Paper

Lupus
2022, Vol. 31(2) 228–237
Antiphospholipid syndrome–mediated © The Author(s) 2022
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acute cerebrovascular diseases and long- sagepub.com/journals-permissions
DOI: 10.1177/09612033221074178
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term outcomes

Miguel Garcı́a-Grimshaw1,* , Diego Rubén Posadas-Pinto1,*, Amado Jiménez-Ruiz2,*,

Sergio Iván Valdés-Ferrer1,3,* , Arturo Cadena-Fernández1, José Jiram Torres-Ruiz4,
José Domingo Barrientos-Guerra1, Margarita Amancha-Gabela1, Erwin Chiquete1,† ,
Fernando Daniel Flores-Silva1,†  and Carlos Cantú-Brito1,†

Abstract
Objectives: The antiphospholipid syndrome (APS) is an autoimmune disease associated with thrombotic and non-
thrombotic neurologic manifestations. APS is classified as primary (PAPS) or secondary (SAPS) when it co-exists with
another autoimmune disease. We aim to describe the spectrum of acute cerebrovascular disease among patients with APS,
their differences between stroke subtypes, and long-term functional outcomes.
Methods: Retrospective cohort study including adult (≥18 years) patients with APS followed in the stroke clinic of a
tertiary-care reference center for autoimmune diseases in Mexico from 2009 to 2019.
Results: We studied 120 cases; 99 (82.5%) women; median age 43 years (interquartile range 35–52); 63.3% with SAPS.
Demographics, comorbidities, and antiphospholipid antibodies (aPL) positivity were similar between APS type and stroke
subtypes. Amongst index events, we observed 84 (70%) acute ischemic strokes (AIS), 19 (15.8%) cerebral venous
thromboses (CVT), 11 (9.2%) intracerebral hemorrhages (ICH), and six (5%) subarachnoid hemorrhages (SAH). Sixty-
seven (55.8%) were known patients with APS; the median time from APS diagnosis to index stroke was 46 months
(interquartile range 12–96); 64.7% of intracranial hemorrhages (ICH or SAH) occurred ≥4 years after APS was diagnosed
(23.5% anticoagulation-related); 63.2% of CVT cases developed before APS was diagnosed or simultaneously. Recurrences
occurred in 26 (22.8%) patients, AIS, in 18 (69.2%); intracranial hemorrhage, in eight (30.8%). Long-term functional
outcomes were good (modified Rankin Scale ≤2) in 63.2% of cases, during follow-up, the all-cause mortality rate was 19.2%.
Conclusion: We found no differences between stroke subtypes and APS types. aPL profiles were not associated with any
of the acute cerebrovascular diseases described in this cohort. CVT may be an initial thrombotic manifestation of APS with
low mortality and good long-term functional outcome.

Keywords
Antiphospholipid syndrome, stroke, cerebrovascular disease, systemic lupus erythematosus, stroke recurrence,
mechanism of disease 1
Date received: 24 June 2021; accepted: 31 December 2021
Introduction
The antiphospholipid syndrome (APS) (also known as
Hughes syndrome) is a systemic autoimmune disease
characterized by arterial or venous thrombosis and/or
pregnancy morbidity in the presence of persistently posi-
tive circulating antiphospholipid antibodies (aPL).1,2 APS
may be classified as primary (PAPS) or secondary (SAPS)
when it co-exists with another systemic autoimmune
disease.1,3 Both syndromes are associated with a broad
spectrum of neurologic and non-neurologic thrombotic
Department of Neurology and Psychiatry, Instituto Nacional de Ciencias
Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
2
Stroke, Dementia & Heart Disease Laboratory, Western University,
London, ON, Canada
3
Feinstein Institutes for Medical Research, Manhasset, NY, USA
4
Department of Immunology and Rheumatology, Instituto Nacional de
Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
*These authors contributed equally to this work as co-first authors.
†
Senior co-authors.
Corresponding authors:
Fernando Daniel Flores-Silva, Vasco de Quiroga #15, Sección XVI
Belisario Domı́nguez, Tlalpan, CDMX 14080, México.
Email: ferfs98@gmail.com
Co-corresponding author: Carlos Cantú-Brito, Vasco de Quiroga #15,
Sección XVI Belisario Domı́nguez, Tlalpan, CDMX, 14080, México.
Email: carloscantu_brito@hotmail.com
Garcı́a-Grimshaw et al.
manifestations and pose a high risk for recurrence.4,5
Among APS patients, the most common acute cerebro-
vascular disease (stroke) subtype is acute ischemic stroke
(AIS), followed by transient ischemic attacks (TIA) and
cerebral venous thrombosis (CVT). In addition, intracranial
hemorrhage (intracerebral hemorrhage [ICH] or subarach-
noid hemorrhage [SAH]) has been mostly reported as a
consequence of antithrombotic treatments.4,6 Although
APS has been studied for almost four decades, information
about APS-patients characteristics, stroke subtypes, lesion
topography, concurrent causes, and long-term outcomes is
limited to a few case series. Therefore, the objective of this
study is to describe the spectrum of acute stroke among
patients with APS, the differences between APS type and
stroke subtypes, and their long-term functional outcomes in
a cohort of patients followed in a stroke clinic over a 10-year
period.
Methods
Study design, setting, and patient selection
This observational retrospective cohort study was con-
ducted at the Instituto Nacional de Ciencias Médicas y
Nutrición Salvador Zubirán, a tertiary-care reference center
for autoimmune diseases in Mexico. The study was revised
and approved by our institutional Ethics and Research
Committees (Reference NER-2046-16-17-1). Due to the
nature of the study, both Committees waived the need for
signed informed consent. We reviewed electronic medical
records of all patients aged ≥18 years with a history of an
acute stroke, and APS followed in our outpatient stroke
clinic from January 2009 to December 2019. We excluded
patients not fulfilling the APS classification criteria, cases
where the time of APS diagnosis or index stroke could not
be accurately determined, and those with missing data re-
garding neuroimaging studies on the medical records.
Antiphospholipid syndrome diagnosis and treatment
APS diagnosis was made according to the revised Sydney
classification criteria.6 The aPL profile included lupus an-
ticoagulant (LA), anticardiolipin antibodies (aCL), and anti-
β2-glycoprotein I (anti-β2-GPI) antibodies. According to
recommendations from the International Society on
Thrombosis and Hemostasis, IgG and IgM isotypes of anti-
β2-GPI and aCL in serum or plasma were measured by
enzyme-linked immunosorbent assay and considered pos-
itive in titers >99th percentile of normal controls; LA
positivity was determined by dilute Russell viper venom
time; positive aPL were confirmed in two or more occa-
sions, 12 weeks after the initial testing.7,8 Cases were
categorized according to aPL positivity profile as double-
positive (any combination of LA, aCL, or anti-β2-GPI) or
229
triple-positive (all three aPL subtypes).2,9 Patients with co-
existing autoimmune diseases were classified as SAPS
cases.1,3 To evaluate risk of recurrent AIS we calculated the
adjusted global antiphospholipid syndrome score
(aGAPSS), which considers aPL positivity (aCL IgG/IgM,
5 points; anti-B2GPI IgG/IgM, 4 points; LA, 4 points) and
CVD risk factors (hyperlipidemia, 3 points; hypertension, 1
point).10,11 After the initial diagnosis, patients without
contraindications for anticoagulation were treated with
vitamin K antagonists (VKA) with a target international
normalized ratio (INR) of 2–3.5;12 or with antiplatelet
drugs, according to the attending physician’s criteria. As for
cases of intracranial hemorrhage, initial treatment included
antiplatelet drugs followed by VKA initiated 4–12 weeks
after the event depending on patient characteristics.13,14
Stroke subtypes and clinical outcomes
Stroke subtypes were classified according to the 2013
American Heart Association/American Stroke Association
Updated Definition of Stroke as AIS, TIA, CVT, ICH, or
SAH, and confirmed by either computed tomography (CT),
magnetic resonance imaging (MRI) with angiography/
venography, or digital subtraction angiography (DSA), as
deemed appropriate.15 Besides presence of circulating aPL,
the approach to determine other causes of AIS included a
transthoracic or transesophageal echocardiogram, an elec-
trocardiogram, 24-h Holter monitoring, assessment of the
carotid/vertebral arteries by duplex ultrasound, and intra-
cranial vessels by transcranial Doppler ultrasound. Testing
for other prothrombotic states was performed according to
attending neurologist criteria. The approach for all CVT
cases included testing for antithrombin III, protein C and S
deficiency, hyperhomocysteinemia, factor V Leiden and
prothrombin gene (G20210A) mutations, aside from con-
sidering other related conditions (e.g., pregnancy and pu-
erperium, oral contraceptives, drugs, or cancer), as proposed
by expert international consensus.16 As for intracranial
hemorrhage (ICH and SAH), we included other possible
causes after excluding CVT, such as severe thrombocy-
topenia (platelet count ≤20 × 109/L), over-anticoagulation
(INR ≥4.5), hypertension, trauma, and ruptured
aneurysm.17,18 All cases were evaluated in consensus by
two experienced vascular neurologists (C.C-B and F.D.F-
S). Stroke-related death was defined as that occurring
within the first 30 days after the event.19 Follow-up
functional outcome was assessed using the modified
Rankin scale (mRS) and defined as good (mRS ≤1) or poor
(mRS ≥2).20
Data collection
De-identified data were extracted from electronic medical
records using a standardized case report format and entered
230
into a secure online database. Data collection included age,
sex, cardiovascular disease (CVD) risk factors including
hypertension, diabetes, obesity (BMI ≥30 kg/m2), hyper-
cholesterolemia, smoking, alcoholism, history of myocar-
dial infarction, and use of corticosteroids and hormonal
contraceptives drugs at the time of index stroke. We also
registered the history of APS-related obstetric complica-
tions (abortions and preeclampsia) and extracranial sites of
thrombosis (arterial or venous) at the time of the first (index)
stroke; aPL positivity (LA, IgG/IgM aCL, and IgG/IgM
anti-β2-GPI) and titers at the time when APS was con-
firmed, co-existence of another rheumatic autoimmune
disease such as systemic lupus erythematosus (SLE),
rheumatoid arthritis (RA), Sjögren’s syndrome (SS), mixed
connective tissue disease (MCTD), or systemic sclerosis
(SSc), diagnosed before or during the study period; the
interval in months from APS diagnosis to index stroke and
first recurrence, stroke subtype, neuroimaging studies, for
AIS cases we recorded the presence of carotid and intra-
cranial atherosclerosis, determined by any imaging study as
either present or absent and categorized it by the percentage
of stenosis (≤50% or >50%); also, the involved arterial
territories; diagnostic approach for all stroke subtypes, use
of VKA or antiplatelet drugs before the events, platelet
count and INR level at the time of presentation; in-hospital
mortality, long-term clinical outcome, and interval in
months from index stroke to last follow-up visit. Two re-
searchers reviewed all data, and a third researcher adjudi-
cated any difference in interpretation between the two
primary reviewers.
Statistical analysis
We compared the characteristics of patients with PAPS or
SAPS and index events; recurrences were analyzed inde-
pendently. To analyze the differences between stroke sub-
types, we categorized them as AIS, intracranial hemorrhage
(ICH or SAH), and CVT. Categorical variables are reported
as frequencies and proportions; continuous variables as
median with interquartile range (IQR) or mean with stan-
dard deviation (SD). Analyses of categorical variables were
performed with the χ 2 or Fisher’s exact tests; non-
parametric continuous variables with the Mann–Whitney
U test or Kruskal–Wallis test; normally distributed con-
tinuous variables using the t-test for unpaired data, or
analysis of variance, as appropriate. Kaplan–Meier survival
curves were created to assess the overall mortality by stroke
subtypes during the 5 years after the event and analyzed
using the log-rank test. All p-values were two-tailed and
considered significant when <0.05. Statistical analyses were
performed with IBM SPSS Statistics, version 26 (IBM
Corp., Armonk, NY, USA), and statistical figures were
created using GraphPad Prism, version 9 (GraphPad
Software, La Jolla, CA, USA).
Lupus 31(2)
Results
We found 142 patients with APS and stroke. Twenty-two
cases were excluded; four did not fulfill the APS classifi-
cation criteria, 11 had incomplete data to accurately de-
termine either the timing of APS or index stroke diagnosis
and seven had missing data on neuroimaging studies. Thus,
we studied 120 cases with a total of 146 stroke events; 99
(82.5%) women and 21 (17.5%) men; median age 43 years
(IQR 35–52 years) (Table 1); 71 (61.7%) patients had at
least one CVD risk factor, 49 (40.8%) a history of extra-
cranial thrombosis before the index stroke, and 67 (55.8%)
were known patients with APS; 28 (23.3%) were taking
corticosteroids at the time of the index stroke, all were
patients previously diagnosed with SAPS. The most fre-
quent index stroke subtype was AIS (70%), followed by
CVT (15.8%), ICH (9.2%), and SAH (5%).
Antiphospholipid syndrome type
Regarding the APS type, SAPS was frequent (63.3%), with
SLE accounting for 96% (73 patients) of cases; co-existence
of SLE with another autoimmune disease was detected in
two patients (RA and secondary SS, respectively). Other
causes included primary SS, SSc, and MCTD, one case
each. Demographics and CVD risk factors were similar, as
well as the proportion of patients with a known history of
APS, extracranial thrombosis (PAPS 38.6% vs. SAPS
42.1%, p = 0.709), or preventive treatments (Table 1). There
were no statistical differences between aPL subtypes,
positivity profiles, or titers between groups (Table S1).
Supplemental Table S2 shows aPL titers by stroke subtype.
Among patients with a known history of APS, the median
time from APS diagnosis to index stroke was 46 months
(IQR 12–96), and in 15.8%, the diagnosis was simultaneous
(Figure 1). Index stroke subtypes and stroke-related death
rates were similar between APS types (Table 2).
Index stroke subtypes
Of the 84 patients with AIS, four (4.8%) had a history of
TIA, and 46 (54.8%) were known patients with APS; the
median time from APS diagnosis to AIS was 40.6 months
(IQR 10.8–93.2). Twelve (14.3%) patients had athero-
sclerosis without statistical differences between the type of
APS (PAPS 16.1% vs. SAPS 13.2%, p = 0.753); in three of
them, the stenosis was >50%; the internal carotid artery in
two and the middle cerebral artery (MCA) in one more. A
cardioembolic source was detected in 11 (13.1%) patients;
six cases were secondary to Libman–Sacks endocarditis,
four to valve disease (mitral stenosis in three; prosthetic
aortic valve in one more), and one was classified as a
paradoxical embolism due to an atrial septal defect, car-
dioembolism was more frequent in SAPS patients, but
Garcı́a-Grimshaw et al. 231

Table 1. Characteristics of patients with stroke by antiphospholipid syndrome type.

All patients (n = 120) Primary (n = 44) Secondary (n = 76) p-value

Sex, n (%), female 99 (82.5) 33 (75) 66 (86.8) 0.100

Age, median (IQR), years 43 (35–52) 46 (35–56) 43 (36–50) 0.245
Risk factors, n (%)
Hypertension 41 (34.2) 17 (38.6) 24 (31.6) 0.432
Diabetes 13 (10.8) 7 (15.9) 6 (7.9) 0.225
Obesity 36 (30) 17 (36.8) 19 (25) 0.116
Hypercholesterolemia 43 (35.8) 14 (31.8) 29 (38.2) 0.485
Smoking 22 (18.3) 7 (15.9) 15 (19.7) 0.602
Alcoholism 20 (16.7) 11 (25) 9 (11.8) 0.062
Acute myocardial infarction 6 (5) 3 (6.8) 3 (3.9) 0.668
Hormonal contraceptives 14 (14.1) 4 (12.1) 10 (15.2) 0.769
Preeclampsia, n (%) 5 (5.1) 2 (6.1) 3 (4.5) 0.746
History of abortions, n (%) 29 (29.3) 10 (30.3) 19 (28.8) 0.876
Extracranial sites of thrombosis, n (%)
Pulmonary embolism 17 (14.2) 5 (11.4) 12 (15.8) 0.503
Deep vein thrombosis 32 (26.7) 8 (18.2) 24 (31.6) 0.110
Retinal venous occlusion 9 (7.5) 3 (6.8) 6 (7.9) 0.782
Mesenteric 2 (1.7) 2 (4.5) 0 (0) 0.132
Other sites of thrombosis 6 (5) 3 (6.8) 3 (3.9) 0.668
Type of positive aPL, n (%)
aCL, IgG 89 (74.2) 33 (75) 56 (73.7) 0.847
aCL, IgM 70 (58.3) 23 (52.3) 47 (61.8) 0.306
anti-β2-GPI, IgG 66 (55) 26 (59.1) 40 (52.6) 0.493
anti-β2-GPI, IgM 55 (45.8) 16 (36.4) 39 (51.3) 0.113
Lupus anticoagulant 111 (92.5) 42 (95.5) 69 (90.8) 0.483
Double-positive profile, n (%) 41 (34.2) 13 (29.5) 28 (36.8) 0.417
Triple-positive profile, n (%) 69 (57.5) 27 (61.4) 42 (55.3) 0.515
aGAPSS points, mean (±SD) 12.2 (3.4) 12.2 (3.4) 12.2 (3.5) 0.924
APS diagnosis before stroke, n (%) 67 (55.8) 23 (52.3) 44 (57.9) 0.550
Months from APS to stroke, median (IQR)a 45.1 (12.5–93.2) 32 (6–116) 47.2 (19.5–93.2) 0.357
Treatments at the time of stroke, n (%)
Antiplatelets 24 (20) 10 (22.7) 14 (18.4) 0.570
Vitamin K antagonist 28 (23.3) 6 (13.6) 22 (28.9) 0.056
Stroke subtype, n (%)
Acute ischemic stroke 84 (70) 31 (70.5) 53 (69.7) 0.779
Intracerebral hemorrhage 11 (9.2) 4 (9.1) 7 (9.2)
Subarachnoid hemorrhage 6 (5) 2 (4.5) 4 (5.3)
Cerebral venous thrombosis 19 (15.8) 7 (15.9) 12 (15.8)
Index stroke-related death, n (%) 6 (5) 0 (0) 6 (7.9) 0.084
Good functional outcome, n (%)b 72 (60) 30 (68.2) 42 (55.3) 0.164
Follow-up, median (IQR), monthsb 82 (37–97) 72 (21–101) 83 (39–96) 0.535
IQR: interquartile range; APS: antiphospholipid syndrome; aPL: antiphospholipid antibodies; aCL: anticardiolipin antibodies; anti-β2-GPI: anti-β2-gly-
coprotein I antibodies; aGAPSS: adjusted global antiphospholipid syndrome score.
a
Analysis for the 67 patients with a history of APS before index stroke.
b
Data for 114 surviving patients.

without statistical differences (17% vs. 6.5%, p = 0.201).
None had known atrial fibrillation (KAF) or atrial fibril-
lation detected after stroke (AFDAS). Other prothrombotic
states were tested in 27/84 (32.1%) patients; the performed
approach was negative for all. Of the 17 patients taking
VKA, five (29.4%) were within therapeutic goals of
anticoagulation. On neuroimaging, bilateral lesions were
detected in 24 (28.6%) patients; 19 (22.6%) had multivessel
disease, and 33 (39.3%) had multiple lesions. Fifty-one
(60.7%) had anterior circulation lesions, 18 (21.4%) had
posterior circulation lesions, and 15 (17.9%) had lesions in
both. The MCA territory was the most commonly involved
232
Figure 1. Temporality of stroke subtype with the diagnosis of antiphospholipid syndrome. APS: antiphospholipid syndrome.
in 62 (73.6%) patients, followed by the posterior cerebral
artery in 15 (17.9%). Figure 2 shows the overall distribution
of the lesions, and Supplemental Table S3 their differences
between APS types.
Among the 19 patients with CVT, the index event oc-
curred before or at the time of APS diagnosis in 66.2% of
cases (Figure 2); the median time from APS diagnosis to
CTV was 29.8 months (IQR 9.5–76.6). None tested
positive for other prothrombotic states; at the time of the
event, two out of four patients taking VKA were within
therapeutic goals. The superior sagittal sinus (8/19,
42.1%) was the most common site involved, followed
by the transverse (lateral) sinus (6/19, 31.6%), deep
cerebral venous system (3/19, 15.8%), and cortical veins
(2/19, 10.5%); four had a concomitant hemorrhagic
component (superior sagittal sinus in three; transverse
sinus in one), none of them were anticoagulated at the
time of CVT onset.
There were 17 cases of intracranial hemorrhage, 14
(82.4%) in patients with a known history of APS, within a
median time of 67.8 months (IQR 52.1–150.2) after the
diagnosis. Of all hemorrhages, 11 were ICH, seven were
lobar, three were within the basal ganglia, and one was
intraventricular; five patients were taking VKA. Putative
causes included severe thrombocytopenia (lobar in two
cases; basal ganglia and intraventricular in one case each),
uncontrolled hypertension (basal ganglia and lobar; two
cases each), and three were over-anticoagulation-related
(lobar in all cases). In addition, there were six SAH ca-
ses; two were related to an intracranial aneurysm located
within the right proximal MCA and right anterior com-
municating artery in one case each, two more were asso-
ciated to severe thrombocytopenia, located within the
frontoparietal region (bilateral) and the right parieto-
occipital sulcus (one case each), one case was due to
Lupus 31(2)
over-anticoagulation (anterior interhemispheric fissure),
and in one, the mechanism remained undetermined (peri-
mesencephalic); none had a history of recent trauma.
Among patients receiving VKA, over-anticoagulation ac-
counted for 23.5% (4/17) of intracranial hemorrhages.
Clinical outcome
There were six (5%) index stroke-related deaths; the median
follow-up time for the 114 surviving patients was 82 months
(IQR 37–97). During follow-up, the all-cause mortality rate
for the entire cohort was 19.2% (stroke-related in 10 [8.3%]
cases and non-stroke–related in 13 [10.8%]), which was
significantly higher in those who suffered an intracranial
hemorrhage either during index stroke or during follow-up,
and the 5-year survival probability was higher for patients
with CVT (Figure 3(a)). Among the 13 patients who died of
a non-stroke-related cause during follow-up, eight deaths
were associated with an infectious cause, two were related
to status epilepticus, one due to acute gastrointestinal
bleeding, decompensated chronic heart failure, and chronic
kidney disease in one case each. Long-term functional
outcome was good for 72 (63.2%) and poor for 42 (36.8%)
of the index stroke survivors. Patients diagnosed with CVT
had a better functional prognosis than those with other
stroke subtypes (Figure 3(b)).
Recurrences
Twenty-six patients (22.8%) had recurrent events (PAPS
25% vs. SAPS 19.7%, p = 0.5) within a median time of
37.8 months (IQR 25–57). There were 18 (69.2%) cases of
AIS (median time to recurrence 35.5 months, IQR 25–55),
16 were taking VKA, but only six (37.5%) were within
therapeutic goals. Intracranial hemorrhage occurred in eight
Garcı́a-Grimshaw et al. 233

Table 2. Characteristics of patients with antiphospholipid syndrome by stroke subtype.

Acute ischemic stroke Intracranial hemorrhage Cerebral venous thrombosis

(n = 84) (n = 17) (n = 19) p-value

Sex, n (%), female 69 (82.1) 14 (82.4) 16 (84.2) 0.977

Age, median (IQR), years 44 (36–52) 44 (35–50) 38 (32–53) 0.701
Risk factors, n (%)
Hypertension 27 (32.1) 8 (47.1) 6 (31.6) 0.481
Diabetes 7 (8.3) 3 (17.6) 3 (15.8) 0.398
Obesity 26 (31) 4 (23.5) 6 (31.6) 0.820
Hypercholesterolemia 30 (35.7) 4 (23.5) 9 (47.4) 0.330
Smoking 17 (20.2) 2 (11.8) 3 (15.8) 0.679
Alcoholism 15 (17.9) 2 (11.8) 3 (15.8) 0.823
Systemic lupus erythematosus 51 (60.7) 10 (58.8) 12 (63.2) 0.964
Acute myocardial infarction 4 (4.8) 1 (5.9) 1 (5.3) 0.980
Hormonal contraceptives 11 (15.9) 1 (7.1) 2 (12.5) 0.676
Corticosteroids 19 (22.6) 5 (29.4) 4 (21.1) 0.806
History of abortions, n (%) 20 (29) 3 (21.4) 6 (37.5) 0.625
Preeclampsia, n (%) 4 (5.8) 0 (0) 1 (6.3) 0.646
Extracranial sites of thrombosis, n (%)
Pulmonary embolism 9 (10.7) 4 (23.5) 4 (21.1) 0.248
Deep vein thrombosis 23 (27.4) 7 (41.2) 2 (10.5) 0.112
Retinal venous occlusion 5 (6) 2 (11.8) 2 (10.5) 0.611
Mesenteric 0 (0) 1 (5.9) 1 (5.3) 0.092
Other sites of thrombosis 4 (4.8) 1 (5.9) 1 (5.3) 0.980
Type of positive aPL, n (%)
aCL, IgG 63 (75) 14 (82.4) 12 (63.2) 0.401
aCL, IgM 49 (58.3) 11 (64.7) 10 (52.6) 0.764
anti-β2-GPI, IgG 49 (58.3) 10 (58.8) 7 (36.8) 0.222
anti-β2-GPI, IgM 39 (46.4) 8 (47.1) 8 (42.1) 0.938
Lupus anticoagulant 75 (89.3) 17 (100) 19 (100) 0.124
Double-positive profile, n (%) 26 (31) 8 (47.1) 7 (36.8) 0.427
Triple-positive profile, n (%) 51 (60.7) 9 (52.9) 9 (47.4) 0.523
aGAPSS points, mean (±SD) 12.4 (3.3) 12.1 (3.3) 11.7 (4.2) 0.494
APS diagnosis prior to index stroke, 46 (54.8) 14 (82.4) 7 (36.8) 0.022
n (%)
Months from APS to stroke, median 40.6 (10.8–93.2) 67.8 (52.1–150.2) 29.8 (9.5–76.6) 0.261
(IQR)a
Treatments at the time of stroke, n (%)
Antiplatelets 20 (23.8) 1 (5.9) 3 (15.8) 0.213
Vitamin K antagonist 17 (20.2) 7 (41.2) 4 (21.1) 0.171
Index stroke-related death, n (%) 2 (2.4) 3 (17.6) 1 (5.3) 0.031
Good functional outcome, n (%)b 49 (58.3) 8 (47.1) 15 (78.9) 0.127
Follow-up, median (IQR), monthsb 82 (41–96) 36 (12–112) 87 (25–100) 0.304

IQR: interquartile range; APS: antiphospholipid syndrome; aPL: antiphospholipid antibodies; aCL: anticardiolipin antibodies; anti-β2-GPI: anti-β2-gly-
coprotein I antibodies; aGAPSS: adjusted global antiphospholipid syndrome score.
a
Analysis for the 67 patients with a history of APS before index stroke.
b
Data for 114 surviving patients.

(30.8%) patients (ICH, in seven; SAH, in one) within a
median time of 49.5 months (IQR 27–63.5); six were taking
VKA, four within therapeutic ranges, and two were over-
anticoagulated, none had thrombocytopenia. There were no
recurrent cases of CVT. Recurrent stroke subtypes and APS
type were similar (p = 0.741).
Of the initial 84 cases of AIS, 14 (16.7%) had a recurrent
arterial event; five (41.7%) out of 12 patients taking VKA
were within anticoagulation goals; two were diagnosed with
Sneddon syndrome with skin biopsy after the initial event.
The proportion of patients according to APS type was
similar (PAPS 7/31, 22.6% vs. SAPS 7/31; p = 0.266). On
234 Lupus 31(2)

Figure 2. Distribution and frequency of acute ischemic stroke lesions by arterial territories. (A) Frequency of the lesions by their main
arterial vascular territory and infratentorial structures. (B) Frequency of the lesions located within the territory of the main cerebral
arteries perforating branches. (C) Frequency of subcortical lesions (includes watershed infarcts and non-specific white matter lesions)
located within the territory of the main cerebral arteries perforating branches. (D) Frequency of lesions (cortical/subcortical) involving a
well-defined vascular territory. ACA: anterior cerebral artery; MCA: middle cerebral artery; PCA: posterior cerebral artery.

univariable analysis, there were no statistical differences of
mean aGAPSS points between recurrent and non-recurrent
AIS patients (13.9 ± 2 vs 12.1 ± 3, p = 0.065). There were
four deaths related to stroke recurrence; three occurred in
patients with ICH.
Discussion
This study describes the spectrum of APS-related acute
stroke in a national tertiary-care reference center for au-
toimmune diseases. Interestingly, most SAPS cases in our
cohort were SLE-related (96%), a well-known risk factor for
intracranial thrombotic events and atherosclerosis;21–23
however, there were no differences between APS types
and stroke subtypes, aPL positivity profiles, recurrences, or
long-term functional prognosis. Similar to the reported in
the Euro-Phospholipid Project, which included patients
with PAPS and SAPS, AIS was the most frequent stroke
subtype in our cohort.6 In the present study, CVT was the
second most common type of stroke, while TIA’s took this
place in their cohort. This finding may be due to differences
in methodological approaches or because in our center, the
diagnosis and reference of TIA’s to the stroke clinic relied
upon attending physician criteria, and as we only detected
four patients who later developed an AIS, we took the latter
as the qualifying event.
The timing from APS diagnosis to stroke onset was
highly variable; most intracranial hemorrhages occurred ≥4
years after the diagnosis, despite a low frequency of
anticoagulation-related hemorrhages. On the other hand,
AIS occurred early in 45% of cases (before or at the time of
APS diagnosis) or late after several years of the course of the
APS, and most CVT cases (63%) developed before or at the
time of APS diagnosis, suggesting that CVT may be the first
clinical manifestations of APS. Also, it has been reported
that LA positivity increases the risk for AIS;24 however, we
detected LA in 92.5% of our studied population, including
those with intracranial hemorrhage and CVT. Interestingly,
we found no differences between CVD risk factors or aPL
profiles and stroke subtypes. The aforementioned suggests
that multiple potentially preventable systemic factors, not
solely APS, may cause the spectrum of cerebrovascular
diseases hereby described.
Among our 84 index AIS cases, 22.6% had multivessel
disease, and lesions of the MCA territory accounted for
73.6% of cases, comparable with the 68% reported in a
Garcı́a-Grimshaw et al.
Figure 3. Mortality over time and functional outcome during follow-up. (a) Kaplan–Meier analysis of 5-year mortality according to
stroke subtype. (b) Overall long-term functional outcome during the median follow-up time of 82 months (interquartile range 37–97
months) by stroke subtype.
series analyzing the lesion topography of 25 patients.25
Additionally, 34.5% of our cases had lesions of the
large vessels perforating branches. In a study of 53 patients
with PAPS using the Oxfordshire Community Stroke
Project classification system, clinically, the lesion was
located within the posterior circulation in 22.6% of their
patients,26 whereas when taking into account multivessel
disease restricted to the posterior circulation (including
vertebral and basilar arteries perforating branches), we
found a frequency of 42.9%. This high proportion of si-
multaneous involvement of several arterial territories and
vessel size shows that the cerebral arterial system can be
globally affected in APS.
APS patients develop endothelial cell dysfunction during
the early stages of the disease, followed by accelerated
systemic atherosclerosis and microvascular endothelial
dysfunction that may also present as small vessel
disease,5,27 which in some series of APS and non-APS
patients has shown to predict cognitive impairment.28,29
Atherosclerosis was detected in 14.3% of AIS cases without
differences between APS types, falling within the reported
frequency by other authors among APS patients, regardless
of the type.30–32 Furthermore, 60% of our patients had an
associated CVD risk factor despite a relatively young age or
an APS-related cardiac manifestation (e.g., Libman–Sack
endocarditis and valvular disease), implying that in APS,
multiple AIS etiologies may co-exist, not solely in-situ
thrombosis.4,33 Therefore, a broad range of mechanisms
should be considered when approaching these patients.
SLE patients have a threefold higher risk for ICH or
SAH.34 However, little is known about intracranial hem-
orrhage in APS. During the 10-year follow-up of the Euro-
Phospholipid Project, 61 (24.6% intracranial) major
bleeding episodes were reported, all in patients with an-
tithrombotic treatments.6 Of our 17 index intracranial
hemorrhage cases, over-anticoagulation accounted for
23.5% of these cases, suggesting that intracranial bleeding
235
disorders among these patients are not merely related to
anticoagulant complications; other identifiable risk factors
included hypertension and platelet disorders; as the exact
mechanisms for intracranial hemorrhage in these patients
are still unclear, we hypothesize that chronic thrombotic
microangiopathy may predispose APS patients for both ICH
and SAH in combination with other CVD risk factors,27
especially in patients with SAPS where the chronic in-
flammatory state by the underlying autoimmune disease
may promote vascular fragility.23,27
Stroke-related mortality in this group of young patients
was 8.3%, higher than the 4–5% of stroke-related deaths
foreseen for this age group;35,36 however, during long-term
follow-up, the overall mortality rate of 19.2% is similar to
that of 20% reported among non-APS adults aged 18–50
years during an 11-year follow-up period, regardless of the
stroke subtype.35 As for the functional prognosis, more than
60% of patients with AIS and CVT had a good functional
outcome, contrary to those who presented with an intra-
cranial hemorrhage, as expected for the general population
within the studied age group.23,36–40
Our AIS recurrence rate (16.7%) falls within the 15–37%
reported among APS patients;26,41 despite this high fre-
quency, to date there is no reliable biomarker or prediction
tool to help distinguish patients most likely to have a re-
current event. The aGAPSS is a tool that has proven to
predict extracranial thrombotic events;10,11 therefore, as
there is no defined cut-off value for intracranial events, we
explored by univariable analysis if there was a difference in
the total score of this prediction tool between patients who
had an AIS recurrence and those who did not, finding that
there was no statistical difference. Furthermore, despite
adequate anticoagulation, our AIS recurrence rate also falls
within the 5-year recurrence rate of 14–26% reported in
non-APS patients,42,43 reinforcing the need for strict goal-
oriented care of comorbidities as in patients without
APS.1,34
236
This study has several limitations. First, due to our
retrospective and observational design, where we retro-
spectively collected data from electronic medical records,
we could not accurately determine the acute clinical pre-
sentation to assess the significance of the neuroimaging
findings herby described, the short-term functional outcome
to evaluate its evolution during follow-up, cumulative doses
of corticosteroids, as well as treatment strategies, adherence,
or INR fluctuations for patients receiving VKA. Second,
although the study was conducted in a national reference
hospital for autoimmune diseases, as it is a single-center,
hospital-based study, our findings may not represent our
entire population due to referral bias. In line with the
previous limitation, we were unable to record and analyze
other well-known risk factors such as pregnancy or puer-
perium because in our center as standard practice, those
cases are referred to a third-level hospital specialized in
maternal and child health care; however, none of the cases
presented within this timeframe. Third, as anti-
phosphatidylserine/prothrombin antibodies (aPS/PT) in-
cluded in the original global antiphospholipid syndrome
score (GAPSS) are not routinely tested in our center, we
were unable to evaluate the predictive accuracy of the al-
ready validated cut-off values for this version.44 Last, as
APS is a relatively rare disease, in addition to the low
number of recurrences we observed, statistical power was
limited to accurately evaluate the risk of AIS or CVT re-
currences by multivariable analysis or derive cut-off values
for the aGAPSS; therefore, our results should be taken with
caution.
In conclusion, we found no differences between the
analyzed stroke subtypes and the APS type. APL profiles
were not associated with any of the acute cerebrovascular
diseases hereby described. CVT may be an initial throm-
botic manifestation of APS with low mortality and good
long-term functional outcome. In this relatively young
cohort, well-known CVD risk factors for acute cerebro-
vascular events were detected in more than half of cases;
therefore, close follow-up and strict goal-oriented care of
comorbidities are imperative for patients with APS. More
extensive prospective studies to detect patients who will
develop a recurrent stroke and accurately determine the
pathophysiological mechanisms of the different cerebro-
vascular events that patients with APS can develop are still
required.
Data availability
The manuscript provides all the collected data. De-identified
data to replicate our results will be available to qualified
researchers upon written request to the corresponding author.
Acknowledgments
None.
Lupus 31(2)
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with re-
spect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, au-
thorship, and/or publication of this article.
ORCID iDs
Miguel Garcı́a-Grimshaw  https://orcid.org/0000-0001-5287-1068
Sergio Iván Valdés-Ferrer  https://orcid.org/0000-0002-4863-6484
Erwin Chiquete  https://orcid.org/0000-0002-1142-295X
Fernando Daniel Flores-Silva  https://orcid.org/0000-0002-
3324-3565
Supplemental Material
Supplemental material for this article is available online.
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