Anti-phospholipid syndrome is an autoimmune pro-thrombotic condition that can have devastating effects on patients and their families1. The presence of antiphospholipid antibodies (aPL) do not always lead to thromboembolic events.1 Current consensus recommends maximizing control of cardiovascular disease (CVD) risk in aPL carriers2. However, the exact role of quantified CVD risk in thrombogenesis among aPL carriers has not be evaluated. Atherosclerotic CVD 10-Year Risk Score (ASCVD) is a convenient tool designed to determine the absolute CVD risks among healthy individuals and to guide primary prevention3,4. Our study aims to evaluate the role of quantified CVD risk in thrombosis risk stratification among ethnically diverse aPL positive carriers.
This study included a convenience sample of 147 patients with persistent high titer (≥99 percentiles) criteria aPL or positive lupus anticoagulant (LA) who attended University of Texas Southwestern Medical Center clinics from 2000–2017 (table 1). Persistent positive aPL is defined by having at least one positive test at ≥99th percentile cut-off values at two time points. 99th percentile cut-off values for aPL were established using 110 healthy controls. Cut-off values for anti-cardiolipin IgG/IgM are > 40 GPL/>40 MPL and for anti-β2 Glycoprotein-I IgG/IgM are >16 GPL/>14 MPL. aPL testing was performed using FDA approved commercial kits. Lupus anticoagulant (LA) was tested by dilute Russell’s viper venom time, partial thromboplastin time–LA and silica clotting time, with appropriate cut-offs established in the laboratory. ASCVD was calculated based on patient’s age, sex, race, total cholesterol, HDL, most recently documented systolic blood pressure, hypertension treatment, diabetes status, and smoking status. Pearson Chi-squared analysis was used to determine the association between increased ASCVD>7.5% or increased ASCVD>10% and various thromboembolic events. Non-parametric comparison of ASCVD as a continuous variable was performed among different groups using Mann-Whitney test.
Table 1.
Demographic summary of 147 aPL positive carriers HTN: hypertension. HLD: hyperlipidemia. SLE dx: systemic lupus erythematosus diagnosis. aCL:
| Characteristics | Arterial thrombosis aPL carriers (n=32*) | Venous Thrombosis aPL carriers (n=58) | A-sx aPLs Carriers (n=63) |
|---|---|---|---|
| Age, mean (S.D.) | 60.8 (12.6) | 52.7 (13.7) | 55.9 (14.7) |
| Female | 17 (53.1%) | 32 (55.2%) | 42 (66.7%) |
| African American | 10 (31.3%) | 17 (47.1%) | 18 (28.6%) |
| Caucasian | 18 (56.3%) | 28 (48.2%) | 38 (60.3%) |
| Hispanic | 4 (12.5%) | 13 (22.4%) | 4 (6.3%) |
| Asian | 0 | 0 | 3 (4.8%) |
| Smoking | 18 (56.3%) | 19 (32.8%) | 13 (20.6%) |
| SLE dx | 3 (9.4%) | 11 (19.0%) | 11 (17.5%) |
| Obstetric manifestation | 0 | 4** (6.9%) | 0 |
| Hypertension | 28 (87.5%) | 33 (56.9%) | 34 (54.0%) |
| Hyperlipidemia | 11 (34.4%) | 14 (24.1%) | 14 (25.2%) |
| Diabetes | 11 (34.4%) | 13 (22.4%) | 13 (27.0%) |
| aCL IgG/IgM | 2 (6.3%) | 5 (8.6%) | 2 (3.2%) |
| aβ2GPI IgG/IgM | 29 (90.6%) | 38 (65.5%) | 54 (85.7%) |
| LA | 6 (18.8%) | 24 (41.4%) | 14 (22.2%) |
| Triple Positive | 1 (3.1%) | 2 (3.4%) | 2 (3.2%) |
| 10 years CVD risk, mean (S.D.) | 20.4% (17.5) | 9.3% (10.0) | 12.2% (12.9) |
Anti-cardiolipin. aβ2GPI: Anti-β2 Glycoprotein-I. LA: lupus anticoagulant. Triple positive: positive aCL, aβ2GPI, and LA.
: Six patients had both arterial and venous thrombosis.
:One patient had 1 × third trimester miscarriage and 1× first trimester miscarriage, two patients had intra-uterine growth retardations, one patient had 2 × first trimester miscarriages and 1× intra-uterine growth retardation.
Significantly higher 10-year CVD risk was seen among aPL patients with arterial thrombosis compared to asymptomatic carriers (P=0.0063). When comparing thrombotic APS patients to asymptomatic aPL positive carriers, 10-year CVD risk >7.5% (OR= 2.579, 95% CI 1.063–6.595, P=0.036) and 10-year CVD risk >10% (OR= 2.902, 95% CI 1.207–7.075, P=0.017) were significantly associated with arterial thrombosis but not venous thrombosis or any thrombosis. There were no significant CVD risk differences observed between aPL patients with venous thrombosis/or any thrombosis and asymptomatic carriers. 33.9% of aPL carriers who had a 10-year CVD risk >10% were on aspirin. 40.8% of aPL carriers who had a 10-year CVD risk >7.5% were on a statin.
Risk stratification of asymptomatic aPL carriers is challenging. The exact role of non-aPL thrombotic risks such as CVD risk in thrombotic APS pathogenesis is not fully understood5. We observed that aPL carriers with arterial thrombosis have significantly higher CVD risks compared to asymptomatic carriers. We demonstrated that a 10-year CVD risk >7.5% and >10% assessed by ASCVD score among aPL carriers is associated with arterial thrombosis but not venous thrombosis. The US Preventative Service Task Force (USPSTF) grants grade B recommendation for initiating a statin among individuals with ASCVD risk >7.5% and for initiating low dose aspirin among individuals with ASCVD risk >10%6. While a well-accepted APS specific risk stratification tool does not exist, general population CVD risk assessment models such as ASCVD may represent a convenient alternative tool to help determine CVD risks among aPL carriers to guide primary prophylaxis.
Figure 1.
Non-parametric comparison of 10-year CVD risk assessed by ASCVD score among different groups of aPL carriers. Box and whisker graph shows median, 25th and 75th percentile values, and CVD risk range. A-sx: asymptomatic. aPL: antiphospholipid antibodies
Acknowledgments
Financial support: Dr. Zuo is supported by the Center for Translational Medicine at UT Southwestern Medical Center, NIH/NCATS Grants (UL1TR001105).
Footnotes
Conflict of Interest statement: The authors whose names are listed certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.
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