**3. Epidemiology of stroke in the setting of APS**

#### **3.1 How many strokes can be attributed to antiphospholipid antibodies?**

APS has been a recognized cause of cerebrovascular events (CVE) especially in those without classic cardiovascular risk factors. Traditionally, it has been estimated that one in five strokes in patients younger than 45 could be associated with APS, but there have been concerns that this is an over-estimate due to referral bias [53]. Systematic reviews have provided much of our current knowledge on the prevalence of aPL in patients with vascular events, however broad population studies are lacking. One large study evaluating stroke, pregnancy morbidity, myocardial infarction, and deep vein thrombosis estimated that aPL antibodies were present in 14% of stroke patients [22].

APS, either primary or secondary, garners consideration especially in young patients with CVE. To address events in the young, the previous study [21] was repeated for those less than 50 years of age and positive aPL was found in 17.4% of cases [54]. Regardless of diagnosis, the presence of any aPL increased the risk of CVE by 5.48-fold for those under the age of 50, and the risk of thrombosis progressively increases with the increasing number of positive antibodies [54]. It has also been reported that patients with stroke and aPL positivity are younger and more likely to be female than patients with strokes who are aPL negative [51]. A similar risk for CVE has been recently reported in another study, where persistently positive aPL increased the risk of CVE by 4.62-fold and where the positive criteria and non-criteria aPL was found in 20/89 (22%) CVE patients [55].

#### **3.2 How common are cerebrovascular events among patients with APS?**

The Euro-Phospholipid Project cataloged the largest group of patients with APS. At the initiation of this study, prevalence data were obtained with 13.1% of patients having a stroke as their presenting manifestation [52]. Stroke was the fourth most common presenting symptom behind deep vein thrombosis, thrombocytopenia, and livedo reticularis. Of the 1000 patients, 204 (about 20%) experienced a stroke at some point during their disease course [52]. Cervera et al. [52] made a delineation regarding age-of-onset, defining "older-onset" APS as diagnosis after the age of 50. Comparatively, the over-50 patients were more likely to have strokes (30%) and were more likely to be male (34%), and were more likely to experience angina pectoris (9%) [52]. These patients were followed over a 10-year time period, and over that time period, 5.3% of the patients experienced a stroke. Stroke was the
