Concordance between Acr/EULAR and Sapporo Criteria for Antiphospholipid Syndrome: New Domains Unveil Associations with Procoagulant Platelets

Introduction

The antiphospholipid syndrome (APS) is an autoimmune thrombotic disorder historically defined by the Sapporo Criteria as thrombotic or obstetric morbidity with persistent antiphospholipid antibodies (aPL). The 2023 ACR/EULAR APS Classification Criteria established a new system incorporating additional clinical manifestations, and a weighted score based on risk stratification by aPL profile, that claimed improved specificity compared with Sapporo Criteria. However, concordance between ACR/EULAR and Sapporo criteria has not been widely assessed. We previously reported that circulating platelets in APS display high levels of procoagulant activity and surface complement deposition, which correlates with a history of thrombosis (Kulkarni Blood supp 2023). Here, we assess platelet biomarkers of procoagulant activity and complement activation for their association with ACR/EULAR domain scores and APS diagnosis.

Methods

Consecutive patients with positive aPL registered in our biorepository were assessed for Sapporo and ACR/EULAR Criteria by two independent reviewers. Venous blood was collected in 3.2% sodium citrate from patients and healthy controls and washed platelets prepared by differential centrifugation. Platelets were maintained unstimulated or treated with thrombin (0.1, 0.25, 0.5 U/ml) for 5 min and then analyzed by flow cytometry for activated GPIIbIIIa, p-selectin expression, complement C4d deposition, and PS exposure (using annexin V). Platelet markers were correlated with ACR/EULAR domain scores and APS diagnosis. Categorical data are presented as counts and percentages and numerical data as mean ± standard deviation (SD).

Results

Of fifty-three patients with positive aPL (54 ±14 years, 68% female), 23/53 (43.4%) met Sapporo Criteria for APS while only 14/53 (26.4%) met ACR/EULAR criteria, and 30/53 (56.6%) were negative by both criteria. A discordant outcome occurred in 9/53 (17%) who met Sapporo but not ACR/EULAR criteria for APS. None were negative by Sapporo but positive by ACR/EULAR. Discordance in diagnosis was due to clinical criteria in 2 patients with VTE or ATE with high-risk features but with high risk aPL profile; discordant laboratory criteria in 4 patients with persistent high positive isolated IgM aPL and thrombotic events; and discordant clinical and laboratory domains in 3 patients (2 with recurrent pregnancy losses and 1 with ATE with risk factors, all with IgM apL).

Platelet studies were conducted on a subset of 28 patients (15 APS by Sapporo, 8 APS by ACR/EULAR, remainder negative) and 15 healthy controls. In aPL positive patients, p-selectin expression strongly correlated with scores for D3 (Microvascular), D5 (Cardiac Valve) and D6 (Hematology); C4d binding positively correlated with D8 (solid phase aPL); and PS exposure with D1 (Macrovascular VTE), D6, D8 and total ACR/EULAR score. In patients with APS by ACR/EULAR criteria, strong positive correlations were seen in platelet integrin IIbIIIa activation and D5 and D6; p-selectin expression and D1, D6, and total ACR/EULAR score; and PS exposure and D2 (Macrovascular ATE), D8 and total ACR/EULAR score. Resting platelet PS exposure was significantly increased in patients with APS by EULAR (413.5 ±179.84, p=0.028) or Sapporo (453.27±227.736, p=0.014) compared with healthy controls (266.7 ± 95.1).

Conclusion

Discordance in APS diagnosis by ACR/EULAR and Sapporo Criteria in our cohort was 9/53 (17%), with fewer meeting EULAR criteria than Sapporo. Discordance was largely due to the de-emphasis of IgM aPL isotypes, the incorporation of traditional VTE risk factors into the ACR/EULAR score, and changes in obstetric criteria. Procoagulant platelet biomarkers demonstrated strong correlations with aPL and thrombosis history, as well as microvascular disease, cardiac valve disease and thrombocytopenia. Procoagulant platelet PS exposure correlated with APS diagnosis by both Sapporo and ACR/EULAR. In the absence of a gold-standard for APS diagnosis, researchers and clinicians should be aware of discordance in Sapporo and ACR/EULAR scores, as well as the differences in sensitivity and specificity of each. APS remains a clinical diagnosis. Further study of novel biomarkers such as markers of platelet procoagulant activity and complement deposition may improve our ability to stratify thrombotic risk in APS.

*MP and AH contributed equally as co-first authors