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Antiphospholipid syndrome: an update for clinicians and
scientists
Andrew P. Vreede, M.D.1, Paula L. Bockenstedt, M.D.2, and Jason S. Knight, M.D., Ph.D.1
1Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical
School, Ann Arbor, Michigan, USA
2Division of Hematology, Department of Internal Medicine, University of Michigan Medical School,
Ann Arbor, Michigan, USA
Abstract
Purpose of review—Antiphospholipid syndrome (APS) is a leading acquired cause of
thrombosis and pregnancy loss. Upon diagnosis (which is not made until at least one morbid event
has occurred), anticoagulant medications are typically prescribed in an attempt to prevent future
events. This approach is not uniformly effective and does not prevent associated autoimmune and
inflammatory complications. The goal of this review is to update clinicians and scientists on
mechanistic and clinically-relevant studies from the past 18 months, which have especially
focused on inflammatory aspects of APS pathophysiology.
Recent findings—How antiphospholipid antibodies leverage receptors and signaling pathways
to activate cells are being increasingly defined. While established mediators of disease
pathogenesis (like endothelial cells and the complement system) continue to receive intensive
study, emerging concepts (such as the role of neutrophils) are also receiving increasing attention.
In vivo
animal studies and small clinical trials are demonstrating how repurposed medications
(hydroxychloroquine, statins, rivaroxaban) may have clinical benefit in APS, with these concepts
importantly supported by mechanistic data.
Summary—As anticoagulant medications are not uniformly effective and do not
comprehensively target the underlying pathophysiology of APS, there is a continued need to reveal
the inflammatory aspects of APS, which may be modulated by novel and repurposed therapies.
Keywords
Antiphospholipid syndrome; thrombosis; pregnancy loss; endothelial cells; neutrophils;
complement
Introduction
Vascular complications, including thrombotic events, are among the leading causes of
morbidity and mortality in lupus. Antiphospholipid antibodies (aPL), a major driver of
Correspondence: Jason S. Knight, M.D., Ph.D., 5520A MSRB 1, 1150 W Medical Center Drive, SPC 5680, Ann Arbor, MI
48109-5680, Tel: 734-936-3257, jsknight@umich.edu.
Conflicts of interest: The authors have no conflicts of interest to disclose.
HHS Public Access
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Curr Opin Rheumatol
. Author manuscript; available in PMC 2018 September 01.
Published in final edited form as:
Curr Opin Rheumatol
. 2017 September ; 29(5): 458–466. doi:10.1097/BOR.0000000000000410.
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thrombosis risk, are present in up to one-third of lupus patients. When aPL are associated
with certain clinical complications (either thrombotic or obstetric), a diagnosis of
antiphospholipid syndrome (APS) is assigned (Table 1) [1]. Beyond lupus-associated APS,
approximately half of APS cases will be diagnosed as a standalone syndrome (i.e., primary
APS) [2].
APS is a leading acquired cause of thrombosis and pregnancy loss, with an estimated
prevalence of 1 in 2,000 [3]. Framing this risk another way, aPL can be detected on the order
of 10% of the time in the setting of certain events including pregnancy morbidity, stroke,
myocardial infarction, and deep venous thrombosis (DVT) [4]. Emphasizing the systemic
nature of APS, the diagnosis also portends risk for cytopenias (especially hemolytic anemia
and thrombocytopenia), mitral and aortic valve lesions, seizure disorder, accelerated
cognitive decline, and nephropathy in the form of thrombotic microangiopathy [5]. The
approach to treatment is typically with anticoagulant drugs, which are not uniformly
effective in preventing recurrent aPL-mediated thrombosis and pregnancy loss, and offer
insufficient protection against the varied “non-criteria” manifestations of APS. Indeed, 44%
of “triple-positive” APS patients (positive testing for anticardiolipin, anti-beta-2-
glycoprotein I,
and
lupus anticoagulant) will develop recurrent thrombosis over a 10-year
follow-up period (even with the majority being prescribed anticoagulants) [6]. Furthermore,
at least 20% of obstetric APS patients have adverse outcomes in spite of therapy with aspirin
and low-molecular-weight heparin [7].
Despite its high prevalence and potential for devastating morbidity, APS pathophysiology
has yet to be fully defined. APS was historically viewed as a coagulation problem; however,
clinical observations and basic science discoveries are increasingly highlighting a more
multifaceted syndrome with an associated (and perhaps even central) inflammatory
component [8]. Herein we will discuss recent discoveries over the past 18 months, which
have continued to increase our understanding of APS pathophysiology. We will also discuss
how this improved basic understanding may translate to new and repurposed therapeutics for
APS (Table 2)
Cell activation and signaling pathways: new concepts
Understanding the cellular signaling pathways that mediate APS pathogenesis has remained
somewhat elusive, at least partially the consequence of study heterogeneity. Studies have
utilized different types of aPL (monoclonal vs. patient-derived; protein cofactor-dependent
vs. -independent) and have focused on a variety of cellular targets (endothelial cells,
platelets, monocytes, neutrophils, trophoblast cells, etc.).
Many (perhaps most) pathogenic antibodies in APS do not target phospholipids themselves,
but rather phospholipid-binding protein cofactors. The best characterized of these cofactors
is beta-2 glycoprotein I (β2GPI), a lipid-binding protein present at high levels in plasma
[22,23], albeit with largely unknown endogenous function. The mechanistic schema is that
anti-β2GPI antibodies potentiate thrombosis by engaging β2GPI protein that has been
recruited to cell surfaces—and thereby promote cell activation [24–26]. The mechanisms by
which anti-β2GPI antibodies activate cells have been recently reviewed [27], with roles
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especially suggested for the cell surface proteins annexin A2, apolipoprotein E receptor 2
(ApoER2), Toll-like receptor 2 (TLR2), and TLR4 [27].
ApoER2 (also known as LDL receptor-related protein 8) is one receptor for β2GPI (and
consequently β2GPI-dependent aPL) on monocytes, endothelial cells, and platelets. Indeed,
in a 2011 study, Ramesh and colleagues demonstrated ApoER2−/− mice are relatively
resistant to thrombosis when confronted with aPL [28]. More recently, it has been revealed
that ApoER2 may play an important role in obstetric APS [29]. Specifically, Ulrich and
colleagues demonstrated enhanced placental trophoblast cell proliferation and migration
in
vitro
when aPL engage β2GPI/ApoER2 complexes on the trophoblast cell surface [29].
Extending these studies to an
in vivo
model of aPL-mediated pregnancy loss, they
demonstrated protection in ApoER2−/− mice [29]. In another recent study, Mineo and
colleagues developed a monoclonal antibody against β2GPI that prevents pathogenic aPL
binding, thereby protecting against aPL-mediated cell activation [30]*. The antibody
attenuated the association of β2GPI with ApoER2, thereby normalizing endothelial and
trophoblast cell function
in vitro
, as well as preventing thrombosis and fetal loss
in vivo
[30]*. Although further study is clearly needed, the intersection of aPL, β2GPI, and ApoER2
warrants further investigation as a potential therapeutic target in patients.
Since neither β2GPI itself, nor some β2GPI “receptors” such as annexin A2, have a
cytoplasmic domain to mediate signaling, there has been interest in additional partner
proteins that may convey activating signals to the cytoplasm. On this front, particular
attention has been given to the cell-surface TLRs, TLR2 and TLR4. In mouse models, TLR4
deletion protects against venous and arterial thrombosis in some [31–33], but not all [34]*,
studies (it is worth pointing out that the latter study utilized cofactor-independent aPL).
Studies of obstetric APS have also yielded mixed results with an older study demonstrating
no role for TLR4 in an
in vivo
model of pregnancy loss [35]. In contrast, Azuma and
colleagues recently suggested that, at least
in
vitro, TLR2 and TLR4 facilitate inflammatory
cytokine production by trophoblast cells in response to anti-β2GPI antibodies [36].
Signaling pathways downstream of the aforementioned receptors, at least as they relate to
APS pathogenesis, remain incompletely understood. Terrisse and colleagues recently
investigated downstream signaling pathways by which aPL (especially IgG isolated from
APS patients) activate platelets [37]*. The authors demonstrated that aPL potentiate
ex vivo
platelet activation through surface glycoprotein Ibα (the platelet receptor for von Willebrand
factor) and TLR2, via a mechanism involving class IA phosphoinositide 3-kinase (PI3K) α
and β isoforms [37]*. At least one downstream consequence of PI3K signaling is activation
of the serine/threonine kinase Akt, a pathway that supports cell survival, proliferation, and
migration [37]*. Indeed, PI3K inhibitors, which are being explored as potential drug targets
in other contexts [38], are effective at preventing aPL-mediated platelet activation [37]*.
Interestingly, another study has suggested that Akt activation is a downstream consequence
of trophoblast cell activation by aPL [29].
Beyond the engagement of aPL with cell surfaces, a recent report by Wu and colleagues
suggests an intriguing new mechanism by which aPL-activated endothelial cells may
propagate this activation in paracrine fashion to other endothelial cells [39]*. Anti-β2GPI
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antibodies trigger the release of “extracellular vesicles” from endothelial cells, which the
authors define as inclusive of both microparticles and exosomes [39]*. These vesicles then
activate endothelial cells through a mechanism that is not dependent upon packaged
cytokines such as IL-1, but rather single-stranded RNA that signals through TLR7 in the
recipient cell [39]*. They also speculate that these vesicles may be a mechanism for delivery
of specific and functionally-relevant micro-RNA, although this hypothesis requires further
study.
The vessel wall: endothelial progenitors and interferons
Our group recently looked “upstream” of endothelial cells, asking whether a deficiency in
reparative, circulating endothelial progenitors might contribute to defective maintenance and
health of the endothelium over time. Indeed, a deficiency in the number and function of such
progenitors is a well-recognized aspect of both lupus and rheumatoid arthritis [40]. We
found that primary APS patients have a reduction in functional endothelial progenitors,
which was interestingly not dependent upon patient IgG; rather, we discovered a type I IFN
signature in the APS patients, abrogation of which could restore normal progenitor function
[41]*. These findings were recently replicated by van den Hoogen and colleagues, who
found that approximately 50% of primary APS patients have a type I IFN signature, which
was less likely to be present in patients taking either hydroxychloroquine or statins [20]**.
Interestingly, they also found that the IFN signature correlated with expansion of
“intermediate” and “non-classical” monocytes (which have been previously linked to
cardiovascular disease in lupus and rheumatoid arthritis) [20]**. How these monocytes
intersect with endothelial progenitors [42], and whether there is a role for anti-interferon
therapy in APS [43], are questions that deserve further consideration.
One potential consequence of endothelial cell (and progenitor) dysfunction is
atherosclerosis, an accelerated version of which is a well-known complication of lupus [44],
and which has also been reported in APS [45,46]. The recent work of Benagiano and
colleagues has examined the role of TH1 specific inflammatory responses to β2GPI in
established atherosclerotic lesions of primary APS patients. Their work demonstrated that
plaque-derived, β2GPI-specific CD4+ T lymphocytes facilitate perforin- and Fas ligand-
mediated cytotoxicity, pointing to a role for these autoreactive T cells in plaque
destabilization (and potentially the arterial thrombotic events that are known to occur at
higher frequency in APS) [47]**. They also demonstrated that β2GPI can induce
proliferation of (and IFN-γ expression by) plaque-derived T cell clones [47]**.
Furthermore, these T cells amplify monocyte responses, such as the production of tissue
factor and matrix metalloproteinases, which can be inhibited with an anti-IFN-γ antibody
[47]**.
Myeloid-lineage cells: neutrophil extracellular traps (NETs) and monocyte
NOX2
The role of neutrophils in APS pathogenesis has only recently been investigated. This
interest was precipitated by emerging descriptions of neutrophils as mediators of both
pathologic clotting and autoimmune diseases [48,49]. In particular, NETs (extracellular
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chromatin-based structures released by activated neutrophils) have been described as triggers
of autoimmunity and tissue damage, as well as important instigators of thrombosis [50].
With this background in mind [51], our group recently identified increased levels of cell-free
DNA and NETs in the circulation of primary APS patients, as compared with healthy
controls [52]**. When APS neutrophils were cultured
in vitro
, they demonstrated an
enhanced propensity to spontaneously release NETs [52]**. Mechanistically, anti-β2GPI
IgG appears to be at least one factor in patient blood that supports NET release, with the
mechanism dependent upon both TLR4 and formation of reactive oxygen species [52]**.
Furthermore, the prothrombotic potential of aPL-mediated NETs was demonstrated in a
thrombin generation assay, with this potential abrogated by treatment with
deoxyribonuclease (DNase) [52]**. In parallel to our work, van den Hoogen and colleagues
reported increased levels of circulating “low-density granulocytes” or LDGs in patients with
primary APS [53]. This pro-inflammatory subset of neutrophils has been well characterized
in SLE and other autoimmune disorders, where they are reported to release NETs in
exaggerated fashion [54]. Whether LDGs are important sources of NETs in APS awaits
further study [55].
The
in vivo
relevance of NETs was recently confirmed by our group in a mouse model of
APS. In this model, IgG from triple-positive APS patients potentiated venous thrombosis in
mice that had been subjected to flow restriction in the inferior vena cava by a standard
surgical stenosis [56]*. As compared with control mice, mice treated with APS IgG were
twice as likely to develop macroscopic thrombi in response to flow restriction.
Mechanistically, APS thrombi were enriched for NETs, while patient IgG could be detected
on the surface of circulating neutrophils [56]*. Furthermore, APS IgG-mediated thrombosis
could be reversed by either neutrophil depletion or administration of systemic DNase [56]*.
Around the same time, Manukyan and colleagues published an elegant study demonstrating
that cofactor-independent aPL could similarly potentiate thrombosis in an inferior vena cava
flow-restriction model [34]*. Their interesting work found a major role for leukocyte
activation in thrombus formation, which could be abrogated by deletion of NOX2 (the
catalytic subunit of NADPH oxidase) from bone marrow-derived cells. While the authors’
primary interest was in monocyte NOX2 and its role in tissue factor expression, there is also
a well-accepted role for neutrophil NOX2 in NET formation [57]. Further studies may assess
the role of these cofactor-independent antiphospholipid antibodies in inducing NET release
in vitro
and
in vivo
.
Complement: at the intersection of coagulation and inflammation in APS
Animal models of APS have supported a role for complement activation in both thrombotic
events and pregnancy loss [58,59]. Studies in APS patients have demonstrated smoldering
activity of the complement cascade [60–62], while a recent case report revealed deposition
of β2GPI protein, IgG, and complement components C1q, C4, C3, and C5b-9 at the
endothelial surface of an occluded artery in an APS patient [63]. Furthermore, this patient,
who had suffered recurrent arterial occlusions, was successfully revascularized while under
treatment with eculizumab, a terminal complement inhibitor [63].
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In lupus, antibodies to C1q (a complex that initiates the complement cascade in response to
immune complexes) amplify complement activation and strongly correlate with certain
clinical manifestations such as proliferative nephritis [64]. Oku and colleagues recently
investigated these antibodies in primary APS patients, demonstrating that 36% of patients
had detectable anti-C1q (compared to 55% of lupus patients) [65]. Interestingly titers of
anti-C1q were significantly higher in patients with refractory APS [65].
Rivaroxaban, a direct factor Xa inhibitor, has recently been proposed as an alternative agent
to vitamin K antagonists in APS. The first randomized, prospective study investigating use
of rivaroxaban in APS (RAPS trial) was recently published. In patients with a history of
venous thromboembolism (who had already demonstrated stable disease on warfarin), both
warfarin and rivaroxaban prevented new thrombotic events for 210 days in every study
patient [14]**. Bleeding events and overall adverse events were also similar between the
groups [14]**. While a full recounting of this important trial is beyond the scope of this
brief review, we would refer you to a detailed comment on the topic [66]. Related to our
discussion of the complement pathway, a post-hoc analysis of the RAPS trial revealed that,
prior to randomization, APS patients had significantly higher markers of complement
activation as compared with normal controls [19]*. While patients in the warfarin group
showed stable elevation of these markers over time, patients randomized to rivaroxaban
demonstrated decreased C3a, C5a, and soluble C5b-9 (all markers of classical pathway
activation) [19]*. In contrast, the alternative pathway marker, Bb, was unchanged with
rivaroxaban treatment [19]*. Whether direct oral anticoagulants have additional anti-
inflammatory properties is a topic that certainly warrants further study.
Repurposing medications: statins and hydroxychloroquine as adjuvant
therapies in APS?
HMG-CoA reductase inhibitors (or statins) have long been recognized to have pleotropic
anti-inflammatory effects supportive of vascular health, including reductions in
inflammation, oxidative stress, and coagulation [67]. Clinically, statins appear to reduce the
risk of venous thromboembolism in the general population [13]. In mouse models of APS,
statins mitigate aPL-mediated thrombotic events and fetal death [11,16]. Furthermore, when
administered to APS patients, statins decrease both prothrombotic and proinflammatory
biomarkers [68].
The standard of care for managing pregnancy complications in APS is the administration of
low-dose aspirin and low-molecular-weight heparin (the latter at either prophylactic or
therapeutic doses, depending on the patient’s thrombosis history) [69,70]. However, as
detailed in recent review articles [69,70], pregnancy complications in APS are often not
based in frank placental thrombosis, but rather spiral artery vasculopathy, as well as acute
and chronic inflammation—with increased infiltration of inflammatory cells and deposition
of complement in the placentae of women with APS [71–73]. Lefkou and colleagues
recently investigated the use of pravastatin in refractory obstetric APS [18]**. In their
clinical trial, 21 patients with refractory obstetric APS (emergence of preeclampsia and/or
intrauterine growth restriction [IUGR] despite treatment with low-dose aspirin and low-
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molecular-weight heparin) were randomized either to continue standard therapy or to receive
pravastatin 20 mg/day at the onset of preeclampsia/IUGR [18]**. There was a remarkable
therapeutic benefit, with all the patients receiving pravastatin delivering healthy infants at
34–38 weeks [18]**. In contrast, the 10 patients who remained on standard therapy had
three stillbirths at 25–26 weeks, and seven pre-term Cesarean sections (resulting in two fetal
deaths) [18]**.
Hydroxychloroquine (which is nowadays prescribed to essentially all patients with lupus)
was utilized in the 1970s to reduce the risk of venous-thromboembolism in post-operative
patients [12]. In the 1990s, hydroxychloroquine was demonstrated to protect against aPL-
mediated thrombosis in mice [9]. Furthermore, there have been hints of a reduction in
thrombosis risk in lupus patients taking hydroxychloroquine, as compared to those who are
not [74,75]. Mechanistically, a recent study demonstrated that hydroxychloroquine inhibits
the translocation of monocyte NOX2 to the endosome in response to stimulants such as
TNFα, IL-1β, and aPL [10]**. This was accompanied by mitigation of aPL-induced,
NOX2-mediated thrombus formation
in vivo
[10]**. As the related drug chloroquine has
been shown to antagonize NET release [21], further studies should continue to explore the
intersection of hydroxychloroquine, activated monocytes/neutrophils, and APS.
Given its excellent safety profile in pregnancy [76], and its nearly standard-of-care
application in lupus pregnancies, hydroxychloroquine has been increasingly considered as
adjuvant therapy in APS pregnancies. Indeed, recent retrospective studies have suggested a
beneficial effect of hydroxychloroquine in APS pregnancies [7,17]. In a mouse model of
obstetric APS, Bertolaccini and colleagues recently demonstrated that hydroxychloroquine
prevents fetal death and placental metabolic changes [15]*. Going further, they
demonstrated that labeled aPL especially localize to the placenta and the developing fetal
brain, and that hydroxychloroquine mitigates complement deposition at both sites (which
correlated with lower levels of C3a and C5a in blood) [15]*. Intriguingly, C3a and C5a were
also reduced in the blood of APS patients after 6 months of hydroxychloroquine treatment
[15]*.
Conclusion
Since its description in the 1980s, APS has been managed primarily with anticoagulant
medications. These medications are not universally protective against subsequent thrombotic
events and pregnancy loss, and have little proven track record in treating “non-criteria”
manifestations of APS such as cytopenias and cardiac valvular disease. Basic science studies
continue to refine the signaling pathways, activated cells, and non-cellular effectors critical
for APS pathogenesis (Figure 1). In addition to a search for novel therapeutics, established
medications such as rivaroxaban, statins, and hydroxychloroquine are receiving increasing
interest as adjuvant therapies. In the near future, we hope to see more well-designed clinical
trials with both mechanistic and clinical endpoints.
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Acknowledgments
Financial support and sponsorship: JSK was supported by NIH K08AR066569 and career development awards
from the Burroughs Wellcome Fund, the Rheumatology Research Foundation, and the Arthritis National Research
Foundation.
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Key points
1. Current standard-of-care therapy for APS does not explicitly target
inflammatory aspects of APS pathophysiology.
2. A better understanding of inter- and intra-cellular signaling pathways in APS
has revealed potential drug targets (i.e., interferons, phosphoinositide 3-
kinase, etc.).
3. In addition to the well-established cellular mediators of APS pathogenesis
(endothelial cells, platelets, etc.), there is emerging interest in the contribution
of myeloid-lineage cells to APS pathogenesis. The role of neutrophil
extracellular trap release, in particular, warrants further study.
4. Complement activation and deposition continue to be recognized for their role
in APS pathogenesis. Activity of this pathway may be mitigated by several
medications including rivaroxaban and hydroxychloroquine.
5. Adjuvant therapeutics including statins and hydroxychloroquine have the
potential to improve APS pregnancy outcomes, based upon animal studies
and small clinical trials.
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Figure 1.
Recent mechanistic insights into the pathophysiology of antiphospholipid antibodies (aPL)
and APS. Starting at the bottom of the figure and moving roughly clockwise: In the vessel
wall of atherosclerotic plaques, beta-2 glycoprotein I (β2GPI)-specific TH1 cells trigger cell
death and release interferons (IFNs). Endothelial cells (ECs) release vesicles (like
microparticles) that activate TLR7 in other ECs by delivery of single-stranded RNA. aPL-
mediated platelet activation relies on phosphoinositide 3-kinase (PI3K). Type I IFNs reduce
the function of restorative circulating endothelial progenitors, which may lead to the accrual
of endothelial damage over time. Cofactor-independent aPL activate monocytes via
endosomal reactive oxygen species (ROS), resulting in increased expression of tissue factor
(TF). In response to aPL, neutrophils release neutrophil extracellular traps (NETs), which
help facilitate thrombin activation. Complement activation, especially through the classical
pathway, leads to the assembly of the membrane attack complex (MAC) on the endothelial
surface, while also facilitating the recruitment and activation of inflammatory cells.
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Table 1
Classification Criteria for Antiphospholipid Syndrome [1]
APS is present if 1 of the clinical criteria and 1 of the laboratory criteria are met
Clinical criteria 1. Vascular thrombosis ≥1 clinical episode of arterial, venous, or small-vessel thrombosis.
2. Pregnancy morbidity a. ≥1 unexplained death of a morphologically normal fetus at ≥10 weeks of
gestation
b. ≥1 premature delivery of a morphologically normal fetus at <34 weeks
gestation because of:
i. Severe pre-eclampsia or eclampsia defined according to standard
definition
ii. Recognized features of placental insufficiency
c. ≥3 unexplained consecutive miscarriages at <10 weeks gestation, with
maternal and paternal factors (anatomic, hormonal or chromosomal
abnormalities) excluded
Laboratory criteria The presence of antiphospholipid antibodies on ≥2 occasions ≥12 weeks apart:
a. Presence of lupus anticoagulant in plasma
b. Medium- to high-titer anticardiolipin antibodies of IgG or IgM isoforms
c. Medium- to high-titer anti-beta-2 glycoprotein-I (anti-β2GPI) antibodies of IgG or IgM isoforms
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Table 2
Summary of efficacy and mechanisms by which adjuvant therapeutics could potentially benefit APS patients
Hydroxychloroquine Statins Rivaroxaban
Summary of efficacy:
Thrombotic risk
Mouse models Protects [9,10] Protects [11]
APS patients No prospective studies in APS, but
protects in post-operative setting [12]
No studies in APS, but
protects in the general
population [13]
Efficacy may be similar to
warfarin (although further study
is needed) [14]
Obstetric events
Mouse models Prevents fetal death and metabolic
changes [15] Prevents fetal death [16]
APS patients May prevent pregnancy loss [7,17] May prevent fetal
morbidity and mortality
[18]
Potential anti-inflammatory mechanisms:
Complement Inhibits activation and deposition [15] Decreases activation [19]
Type I IFN signature Decreases [20] Decreases [20]
NET release Possibly inhibits [21]
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