JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 69, NO.

18, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2017.02.058

THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Antiphospholipid Syndrome
Role of Vascular Endothelial Cells and Implications for
Risk Stratification and Targeted Therapeutics

Michel T. Corban, MD,a Ali Duarte-Garcia, MD,b Robert D. McBane, MD,a Eric L. Matteson, MD, MPH,b,c
Lilach O. Lerman, MD, PHD,a,d Amir Lerman, MDa

ABSTRACT

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by venous thromboembolism, arterial thrombosis,
and obstetric morbidities in the setting of persistently positive levels of antiphospholipid antibodies measured on 2 different
occasions 12 weeks apart. Patients with APS are at increased risk for accelerated atherosclerosis, myocardial infarction,
stroke, and valvular heart disease. Vascular endothelial cell dysfunction mediated by antiphospholipid antibodies and sub-
sequent complement system activation play a cardinal role in APS pathogenesis. Improved understanding of their pathogenic
function could help in the risk stratification of patients with APS and provide new molecular therapeutic targets.
(J Am Coll Cardiol 2017;69:2317–30) © 2017 by the American College of Cardiology Foundation.

T he term antiphospholipid syndrome (APS) was

coined in the 1980s to describe a condition
of autoantibody-induced thrombophilia (1).
This autoimmune prothrombotic condition is charac-
terized by venous thromboembolism, arterial throm-
bosis, and pregnancy morbidity in the setting of
laboratory evidence of elevated levels of antiphos-
pholipid antibodies (aPLs). aPLs can be identified by
1 of 3 assay platforms, namely, clot-based assays
to identify lupus anticoagulant, or enzyme-linked
immunosorbent assays to identify anticardiolipin
(aCL) or anti– b2 -glycoprotein 1 ( b2-GP1) antibodies
(immunoglobulin G or immunoglobulin M). Regard-
less of the assay, this class of antibodies targets
antiphospholipid-bound proteins. The prevalence of
aPLs in a random sample of 552 healthy blood
donors was found to be 6.5% and 9.4% for aCL immu-
noglobulin G and immunoglobulin M antibodies,
respectively. None of those normal subjects with
positive aPLs developed thrombotic events at 1-year
follow-up (2).
A definite diagnosis of APS requires the presence of
at least 1 clinical and 1 laboratory criterion. Clinical
criteria may include objectively confirmed venous,
arterial, or small-vessel thrombosis or pregnancy
morbidity attributable to placental insufficiency,
including pregnancy loss or premature birth. Labo-
ratory criteria encompass persistently positive test
results for at least 1 of these 3 aPLs measures on 2 or
more occasions 12 weeks apart. The 12-week testing
interval is particularly important, given that some
infections and medications can cause transient
aPL-positive testing (3,4).
APS typically presents in the fourth decade of life
and is classified as either a primary disease or sec-
ondary to another underlying autoimmune disease,
solid tumor, or hematologic disorder. Approximately
10% to 40% of patients with systemic lupus

Listen to this manuscript’s

audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the aDepartment of Cardiovascular Diseases, Mayo Clinic College of Medicine and Science, Rochester, Minnesota; bDivision
of Rheumatology, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota; cDivision of
Epidemiology, Department of Health Sciences Research, Mayo Clinic College of Medicine and Science, Rochester, Minnesota; and
the dDivision of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester,
Minnesota. Dr. McBane has a research grant from Bristol-Myers Squibb. Dr. Leman is a consultant for Itamar Medical. All other
authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Manuscript received January 2, 2017; revised manuscript received February 21, 2017, accepted February 28, 2017.
2318 Corban et al.
Antiphospholipid Syndrome
ABBREVIATIONS erythematosus (SLE) (5) and up to 20% of
AND ACRONYMS patients with rheumatoid arthritis (6) have
positive aPL serologies. Moreover, patients
aCL = anticardiolipin antibody
with SLE who have positive lupus anticoagu-
aPL = antiphospholipid
lant have a 50% chance of developing venous
antibody
or arterial thrombotic events within a 20-year
apoER2 = apolipoprotein E
receptor 2 follow-up period (5). APS can affect any body
APS = antiphospholipid
organ, and patients with APS have increased
syndrome risk for thrombosis, accelerated atheroscle-
b2-GP1 = b2-glycoprotein 1 rosis, myocardial infarction, and stroke (7,8).
CAPS = catastrophic In a large prospective cohort study of 1,000
antiphospholipid syndrome patients with APS followed over a 10-year
eNOS = endothelial nitric oxide period, deep vein thrombosis was the most
synthase common presenting clinical manifestation
HCQ = hydroxychloroquine (39%), followed by thrombocytopenia (30%),
INR = international normalized livedo reticularis (24%), stroke (20%), pul-
ratio
monary embolism (14%), and myocardial
mTORC = mammalian target of infarction (6%). In that study, thrombotic
rapamycin complex
events occurred in 16.6% of patients during
NO = nitric oxide
the first 5-year period and in 14.4% during the
NOAC = new oral
second 5-year period; 90.7% of patients were
anticoagulant agents
still alive at 10 years (9). Despite high survival
SLE = systemic lupus
erythematosus
rates, these data reflect a substantial disease
burden and morbidity in patients with APS on
current treatment.
Obstetric morbidities in APS are thought to be
secondary to placental vascular insufficiencies,
with early (<10 weeks) and late ($10 weeks) mis-
carriages being the most common obstetric manifes-
tations (35% vs. 17%, respectively) of APS, followed
by premature labor (11%), pre-eclampsia and/or
eclampsia (5%), and intrauterine growth restriction
(2%) (9).
A recent meta-analysis demonstrated that APS is
associated not only with clinical adverse cardiovas-
cular events but also with subclinical cardiovascular
risk factors associated with endothelial cell dysfunc-
tion, such as increased carotid artery intima-media
thickness and lower flow-mediated dilation, higher
frequency of carotid plaques, and increased preva-
lence of pathological ankle-brachial indexes (10). The
renal vasculature may also be affected in APS, leading
to nephropathy, renal vein thrombosis, renal artery
stenosis, thrombotic microangiopathy, hypertension,
kidney infarction, and ultimately end-stage kidney
disease (11,12). The most severe, yet fortunately
infrequent form of APS is catastrophic APS (CAPS).
CAPS, with an incidence of 0.9% (9) and mortality
>50% (9,13), is defined as small-vessel thrombosis
involving $3 organs, organ systems, and/or tissues,
occurring simultaneously or in <1 week, along with
positive laboratory evidence of aPLs and no alterna-
tive diagnosis (13).
JACC VOL. 69, NO. 18, 2017
MAY 9, 2017:2317–30
PATHOGENESIS
THE CARDINAL ROLE OF ENDOTHELIAL CELLS. The
fact that normal healthy subjects with circulating aCL
antibodies remained free of thrombotic events at
1-year follow-up on one hand and the important direct
role of aPLs in the pathogenesis of APS on the other
hand imply that additional underlying host suscepti-
bility characteristics are necessary for the develop-
ment of the disease. More than a decade ago, it was
suggested that endothelial cells play a central role in
APS pathogenesis and may represent the common
pathway through which autoimmunity and inflam-
mation participate in APS (14). Although circulating
aPLs and underlying endothelial dysfunction are a
necessary “first hit” for thrombosis in APS, an inflam-
matory “second hit” is needed to precipitate a throm-
botic event (15–17). Although elevated levels of aPLs
have been associated with both vascular thrombosis
and pregnancy morbidity in patients with APS (18,19),
human aPLs injected into mice did not promote
thrombosis in the absence of endothelial injury (20,21).
Growing evidence demonstrates that endothelial cell
dysfunction, mediated by aPLs binding to endothelial
cell b2-GP1 receptors, results in increased risk for
thrombosis, accelerated atherosclerosis, myocardial
infarction, and stroke in patients with APS (7). Simi-
larly, a recent in vitro study associated obstetric
morbidity in APS to placental inflammatory response
mediated by binding of aPLs to b 2-GP1 receptors on the
surface of placental trophoblasts (22). Moreover, an
inflammatory insult secondary to surgery, trauma, or
infection has been demonstrated to up-regulate
expression of b2-GP1 receptors on the endothelial cell
surface (Figure 1A) (15,17).
Endothelial nitric oxide synthase inhibition and
t h r o m b o s i s . Endothelium-derived nitric oxide (NO),
produced by endothelial NO synthase (eNOS), is
important for normal endothelial function and
vascular health (23–25). Patients with APS have lower
plasma nitrite levels and an impaired endothelium-
dependent vascular response, suggestive of
impaired eNOS activity and reduced NO production
and endothelial function (26,27). The antithrombotic
effects of eNOS and NO secreted from endothelial
cells and platelets have been demonstrated in multi-
ple animal and human studies. Indeed, eNOS-
knockout mice demonstrated enhanced platelet
aggregation (28) and increased predisposition to
thrombosis, stroke, and atherosclerosis (29–32), and
decreased endogenous NO production in humans
has also been associated with increased risk for
thrombosis (33–35).
JACC VOL. 69, NO. 18, 2017 Corban et al. 2319
MAY 9, 2017:2317–30 Antiphospholipid Syndrome

F I G U R E 1 Antiphospholipid Syndrome Pathogenesis

(A) Up-regulation of beta-2 glycoprotein 1 (b2-GP1) receptors on endothelial cells following a “second hit” inflammatory insult. (B) Antiphospholipid antibody
(aPL)–mediated endothelial nitric oxide synthase (eNOS) inhibition, impaired nitric oxide (NO) production and release, and endothelial dysfunction. “First hit.”
(C) aPL-mediated endothelial cell proliferation, intimal hyperplasia, and nonatherosclerotic vascular stenosis. (D) Antiphospholipid syndrome (APS)–associated
accelerated atherosclerosis. (E) aPL-mediated platelet cell activation, aggregation, and thrombosis. (F) Complement system activation and thrombosis.
apoER2 ¼ apolipoprotein E receptor 2; C5a ¼ complement component 5a fragment; C5aR ¼ complement component 5a fragment receptor; C5b ¼ complement
component 5b fragment; C5bR ¼ complement component 5b fragment receptor; DI ¼ domain I of b2-GP1 receptor; DV ¼ domain V of b2-GP1 receptor;
LDL ¼ low-density lipoprotein; MAC ¼ membrane attack complex; mTORC ¼ mammalian target of rapamycin complex; PI3K-AKT ¼ phosphatidylinositol 3-kinase–AKT
pathway; PP2A ¼ protein phosphatase 2 A; VCAM ¼ vascular cell adhesion molecule.

Recent elegant in vitro and animal studies have
demonstrated that aPL-mediated eNOS inhibition is
the molecular basis of endothelial dysfunction,
increased leukocyte–endothelial cell adhesion, and
thrombus formation in patients with APS (36,37).
Binding of circulating aPLs to domain I of the b2-GP1
receptor on endothelial cells induces b2-GP1 dimer-
ization (38,39). Subsequent interaction
domain V of dimerized b 2-GP1 and low-density
lipoprotein–binding domain 1 of apolipoprotein E
receptor 2 (apoER2) mediates aPL-induced eNOS
inhibition, up-regulation of adhesion
expression, and increased production of endothelin-1
and tissue factor, ultimately leading to thrombus
formation (37,38,40–44). It was recently shown that
the intracellular pathway of aPL-induced eNOS inhi-
bition following aPL, b2-GP1, and apoER2 interaction
is mediated by protein phosphatase 2 A dephosphor-
ylation of a critical serine residue (Ser1177) of
between eNOS (Figure 1B) (37,45,46). Thus, circulating
aPL-associated NO-dependent endothelial dysfunc-
tion, mediated by inhibitory dephosphorylation of
eNOS, plays an important role in the pathogenesis of
molecule APS-related thrombosis.
2320 Corban et al.
Antiphospholipid Syndrome
Endothelial cell dysfunction and vasculopathy.
Circulating aPL-induced endothelial cell dysfunction
may also lead to vasculopathy. Steps to aPL-mediated
vasculopathy include diffuse intimal hyperplasia,
accelerated atherosclerosis, and microvascular
dysfunction.
Endothelial cell proliferation and
hyperplasia. Patients with APS have significantly
increased carotid intima-media thickness
smaller carotid luminal diameter in the absence
of atherosclerotic disease (47,48).
pathological specimens of patients
nephropathy show evidence of vascular cellular
infiltrates, severe intimal hyperplasia, and fibrosis
of the intima and media (49–51).
Interestingly, the pathogenesis of acute peripheral
arterial occlusion (49) and ischemic cerebrovascular
events (52,53) in patients with APS has been associ-
ated primarily with severe concentric intimal and
medial hyperplasia and fibrous occlusions with vari-
able evidence of thrombosis and thrombus stages.
Two important recent studies by Canaud et al. (54,55)
have demonstrated that aPLs, specifically aCL and
anti- b2-GP1 antibodies, induce endothelial cell pro-
liferation and intimal hyperplasia through activation
of the phosphatidylinositol 3-kinase–AKT pathway
and, subsequently, the mammalian target of rapa-
mycin complex (mTORC) (Figure 1C). Moreover,
mTORC pathway activation in endothelial cells
correlated with aPL titers, and an mTORC pathway
inhibitor (sirolimus) prevented recurrent renal allo-
graft vasculopathy in patients with APS (54,55).
Endothelial cell dysfunction and accelerated
atherosclerosis. Endothelial dysfunction
earliest detectable stage of atherosclerosis (56–59).
Circulating aPL-mediated endothelial dysfunction is
associated with accelerated peripheral and coronary
atherosclerosis (60–66) relative to the
population with comparable risk factors
Circulating aCL and anti- b2 -GP1 antibodies mediate
internalization of oxidized low-density lipoprotein–
b2-GP1 complexes into macrophages
foam cells, which leads to the development of
atherosclerotic lesions (Figure 1D) (68–70).
Multiple clinical studies have demonstrated a
strong correlation between circulating aPLs and
systemic atherosclerosis in humans, including pe-
ripheral arterial disease, coronary artery disease,
acute myocardial infarction, and ischemic stroke
(8,66,71–76). Moreover, aPL levels have been associ-
ated with increased mortality rates due to coronary
artery disease (73). Premature atherosclerosis in
these patients has been linked to localized proin-
flammatory nontraditional immunopathological risk
JACC VOL. 69, NO. 18, 2017
MAY 9, 2017:2317–30
factors mediated by circulating aPLs. Aggressive
control of traditional cardiovascular risk factors is
therefore recommended to prevent further endothe-
lial injury.
Interestingly, recurrent thrombosis was recently
suggested to be a potential mechanism for coronary
intimal plaque progression in cardiac allograft transplant
vasculopathy (77). Taking into account a similarity
and between these 2 features of accelerated atheroscle-
rosis, the association between recurrent clinical or
Moreover, subclinical thrombosis and accelerated atheroscle-
with APS rosis in patients with APS warrants further
investigation.
Endothelial cell dysfunction and coronary microvascular
obstruction. Coronary microvascular endothelial
dysfunction in APS has also been associated with
ischemic heart disease. Cardiac magnetic resonance
studies of these patients with otherwise low pre-test
probability for coronary artery disease revealed a
higher than anticipated incidence of late myocardial
gadolinium enhancement consistent with subclinical
coronary microvascular dysfunction (78). Similarly,
60% of asymptomatic patients with APS and no
known systemic risk factors had subclinical
myocardial perfusion abnormalities (23% exercise
induced and 42% persistent) on single-positron
emission computed tomography (technetium-99m
sestamibi) imaging, suggestive of endothelial
dysfunction and associated thrombosis in coronary
microvasculature (79). In both studies, the level of
circulating aPLs positively correlated with detected
myocardial perfusion defects.
is the THROMBOSIS: ACTIVATION OF PLATELETS AND
COMPLEMENT SYSTEM. Binding of circulating aPLs
to domain I of b 2-GP1 receptors on platelets induces
venous and/or arterial thrombosis through increased
general production of thromboxane B2 . Thromboxane A 2, a
(67). potent platelet activator, results in enhanced adhe-
sion of platelets to collagen and increased platelet
aggregation before being degraded to thromboxane B 2
to form (Figure 1E) (80). Indeed, a strong correlation has been
reported between the level of anti- b 2-GP1 domain 1
aPLs and adverse clinical outcomes in patients with
APS (81,82).
In addition to eNOS inhibition and platelet aggre-
gation, the thrombogenic effects of aPLs also involve
activation of the classical complement system
(21,83,84). Complement activation and deposition
have been associated with placental injury in female
patients with APS experiencing obstetric complica-
tions (85).
Girardi et al. (86) suggested that heparin prevented
obstetric complications by blocking complement
JACC VOL. 69, NO. 18, 2017 Corban et al. 2321
MAY 9, 2017:2317–30 Antiphospholipid Syndrome

F I G U R E 2 Libman-Sacks Endocarditis

Transthoracic echocardiographic (TTE) and transesophageal echocardiographic (TEE) images of a 33-year-old woman who presented with
acute-onset shortness of breath secondary to flash pulmonary edema in the setting of new diagnosis of antiphospholipid syndrome (strongly
positive anticardiolipin immunoglobulin G antibody, >100 GPL), Libman-Sacks endocarditis, and moderate-to-severe mitral regurgitation.
(A) TTE parasternal long-axis view of the mitral valve with thickened anterior and posterior leaflets and adherent deposits on the leaflets
coaptation point. (B) TEE images demonstrating mitral valve vegetations on the atrial aspect of both leaflets tips consistent with
Libman-Sacks endocarditis. (C) Moderate-to-severe mitral valve regurgitation associated with incomplete coaptation of mitral valve leaflets
secondary to Libman-Sacks endocarditis lesions.

activation, rather than by directly
placental thrombosis. In mice, C3 and C5 activation
was required for aPL-induced thrombosis
increased leukocyte adhesion to endothelium (84,87).
In addition, interaction between C5a and C5aR was
required for aPL-induced pregnancy
Furthermore, C5a binding to endothelial cells resul-
ted in increased neutrophil adhesion, tissue factor
expression, and release of other procoagulant sub-
stances (89,90). C5b-initiated assembly of the mem-
brane attack complex subsequently
proinflammatory signaling pathways and promotes
thrombus formation (Figure 1F) (91). In contrast, C3
convertase inhibitor and anti-C5 mouse antibodies
blocked aPL-induced thrombus formation in this
model (84,87). Similarly, blockade of C5aR prevented
thrombus formation in a rat model of antibody-
mediated thrombotic glomerulonephritis (92). Eculi-
zumab, a C5 inhibitor, prevented APS-associated
thrombotic microangiopathy in a post–renal trans-
plantation patient with CAPS and in other patients
with recurrent CAPS (93,94).
VALVULAR HEART DISEASE IN APS
Between 15% and 30% of patients with APS have
valvular heart disease, known as Libman-Sacks
endocarditis or nonbacterial thrombotic endocarditis
(9,95). The reported incidence rate is 5% over a
10-year period (9). Although the revised classification
preventing criteria for definite APS diagnosis do not include
valvular heart disease, the international consensus
and statement defines aPL-associated cardiac valve dis-
ease as the coexistence of aPLs and echocardio-
graphic evidence of mitral or aortic valve lesions.
loss (88). These criteria include valve thickness >3 mm, local-
ized thickening of the proximal or middle portion of
the valve leaflet, irregular nodules on the atrial aspect
of the mitral valve or the vascular surface of the aortic
valve, and/or moderate-to-severe valvular regurgita-
triggers tion or stenosis (Figure 2). Infective endocarditis
and rheumatic heart disease history are important
exclusions (4).
Histologically, Libman-Sacks endocarditis lesions
are small (up to 3 to 4 mm), sterile, fibrinous vege-
tations with varying fibroblastic organization, neo-
revascularization, and mononuclear inflammatory
cell infiltration. Fibrous plaque formation, scarring,
and focal calcifications may be seen in advanced
stages (96).
Although the risk for valvular heart disease is 3-fold
higher in patients with circulating aPLs (97), its precise
pathophysiology remains unclear. Ziporen et al. (98)
demonstrated deposits of aPLs and complement
on deformed heart valves of patients with APS.
Blank et al. (99) identified target epitopes of anti-
b2-GP1 antibodies on valvular endothelial cell b 2-GP1
receptors. These findings suggest that the pathogen-
esis could include aPL-mediated valvular endothelial
cell activation with complement fixation, similar to
2322 Corban et al. JACC VOL. 69, NO. 18, 2017

Antiphospholipid Syndrome MAY 9, 2017:2317–30

endothelial cell injury in other vascular beds. It is

T A B L E 1 Primary Thromboprophylaxis in
unclear whether antithrombotic therapy limits the Antiphospholipid Syndrome
development of valvular injury in this setting.
General measures for all  Assessment and management of
antiphospholipid- traditional cardiovascular risk factors
RISK STRATIFICATION: INCREMENTAL positive patients  In high-risk situations (puerperium,
VALUE OF ENDOTHELIAL FUNCTION TESTING surgery, prolonged immobilization),
use usual doses of LMWH for
AND CLINICAL IMPLICATIONS thromboprophylaxis
Antiphospholipid-positive  Low-dose aspirin (75–100 mg/day) in
Tools capable of early and reliable identification of non-SLE patients those with a high-risk aPL profile,
(obstetric APS and especially in the presence of other
the high-risk APS patient population would be clini- asymptomatic carriers) thrombotic risk factors
cally useful. Known thrombotic risk variables include Patients with SLE and  Hydroxychloroquine (200–400 mg/day)
positive aPLs þ low-dose aspirin (75–100 mg/day)
a “triple-positive” aPL profile (positive for lupus
anticoagulant, aCL, and anti- b 2-GP1 antibodies) aPL ¼ antiphospholipid antibody; APS ¼ antiphospholipid syndrome;
(100,101), high mean platelet volumes as a surrogate LMWH ¼ low–molecular weight heparin; SLE ¼ systemic lupus erythematosus.

for increased platelet activation (102), and decreased

plasminogen and elevated plasminogen activator in-
hibitor-1 levels (103). The Global APS Score, a novel,
prevention is a major goal of therapy. Asymptomatic
promising risk assessment tool, may be useful for this
patients with positive APS-related antibodies may
purpose. The tool, on the basis of prospective studies
develop thrombotic events at a rate of 0% to 4% per
in primary and secondary APS (104,105), uses the aPL
year, especially in the setting of SLE (108). Although
profile, hypertension, dyslipidemia, diabetes melli-
thromboembolic risk stratification tools for patients
tus, and the presence of other autoimmune anti-
with APS are limited, contemporary recommenda-
bodies, namely, antinuclear antibodies, extractable
tions for primary thromboprophylaxis in high-risk
nuclear antibodies (anti-Ro, La, Smith, ribonucleo-
SLE and non-SLE patients with positive aPL serology
protein, scleroderma-70, Jo-1 antibodies), and
have been proposed (Table 1).
double-stranded deoxyribonucleic acid antibodies to
The 13th International Congress on Anti-
predict thrombosis risk (106).
phospholipid Antibodies Prevention and Manage-
Measures of endothelial cell dysfunction are not
ment Task Force recommended evaluation and tight
included in this risk assessment tool. Other important
control of traditional cardiovascular risk factors as
risk factors, including obesity and cigarette smoking,
part of primary prophylaxis in APS (108). Although
are also not used. Given the central role of endothelial
hypertension has been associated with thrombosis in
dysfunction in APS, future risk stratification tools
aPL-positive patients, hypertriglyceridemia, low
might benefit from incorporating either invasive or
high-density lipoprotein levels, and central obesity
noninvasive measures of endothelial function, such
are the most common cardiovascular risk factors
as intracoronary acetylcholine challenge testing, or
associated with primary APS (109). Control of tradi-
brachial reactivity and plethysmography finger arte-
tional cardiovascular risk factors is indeed important
rial pulsatile volume changes (EndoPAT, Itamar
to help prevent additional insult to the vascular
Medical, Caesarea, Israel). On the basis of the growing
endothelium in patients with APS. The task force also
body of evidence that endothelial dysfunction is a
recommended that all aPL-positive patients receive
predictor of adverse cardiovascular events indepen-
appropriate thromboprophylaxis with heparin in
dently of traditional risk factors (107), the role of
high-risk situations, such as surgery, postpartum, and
endothelial function assessment for risk stratification
prolonged immobilization (108).
and potential therapeutic implications in APS needs
Two recent meta-analyses have suggested that the
further investigation. Moreover, the benefit of the
risk for first thrombotic event was significantly
assessment of APS score in individuals with unex-
decreased by low-dose aspirin among asymptomatic
plained endothelial dysfunction and accelerated
aPL-positive subjects, patients with SLE, and patients
atherosclerosis may be explored.
with obstetric APS (110,111). A recent open-label
PHARMACOLOGICAL THERAPY: CURRENT randomized trial showed no incremental primary
RECOMMENDATIONS, EMERGING THERAPIES, thromboprophylaxis benefit in adding anticoagu-
AND POTENTIALLY PROMISING lation with warfarin to low-dose aspirin alone (112).
TARGETED THERAPIES As such, primary prophylaxis with anticoagulant
agents is not recommended in otherwise healthy
PRIMARY THROMBOPROPHYLAXIS. Thrombophilia ambulatory patients with no prior thrombotic history.
remains the hallmark of APS, and thrombosis Currently, guidelines recommend the use of low-dose
JACC VOL. 69, NO. 18, 2017
MAY 9, 2017:2317–30
aspirin in aPL-positive patients, with or without SLE,
with a high-risk aPL profile and/or additional throm-
botic risk factors (108).
Hydroxychloroquine (HCQ) is an antimalarial used
extensively in autoimmune disease that has immu-
nomodulatory and possibly antithrombotic proper-
ties. HCQ has been shown to reduce thrombus size
and platelet aggregation in mouse models (113,114).
The antithrombotic efficacy of HCQ in humans has
been shown during its use for deep vein thrombosis
prophylaxis after hip surgery (115). HCQ is widely
used in SLE for its disease-modifying effects (116),
and its use in asymptomatic patients with positive
aPL serologies resulted in a reduction of thrombo-
embolic events (117). In patients with obstetric APS,
HCQ has been considered after failure of standard
treatment with heparin and aspirin (118). Current
guidelines recommend the use of HCQ in addition to
low-dose aspirin only in aPL-positive patients with
SLE (108). There are no recommendations regarding
the use of HCQ for primary thrombosis prevention in
other aPL-positive populations.
SECONDARY THROMBOPROPHYLAXIS. Anticoagulation
is the mainstay therapy for secondary thrombopro-
phylaxis in patients with APS. Current guidelines for
secondary thromboprophylaxis, summarized in
Table 2, recommend consideration of whether the
first thrombotic event was venous or arterial (108). If
the initial event was venous thromboembolism, it is
recommended that moderate-intensity warfarin
therapy targeting international normalized ratio (INR)
values of 2.0 to 3.0 be initiated, with heparin
bridging. Two systematic reviews have confirmed
both the efficacy and safety of this approach in pre-
venting recurrent venous thrombosis (119,120).
In comparison, management of arterial thrombotic
events has been less well studied and more contro-
versial, with 2 approaches proposed: moderate in-
tensity (INR goal 2 to 3) versus high-intensity (INR >3)
warfarin anticoagulation. A systematic review of
observational studies concluded that the rate of
recurrent arterial thrombosis was significantly lower
with INR >3 (3.8%) versus INR <3 (23%) (120). Although
APASS (Antiphospholipid Antibodies and Stroke
Study), a large prospective cohort study of 1,770 pa-
tients, found no difference in recurrent stroke and
death in patients treated with moderate-intensity
warfarin (INR 1.4 to 2.8) versus those treated with
high-dose aspirin (325 mg/day) (121), a small random-
ized controlled trial of 20 patients with APS and
ischemic stroke showed that patients treated with a
combination of low-dose aspirin (100 mg/day) and
moderate-intensity warfarin (INR 2.0 to 3.0) had a
Corban et al. 2323
Antiphospholipid Syndrome
T A B L E 2 Secondary Thromboprophylaxis in
Antiphospholipid Syndrome
Definite APS and a first  Indefinite oral anticoagulant therapy
venous event to a target INR of 2.0–3.0
Definite APS and arterial  Indefinite oral anticoagulant therapy
thrombosis to a target INR >3.0 or combined
antiaggregant-anticoagulant (INR
2.0–3.0) therapy
Patients with venous or  Treatment as per usual recommen-
arterial thrombosis dations for arterial or venous
who do not fulfill thrombosis
criteria for APS
APS ¼ antiphospholipid syndrome; INR ¼ international normalized ratio.
significantly lower incidence of recurrent stroke
compared with those treated with low-dose aspirin
alone (122). However, it is important to note that none
of the patients included in the APASS study met the
currently accepted diagnostic criteria for APS. The
task force of the 13th International Congress on
Antiphospholipid Antibodies recommended high-
intensity warfarin (INR >3.0) or combined moderate-
intensity warfarin (INR 2.0 to 3.0) therapy and an
antiplatelet agent for secondary thromboprophylaxis
in patients with APS with arterial thrombotic events
(108); however, this recommendation did not reach
panel consensus. Importantly, patients with venous or
arterial thrombosis who do not fulfill criteria for a
conclusive APS diagnosis should be treated the same
as aPL-negative patients with similar venous or arte-
rial thrombotic event presentation (108).
Secondary thromboprophylaxis, whether for
venous or arterial thrombosis, should be continued
indefinitely (108). A retrospective study revealed a
significant increase (relative risk: 4.55 [95% confi-
dence interval: 2.67 to 7.43] vs. 0.36 [95% confidence
interval: 0.24 to 0.53] on any treatment, p < 0.001 for
both) in recurrent thrombosis soon after stopping oral
anticoagulant agents (123). Elevated titers of aCL an-
tibodies predict recurrent thrombosis and death in
the 6-month period following the initial episode of
venous thromboembolism (124).
NEW ORAL ANTICOAGULANT AGENTS. The efficacy
of the new oral anticoagulants (NOACs), the direct
thrombin inhibitor dabigatran, and direct anti–factor
Xa inhibitors rivaroxaban, apixaban, and edoxaban,
in APS remains unclear, and is largely on the basis of
case reports and case series. A recent systematic re-
view showed that approximately 20% of patients with
APS on NOACs developed vascular events during a
mean follow-up period of 12 months (125), whereas
one-third of patients developed recurrent events
during 2 years of follow-up (126).
2324 Corban et al. JACC VOL. 69, NO. 18, 2017

Antiphospholipid Syndrome MAY 9, 2017:2317–30

fondaparinux or argatroban, in APS is also limited to

T A B L E 3 Alternative and Adjunctive Therapeutic Options for Specific Clinical
Scenarios in Antiphospholipid Syndrome
Known warfarin allergy,  Treatment with, or addition of, NOAC: direct
warfarin intolerance, or thrombin inhibitor dabigatran or direct anti–
poor anticoagulant control factor Xa inhibitors rivaroxaban, apixaban, or
on warfarin despite edoxaban
therapeutic target (as per
Table 2)
Heparin-induced  Treatment with fondaparinux or argatroban
thrombocytopenia
Refractory APS despite  Consider starting statin therapy
adequate anticoagulation  Consider adding rituximab therapy
(as per Table 2)  Consider adding glucocorticosteroids and
IVIG þ plasma exchange
CAPS  Heparin anticoagulation þ glucocorticosteroids þ
IVIG and/or plasma exchange reduces mortality
 Eculizumab reduces mortality
Renal transplantation patients  Sirolimus decreases recurrent vascular lesions
with APS and vascular proliferation
 Eculizumab for treatment and prevention of
thrombotic microangiopathy in patients with
history of CAPS
Obstetric APS  Heparin (unfractionated or LMWH) þ low
dose aspirin (75–100 mg/day)
 Patients on warfarin should be switched to
heparin (unfractionated or LMWH) immedi-
ately upon pregnancy confirmation to avoid
teratogenicity
 Extended thromboprophylaxis (up to 6 weeks
after delivery) for high-risk patients
 Indefinite anticoagulation for APS patients
with prior thrombotic events
CAPS ¼ catastrophic antiphospholipid syndrome; IVIG ¼ intravenous immunoglobulin;
NOAC ¼ new oral anticoagulant; other abbreviations as in Table 1.
The RAPS (Rivaroxaban Versus Warfarin to Treat
Patients With Thrombotic Antiphospholipid Syn-
drome, With or without Systemic Lupus Erythema-
tosus) trial enrolled only patients with venous
thrombotic events, and a laboratory surrogate
outcome measure (endogenous thrombin potential)
was the primary outcome. Rivaroxaban did not reach
the noninferiority threshold from the laboratory sur-
rogate standpoint, but there was no increase in
thrombotic risk compared with standard-intensity
warfarin (127).
Two currently ongoing randomized controlled
clinical trials, ASTRO-APS (Apixaban for the Second-
ary Prevention of Thromboembolism Among Patients
With the Antiphospholipid Syndrome; NCT02295475)
and TRAPS (Rivaroxaban in Thrombotic Anti-
phospholipid Syndrome; NCT02157272), will help
clarify the role of NOACs in the management of APS.
Currently, the 14th International Congress on Anti-
phospholipid Antibodies task force recommends the
use of NOACs only when there is a known warfarin
allergy, warfarin intolerance, or poor anticoagulation
control (Table 3) (128).
OTHER ANTICOAGULANT AGENTS. The evidence
base for the use of other anticoagulant agents, such as
case reports and case series and is predominantly in
the setting of heparin-induced thrombocytopenia
(129,130). The 14th International Congress on Anti-
phospholipid Antibodies task force recommends the
use of these anticoagulant agents only in the setting
of heparin-induced thrombocytopenia in APS
(Table 3) (128).
STATINS. The immunomodulatory and anti-
inflammatory properties of statins can be beneficial
in APS (131). Simvastatin and fluvastatin suppress
anti-b2 GPI antibody–mediated endothelial activation
(132), and fluvastatin also reduced up-regulation of
tissue factor expression by aPLs on endothelial cells
(133). Moreover, patients with APS treated with flu-
vastatin showed decreases in multiple inflammatory
and prothrombotic biomarkers, including interleukin
1 b, vascular endothelial growth factor, tumor necrosis
factor– a , inducible protein–10, soluble CD40 ligand,
and soluble tissue factor (134). To date, there are no
formal recommendations for the use of statins in
patients with APS who have normal lipid profiles;
however, statins can be considered in patients with
refractory APS despite adequate anticoagulation
(Table 3) (128). Furthermore, we submit that endo-
thelial function assessment may play a role in iden-
tifying patients with APS and normal lipid profiles
who might benefit from statin therapy.
mTOR INHIBITORS. Patients with APS nephropathy
who required transplantation and were receiving
sirolimus had no recurrence of vascular lesions and a
decrease in vascular proliferation on biopsy
compared with patients with aPLs who were not on
sirolimus (Table 3) (54). Although the mTOR pathway
may represent potential future therapeutic targets for
treatment of APS vasculopathy, the prothrombotic
effects of mTOR inhibitors might limit their efficacy
in this syndrome (135–138).
CELL DEPLETION THERAPY. Rituximab, a chimeric
monoclonal antibody targeting CD20 cells, has been
effectively used in cases of CAPS, anticoagulation
failure, recurrent thrombosis, and thrombocytopenia
(139). In a retrospective single-center study, ritux-
imab decreased thrombotic events (average follow-up
period 40 months) in patients with SLE-associated
APS with recurrent thrombosis despite adequate
warfarin therapy or life-threatening active disease
refractory to conventional therapy (140). It is impor-
tant to note that immunosuppression was added to
ongoing anticoagulation therapy (141).
Moreover, rituximab therapy was associated with
clinical response in non-thrombosis-related APS
manifestations, including thrombocytopenia, cardiac
JACC VOL. 69, NO. 18, 2017
MAY 9, 2017:2317–30
valve disease, skin ulcers, nephropathy, and cogni-
tive dysfunction, in a small pilot open-label phase
2 trial of 20 patients with APS. Interestingly, there
was no significant variation in the aPL titers at
follow-up (142).
Although the role of rituximab in APS is not yet
clearly defined, anti-CD20 antibodies may be an
important future tool in the management of hema-
tologic and microangiopathic manifestations, as
well as thrombotic cases of APS refractory to anti-
coagulation therapy (Table 3) (128).
COMPLEMENT INHIBITION. Complement system
activation plays an important role in pathogenesis
and thrombus formation in APS. Eculizumab is a
monoclonal antibody that binds the C5 protein,
inhibiting its cleavage into C5a and C5b. By blocking
the complement cascade, the formation of the
membrane attack complex is inhibited. A small
number of case reports and case series have reported
successful use of eculizumab in acute CAPS, as
well as in treatment and prevention of thrombotic
microangiopathy following renal transplantation in
patients with CAPS (Table 3) (93,94,143). Currently,
there are no recommendations for the global use
of eculizumab in APS; however, selective treatment
in refractory cases remains an attractive tool for
the expanding tool box for these complicated
patients (128).
GLUCOCORTICOSTEROIDS, PLASMA EXCHANGE,
AND INTRAVENOUS IMMUNOGLOBULINS. The use of
glucocorticosteroids, plasma exchange, and intrave-
nous immunoglobulins in APS is limited to refractory
cases of recurrent thrombosis despite adequate
anticoagulation (144,145) and CAPS (Table 3). The
combination of heparin anticoagulation, glucocorti-
costeroids, and plasma exchange, intravenous im-
munoglobulins, or both reduced mortality compared
with other treatment strategies in patients with
CAPS (146).
MANAGEMENT OF OBSTETRIC APS. The ninth
edition of the American College of Chest Physicians
evidence-based clinical practice guidelines and the
14th International Congress on Antiphospholipid
Antibodies task force report on obstetric APS recom-
mend treatment of women with obstetric APS with a
combination of heparin, either unfractionated or
low–molecular weight heparin, and low-dose aspirin
(75 to 100 mg/day) (Table 3) (147,148). Although
2 randomized controlled trials reported a higher rate
of live births with the addition of unfractionated
heparin to low-dose aspirin (149,150), these results
were not confirmed in 2 additional randomized
controlled trials (151,152). Pooled data of all available
Corban et al. 2325
Antiphospholipid Syndrome
randomized controlled trials showed a beneficial
effect on live births with unfractionated heparin and
low-dose aspirin, whereas data on the efficacy of low–
molecular weight heparin and low-dose aspirin were
inconclusive (148).
For patients already receiving warfarin, therapy
should be transitioned to either low–molecular
weight heparin or unfractionated heparin and
low-dose aspirin. This transition should occur
immediately upon pregnancy confirmation to avoid
teratogenicity. The risk for warfarin-induced fetal
effects is highest during the first 6 weeks, especially
for patients requiring more than 5 mg of warfarin
daily. For selected high-risk patients in whom sig-
nificant risk factors persist following delivery, inter-
national guidelines suggest extended prophylaxis
(up to 6 weeks after delivery) following discharge
from the hospital (108,147). For patients with APS
with prior thrombotic events, anticoagulant agents
should be continued indefinitely. Importantly,
maternal warfarin therapy is safe for nursing infants.
b 2 -GP1 DOMAINS I AND V ANTAGONISTS. The
binding of aPLs to domain I of b2-GP1 receptors on
endothelial cells induces a conformational change in
the receptor and promotes binding of domain V to
apoER2. This binding results in eNOS inhibition-
mediated endothelial cell dysfunction and ulti-
mately thrombosis (Figure 1). Similarly, binding of
aPLs to domain I of the b2-GP1 receptor on platelets
induces thrombus formation because of increased
thromboxane B2 secretion, enhanced adhesion
of platelets to collagen, and increased platelet
aggregation.
To date, only a handful of in vitro and mouse
studies investigated potential b 2-GP1 antagonists.
Ioannou et al. (153) demonstrated that the mutated
domain I of b2-GP1 receptors was associated with
reduced binding to aPLs in vitro, and that the
recombinant antigenic target peptide domain I of
b2-GP1 inhibited venous thrombotic events and
decreased vascular cell adhesion molecule–1 expres-
sion on aortic endothelial cells in mice injected with
human aPLs (154). Moreover, Ostertag et al. (155)
demonstrated that TIFI, a 20–amino acid synthetic
peptide with conformational similarities to domain V
of b2-GP1, inhibited APS-induced thrombosis in mice.
Similarly, Kolyada et al. (156) demonstrated that the
A1-A1 molecule, which inhibits binding of apoER2 to
domain V of b2-GP1, reduced arterial thrombus size in
APS mice. These studies support the pursuit of
unique targets, possibly within the b2-GP1 receptor,
for future drug development beyond simple antico-
agulant therapy.
2326 Corban et al. JACC VOL. 69, NO. 18, 2017

Antiphospholipid Syndrome MAY 9, 2017:2317–30

C E NT R AL IL L U STR AT IO N Antiphospholipid Syndrome Pathogenesis

Corban, M.T. et al. J Am Coll Cardiol. 2017;69(18):2317–30.

Pathogenesis of antiphospholipid syndrome and recommended areas for research: “first hit” circulating antiphospholipid antibodies (aPLs) and underlying endothelial
dysfunction and “second hit” inflammatory insult result in impaired nitric oxide (NO)–dependent endothelial function, accelerated atherosclerosis, nonatherosclerotic
vasculopathy, platelet activation and aggregation, and complement system activation. Research in aPL and beta-2 glycoprotein 1 receptor (b2-GP1) interaction,
b2-GP1 and apolipoprotein E receptor 2 (apoER2) interaction, and complement system activation is recommended. C5a ¼ complement component 5a fragment;
C5b ¼ complement component 5b fragment.

CONCLUSIONS patients with APS, with only limited research directed

toward new therapies for primary prevention.
APS is an autoimmune disease characterized by Although anticoagulation is the mainstay therapy for
thrombophilia, adverse obstetric events and recur- secondary thromboprophylaxis in patients with APS,
rent miscarriages, accelerated atherosclerosis, a significant number of those patients develop
increased risk for myocardial infarction and stroke, recurrent thrombosis despite conventional thera-
and valvular heart disease. Morbidity and mortality peutic anticoagulation targets. Simply increasing the
in APS is strongly associated with aPL-mediated doses of anticoagulant agents comes at the expense of
vascular endothelial cell dysfunction and comple- increased risk for bleeding. Indeed, hemorrhage
ment system activation. Although thrombophilia is remains the most common cause of death (23%) in
the hallmark of APS, accurate identification of pa- patients with primary APS (9).
tients at increased risk for thrombosis remains a The cardinal role of vascular endothelial dysfunc-
challenge. tion in APS pathogenesis (summarized in the Central
To date, therapeutic efforts have focused mostly Illustration) calls for more focused research
on preventing recurrent thrombotic events in regarding aPLs and b2 -GP1 interaction, b 2-GP1 and
JACC VOL. 69, NO. 18, 2017
MAY 9, 2017:2317–30
apoER2 interaction, and associated
signaling pathways. Large prospective cohort studies
and randomized clinical trials are warranted to study
the role of endothelial function testing in the
risk stratification of patients with APS, investigate
the association between recurrent thrombosis and
accelerated atherosclerosis in patients with APS, and
evaluate targeted therapies against
dysfunction-mediated APS thrombophilia and vas-
culopathy. A paradigm shift aimed at investigating
new therapeutic targets is of the utmost importance
and is potentially highly rewarding and timely
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KEY WORDS antiphospholipid antibodies,
atherosclerosis, epidemiology,
thrombophilia, vascular endothelium,
warfarin