Extra-criteria manifestations such as thrombocytopenia and livedo are described associated with antiphospholipid syndrome (APS) but are not included in the current classification criteria. Their clinical expression might be important, as they may be associated with a high-risk profile of antiphospholipid antibodies (aPL) and thrombosis. We evaluated the association between the presence of extra-criteria manifestations in primary obstetric-APS (POAPS) and aPL profiles. We also evaluated whether the presence of extra-criteria manifestations in POAPS patients increases the risk of developing thrombosis during the follow-up period (median follow-up 5 years; range 3–9 years). We selected 79 women who were included in our study only if they were first diagnosed with POAPS (with no history of previous thrombosis) and reevaluated for the presence of thrombosis after the follow-up period. We evaluated the association between the aPL profile and extra-criteria manifestations. We also evaluated the relationship of thrombosis during the follow-up period with extra-criteria manifestations and other risk factors. Patients with three or more extra-criteria manifestations presented high rates of triple positivity for the aPL profile (75%) (p < 0.001). We also found a relationship between the presence of extra-criteria manifestations and the presence of high titers of aPL: 91.7% of patients with three or more extra-criteria manifestations had high titers of aPL (p < 0.01). We further evaluated the group of POAPS patients according to thrombotic events during the follow-up. Among these patients, 6 (7.6%) presented thrombosis. Notably, 100% of patients with a thrombotic event during the follow-up had more than three extra-criteria manifestations. POAPS patients with extra-criteria manifestations might have a high-risk aPL profile and a major risk of developing thrombosis.
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Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemostas : JTH. 2006;4(2):295–306. https://doi.org/10.1111/j.1538-7836.2006.01753.x.
Abreu MM, Danowski A, Wahl DG, Amigo MC, Tektonidou M, Pacheco MS, et al. The relevance of “non-criteria” clinical manifestations of antiphospholipid syndrome: 14th International Congress on Antiphospholipid Antibodies Technical Task Force Report on Antiphospholipid Syndrome Clinical Features. Autoimmun Rev. 2015;14(5):401–14. https://doi.org/10.1016/j.autrev.2015.01.002.
Radin M, Ugolini-Lopes MR, Sciascia S, Andrade D. Extra-criteria manifestations of antiphospholipid syndrome: risk assessment and management. Semin Arthritis Rheum. 2018;48(1):117–20. https://doi.org/10.1016/j.semarthrit.2017.12.006.
Stojanovich L, Kontic M, Djokovic A, Marisavljevic D, Ilijevski N, Stanisavljevic N, et al. Association between systemic non-criteria APS manifestations and antibody type and level: results from the Serbian national cohort study. Clin Exp Rheumatol. 2013;31(2):234–42.
Erkan D, Barbhaiya M, George D, Sammaritano L, Lockshin M. Moderate versus high-titer persistently anticardiolipin antibody positive patients: are they clinically different and does high-titer anti-beta 2-glycoprotein-I antibody positivity offer additional predictive information? Lupus. 2010;19(5):613–9. https://doi.org/10.1177/0961203309355300.
Sciascia S, Amigo MC, Roccatello D, Khamashta M. Diagnosing antiphospholipid syndrome: ‘extra-criteria’ manifestations and technical advances. Nat Rev Rheumatol. 2017;13(9):548–60. https://doi.org/10.1038/nrrheum.2017.124.
de Jesus GR, Sciascia S, Andrade D, Barbhaiya M, Tektonidou M, Banzato A, et al. Factors associated with first thrombosis in patients presenting with obstetric antiphospholipid syndrome (APS) in the APS Alliance for Clinical Trials and International Networking Clinical Database and Repository: a retrospective study. BJOG: an international journal of obstetrics and gynaecology. 2019;126(5):656–61. https://doi.org/10.1111/1471-0528.15469.
Kontic M, Stojanovich L, Mijailovic-Ivkovic M, Velinovic M, Srnka J, Zdravkovic M. Are the cutaneous manifestations in patients with primary antiphospholipid syndrome a marker for predicting lung manifestations? Clin Exp Rheumatol. 2018;36(1):56–61.
Pontara E, Banzato A, Bison E, Cattini MG, Baroni G, Denas G, et al. Thrombocytopenia in high-risk patients with antiphospholipid syndrome. Journal of thrombosis and haemostasis : JTH. 2018;16(3):529–32. https://doi.org/10.1111/jth.13947.
Kato M, Hisada R, Atsumi T. Clinical profiles and risk assessment in patients with antiphospholipid antibodies. Expert Rev Clin Immunol. 2019;15(1):73–81. https://doi.org/10.1080/1744666X.2019.1543025.
de Larranaga GF, Forastiero RR, Carreras LO, Alonso BS. Different types of antiphospholipid antibodies in AIDS: a comparison with syphilis and the antiphospholipid syndrome. Thromb Res. 1999;96(1):19–25. https://doi.org/10.1016/s0049-3848(99)00059-6.
Latino JO, Udry S, Aranda FM, Peres Wingeyer SDA, Fernandez Romero DS, de Larranaga GF. Pregnancy failure in patients with obstetric antiphospholipid syndrome with conventional treatment: the influence of a triple positive antibody profile. Lupus. 2017;26(9):983–8. https://doi.org/10.1177/0961203317692432.
Latino JO, Udry S, Wingeyer SP, Romero DF, Micone P, de Larranaga G. What is the best time to assess the antiphospholipid antibodies (aPL) profile to better predict the obstetric outcome in antiphospholipid syndrome (APS) patients? Immunol Res. 2018;66(5):577–83. https://doi.org/10.1007/s12026-018-9024-5.
Amigo MC, Garcia-Torres R, Robles M, Bochicchio T, Reyes PA. Renal involvement in primary antiphospholipid syndrome. J Rheumatol. 1992;19(8):1181–5.
Zigon P, Podovsovnik A, Ambrozic A, Tomsic M, Hocevar A, Gaspersic N, et al. Added value of non-criteria antiphospholipid antibodies for antiphospholipid syndrome: lessons learned from year-long routine measurements. Clin Rheumatol. 2019;38(2):371–8. https://doi.org/10.1007/s10067-018-4251-7.
Martinez-Valle F, Ordi-Ros J, Selva-O’Callaghan A, Balada E, Solans-Laque R, Vilardell-Tarres M. Livedo racemosa as a marker of increased risk of recurrent thrombosis in patients with negative anti-phospholipid antibodies. Med Clin. 2009;132(20):767–71. https://doi.org/10.1016/j.medcli.2008.09.044.
Toubi E, Krause I, Fraser A, Lev S, Stojanovich L, Rovensky J, et al. Livedo reticularis is a marker for predicting multi-system thrombosis in antiphospholipid syndrome. Clin Exp Rheumatol. 2005;23(4):499–504.
Zuily S, Huttin O, Mohamed S, Marie PY, Selton-Suty C, Wahl D. Valvular heart disease in antiphospholipid syndrome. Curr Rheumatol Rep. 2013;15(4):320. https://doi.org/10.1007/s11926-013-0320-8.
Weinstein C, Miller MH, Axtens R, Buchanan R, Littlejohn GO. Livedo reticularis associated with increased titers of anticardiolipin antibodies in systemic lupus erythematosus. Arch Dermatol. 1987;123(5):596–600.
Atsumi T, Furukawa S, Amengual O, Koike T. Antiphospholipid antibody associated thrombocytopenia and the paradoxical risk of thrombosis. Lupus. 2005;14(7):499–504. https://doi.org/10.1191/0961203305lu2145rr.
Hisada R, Kato M, Sugawara E, Fujieda Y, Oku K, Bohgaki T, et al. Thrombotic risk stratification by platelet count in patients with antiphospholipid antibodies: a longitudinal study. Journal of thrombosis and haemostasis : JTH. 2017;15(9):1782–7. https://doi.org/10.1111/jth.13763.
Frances C, Niang S, Laffitte E, Pelletier F, Costedoat N, Piette JC. Dermatologic manifestations of the antiphospholipid syndrome: two hundred consecutive cases. Arthritis Rheum. 2005;52(6):1785–93. https://doi.org/10.1002/art.21041.
Krause I, Lev S, Fraser A, Blank M, Lorber M, Stojanovich L, et al. Close association between valvar heart disease and central nervous system manifestations in the antiphospholipid syndrome. Ann Rheum Dis. 2005;64(10):1490–3. https://doi.org/10.1136/ard.2004.032813.
Shen Y, Chen XW, Sun CY, Dai M, Yan YC, Yang CD. Association between anti-beta2 glycoprotein I antibodies and renal glomerular C4d deposition in lupus nephritis patients with glomerular microthrombosis: a prospective study of 155 cases. Lupus. 2010;19(10):1195–203. https://doi.org/10.1177/0961203310368409.
Zuily S, Regnault V, Guillemin F, Kaminsky P, Rat AC, Lecompte T, et al. Superficial vein thrombosis, thrombin generation and activated protein C resistance as predictors of thromboembolic events in lupus and antiphospholipid patients. A prospective cohort study. Thromb Res. 2013;132(1):e1–7. https://doi.org/10.1016/j.thromres.2013.04.012.
Meroni PL, Borghi MO, Grossi C, Chighizola CB, Durigutto P, Tedesco F. Obstetric and vascular antiphospholipid syndrome: same antibodies but different diseases? Nat Rev Rheumatol. 2018;14(7):433–40. https://doi.org/10.1038/s41584-018-0032-6.
Alijotas-Reig J, Esteve-Valverde E, Ferrer-Oliveras R, Saez-Comet L, Lefkou E, Mekinian A, et al. The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): a survey of 1000 consecutive cases. Autoimmun Rev. 2019;18(4):406–14. https://doi.org/10.1016/j.autrev.2018.12.006.
Drozdinsky G, Hadar E, Shmueli A, Gabbay-Benziv R, Shiber S. Obstetric antiphospholipid syndrome and long term arterial thrombosis risk. J Thromb Thrombolysis. 2017;44(3):371–5. https://doi.org/10.1007/s11239-017-1526-9.
Gris JC, Bouvier S, Molinari N, Galanaud JP, Cochery-Nouvellon E, Mercier E, et al. Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study. Blood. 2012;119(11):2624–32. https://doi.org/10.1182/blood-2011-09-381913.
Erkan D, Merrill JT, Yazici Y, Sammaritano L, Buyon JP, Lockshin MD. High thrombosis rate after fetal loss in antiphospholipid syndrome: effective prophylaxis with aspirin. Arthritis Rheum. 2001;44(6):1466–7. https://doi.org/10.1002/1529-0131(200106)44:6<1466::AID-ART242>3.0.CO;2-C.
We would like to thank Mrs. Analía Lucero and Valentina Lara for their excellent technical support.
Funding was provided through the “Scholarship for research in medicine to a young physician” from the Foundation Florencio Fiorini 2018.
This study was approved by the ethics committee of the respective medical center and was performed according to the principles of the Declaration of Helsinki and the current national law. Informed consent was obtained from all the participants.
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Udry, S., Latino, J.O., Belizna, C. et al. A high-risk laboratory profile of antiphospholipid antibodies and thrombosis is associated with a large number of extra-criteria manifestations in obstetric antiphospholipid syndrome. Immunol Res 67, 478–485 (2019). https://doi.org/10.1007/s12026-019-09110-x
- Livedo reticularis
- Pregnancy morbidity
- Risk factor