Abstract
Antiphospholipid syndrome (APS) is diagnosed when arterial/venous thrombosis and/or pregnancy morbidity occur in persistently antiphospholipid antibody (aPL)-positive patients (Box 1) [1]. The most commonly used tests to detect aPL are: lupus anticoagulant (LA) test (a functional coagulation assay); anticardiolipin antibody (aCL) ELISA; and anti-β2-glycoprotein-I antibody (aβ2GPI) ELISA.
Although the prevalence of aPL is up to 10% in the general healthy population, persistent LA test positivity or moderate-to-high titer aCL/aβ2GPI positivity is relatively uncommon. A prospective follow-up study of healthy blood donors who were tested twice for aPL demonstrated, at baseline, 10 and 1% positivity for the aCL and LA tests, respectively. However, after 1 year, fewer than 1% of healthy blood donors tested positive for the aCL or LA tests [2]. The number of general-population studies analyzing persistent LA test positivity or the moderate-to-high titer aCL/aβ2GPI positivity in thrombosis patients is limited; the prevalence of aPL ranges between 5 and 20%, and is largely dependent upon the aPL test-type and the clinical population studied [3–5]. Of systemic lupus erythematosus patients, 30–40% [4], and approximately 20% of women with recurrent fetal loss [6] possess aPL.
Despite many controversies in APS, there are a number of well-documented and clinically important practice points, including the following:
A positive LA test is a better predictor of aPL-related events compared with other aPL tests [7];
Whenever possible, LA tests should be tested before anticoagulation since both false-negative or false-positive results can occur in anticoagulated patients;
The specificity of aCL and aβ2GPI tests for aPL-related clinical events increases with higher titers;
Transient aPL-positivity is common during infections and, thus, documentation of the persistence (at least 12 weeks apart) of autoimmune aPL is crucial for both diagnostic and therapeutic purposes [1];
The risk of thrombosis in aPL-positive patients rises with increasing numbers of thrombosis risk factors [8,9] (similar to the risk in the general population [10]);
Approximately half of the APS patients with vascular events have at least one non-aPL thrombosis risk factor at the time of their vascular events [11–13].
Keeping the previously described points in mind, this short paper will review a recent population-based case–control study published in the November 2009 issue of Lancet Neurology, which concluded that “lupus anticoagulant is a major risk factor for arterial thrombotic events in young women, and the presence of other cardiovascular risk factors increases the risk even further” [14].
Results
This multicenter, population-based case–control study of women aged 18–49 years analyzed 175 patients with first ischemic stroke, 203 patients with first myocardial infarction (MI), and 628 frequency-matched (age, residence area and index date of the event) healthy controls who were identified by random digit dialing.
Summary of the updated Sapporo classification criteria for antiphospholipid syndrome.
Vascular thrombosis: > 1 arterial, venous or small vessel thrombosis.
Pregnancy morbidity: > 1 fetal death (at or beyond the 10th week of gestation); > 1 premature birth before the 34th week of gestation because of eclampsia, severe pre-eclampsia or placental insufficiency; or > 3 consecutive (pre) embryonic losses (before the 10th week of gestation).
Lupus anticoagulant positivity on > 2 occasions at least 12 weeks apart.
Anticardiolipin antibody (IgG and/or IgM) in medium or high titer (i.e., > 40 U, or above the 99th percentile) on > 2 occasions at least 12 weeks apart.
Anti-β2-glycoprotein-I antibody (IgG and/or IgM) in medium or high titer (i.e., above the 99th percentile) on > 2 occasions at least 12 weeks apart.
The study was performed at different time points: patient recruitment and clinical data collection at 16 centers as part of the the Risk of Arterial Thrombosis In Relation to Oral Contraceptives (RATIO) study (from 1990 to 1995); additional patient recruitment and clinical data collection at a single center (from 1996 to 2001); blood collection from the recruited patients for aPL (assessed using the LA test, aCL IgG, aβ2GPI IgG and antiprothrombin antibody IgG) and genetic hypercoagulable states (including factor V Leiden [G1691A] mutation, prothrombin G20210A mutation and factor XIII 204Phe allele) (from 1998 to 2002); and surveys of recruited patients using a standardized questionnaire regarding the traditional thrombosis risk factors on the index date (the date of MI or ischemic stroke for patients and mid-year of the same year for controls) (from 1997 to 2001).
Lupus anticoagulant tests were positive in 17, 3 and 0.6% of ischemic stroke patients, MI patients and healthy controls, respectively (when the test was deemed positive was based on the International Society on Thrombosis and Homeostasis recommendations [15]). The authors defined the aCL IgG and aβ2GPI IgG positivity based on the 90th, 95th and 99th percentile of the concentrations for the controls; the proportion of aPL ELISA titers in the 99th percentile of the controls (the current recommendation for medium-to-high titer aCL and aβ2GPI positivity [1]) were relatively low (aCL IgG: 3.55% of ischemic stroke patients, 0.99% of MI patients and 0.96% of healthy controls; aβ2GPI IgG: 2.29% of ischemic stroke patients, 1.48% of MI patients and 0.96% of healthy controls).
Lupus anticoagulant positivity increased the odds ratio (OR) of ischemic stroke (OR: 43.1; 95% CI: 12.2-152) and MI (OR: 5.3; 95% CI: 1.4-20.8). ORs were similar when anticoagulated LA-positive patients were excluded from the analysis (for ischemic stroke, OR: 45.7; 95% CI: 12.4-169; and for MI, OR: 4.6; 95% CI: 1.1-19.5). Moreover, additional traditional thrombosis risk factors, such as smoking or oral contraceptives, further increased the risk, supporting the evidence in support of a multifactorial nature of thrombosis in aPL-positive patients (TABLES 1 & 2).
Odds ratios of ischemic stroke in patients who tested positive once for lupus anticoagulant.
NC: Not calculated, due to zero patients with ischemic stroke in the subgroup analysis.
LA: Lupus anticoagulant test; OR: Odds ratio; RF: Risk factor.
Odds ratios of myocardial infarction in patients who tested positive once for lupus anticoagulant.
NC: Not calculated, due to zero patients with myocardial infarction in the subgroup analysis.
LA: Lupus anticoagulant test; OR: Odds ratio; RF: Risk factor.
Significance
The authors performed a ‘risk-stratified’ analysis of a relatively large number of patients with arterial events and matched healthy controls. Their results corroborate those of others who have demonstrated that thrombosis is multifactorial and, more importantly, help us to quantify the thrombosis risk difference in aPL-positive patients based on the presence or absence of non-aPL thrombosis risk factors. However, it is important to note that this study by Urbanus et al. has significant methodological limitations that were discussed extensively by the authors and in an accompanying editorial [16].
The major limitations of this study include: the assessment of aPL only at one point in time (leading to limited certainty regarding the persistence of aPL) and many years after the clinical event (in epidemiological terms, unclear temporality between the exposure [aPL] and the outcome [arterial events]); the recollection of covariates such as oral contraceptive use many years after the vascular events (recall bias); the higher prevalence of cardiovascular risk factors in patients with vascular events compared with controls and unclear adjustments performed between cases and controls; and the noninclusion of patients who died after vascular events (survival bias). Furthermore, the cohort was composed only of women aged 18–49 years who were hospitalized with vascular events, thereby excluding data from different age groups and from males.
Thus, both the internal validity and generalizability of the results are limited owing to the methodological issues and cohort selection. However, the study provides more support, with quantified data, that the risk of thrombosis significantly increases in aPL-positive patients when other non-aPL thrombosis risk factors exist. Therefore, it is essential for aPL-positive patients that non-aPL thrombosis risk factors be monitored regularly. Continuous counseling and patient education should be incorporated into routine care and reversible thrombosis risk factors (e.g., oral contraceptives and smoking) should be eliminated or treated rigorously where possible.
Executive summary
Antiphospholipid syndrome is diagnosed when arterial/venous thrombosis and/or pregnancy morbidity occur in persistently antiphospholipid antibody (aPL)-positive patients.
A persistent and clinically significant aPL profile is only one of the risk factors for thrombosis; the risk of thrombosis in aPL-positive patients rises with increasing numbers of non-aPL thrombosis risk factors.
Results of a national multicenter study in women aged 18–49 years are consistent with the literature that states that lupus anticoagulant test positivity (a functional coagulation assay to detect aPL) is a major risk factor for ischemic stroke and myocardial infarction, and the risk is further increased in aPL-positive patients who also smoke or use oral contraceptives.
It is crucial that aPL-positive patients be monitored and counseled continuously in order to eliminate the reversible thrombosis risk factors.
Future perspective
Risk quantification should be better incorporated in APS research and management. Future collaborative larger-scale APS studies should be designed based on the strengths of the study by Urbanus et al. (e.g., a risk-stratified approach to both aPL tests/titers and non-aPL thrombosis risk factors, a relatively large population-based cohort and consideration of the false-positive LA test results in anticoagulated patients) but not the weaknesses (e.g., single aPL testing, including low-titers of aPL ELISA in the analysis and retrospective data collection). These future studies should aim to develop the ultimate ‘APS thrombosis risk calculator’, where the short- and long-term risk of thrombosis in the aPL-positive patient can be quantified based on other traditional thrombosis risk factors, genetic hypercoagulable states and systemic autoimmune diseases.
Footnotes
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.