This is the first study that compares the epidemiological, clinical, and laboratory profile of PAPS patients from a genetically diversified country, such as Brazil, with patients from other countries.
We found that, even though non-BPAPS patients had a greater proportion of triple aPL-positivity, the rates of arterial and venous thrombotic events did not differ between BPAPS and non-BPAPS groups. Our study identified that BPAPS patients had a higher frequency of LA and a lower frequency of aCL and aβ2GPI. Additionally, the most frequent single isolated aPL in the BPAPS group was LA. This particular aPL profile was also previously reported in another Brazilian cohort .
It is widely known that LA is the aPL associated with the highest risk of thrombosis in APS patients [8, 9]. In a recently published study, Yin et al. analyzed 456 patients (66 APS patients vs. 390 controls) and found that isolated LA positivity was a strong predictor of vascular thrombosis (OR 7.3, CI95% 3.3–16.1), even better than triple positivity (OR 4.3, CI95% 1.6–12.2) . Also, in previously published studies, LA, not triple positivity, was associated with a higher risk of thrombosis  and obstetric complications  in SLE patients. Thus, since rates of thrombotic events were similar between groups, we hypothesize that the lower triple positivity rates in the Brazilian group could be offset by its higher frequency of LA .
Previous Brazilian studies have also shown a high prevalence of livedo in APS patients . Interestingly, in our cohort, livedo was more prevalent in BPAPS (25%), when compared to non-BPAPS (10.4%). Considering that livedo is sensitive to cold exposure  and usually easier to be diagnosed in Caucasian patients due to skin contrast, it is intriguing that Brazilian patients present a higher frequency of livedo. A recent study on SLE patients found that all patients with livedo were positive to LA. Since LA positivity was higher in the BPAPS groups, this specific aPL profile may have contributed to the higher frequency of livedo in our cohort . Further studies could help to elucidate the pathophysiological aspects of this APS vasculopathy.
In our study we also observed a lower frequency of thrombocytopenia in APS patients from Brazil (9.1% vs. 18.3%). These findings corroborate with previous reports that showed a frequency of 8.9% of thrombocytopenia in BPAPS patients . The prevalence of thrombocytopenia in other countries varied more widely, ranging from 6 to 44% according to the cohort . Genetic background could be a possible explanation for these differences.
Regarding neurological non-criteria manifestations, we found that the prevalence of seizures and cognitive dysfunction in the Brazilian population was significantly higher than that of the group of patients from other countries (15.9 vs. 6.7%, and 20.5 vs. 8.0%, respectively). In the Euro-Phospholipid Project study, a similar prevalence of seizures (7%) was observed in the European population of APS patients . Regarding CD, Rosa et al. described an even higher prevalence of this manifestation in BPAPS patients (31.8%). In this study, the prevalence of CD in the matched healthy control group was only 5%, which suggests that this finding cannot be solely attributed to socioeconomic and educational conditions .
The proportion of non-white and female patients was higher in the BPAPS groups. There was also a statistically significant difference in the mean age between groups, but with no clinical relevance. Patients with APS have a high prevalence of metabolic syndrome, similar to other autoimmune diseases . We observed that PAPS patients from Brazil were more often obese and sedentary when compared to the group of patients from other countries. In this regard, both genetic, environmental and socioeconomic status can be responsible for the differences found herein.
Our findings highlight the importance of considering the interethnic variations between different countries for decision making in PAPS. Especially for Brazilian patients, which were the focus of this study, we were able to understand their particularities, and this may help to stratify better their recurrence risk and provide better treatments based on that.
Our study has limitations. First, it was a retrospective analysis of records from a database, with a cross-sectional design; however, future analysis of the registry with prospective design will provide more reliable data. Second, aPL tests were performed locally in each center, not in the APS ACTION core labs; similarly, we will investigate geographical differences in the future based on core laboratory aPL data. Third, enrollment in APS ACTION is at the discretion of the investigator without requirement that, for example, all consecutively seen patients with aPL antibodies are enrolled allowing for biases across centers. However, no a priori reason for this to consequentially vary by geography. Fourth, while a referral bias cannot be totally ruled out, one should consider that most of the APS ACTION centers are mostly tertiary referral academic hospitals, all equally receiving the most severe cases of the syndrome, which may have led to selection bias and reduced external validity. Fifth, some variables were assessed subjectively (for example, sedentary lifestyle and cognitive dysfunction); nonetheless, since these data are derived from a registry, we were not able to reassess them with specific instruments throughout the conduction of this study. Finally, the database used did not provide information about the number of events per patient nor the rates of thrombosis in the presence of adequate anticoagulation for each group.