Application of ACR/EULAR Classification Criteria in Real Life: Thrombotic Patients Positive for Lupus Anticoagulant Only

Abstract

Lupus anticoagulant (LA) positive only (negative anticardiolipin antibodies [aCL] and anti-β2 glycoprotein I antibodies [aβ2GPI]) thrombosis represents a clinical challenge. It is often unclear whether the cause of thrombosis is LA or whether other clinical conditions have led to an episode of venous thromboembolism (VTE) or arterial thromboembolism (ATE). Recent antiphospholipid syndrome (APS) classification criteria assign different scores to thrombotic events based on the presence of confounding risk factors. In the presence of strong associated risk factors, patients are not classified as having APS as a score less than 3 points is assigned to the clinical domain. This study evaluated patients LA positive only included in the group of APS in the START2 Antiphospholipid Registry. The aim of the study was to determine how many of them did not meet the new APS classification criteria due to the presence of associated risk factors. Of the 488 patients enrolled in the START Antiphospholipid Registry, 86 (18%) had LA positive only and 43 had a previous thromboembolic event (33 VTE and 10 ATE). Of the 33 patients with VTE (9%), 3 had a high-risk VTE profile and 2 had a high-risk ATE profile and did not meet the new classification criteria. The updated criteria appropriately limit the inclusion of patients with high-risk thrombotic profiles in APS research studies. Although risk factors and not LA may be the cause of thrombosis, the presence of LA can complicate treatment decisions in clinical practice.

Keywords

lupus coagulation inhibitor - thrombosis - antiphospholipid syndrome - classification - antiphospholipid antibodies

List of START-APS Collaborators

Daniela Poli, Felice Crudele, SOD Malattie Aterotrombotiche, Azienda Ospedaliero Universitaria-Careggi, Firenze; Piera Sivera, SCDU Ematologia, Ospedale Mauriziano Torino, Torino; Doris Barcellona, Struttura Dipartimentale di Emostasi e Trombosi, AOU di Cagliari, Dipartimento di Scienze Mediche e Sanità Pubblica, Università di Cagliari, Cagliari; Attilia Maria Pizzini, UOC Medicina A- Ospedale Maggiore, AUSL Bologna; Domenico Prisco, Maria Canfora, DMSC, Università di Firenze e SOD Medicina Interna Interdisciplinare, Azienda Ospedaliero Universitaria-Careggi, Firenze; Luca Sarti, Centro per la diagnosi e la sorveglianza della malattia tromboembolica, UO Medicina interna d'urgenza, Ospedale Civile di Baggiovara, Azienda Ospedaliero Universitaria Policlinico di Modena, Modena; Giuseppe Vercillo, UO Patologia Clinica - IRCCS Regina Elena National Cancer Institute, Roma; Paolo Bucciarelli, MariaAbbattista, Centro Emofilia e Trombosi “Angelo Bianchi Bonomi,” U.O.C. Medicina Generale Emostasi e Trombosi Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; Walter Ageno, Giovanna Colombo, Dipartimento di Medicina e Chirurgia, Università degli Studi dell'Insubria S.S.D Degenza Breve Internistica e Centro Trombosi, Ospedale di Circolo di Varese, ASST-Sette Laghi, Varese; Sophie Testa, Rossella Morandini, Oriana Paoletti, Centro Emostasi e Trombosi, ASST Cremona – Cremona; Antonella Tufano, UOC Medicina Interna, Università degli Studi Federico II, Napoli; Erica De Candia, Alice Lipari, Malattie emorragiche e Trombosi, Dipartimento di Medicina e chirurgia Traslazionale, Università Cattolica del Sacro cuore, Roma; Antonio Chistolini, Sezione Ematologia, Dipartimento di Medicina Traslazionale e di Precisione Sapienza Università di Roma, Roma; Varusca Brusegan, Luca Barcella, Francesca Schieppati, Anna Falanga, Chiara Ambaglio, Laura Russo, Sara Gamba, Marina Marchetti, Divisione di Immunoematologia e Medicina Trasfusionale and Centro Emostasi e Trombosi, ASST Papa Giovanni XXIII, Bergamo; Simona Pedrini, Servizio di Laboratorio, Istituto Ospedaliero Fondazione Poliambulanza, Brescia; Pasquale Pignatelli, Danilo Menichelli, Daniele Pastori, Centro Trombosi, Dipartimento SCIAC, Sapienza Università di Roma, Roma; Luca Puccetti, Centro emostasi e trombosi, Dipartimento di Scienze Mediche Chirurgiche e Neuroscienze, Università di Siena, Siena; Adriana Visonà, Michela Frulla, UOC Angiologia – Dipartimento di Medicina Clinica – Azienda ULSS 2 Marca Trevigiana – Ospedale San Giacomo Apostolo, Castelfranco Veneto (TV); Eugenio Bucherini, S.S. Medicina Vascolare – AUSL Romagna Ospedale Civile di Faenza, Faenza (RA); Paolo Gresele, Medicina Interna Vascolare, Azienda Ospedaliera di Perugia, Perugia; Vincenzo Oriana, Centro Emofilia, servizio Emostasi e Trombosi, Ospedale Morelli, Reggio Calabria; Andrea Toma, UOC di Patologia Clinica, Ambulatorio Terapia Anticoagulante Orale, O.C. “L. Cazzavillan” Arzignano (Vicenza); Maria Sophia Cotelli, SSD Neurologia-ASST Valcamonica, Esine (BS); Vittorio Fregoni, U.O.C. Medicina Generale, Ospedale di Sondalo, ASST della Valtellina e dell'Alto Lario, Sondalo; Corrado Lodigiani, Centro emostasi e trombosi, IRCCS Humanitas Research Hospital, Milano; Laura Banov, UOC Oncoematologia -IRCCS Gaslini Genova (GE); Elisa Bison, Dipartimento di Scienze Cardio-Toraco-Vascolari e Sanita' Pubblica, Università di Padova, Padova; Ariela Hoxha, UOC Medicina Generale 1, AULSS 8 Berica Ospedale S. Bortolo, Vicenza; Carmine Spataro, UOSD SIMT-Treviglio, Treviglio (BG).

Publication History

Received: 16 July 2025

Accepted: 21 October 2025

Accepted Manuscript online:
28 October 2025

Article published online:
10 November 2025

• References

• 1 Barbhaiya M, Zuily S, Naden R. et al; ACR/EULAR APS Classification Criteria Collaborators. The 2023 ACR/EULAR antiphospholipid syndrome classification criteria. Arthritis Rheumatol 2023; 75 (10) 1687-1702
• 2 Favaloro EJ, Pasalic L, Lippi G. Classification criteria for the antiphospholipid syndrome: not the same as diagnostic criteria for antiphospholipid syndrome. Semin Thromb Hemost 2024; 50 (04) 605-608
• 3 Pengo V, Biasiolo A, Gresele P. et al; Participating Centres of Italian Federation of Thrombosis Centres (FCSA). Survey of lupus anticoagulant diagnosis by central evaluation of positive plasma samples. J Thromb Haemost 2007; 5 (05) 925-930
• 4 Favaloro EJ, Pasalic L. Lupus anticoagulant testing during anticoagulation, including direct oral anticoagulants. Res Pract Thromb Haemost 2022; 6 (02) e12676
• 5 Antonucci E, Poli D, Tosetto A. et al; START-Register. The Italian START-Register on anticoagulation with focus on atrial fibrillation. PLoS One 2015; 10 (05) e0124719
• 6 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
• 7 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
• 8 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
• 9 Pengo V, Denas G, Zoppellaro G. et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 2018; 132 (13) 1365-1371
• 10 Pontara E, Bison E, Cattini MG, Tonello M, Denas G, Pengo V. Close link between antiphosphatidylserine/prothrombin antibodies, lupus anticoagulant, and activated protein C resistance in tetra antiphospholipid antibody-positive subjects. J Thromb Haemost 2023; 21 (11) 3138-3144
• 11 Pengo V, Pozzi N. Lupus anticoagulant and antiprothrombin antibodies: embracing the future. J Thromb Haemost 2025; 23 (07) 2262-2269
• 12 Pengo V, Testa S, Martinelli I. et al. Incidence of a first thromboembolic event in carriers of isolated lupus anticoagulant. Thromb Res 2015; 135 (01) 46-49
• 13 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