Abstract <p>Although IgA isotype testing does not enhance diagnostic accuracy of antiphospholipid syndrome (APS), recent studies suggest that IgA aCL/aβ2GPI are associated with systemic lupus erythematosus (SLE) and thrombosis, contributing to thromboinflammatory responses and potentially serving as prognostic markers. This study’s objective is to determine whether IgA aCL/aβ2GPI are associated with coagulation and inflammatory responses, as well as a high-risk thrombotic APS (t-APS) profile. A total of 81 patients with t-APS were included. IgA aCL and IgA aβ2GPI were measured using chemiluminescence. Coagulation and inflammatory markers (TNF-α, IL-6, IL-8, IFN-α, TF, VWF, ADAMTS13) were measured by ELISA, and then, their levels and activity compared between IgA-positive and negative patients. The association of IgA and relevant outcomes (antiphospholipid [aPL] profile, recurrent thrombosis, SLE), was assessed by logistic models adjusted for age and sex. IgA aCL or aβ2GPI positivity was observed in 24 patients (29.6%), mostly with both antibodies (<i>n</i> = 23). IgA positivity was not associated with demographics, comorbidities or pregnancy complications, but correlated with triple aPL positivity (48% vs. 13%, <i>P</i> = 0.004) and higher risk of progression to SLE (17% vs. 0%, <i>P</i> = 0.004). IgA-positive patients showed significantly elevated TNF-α, IL-8, and TF levels (<i>P</i> = 0.03, <i>P</i> = 0.03 and <i>P</i> = 0.05, respectively). In conclusion, IgA aCL/aβ2GPI positivity is associated with triple aPL positivity, progression to SLE, and altered thromboinflammatory markers, thus highlighting their association with a pronounced thromboinflammatory APS profile. This emphasizes the association of IgA antibodies with a high-risk serological profile and the potential utility of IgA testing in APS.</p> <p><i>Clinical trial registration:</i> This study is not a clinical trial that requires registration.</p> Graphical abstract <p></p>