1150349 WSO International Journal of StrokeMittal et al.

Review

International Journal of Stroke

Antiphospholipid syndrome,
2023, Vol. 18(4) 383­–391
© 2023 World Stroke Organization
Article reuse guidelines:
antiphospholipid antibodies, and stroke sagepub.com/journals-permissions
https://doi.org/10.1177/17474930221150349
DOI: 10.1177/17474930221150349
journals.sagepub.com/home/wso

Prabal Mittal1,2, Graziella Quattrocchi3,4, Ibrahim Tohidi-Esfahani1,2,

Zara Sayar1,5, Arvind Chandratheva3,6 and Hannah Cohen1,2

Abstract
Antiphospholipid syndrome (APS) is a prothrombotic autoimmune disease with heterogeneous clinicopathological
manifestations and is a well-established cause of acute ischemic stroke (AIS) and transient ischemic attack (TIA), particularly
in younger patients. There is growing recognition of a wider spectrum of APS-associated cerebrovascular lesions,
including white matter hyperintensities, cortical atrophy, and infarcts, which may have clinically important neurocognitive
sequalae. Diagnosis of APS-associated AIS/TIA requires expert review of clinical and laboratory information. Management
poses challenges, given the potential for substantial morbidity and recurrent thrombosis, additional risk conferred
by conventional cardiovascular risk factors, and limited evidence base regarding optimal antithrombotic therapy for
secondary prevention. In this review, we summarize key features of APS-associated cerebrovascular disorders, with
focus on clinical and laboratory aspects of diagnostic evaluation. The current status of prognostic markers is considered.
We review the evidence base for antithrombotic treatment in APS-associated stroke and discuss uncertainties, including
the optimal intensity of anticoagulation and efficacy of direct oral anticoagulants. Clinical practice recommendations are
provided, covering antithrombotic treatment, supportive management, and options for anticoagulant-refractory cases,
and we highlight the benefits of adopting a considered, multidisciplinary team approach.

Keywords
Antiphospholipid syndrome, antiphospholipid antibodies, ischemic stroke, cerebrovascular disorders, cognitive
impairment, antithrombotic

Received: 7 July 2022; accepted: 9 November 2022

are arterial, venous, or microvascular thrombosis and/or

Search strategy and selection criteria
obstetric morbidity, including recurrent early miscarriage,
The following search strategy was used in PubMed, limiting to late pregnancy loss, stillbirth, and placental insufficiency.
English language articles from January 1990 to March 2022. The diagnosis requires coexistence with persistent
– Search terms: [“antiphospholipid syndrome” OR
“antiphospholipid antibodies”] AND [“stroke” OR 1
 epartment of Haematology, University College London Hospitals
D
“cerebrovascular”] NHS Foundation Trust, London, UK
2
Haemostasis Research Unit, Department of Haematology, University
This was supplemented with recommendations from senior College London, London, UK
authors and citation searching from key articles. The final 3
Comprehensive Stroke Service, University College London Hospitals
reference list was selected according to relevance to the NHS Foundation Trust, London, UK
broad scope of this review. 4
Department of Neurology, North Middlesex NHS Trust, London, UK
5
Department of Haematology, Whittington Health NHS Trust,
London, UK
6
UCL Stroke Research Centre, Department of Brain Repair and
Rehabilitation, UCL Institute of Neurology and the National Hospital
Introduction for Neurology and Neurosurgery, London, UK
Antiphospholipid syndrome (APS) is an acquired autoim-
Corresponding author:
mune thrombophilia with an estimated incidence and prev- Prabal Mittal, Department of Haematology, University College London,
alence between 1 and 2 cases per 100,000 and 40 and 50 72 Huntley St, London, WC1E 6DD, UK.
cases per 100,000, respectively.1 Cardinal features Email: [email protected]

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384 International Journal of Stroke 18(4)

antiphospholipid antibodies (aPL), detected on two or more individuals being women.17,18 This highlights the impor-
consecutive occasions, at least 12 weeks apart.2 There is tance of aPL testing in CVT, even in cases with possible
clinical overlap with systemic lupus erythematosus (SLE), alternative etiologies, as the literature reports coexistence of
with estimates that 7–15% of SLE patients also have APS.3,4 multiple risk factors in CVT with APS,17 and increased
While SLE-associated APS exhibits female preponderance, thrombotic risk in APS patients with additional risk fac-
primary thrombotic APS is evenly distributed between tors.19,20 The presence of APS may also affect management.
sexes.1 APS is typically diagnosed in younger patients, with Much like the general CVT patient population,21 in
population-based studies suggesting a mean age at diagno- APS-related CVT, the recurrence rate seems low; however,
sis of around 50 years.1 Notably, late-onset APS may be patients can experience subsequent thrombosis in other
associated with a higher frequency of arterial thrombosis.5 locations.17 Retinal veins can be involved, and branched or
Beyond thrombosis and obstetric morbidity, APS can be central retinal vein occlusions have been described.15
also associated with a variety of other manifestations, includ-
ing neurological conditions, such as neuropsychiatric symp-
Catastrophic antiphospholipid syndrome
toms, headache, seizures, movement disorders, multiple
sclerosis-like disease, transverse myelitis, peripheral neu- Catastrophic antiphospholipid syndrome (CAPS) is a life-
ropathy, and autonomic symptoms. These, and their possible threatening variant seen in approximately 1% of APS
pathogenetic mechanisms, have been discussed elsewhere.6 patients, characterized by rapid onset of multifocal, pre-
We focus here on APS-associated stroke and other cerebro- dominantly microvascular, thrombosis (affecting three or
vascular disorders. more organ systems within 1 week).22 Central nervous sys-
tem (CNS) involvement is frequent, along with renal, lung,
and cardiac involvement, with each found in more than
APS-associated cerebrovascular 50% of cases in the international “CAPS Registry”.22 CNS
disorders manifestations include ischemic and hypertensive encepha-
lopathy, ischemic stroke, and CVT.22
Acute ischemic stroke and transient
ischemic attacks
Cognitive impairment
Acute ischemic stroke (AIS) and transient ischemic attack
(TIA) are the most common manifestations of arterial Cognitive impairment, particularly involving memory,
pathology in APS,7 with approximately 20% of patients attention, and executive functions, appears common, affect-
with APS suffering a stroke more than 10 years.8 In indi- ing 11–60% of APS patients, whether primary or SLE-
viduals aged below 50 years, 17% of strokes and 12% of associated, although evidence is limited by the use of
TIA are associated with aPL,9 suggesting APS is an impor- heterogeneous neuropsychological tests and confounders,
tant cause of strokes in younger patients. such as age, gender, and education levels.23 Interestingly,
Thrombosis is thought to be the most common mecha- deficits in global cognition were found to be associated
nism, with intracranial large arteries, particularly the specifically with anticardiolipin (aCL) positivity.23
middle cerebral artery (MCA), being the most common site Cognitive dysfunction might be explained by hyperco-
of occlusion.10 Embolism from valvular heart disease agulability and occlusive thrombosis, due to aPL, causing
(Libman–Sacks endocarditis), extracranial carotid artery not only small vessel ischemic damage but also brain vol-
lesions,11 vasculitis-like manifestations,12 chronic occlu- ume loss. Indeed, the cognitive profile is similar to that
sive vasculopathy affecting small- and medium-sized observed in vascular cognitive impairment, and cognitive
intracerebral arteries,13 and carotid or vertebral artery dis- dysfunction seems to be associated with white matter
section14 are also described. hyperintensities (WMH), ischemic lesions, and cortical
The clinical picture depends on the arterial territory atrophy on structural magnetic resonance imaging (MRI).23
involved. Moreover, in cases with retinal artery involve- However, animal models of cognitive deficits following
ment, eye events, such as branched or central retinal artery exposure to aPL also suggest a possible direct pathogenic
occlusion, can also occur.15 effect of aPL.24,25

Cerebral vein thrombosis Other aPL-associated neurological manifestations

Cerebral vein thrombosis (CVT) is an uncommon manifes- Reversible cerebral vasoconstriction syndrome, a neuro-
tation of APS (7 CVT in 1000 APS cases in the Euro- vascular disorder with headache and radiologically revers-
Phospholipid cohort)16. It has been estimated that about ible vasoconstriction, has been described in APS.26 The
80% of APS-associated CVT cases represent the first APS hypothesis is that aPL may activate endothelial cells, caus-
clinical manifestation.17 CVT in APS patients seems clini- ing vasoconstrictor release.27 Sneddon’s syndrome, a
cally similar to CVT by other causes, with the most affected rare non-inflammatory thrombotic vasculopathy affecting

International Journal of Stroke, 18(4)

Mittal et al. 385

mainly young women with livedo reticularis and recurrent defined by a cut-off threshold of >40 units/mL or >99th
cerebral infarctions or TIAs, can occur in association with centile of a normal reference population.2
APS.28 The role of aPL in these cases is not fully defined. IgG versus IgM isotypes: The thrombotic association of
Acute ischemic encephalopathy, characterized by confu- IgM aPL is suggested to be weaker than that of IgG, and a
sion, hyperreflexia, and asymmetric quadriparesis, has multicentre study concluded that the role of IgM aPL may
been described in ~1% of APS patients.16 APS has also be limited to prognostication rather than diagnosis.37
been reported in association with Moyamoya disease.29 However, patients with ischemic stroke were under-repre-
Two cases of likely APS-related non-thrombotic internal sented. A retrospective study reported that patients with
jugular vein stenosis, possibly due to aPL-mediated vessel isolated IgM accounted for a substantial proportion of their
wall damage, have been reported.30 APS population (24/168; 14.3%) and had a stronger asso-
Coronavirus disease 2019 (COVID-19) is associated ciation with stroke.38 Pending more definitive data, it seems
with arterial thromboembolism, including AIS, with preva- prudent to retain IgM positivity as an independent diagnos-
lence of 4.0% and 1.6%, respectively.31 Increased frequency tic criterion.
of aPL is described in COVID-19 cases.32 However, Table 1 summarizes practical considerations for aPL
COVID-19-associated aPL are often transient and their screening, including recommendations for LA testing in
role (epiphenomenal versus pathogenic) in COVID-19- patients on anticoagulation.
associated thrombosis, as well as any possible long-lasting Non-criteria aPL: Several additional aPL, including
effects, remains unclear.33 antiphosphatidylserine-prothrombin (aPS/PT) antibodies
and antibodies against the domain I of beta2-glycoprotein
(aDI), are recognized as pathogenic and may have prognos-
Diagnostic evaluation tic significance. However, testing in routine practice is not
International consensus classification criteria for APS2 currently recommended, as added diagnostic value has not
were primarily designed for research purposes, rather than been demonstrated.39
rigid application in clinical practice. New classification cri- Age threshold for aPL testing: Current guidance recom-
teria are in development.34 Interpretation of laboratory and mends routine screening for aPL in younger patients
clinical information can be challenging and requires expert (<50 years of age) with stroke,36,40 although this is prag-
review. matic rather than strictly evidence-based. In older patients,
aPL testing should be considered on an individualized
basis, as the constitutional risk of thrombosis increases
Antiphospholipid antibody laboratory testing with age, as does the prevalence of incidental autoantibod-
The discovery and characterization of aPL, from the identi- ies, including aPL.1
fication of lupus anticoagulant (LA) in SLE patients and Timing of aPL testing: The optimal timing of aPL testing
subsequent correlation with false-positive results in the after a thrombotic event is undefined. LA testing in the
cardiolipin-based Venereal Disease Research Laboratory early post-thrombotic phase may be unreliable due to fac-
test (VDRL), are well described.35 According to current tors described earlier. A triple-positive aPL profile, how-
guidance, accurate determination of aPL status requires ever, is likely to be persistent and clinically relevant.41
testing for all three criteria aPL: LA, and IgG and IgM aCL For patients with AIS/TIA who merit APS screening,
and anti-beta 2 glycoprotein 1 (aß2GP1) antibodies, and laboratory testing during the acute presentation may pre-
checking for persistence of positive results beyond vent this being missed later. If a convincingly positive ini-
12 weeks.36 Demonstrating persistence is essential to tial result is obtained, it appears reasonable to consider
exclude patients with false-positive results and transient early anticoagulation, on an empirical basis.
epiphenomenal aPL, such as that described in viral and bac-
terial infections, including hepatitis B/C, HIV, and syphi-
Cerebrovascular workup
lis,33 which are not typically associated with thrombosis.
LA: It refers to the phenomenon of in vitro prolongation Diagnosis of AIS or TIA may be challenging if the patient
of phospholipid-dependent clotting times. LA testing is is not seen in the acute phase or if TIA symptoms do not
susceptible to interference from several factors, notably have an imaging correlate. Differential diagnoses include
anticoagulant therapy. Acute phase reactants may confound migraine, seizures, functional neurological symptoms, and
LA testing immediately post-stroke, with false negatives demyelinating processes. If aPL are identified in the setting
occurring due to raised coagulation factor VIII and false of brain ischemia, their etiological relevance should be
positives due to raised C-reactive protein.36 evaluated, considering features such as aPL profile, patient
aCL and aß2GP1 antibodies: These antibodies are age, and clinical history, and an assessment of alternative
directly quantified by commercially available immunoas- causes and vascular risk factors. A complete workup should
says. Moderate-to-high titer aCL and aß2GP1 antibodies include MRI head, intracranial and extracranial vascular
are considered clinically relevant for thrombosis, generally imaging (MR or computed tomography (CT) angiogram),

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386 International Journal of Stroke 18(4)

Table 1. Practical considerations for aPL laboratory testing, including recommendations for LA testing in patients on
anticoagulation.

Assay methodology Pitfalls / sources of interference

aCL and aß2GP1 Commercially available – Persistent (⩾12 weeks) moderate/high titer levels (>99th
IgG/IgM antibodies immunoassays, using serum or centile) are associated with thrombosis. However, low-titer
platelet-poor plasma. levels and transient epiphenomenal aPL (e.g. infection-associated)
are not considered to be associated with thrombosis.
– Potential false-positive/negative: Interference from hemolysis,
icterus, or lipemia in sample.
– Anticoagulant treatment: no known interference.

LA Functional, phospholipid- – Transient epiphenomenal aPL (e.g. infection-associated) are not

dependent coagulation assay, considered to be associated with thrombosis.
using platelet-poor plasma. – Potential false negative:
   Elevated coagulation factor VIII (acute phase response, pregnancy)
– Potential false positive:
  C-reactive protein (acute phase response) within APTT-based
assays.
– Potential false positive/negative:
Interference from hemolysis, icterus, or lipemia in sample.
– Anticoagulant treatment: can lead to false positives and false
negatives.

LA testing on anticoagulant treatment:

– Ideally, LA testing should be performed in patients not receiving any anticoagulant treatment.
– If discontinuation of anticoagulation is not clinically appropriate, testing should be undertaken as follows:

Specify anticoagulant in clinical information provided to laboratory, as it will influence assay methodology.
• LMWH: Take sample before next dose of LMWH (trough period), alongside a concurrent LMWH anti-FXa activity level
to guide interpretation.
• VKA: Check concurrent full coagulation screen, including INR.
• DOAC: Check concurrent DOAC activity level.

aCL: anticardiolipin; aß2GP1: anti-beta2 glycoprotein 1; APTT: activated partial thromboplastin time; DOAC: direct oral anticoagulant; INR:
International Normalized Ratio; LA: lupus anticoagulant; LMWH: low-molecular-weight heparin; VKA: vitamin K antagonist.

full blood count, prolonged cardiac rhythm assessment, Laboratory prognostic markers
echocardiography, and in selected cases, a “bubble” study
for intracardiac shunts. MR or CT venography should be The “triple aPL-positive” phenotype is considered to carry
performed in cases of suspected CVT. the highest risk of thrombosis, both for first events in
asymptomatic carriers (cumulative 10-year incidence 37%
in a prospective study)43 and recurrent events in established
Neuroimaging findings in APS APS patients.44 However, a prospective cohort study in
Neuroimaging findings in AIS/TIA depend on the involved SLE patients reported that LA was most predictive of
vascular territory—with large vessels and in particular, thrombosis and not augmented by the addition of other cri-
MCA territory most commonly involved.10 teria aPL.45
WMH, cerebral microbleeds, silent cerebral infarcts Thrombocytopenia occurs in 16–53% of APS patients,
(large territorial, cortical, lacunar, or border zone), and cor- and the combination of thrombocytopenia and aPL is asso-
tical atrophy have all been described in APS and appear to ciated with a twofold to fourfold increase in thrombosis
be clinically relevant.23 Data from non-APS populations risk.46 Proposed pathogenic mechanisms for thrombocyto-
indicate that WMH may predict an increased risk of stroke, penia include platelet destruction by autoantibodies against
dementia, and death.42 platelet glycoproteins, and aPL-mediated platelet activa-
Figure 1 shows MR brain images demonstrating APS- tion and consumption. APS-associated thrombocytopenia
associated acute/subacute ischemia (1(a)) and WMH (1(b)). is typically mild-to-moderate (50–150 platelets/L)46 and
does not require intervention, although increased monitor-
ing may be needed with concomitant antithrombotic treat-
Risk stratification
ment. Severe or acutely worsening thrombocytopenia
Delineation of important prognostic markers in individuals is likely to be immune-mediated, and rare causes, includ-
with APS and asymptomatic aPL remains incomplete. ing heparin-induced thrombocytopenia and thrombotic

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Mittal et al. 387

aPL and concluded that aPL are not prognostically signifi-

Figure 1. MRI head images. (a) Diffusion-weighted imaging
(DWI b1000) showed acute right MCA ischemia and cant. However, aPL testing did not meet international con-
subacute left MCA ischemia. (b) FLAIR sequence showed sensus criteria, aPL persistence was not confirmed and the
white matter changes consistent with small vessel disease. International Normalized Ratio (INR) target range (1.4–
2.8) was below that in standard practice.
The role of dual antiplatelet therapy (DAPT) and com-
bined anticoagulant–antiplatelet therapy in APS-associated
arterial thrombosis is of interest. A meta-analysis reported
greater efficacy of DAPT versus single antiplatelet therapy
and combined VKA-antiplatelet versus VKA alone, albeit
with limitations in the number and quality of its constituent
studies.54
Optimal intensity of anticoagulation: The optimal INR
range for APS patients with arterial thrombosis is unde-
fined. Two randomized controlled trials (RCT) concluded
that the optimal target INR after first thrombosis in APS is
MRI: magnetic resonance imaging; MCA: middle cerebral artery; FLAIR:
fluid-attenuated inversion recovery. 2.5 (range: 2.0–3.0)55,56 although patients with arterial
thrombosis were under-represented in both studies. A sys-
tematic review found that most recurrent thromboses
microangiopathies,47 such as CAPS and preeclampsia/ (venous and arterial) occurred in APS patients not receiving
HELLP (Hemolysis, Elevated Liver enzymes, and Low any thromboprophylaxis, or on low-dose aspirin (LDA)
Platelets) syndrome, should also be considered. alone, with recurrence least likely in those on warfarin,
INR >3.57 In a retrospective study, serial MRI showed new
Clinical prognostic markers brain lesions, mainly ischemic, in approximately 45% of
patients, despite antithrombotic treatment. Patients treated
Conventional cardiovascular risk factors likely confer addi- with high-intensity warfarin appeared less likely to develop
tional risk in arterial APS patients. A retrospective cross- ischemic lesions.58
sectional study suggests that the adjusted Global
Antiphospholipid Syndrome Score (aGAPSS), combining Direct oral anticoagulants. Direct oral anticoagulants (DOACs)
aPL phenotype with arterial hypertension and hyperlipi- have several advantages over VKA and are considered stan-
demia, may stratify APS patients at higher risk of recurrent dard of care for treatment of first venous thromboembolism
arterial thrombosis.48 (VTE) and thromboembolic prophylaxis for atrial fibrillation
(AF) in the general population. The European Medicines
Agency recommends against the use of DOACs for APS
Management patients, particularly those who are triple aPL-positive.59
The diagnosis, management, and follow-up of patients with This recommendation was triggered by the results of the
APS and cerebrovascular events can be complex. In our TRAPS RCT60 comparing rivaroxaban 20 mg (standard-
experience, a multidisciplinary approach, with regular intensity dose for first VTE and AF) with warfarin, target
meetings involving neurology, hematology, neuroradiol- INR 2.5, in triple aPL-positive patients. The composite pri-
ogy, and other specialties if needed, for evaluation of diag- mary outcome (thromboembolism, major bleeding, and vas-
nostic information and consideration of optimal secondary cular death) was more frequent in the rivaroxaban arm than
prevention therapy, has proven beneficial. warfarin (18.6% vs 3.3%, hazard ratio (HR), 6.7; 95% confi-
dence interval (CI), 1.5–30.5; p = 0.01), leading to premature
trial closure. Seven patients in the rivaroxaban arm, four of
Antithrombotic treatment whom had previous arterial thrombosis, developed new arte-
Vitamin K antagonist versus antiplatelet therapy. While anti- rial thrombosis, versus none on warfarin.
platelet therapy is the usual antithrombotic choice for non- A meta-analysis61 of four RCTs concluded that DOAC
cardioembolic AIS/TIA in the general population,40,49,50 the treatment was associated with an increased risk of subse-
cornerstone of APS-associated AIS/TIA treatment is anti- quent arterial thrombosis compared to warfarin, particu-
coagulation with warfarin or other vitamin K antagonist larly in triple-positive patients and those with previous
(VKA).49,50 The evidence supporting VKA stems from arterial thrombosis, though subsequent VTE risk was not
early retrospective51and small prospective52 studies. Con- significantly higher.
versely, the Antiphospholipid Antibodies and Stroke Study Proposed explanations for the apparent inferiority of
(APASS) prospective cohort study53 reported no benefit of DOACs versus warfarin in APS include mechanistic differ-
warfarin over aspirin (325 mg/day) for stroke patients with ences and dosing considerations. While DOACs target a

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388 International Journal of Stroke 18(4)

specific activated clotting factor (Xa or thrombin (IIa)), changing anticoagulation to low-molecular-weight heparin
warfarin inhibits synthesis of all vitamin K-dependent clot- or fondaparinux.68 Immunomodulatory treatments, such as
ting factors (II (prothrombin), VII, IX, X) and might there- rituximab and IVIg, have also been used.67
fore have broader interactions with aPL-associated
thrombogenic pathways. For example, antiprothrombin Clinical Learning Points
antibodies with LA activity have been shown to induce
platelet aggregation in a manner that is dependent on pro- • AIS/TIA is an important neurological complication of
thrombin levels,62 which would be reduced with warfarin APS. Testing for aPL should be considered in individuals
with AIS/TIA, particularly those under the age of
but not direct anti-Xa inhibitors. Regarding dose, the effi-
50 years, and/or with a history of autoimmune disease,
cacy of standard-intensity DOACs for secondary preven- venous thromboembolism or obstetric morbidity.
tion of non-cardioembolic arterial thrombosis in the general
population has not been demonstrated; hence, there is no • aPL testing should include all three criteria aPL: LA, IgG
precedent for their use in APS-associated arterial thrombo- and IgM aCL and aß2GP1. Ensure key clinical information
is provided to the laboratory to guide LA assay
sis. Animal experiments with rivaroxaban indicate that
methodology and interpretation of results (see Table 1).
stronger inhibition of factor Xa is required to protect against
arterial thrombosis compared to venous.63 • A multidisciplinary approach, involving expert hematology
DOACs at high-intensity dose may have a role; further and neurology/stroke input, is recommended for the
clinical studies are required that recognize the heteroge- evaluation of diagnostic information and consideration of
neity of the condition and need for a tailored approach optimal secondary prevention therapy.
according to thrombotic and laboratory phenotype. The • Optimal management of APS-associated stroke is
Rivaroxaban in Stroke Patients with APS (RISAPS) trial undefined. Within current clinical practice guidelines,
aims to assess the efficacy of high-intensity rivaroxaban options for the treatment of initial APS-associated
15 mg twice-daily (rather than the standard 20 mg daily ischemic stroke include a vitamin K antagonist at target
dose), to match our current approach of high-intensity war- INR range 2.0–3.0, with or without low-dose aspirin,
or target INR range of 3.0–4.0. DOAC use should be
farin, target INR 3.5 (range 3.0–4.0) in patients with APS,
confined to clinical studies.
and previous ischemic stroke or other ischemic brain mani-
festations (ClinicalTrials.gov Identifier: NCT03684564). • Conventional cardiovascular risk factors should be
actively managed.
Clinical practice recommendations. Antithrombotic treat-
aß2GP1: anti-beta2 glycoprotein 1 antibodies; aCL: anticardiolipin
ment: Antithrombotic treatment approaches in APS are antibodies; AIS: acute ischemic stroke; aPL: antiphospholipid antibodies;
summarized elsewhere.64 Current guidance recommends APS: antiphospholipid syndrome; DOAC: direct oral anticoagulant; INR:
against using DOACs in APS patients with arterial throm- International Normalized Ratio; LA: lupus anticoagulant; TIA: transient
ischemic attack.
bosis.49,50,65,66 Antithrombotic options for the treatment of
initial ischemic stroke in patients with APS include a VKA
at target INR range 2.0–3.0, with or without LDA, or target Author contributions
INR range of 3.0–4.0, taking into account bleeding risk fac- P.M. and G.Q. drafted the article. A.C., H.C., Z.S., and I.T.-E. criti-
tors.50,65 Surveillance brain MRI could be considered to cally revised the article. All authors approved the final version.
guide the treatment approach.
Supportive management: Conventional cardiovascular Declaration of conflicting interests
risk factors require active management. Estrogen-containing The author(s) declared the following potential conflicts of interest
hormonal preparations should be avoided in APS patients.64 with respect to the research, authorship, and/or publication of this
Adjunctive treatments include vitamin D, hydroxychloro- article: H.C. reports, outside the submitted work, institutional
quine, and statins.67 research support and support to attend scientific meetings from
CAPS: Early, aggressive management of CAPS is vital, Bayer Healthcare; Roche Advisory Board; Consultancy fees from
and current practice guidelines recommend combination UCB Biopharma and Speaker fees from Technoclone paid to
therapy with glucocorticoids, heparin and plasma exchange, University College London Hospitals Charity. P.M., G.Q., I.T-E.,
and/or IVIG.22 Despite this treatment, mortality is high Z.S., and A.C. have nothing to disclose.
(36% in the CAPS Registry).22 Additional immunomodula-
tory therapy, including B-cell depletion and complement Funding
inhibition, may have a role in refractory cases.22 The author(s) received no financial support for the research,
Anticoagulant-refractory APS: Management of break- authorship, and/or publication of this article.
through thrombosis in APS patients on standard-intensity
warfarin is largely empirical. Options include escalating to ORCID iD
high-intensity warfarin, addition of an antiplatelet agent, or Arvind Chandratheva https://orcid.org/0000-0003-4967-3508

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Mittal et al. 389

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