kveder T, De MP, Boffa MC, Arvieux J (2002) Inter-laboratory variability of anti-beta2-glycoprotein I measurement. A collaborative study in the frame of the European forum on antiphospholipid antibodies standardization group. ThrombHaemost 88(1):66–73
Chighizola CB, Raschi E, Banzato A, Borghi MO, Pengo V, Meroni PL (2016) The challenges of lupus anticoagulants. Expert Rev Hematol 9(4):389–400. https://doi.org/10.1586/17474086.2016.1140034
Mattia E, Ruffatti A, Tonello M, Meneghel L, Robecchi B, Pittoni M, Gallo N, Salvan E, Teghil V, Punzi L, Plebani M (2014) IgA anticardiolipin and IgA anti-beta2 glycoprotein I antibody positivity determined by fluorescence enzyme immunoassay in primary antiphospholipid syndrome. Clinical chemistry and laboratory medicine : CCLM / FESCC 52:1329–1333. https://doi.org/10.1515/cclm-2014-0039
Sciascia S, Sanna G, Murru V, Roccatello D, Khamashta MA, Bertolaccini ML (2013) Anti-prothrombin (aPT) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies and the risk of thrombosis in the antiphospholipid syndrome: a systematic review. Thrombosis and Haemostasis 111(2):354–364. https://doi.org/10.1160/TH13-06-0509
Amengual O, Forastiero R, Sugiura-Ogasawara M, Otomo K, Oku K, Favas C, Delgado Alves J, Zigon P, Ambrozic A, Tomsic M, Ruiz-Arruza I, Ruiz-Irastorza G, Bertolaccini ML, Norman GL, Shums Z, Arai J, Murashima A, Tebo AE, Gerosa M, Meroni PL, Rodriguez-Pinto I, Cervera R, Swadzba J, Musial J, Atsumi T (2016) Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study. Lupus 26:266–276. https://doi.org/10.1177/0961203316660203
Zigon P, Ambrozic A, Mali P, Tomsic M, Sodin Semrl S, Cucnik S (2017) The prevalence and clinical significance of Iga anti-phosphatidylserine/ prothrombin antibodies in systemic autoimmune diseases. Immunome research 13:130. https://doi.org/10.4172/1745-7580.1000130
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The study was approved by the National Medical Ethics Committee, Ljubljana, Slovenia (#99/04/15), and all patients provided informed consent. We confirm that all experiments were performed in accordance with relevant guidelines and regulations.
Disclosures
None.
Additional information
Rheumatology in Slovenia: Clinical practice and translational research
Rights and permissions
About this article
Cite this article
Žigon, P., Podovšovnik, A., Ambrožič, A. et al. Added value of non-criteria antiphospholipid antibodies for antiphospholipid syndrome: lessons learned from year-long routine measurements. Clin Rheumatol 38, 371–378 (2019). https://doi.org/10.1007/s10067-018-4251-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10067-018-4251-7