Clinical manifestations, management, and outcomes in patients with triple positive antiphospholipid antibodies

Abstract Introduction Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by arterial, venous, or microvascular thrombosis and/or pregnancy morbidity with persistent antiphospholipid antibodies (aPLs), namely lupus anticoagulant (LA), anti-cardiolipin antibody (aCL), and antiß2-glycoprotein 1 antibody (aß2GP-1). Individuals with triple positivity aPLs have the highest risk for developing thrombosis. While the IgG isotype confers the highest risk of thrombosis, data is limited on the specific differences in clinical manifestations, management, and outcomes between individual carriers of IgG or IgM isotypes. The Sapporo criteria has been used clinically to diagnose APS. The 2023 ACR/EULAR APS classification criteria recognize additional clinical manifestations and characterizes risk factors. Our study sought to compare clinical manifestations, management, and outcomes in triple positive aPL individuals with IgG or IgM isotypes using the 2023 ACR/EULAR APS classification criteria. Methods Retrospective review of electronic medical records of individuals with triple positive IgG or IgM aPLs followed at a hematology clinic of a university hospital from 2006 to 2024. Demographics, risk factors, aGAPSS score, clinical manifestations, management, and outcomes were collected. Clinical manifestations and risk factors were collected using the ACR/EULAR APS Classification Criteria. Venous, arterial, microvascular thrombosis and obstetric complications were recorded. Current and prior antithrombotic management was obtained. Descriptive statistics were calculated to characterize the study cohort. A two-tailed Fisher's exact test was used to assess the association between aPL isotype and risk factors, clinical manifestations, treatment and outcomes. Results 84 individuals were identified; mean age (SD) at diagnosis was 40 ± 15 years; 56% were female, 67% White, 72% non-Hispanic, and 76% had IgG aPL isotype. Autoimmune disease was significantly higher in triple positive IgG isotype individuals (p=0.01). Risk factors for venous thrombosis were significantly greater in the IgG isotype (p=0.02) and similar for arterial thrombosis. The distribution of aGAPSS scores was similar between the IgG and IgM isotypes. Pulmonary embolism was most common in triple positive IgG isotype individuals (p=0.05). There was a trend towards more venous and microvascular thrombosis in triple positive IgG isotype individuals, and more strokes in IgM isotype individuals. Pregnancy morbidity, thrombocytopenia, and valvular disease were similar between the two isotypes. Four individuals all triple positive IgG isotype experienced catastrophic APS. Recurrent thrombosis was more frequent in individuals with IgG isotype, although not statistically significant. Prior use of warfarin was more common in individuals with IgG isotype (p=0.04) while current use was similar between both isotypes. Triple positive IgG individuals had more frequent prior use of hydroxychloroquine (p=<0.01), however current use was comparable between both isotypes. Conclusions Our results suggest that individuals with triple positive aPLs IgG isotype may be more prone to venous thrombosis and have underlying autoimmune disease. Additional larger studies are required to confirm our findings.