Baseline characteristics
As shown in Figure 1, 417 patients finished the first visit and provided informed consent. Twelve patients were excluded because of missing data. Twenty-two patients were lost to follow-up. A total of 383 patients (70.2% female; mean age 37.7 years) were included in the analysis, and the baseline characteristics were summarized in Supplementary Table 1. They were followed for 3.0 ± 2.2 years, of whom 24.3% with a coexisting SLE. The mean age of onset was 31.3 years. Patients with a history of arterial thrombosis, deep venous thrombosis and obstetric morbidity at baseline were 127 (33.2% of the total), 164 (42.8% of the total) and 142 (64.0% of female patients), respectively. Cluster analysis classified patients into 4 clusters (Supplementary Figure 1). Multiple comparison of baseline characteristics among 4 clusters was shown in Supplementary Table 1.
Cluster 1
Cluster 1 included 138 patients (36.0% of the total), 44.2% with a coexisting SLE. Non-criteria manifestations, especially thrombocytopenia, hemolytic anemia, heart valve disease, livedo reticularis and non-stroke centre nervous system (CNS) manifestations (including cognitive impairment, seizure and chorea), presented the most in Cluster 1. Cluster 1 presented with high AT rate (42.8%) and moderate DVT (33.3%) rate, with 57.2% positive of triple aPLs.
Cluster 2
Cluster 2 (112 patients, 29.2% of the total) represented male patients with multiple cardiovascular risk factors, of whom 77.7% were male, 45.5% with a smoking history, 35.7% with hypertension, 42.0% with hyperhomocysteinemia and the mean BMI was 24.7 kg/m2. Cluster 2 showed the highest rate of AT (45.5%) and DVT (73.2%), and moderate rate of non-criteria manifestations (48.2%), with 46.4% positive of triple aPLs.
Cluster 3
Women with obstetric morbidity were aggregated in cluster 3 (83 patients, 21.7% of the total), in which 43.6% with history of early miscarriages, 37.2% with fetal death >10th week, 10.3% with premature birth of fetus. Twenty-five patients (30.1%) were positive for more than one aPL, while only 2 patients (2.4%) were triple aPLs positive. The proportions of AT (3.6%), DVT (16.9%) and non-criteria manifestations (14.5%) were all the lowest in cluster 3.
Cluster 4
Cluster 4 represented patients with isolated LA positivity (98.0%). Fifty patients (13.1%) were included, with 36.0% being male and 38.0% coexisting with SLE. High AT rate (28.0%), and moderate DVT (44.0%) and non-criteria manifestations rates (46.0%) were shown in cluster 4.
Cluster analysis of variables
Four clusters of variables were identified (Figure 2): (A) early miscarriages and fetal death >10th week; (B)venous thrombosis, male sex, smoking history, hypertension, dyslipidemia and BMI≥25 kg/m2; (C)premature birth, aCL and aβ2-GPI; (D)arterial thrombosis, LA, SLE and non-criteria manifestations.
Follow-up
The mean follow-up was 36.4 months. Primary endpoint occurred in 56 patients, with an event occurrence rate of 4.82 per 100 person-years (Supplementary Table 2). From Kaplan Meier analysis, 1-, 3- and 5-year event-free survival rates were 92.6% (95% confidence interval [CI], 90%-95.3%), 85.2% (95%CI, 81.3%-89.4%) and 79.8% (95%CI, 74.4%-85.5%), respectively (Figure 3,Supplementary Table 3). Cluster 1, 2, 3 and 4 showed the 5-year event-free survival rate of 79.4% (95%CI, 71.3%-88.4%), 71.0% (95%CI, 60.3%-83.5%), 94.3% (95%CI, 88.1%-100%) and 79.4% (95%CI, 63.9%-98.7%), respectively (Figure 3, Supplementary Table 3). For primary endpoint and thrombosis endpoint, patients in cluster 3 showed the lowest risks, while patients in cluster 1, 2 and 4 suffered similar risks (Figure 4, Supplementary Table 3). For the AT endpoint, cluster 2 showed significant higher rate (2.57 per 100 person-years) than the other clusters (Figure 4, Supplementary Table 3). For endpoints of DVT, non-criteria manifestations, major bleeding events or mortality, no difference was found among clusters.