Background Platelet-bound complement activation products (PC4d) are associated with a history of thrombosis in systemic lupus erythematosus (SLE) (Gartshteyn al., 2021; Petri et al., 2017). The current study evaluated the role of PC4d in assessing the risk of future thrombosis.
Methods PC4d (expressed at net mean fluorescence intensity [MFI]) was measured by flow cytometry from patients enrolled in the Lupus Cohorts at Columbia Univ (COL), Johns Hopkins Univ (JH) and Beth Israel Deaconess Medical Center (BI) between Apr-Sep 2017 (JH), Aug 2018-Jan 2020 (COL), and Oct 2018-Mar 2022 (BI). History of thrombotic vascular events was confirmed by medical record review. Data were analyzed by chi-square and logistic regression. Diagnostic odds ratio (DOR) was calculated. If a patient had 2 arterial or 2 venous events, only the closest in time to PC4d measurement was included in the analysis.
Results A total of 419 SLE patients were enrolled. Main demographic and clinical characteristics are in table 1. Seventy-four thrombotic events occurred in the 5 years pre- to 3 years post-PC4d measurement. Of these 74, 50% had PC4d≥10 MFI at enrollment while 72% of patients without thrombosis had PC4d<10 (p< 0.001). 19 events occurred in 15 subjects in the 3 years after PC4d measurement: 8 cerebrovascular accidents, 3 deep vein thrombosis, 2 gastrointestinal infarctions, 2 myocardial infarctions, 1 pulmonary infarction, 1 arterial thrombosis and 2 venous thrombosis not specified. Median PC4d was higher in the 15 patients with than in the 404 patients without thrombosis (12.2 MFI, IQR: 4.7-19.6 vs. 4.9 MFI, IQR: 2.6-13.6, p=NS) (figure 1).
When the arterial events closest to PC4d measurements (8 of 14 total arterial events) were included, PC4d>13 MFI had sensitivity=62%, specificity=74%, DOR=4.8 (95%CI: 1.1, 20.3), p=0.034 in predicting future arterial thrombosis in patients with a previous arterial thrombosis. As expected, a previous arterial thrombosis was a strong predictor of a subsequent arterial event (p=0.0042). PC4d≥10 or ≥20 MFI did not reach statistical significance for future thrombosis neither in the entire population (p=0.055 and 0.51, respectively) nor in the subgroup younger than 65 years old (p = 0.99 for both). However, the negative predictive value of PC4d<10 MFI was 98%, indicating that probability of not having a thrombosis within 3 years is 98% if PC4d<10 MFI. Of the 285 patients with PC4d<10 MFI, 105 (37%) were positive for at least 1 of 8 anti-phospholipid antibodies (aPL) (3 aCL, 3 anti-B2GP1, or 2 anti-PS/PT antibodies), and 22 (7.8%) were positive for 3 aPL, indicating that the probability of not having a thrombosis if PC4d<10 MFI holds true for the population aPL positive and presumed at higher risk.
Conclusions PC4d≥10 MFI is associated with thrombosis in SLE and predicts future arterial thrombosis (DOR=4.8), despite the small number of events post-PC4d. Interestingly, patients with PC4d < 10 MFI have a 98% probability of not experiencing a thrombotic event in the following 3 years. Taken together, these findings suggest that PC4d levels help evaluate the risk of thrombosis in SLE and can guide the decision to start low dose aspirin.
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