Credit: Original article published here.
A recent publication in JAMA Network Open explores two clinical questions related to antiphospholipid antibodies (aPL): (1) what is the prevalence of aPL positivity at a single time point, and (2) are aPL antibodies associated with future atherosclerotic cardiovascular disease (ASCVD) risk? [1]. Antiphospholipid syndrome (APS) is an acquired condition that is characterized by a thromboinflammatory state, with arterial or venous thrombotic events and/or obstetric complications, in the presence of persistently circulating aPL antibodies. Arterial thrombotic events in APS include stroke or myocardial infarction (MI).
With a recent study suggesting autoantibodies can be present in up to 18-32% of individuals [2], the authors of this study postulated whether presence of these autoantibodies may put individuals at higher risk for ASCVD morbidity than is currently recognized. Previous studies have demonstrated aPL are acutely present in up to 17.4% of patients with cardiovascular events such as stroke and transient ischemic attack, and some incidental positive aPL can be present in 1-12% of otherwise healthy individuals. Thus, this study sought to determine association of aPL and future ASCVD events and investigate association of sex, race, and ethnicity with aPL prevalence [1].
Zuo et al performed this population-based cohort study in approximately 2400 participants from the Dallas Heart Study phase 2 (DHS2). These participants were free of ASCVD events at the time of blood collection and had no self-reported autoimmune diseases requiring immunosuppressive medications. ASCVD events included first nonfatal MI, first nonfatal stroke, coronary or peripheral artery revascularization or cardiovascular death. They measured 8 aPL (anticardiolipin, beta-2 glycoprotein, and antiphosphatidylserine/prothrombin) antibodies by solid-phase assays in plasma. Samples were collected between 2007-2009 with median follow-up of 8 years. Associations of aPL with future ASCVD events were assessed by Cox proportional hazards models, adjusting for known CVD risk factors and medications.
In this cohort, 57.6% were female and 51.3% Black, 32.8% White; the mean age at time of sampling was 50.6 years. All were free of CVD, and none had autoimmune disease requiring immunosuppressive medications. The authors found 14.5% of the cohort (n=353) tested positive for at least 1 aPL. The aCL IgM had the highest prevalence in 156 participants (6.4%). There were no significant differences were found in the frequency of aPL positivity between Black, Hispanic, and White participants. Over the median follow-up period (8 years), ASCVD events occurred in 125 participants. After adjusting for comorbidities and medications, positive testing for aCL IgA and aβ2GPI IgA were each significantly associated with future ASCVD events.
This study demonstrated presence of at least 1 type of aPL was in 14.5% of individuals in this racially and ethnically diverse cohort, with 1/3 of those positives at a moderate to high titer (>=40). There was no major variation in presence of the antibodies based on race or ethnicity. They found the presence of aCL IgA and aβ2GPI IgA, even at low titer and tested at a single time point, are independently associated with future ASCVD events. The authors postulate exposure to aβ2GPI IgA may shift coronary endothelial cells to a pro-adhesive, atherogenic phenotype, and that future research should explore the role of aPL being utilized as nontraditional markers of ASCVD risk.
Limitations of the study included the fact sufficient citrated plasma was not available for testing lupus anticoagulant, so all relevant aPL were not comprehensively tested. Additionally, serial repeat samples taken 12 weeks apart were not performed to confirm aPL persistence required for formal classification of antiphospholipid antibody syndrome (APS); thus, the prevalence of APS in the general population is unable to be determined. Since the DHS cohort only captured ASCVD events, they could not evaluate associations between circulating aPL and other APS clinical manifestations. Finally, because of the use of a single-time point, the authors acknowledge possible misclassification bias could contribute to lack of observed associations between other aPL subtypes and ASCVD events; further studies are needed to confirm this initial hypothesis-generating study.
References:
[1] Zuo Y, Navaz S, Liang W et al, Prevalence of Antiphospholipid Antibodies and Association With Incident Cardiovascular Events. JAMA network open 2023;6(4):e236530.
[2] Dillon CF, Weisman MH, Miller FW. Population-based estimates of humoral autoimmunity from the U.S. National Health and Nutrition Examination Surveys, 1960-2014. PLoS One. 2020;15(1):e0226516.
