Article

An update on the management of antiphospholipid syndrome

Abstract

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent venous or arterial thrombosis with or without pregnancy morbidity in the presence of persistent antiphospholipid (aPL) autoantibodies. Anticoagulation has, until now, formed the cornerstone of treatment but a significant proportion of patients continue to experience thrombosis and pregnancy morbidity despite this treatment. Thrombosis is the most common cause of mortality and accounts for two fifths of deaths. Direct oral anticoagulant drugs represent an attractive alternative to conventional vitamin K antagonist drugs but emerging evidence suggests these may not be suitable for high-risk patients with thrombotic APS. Laboratory studies and case reports of the successful use of different classes of drugs in APS is increasing our understanding of the other pathophysiological mechanisms which may contribute to the high morbidity of APS. This review summarizes current accepted anticoagulant treatment for APS and examines other potential drugs such as immunomodulating agents, statins and novel agents such as sirolimus and defibrotide.
https://doi.org/10.1177/1759720X20910855
https://doi.org/10.1177/1759720X20910855
Ther Adv Musculoskel Dis
2020, Vol. 12: 1–10
DOI: 10.1177/
1759720X20910855
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Introduction
Antiphospholipid syndrome (APS) is a systemic
autoimmune disorder characterized by recurrent
venous or arterial thrombosis with or without
pregnancy morbidity in the presence of persistent
antiphospholipid (aPL) autoantibodies. These
include the lupus anticoagulant (LA), anticardi-
olipin (aCL) and antibeta-2 glycoprotein (anti-
β2GPI) autoantibodies, which should be present
in moderate-to-high titre on two occasions at least
12 weeks apart. The condition was first described
in association with systemic lupus erythematous
(SLE) but in 53% of patients, it exists alone as
primary APS (PAPS).1 Classification criteria for
definite APS were devised in Sapporo, Japan, in
19992 and were later updated in Sydney, Australia,
in 20063 (Table 1). APS is also less commonly
associated with other autoimmune rheumatic dis-
eases such as rheumatoid arthritis, dermatomyosi-
tis, systemic sclerosis and Sjögren’s syndrome.
APS is a significant cause of morbidity and mortal-
ity. It is estimated to account for 6% of all preg-
nancy morbidity, 13.5% of stroke, 11% of
myocardial infarction and 9.5% of deep vein
thromboses.4 Other commonly reported but non-
classification criteria manifestations include throm-
bocytopenia, autoimmune haemolytic anaemia,
livedo reticularis, superficial thrombophlebitis, aPL-
associated nephropathy, cognitive dysfunction,
skin ulcers, epilepsy, cardiac valve dysfunction and
vegetations. Obstetric manifestations include recur-
rent early and late pregnancy loss, pre-eclampsia,
eclampsia and intrauterine growth restriction.
A striking feature of the disease is that thrombo-
ses can occur in any vascular bed. Catastrophic
APS (CAPS) is a rare, life-threatening variant of
APS. It is characterized by the acute development
of widespread thrombosis resulting in the failure
of three or more organs in less than 1 week. It can
occur as the presenting event or in those with
known APS. The mortality rate is high, 30–50%
despite treatment.1,5
In patients with previous thrombosis attributable to
APS, anticoagulation has formed the cornerstone
of treatment to date. Active inflammation in any
An update on the management of
antiphospholipid syndrome
Mia Rodziewicz and David P. D’Cruz
Abstract: Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized
by recurrent venous or arterial thrombosis with or without pregnancy morbidity in the
presence of persistent antiphospholipid (aPL) autoantibodies. Anticoagulation has, until
now, formed the cornerstone of treatment but a significant proportion of patients continue
to experience thrombosis and pregnancy morbidity despite this treatment. Thrombosis
is the most common cause of mortality and accounts for two fifths of deaths. Direct oral
anticoagulant drugs represent an attractive alternative to conventional vitamin K antagonist
drugs but emerging evidence suggests these may not be suitable for high-risk patients
with thrombotic APS. Laboratory studies and case reports of the successful use of different
classes of drugs in APS is increasing our understanding of the other pathophysiological
mechanisms which may contribute to the high morbidity of APS. This review summarizes
current accepted anticoagulant treatment for APS and examines other potential drugs such as
immunomodulating agents, statins and novel agents such as sirolimus and defibrotide.
Keywords: antiphospholipid antibodies, antiphospholipid syndrome, treatment
Received: 21 March 2019; revised manuscript accepted: 30 January 2020.
Correspondence to:
Mia Rodziewicz
Louise Coote Lupus Unit,
Guy’s Hospital, 4th Floor
Tower Wing, Great Maze
Pond, London SE1 9RT, UK
mia.rodziewicz@nhs.net
David P. D’Cruz
Louise Coote Lupus Unit,
Guy’s Hospital, London, UK
910855TAB0010.1177/1759720X20910855Therapeutic Advances in Musculoskeletal DiseaseM Rodziewicz and DP D’Cruz
review-article20202020
Review
Therapeutic Advances in Musculoskeletal Disease 12
2 journals.sagepub.com/home/tab
associated autoimmune disease such as SLE, and
especially in the presence of aPL, is associated
with an increased thrombotic risk,6 and medical
management of such conditions is imperative.
Anticoagulation appears to have improved the
morbidity and mortality associated with throm-
botic APS but significant challenges remain in pre-
venting APS-related morbidity. Treatment of
patients with obstetric APS has improved live birth
rates from 40% to 85%,7 but 15% still fail to achieve
a live birth. Data from the largest published cohort
study of APS, the Euro-Phospholipid cohort,
reported a reduction in mortality from 5.3% in the
initial 5 years of follow up to 4.5% in the latter
5 years.1 In the same cohort, however, severe
thrombotic events still accounted for the majority
of deaths (37%), infection and major haemorrhage
were the second and third most common causes of
death and accounted for 27% and 11% of deaths,
respectively.1 The increased risk of infection
appears not only to be limited to SLE-associated
APS (SLE-APS) individuals receiving immuno-
suppressive drugs, but also to patients with PAPS.1
Several nonanticoagulant drugs have demonstrated
therapeutic potential in the treatment of the
disease, and our increasing understanding of the
pathophysiology may lead to a more multifaceted
approach to treatment and further reduction of
such complications. In this review, we aimed to
summarize the current recommended and emerg-
ing treatment for thrombotic, obstetric and noncri-
teria manifestations of APS.
Primary antithrombotic prophylaxis:
antiplatelet agents
Low-dose aspirin (LDA) is used in the general
population for the secondary prevention of arterial
thrombosis.8 In patients with SLE and persistent
aPL, but no prior thrombosis, there is evidence
that aspirin reduces the incidence of first throm-
bosis (arterial or venous).9 The role of aspirin for
primary prevention in asymptomatic patients with
persistent aPL is less clear. Retrospective studies
suggest that aspirin reduces the incidence of
thrombosis in this population, but no prospective
studies have demonstrated the same effect.
Retrospective studies also suggest a stronger pro-
tective effect for arterial events.10 Recently pub-
lished European League Against Rheumatism
(EULAR) guidance recommends prophylactic
Table 1. Revised classification criteria for APS 2006 (adapted from Myakis et al.3).
Clinical criteria*
(1) Vascular thrombosis: one or more clinical episodes of arterial, venous, or small vessel thrombosis, in
any tissue or organ
(2) Pregnancy morbidity:
(a) one or more unexplained deaths of a morphologically normal foetus at or beyond the 10th week
of gestation; or
(b) one or more premature births of a morphologically normal neonate before the 34th week of
gestation because of: (i) eclampsia or severe pre-eclampsia; or (ii) recognized features of
placental insufficiency; or
(c) three or more unexplained consecutive spontaneous abortions before the 10th week of gestation,
with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal
causes excluded
Laboratory criteria*+
(1) Lupus anticoagulant present in plasma
(2) Anticardiolipin antibody of IgG or IgM isotype in serum, in medium or high titre (i.e. >40 GPL or MPL,
or >99th percentile measured by a standardized ELISA)
(3) Anti-β2 glycoprotein-I antibody of IgG or IgM isotype in serum (in titre > 99th percentile) measured by
a standardized ELISA
*At least one clinical and one laboratory criterion are required for the diagnosis of definite APS.
include abnormal foetal surveillance tests, abnormal Doppler velocimetry waveform analysis, oligohydramnios or a
postnatal birth weight less than the 10th percentile for the gestational age.
+must be present on two occasions at least 12 weeks apart.
APS, antiphospholipid syndrome; ELISA, enzyme-linked immunosorbent assay; GPL, IgG antiphospholipid units/mL; IgG,
immunoglobulin G; MPL, IgM antiphospholipid units/mL.
M Rodziewicz and DP D’Cruz
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LDA in asymptomatic aPL carriers with a high-
risk profile [persistently high aPL titres, ‘double’
or ‘triple positivity’ (a combination of LA and one
of aCL or β2GPI, or all three)].11
Secondary antithrombotic prophylaxis:
anticoagulant treatment
Vitamin K antagonists
The gold standard treatment for APS patients
who have suffered a thrombosis is treatment with
an oral vitamin K antagonist (VKA) to achieve a
target international normalized ratio (INR) of
2.0–3.0.9 Recurrence rates without anticoagula-
tion are high and given this, it is generally accepted
that anticoagulation should be continued lifelong.
The Euro-Phospholipid cohort, a descriptive
study of 1000 patients followed up over a 10-year
period found 17.7% of patients had recurrent
thromboses despite standard anticoagulant treat-
ment.1 Retrospective studies have suggested that
this risk is reduced with higher-intensity antico-
agulation.12 Two randomized controlled trials
(RCTs), however, concluded that a target INR of
3.0–4.0 does not confer any increased benefit
compared with standard-intensity anticoagula-
tion (target INR 2.0–3.0).13,14 These studies,
however, did not consider the heterogeneity of
clinical and laboratory features of individuals
included in the study. It is well recognized that
previous arterial thromboses, recurrent thrombo-
ses (venous or arterial) while on anticoagulation
and autoantibody ‘triple positivity’ (the presence
of LA, aCL and β2GPI) convey a high risk of
recurrent thrombosis. Neither study tested for
β2GPI and the rate of triple positivity was there-
fore not determined. The Warfarin in the
AntiPhosholipid Syndrome (WAPS) study
included less than 30% of patients with previous
arterial thrombosis and the study by Crowther
and colleagues excluded patients with previous
recurrent thrombosis on anticoagulation.
Crowther and colleagues found a higher rate of
thrombotic recurrence in the group assigned
high-intensity anticoagulation but this did not
reach statistical significance (10.7% versus 3.4%).
Actual INRs at the time of thrombosis were also
<3.0 in four of the six individuals who developed
thrombotic recurrences in the high-intensity
group.14 Furthermore, the INR was below target
in all individuals for a significant proportion of
time in both the Crowther and colleagues’ and
WAPS studies (43% and 19%, respectively). This
supports clinical evidence that it is often difficult
to consistently maintain INRs in the target range
in APS, particularly in those with high-intensity
target ranges. This is often due to difficulty in
managing dosing by prescribers and the poten-
tially lower acceptability to patients. A systematic
review by Ruiz-Irastorza and coworkers included
both prospective and retrospective studies, and
found that 86% of recurrences occurred with
actual INRs < 3.0. Recurrent arterial thromboses
that occur at a target INR 2.0–3.0, appear to
occur more commonly than venous events and
are more likely to be fatal.15 A metanalysis by
Finazzi and colleagues, the review by Ruiz-
Irastorza and coworkers and a recent EULAR
review all supported standard-intensity anticoag-
ulation for APS patients with first venous events,
but the latter two reviews recommended a target
INR > 3.0 in those with recurrent venous or arte-
rial events.8,13,15
Thrombosis is the major cause of death in
APS and accounts for around three times as
many deaths as haemorrhage1 but the correlation
between high-intensity anticoagulation and
bleeding risk has not been clearly elucidated. In
the Euro-Phospholipid study, 33% of major
bleeds occurred at INR > 3.0 but clinical studies
have suggested no significant difference in bleed-
ing between target INRs of 2.0–3.0 and 3.0–4.0.16
As noted above, however, actual time spent within
target is frequently suboptimal. Further studies
with larger numbers of high-risk APS patients are
required but are difficult to conduct.
The 13th International Congress on Anti-
phospholipid Antibodies task force, as well as cur-
rent EULAR guidance recommend that patients
with definite APS and a first venous event receive
lifelong oral anticoagulation to a target INR of
2.0–3.0. EULAR also distinguishes those patients
with unprovoked first venous thrombosis and rec-
ommend that anticoagulation in this group be
continued for a duration for patients without APS,
unless a high-risk aPL profile or other risk factors
for recurrence are present.11Lifelong high- or
standard-intensity anticoagulation plus an anti-
platelet drug (APD) are advised; however, for
those with arterial thrombosis or recurrent venous
thromboembolism (VTE) on standard intensity
treatment.9,11
Direct oral anticoagulants
Direct oral anticoagulants (DOACs) such as
rivaroxaban, apixaban and dabigatran are licensed
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for use in the general population for the second-
ary prevention of VTE and the prevention of arte-
rial thrombosis in nonvalvular atrial fibrillation.
They are attractive alternative agents to VKAs
because they do not require blood monitoring,
have fewer dietary and drug interactions and have
a rapid and predictable onset of action which pre-
cludes the need for heparinization in the acute
setting. It should be noted that several commonly
prescribed drugs can potentiate or inhibit DOAC
activity and include diltiazem, ketoconazole and
carbamazepine. Such interactions have recently
been reviewed in detail elsewhere.17
To date, two RCTs have been published comparing
warfarin treatment with rivaroxaban for secondary
thrombotic prophylaxis in APS. The Rivaroxaban
in APS (RAPS) study used a laboratory surrogate:
the percentage change in endogenous thrombin
potential (ETP) time as its primary outcome meas-
ure. It was not powered to assess clinical outcomes
and patients with previous arterial thromboses and
recurrent venous thrombotic events were excluded.
The authors concluded inferiority of rivaroxaban
based on the ETP surrogate outcome measure but
suggested that the drug may be a safe alternative to
warfarin in uncomplicated APS patients with a sin-
gle previous VTE, as no thromboses and no epi-
sodes of major bleeding occurred during the short
follow-up period of 6 months.18
Several observational cohort studies of DOACs for
secondary thrombotic prophylaxis have been pub-
lished. The patients included in these studies are
heterogenous in terms of aPL profiles, history of
previous venous/arterial events and length of fol-
low up. Of note, in all studies, the majority of
recurrent thrombotic events during treatment with
a DOAC occurred in triple-positive patients.19
The Trial on Rivaroxaban in Anti-Phospholipid
Syndrome (TRAPS) study was a noninferiority
trial, designed to compare rivaroxaban with
standard-intensity anticoagulation with warfarin
in triple-positive patients.20 It was prematurely
terminated after the enrolment of 120 patients,
due to an excess risk of thrombotic events in seven
subjects treated with rivaroxaban (versus zero in
the arm randomized to warfarin). DOACs may
therefore not be suitable for triple-positive APS
patients with arterial events/recurrent venous
events until further data are available. They might
be considered for the prevention of VTE in
patients with low-risk aPL profiles who are intol-
erant of, or poorly compliant with, VKAs. When
there are concerns regarding VKA compliance, it
should also be considered that such individuals
may also be nonadherent to DOACs where moni-
toring of the anticoagulant effect is not routinely
measured. Moreover, the European Medicines
Agency also recently issued a special warning that
DOACs are not recommended for APS patients
with a history of thrombosis, especially in those
that are triple positive.21
There have been no trials using DOACs for non-
criteria APS manifestations but one case report
has described the successful use of apixaban in
the treatment of pyoderma gangrenosum which did
not respond to VKA or rivaroxaban. The authors
postulate that the twice-daily dosing of apixaban
may have explained a poor response to rivaroxa-
ban administered once daily.22 ASTRO-APS is a
pragmatic phase II open label RCT comparing
apixaban with standard-intensity warfarin (target
INR 2.0–3.0) for secondary thrombosis preven-
tion, and is currently ongoing.23
Pregnancy morbidity
Prepregnancy counselling in patients with known
APS is vital to ensure conventional cardiovascular
and APS-specific risk factors can be identified
and managed. Previous pregnancy outcomes and
triple-antibody positivity are the best predictors
of adverse pregnancy outcomes in APS, but other
factors include SLE-APS and previous history of
thrombosis. Of the three diagnostic aPLs, LA is
most predictive of adverse pregnancy outcome.24
VKAs are teratogenic; therefore, in APS patients
with prior thrombosis or pregnancy morbidity,
therapeutic dose low-molecular-weight heparin
(LMWH) and LDA is accepted treatment. For
those patients with purely obstetric APS and no
prior thrombosis (OAPS), prophylactic dose
LMWH and LDA until 6 weeks postpartum is
recommended.7 In addition to routine foetal
monitoring scans, monthly ultrasound scans with
power Doppler imaging, are recommended dur-
ing the third trimester of pregnancy to assess for
signs of placental insufficiency.7 These measures
have improved live birth rates from 40% to 85%.7
aPL antibodies themselves bind and cause a
direct cytotoxic effect to syncytiotrophoblasts.25
Prednisolone in the first trimester, intravenous
immunoglobulin and plasmapheresis have all
been suggested as treatment for refractory
cases but well-conducted studies are lacking.
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Interestingly, low-dose prednisolone was shown
in a small RCT to improve pregnancy outcomes
in women with unexplained recurrent pregnancy
loss unrelated to APS.26 Low-dose prednisolone
might therefore reasonably be trialled in refrac-
tory APS cases under specialist obstetric care.11
A logical assumption is that pregnancy morbidity
in APS is caused only by thrombosis, but studies
examining placental histology have found that
this is not invariable, and microvascular thrombo-
sis is also found in miscarriage secondary to other
aetiologies.27 A recent systematic review identi-
fied six histological obstetric APS hallmark fea-
tures, including placental infarction, impaired
spiral artery remodelling, decidual inflammation
and complement deposition.28 The role of com-
plement in the pathophysiology of OAPS, is sup-
ported by the finding that anticoagulant treatment
with fondaparinux, a factor Xa inhibitor, and
hirudin, a thrombin inhibitor, does not confer the
same benefits as heparin. The therapeutic effect
conferred by heparin appears therefore to be due
to its effect on complement and not solely its anti-
coagulant effect.29
OAPS and thrombosis
There is no real consensus on whether patients
with OAPS should continue long-term antithrom-
botic or anticoagulant treatment.9 These patients
are at increased risk of thrombotic manifestations
compared with the general population. One longi-
tudinal cohort study included 517 individuals with
OAPS and reported annual rates of deep vein
thrombosis of 1.46%, pulmonary embolism
0.43%, superficial vein thrombosis 0.44% and
stroke 0.32% over a 10-year follow-up period.30
These rates were significantly higher than in
women with a history of recurrent miscarriage
with/without hereditary thrombophilia and despite
treatment with low-dose aspirin.30 A more recent
but smaller retrospective study included 47 OAPS
patients and found a much higher thrombosis risk
of 63%.31 These occurred a mean of 7.6 years after
initial pregnancy morbidity and were associated
with multiple aPL positivity, noncriteria APS man-
ifestations and conventional cardiovascular risk
factors.31 EULAR recommends that individuals
with a history of OAPS be offered prophylactic-
dose LDA8 and pending further studies, it seems
appropriate to consider LDA ± anticoagulant
treatment in patients with OAPS and other risk
factors for thrombosis.
Immune-modulating therapies in thrombotic
and pure obstetric APS
Hydroxychloroquine
In the 1970s, antimalarials were used as postoper-
ative VTE prophylaxis following the observation
that in vitro, hydroxychloroquine (HCQ) reduced
erythrocyte aggregation and in rabbits reduced
thrombus size.32 It is a low-cost drug that is gener-
ally well tolerated. The benefits associated with its
long-term use in patients with SLE are well recog-
nized and it is recommended treatment for all SLE
patients (with and without APS) without contrain-
dication to the drug. In SLE-APS, and also those
without aPL, HCQ use is associated with a reduc-
tion in the rates of arterial and venous thrombo-
ses.33 It has been suggested to also have a similar
effect in PAPS. HCQ administration in mouse
models of APS limits aPL binding on target cells
and causes a reduction in pro-inflammatory activ-
ity, and the size and duration of thrombus.34–36
The role of HCQ in primary prophylaxis in PAPS
is yet to be determined. A small, nonrandomized
study of HCQ use in the prevention of VTE in
PAPS suggested a significant reduction in arterial
recurrence when given alongside a VKA, com-
pared with a VKA alone.37 A recent multicentre
international RCT was designed to test these find-
ings but was terminated early due to low recruit-
ment and a low rate of clinical events.38 Another
recent study, HIBISCUS, plans to examine the
effect of HCQ on secondary thrombosis and APS-
related pregnancy morbidity in PAPS.39 Pending
these results and given the long-term relative safety
of HCQ, it seems reasonable to consider the addi-
tion of HCQ to VKA in the treatment of PAPS
patients with previous arterial or recurrent throm-
bosis especially in high-risk patients.
In vitro HCQ appears to partially reverse aPL-
induced impaired trophoblast migration40 and
in a murine APS model, HCQ inhibits comple-
ment and prevents placental insufficiency and
cerebral foetal abnormalities.41 Retrospective
studies in humans, have suggested that the
addition of HCQ to conventional treatment
may be associated with a reduction of first-tri-
mester miscarriages and an increase in live
births,42,43 but only one study has examined this
in PAPS patients, specifically.44 The first RCT
in this context, the HYPATIA trial, is a multi-
centre trial currently ongoing. It will examine
the use of HCQ versus placebo in aPL-positive
women planning to conceive.45 Pending the
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results, it again seems reasonable to consider
the addition of HCQ to those patients with
obstetric PAPS refractory to conventional treat-
ment and before any consideration of low-dose
prednisolone given its more favourable safety
profile in pregnancy.
Rituximab
In vitro studies have shown that B lymphocytes are
involved in aPL production and rituximab is an
anti-CD20 monoclonal antibody which deletes
CD20-positive B cells. The RITAPS study, an
open label phase II trial, examined the safety of
rituximab in 19 patients with noncriteria APS
manifestations. Thrombocytopenia and skin
ulcers appeared to respond most favourably to
rituximab treatment.46 There was no significant
difference in aPL titres before and after treatment,
which led authors to suggest that clinical benefits
may occur through mechanisms independent of
autoantibody production.
Two published cohort studies suggest that rituxi-
mab may be effective for preventing thromboses
in patients with SLE-APS. Wang and coworkers
described five patients treated with rituximab for
recurrent thromboses despite anticoagulation with
VKA and a target INR 2.0–3.0.47 Only one patient
developed thrombosis, but this was CAPS,
36 months after treatment. aPL titres were noted
to reduce in all patients. Emmi and colleagues
reported seven patients given rituximab for active
SLE and, similar to the study by Wang and cow-
orkers, only one patient developed thrombosis
(again, CAPS).48 There was, however, no signifi-
cant difference in aPL titres before and after treat-
ment. Of note, 5/7 had had previous arterial events
and 4/7 were taking anticoagulants. Further study
is needed to confirm these positive effects, but
rituximab appears to be a promising treatment for
SLE-APS patients with thrombotic disease refrac-
tory to conventional anticoagulant treatment, par-
ticularly if they have evidence of active SLE.
Belimumab
Belimumab has recently been reported in the
treatment of two patients with PAPS. One
achieved clinical remission after treatment for
6 months with belimumab for recurrent pulmo-
nary necrotizing neutrophilic capillaritis. The
other patient suffered recurrent skin ulcers and
demonstrated an initially good healing response
but treatment had to be stopped due to infection
of the biopsy site.49 Despite these promising data,
it is highly unlikely that B-cell-directed therapies
will replace conventional anticoagulant thera-
pies, particularly in PAPS patients, given the
high cost of these drugs and the extensive data
supporting VKAs.
Future treatment: the emerging role of
vasculopathy
Thrombosis has been traditionally regarded as
the hallmark of APS but there is increasing evi-
dence that APS is a disease not only of thrombo-
sis, but also of chronic vasculopathy, which can
develop in patients despite anticoagulation. In
vitro, complement activation by aPL of varying
specificities induce the expression of tissue factor
and adhesion molecules and the activation of
platelets and polymorphonuclear cells.50 Through
a number of different signalling pathways, pro-
inflammatory cytokine expression results in sev-
eral outcomes, including neointimal proliferation,
fibrosis, neutrophil extracellular trap activation
and release (NETosis), thrombosis with or with-
out atherosclerosis. In APS patients with preg-
nancy morbidity, decidual vasculopathy is
ubiquitous, and vascular lesions have also been
implicated in cognitive impairment caused by
APS (a noncriteria manifestation). aPL positivity
in SLE patients also, somewhat paradoxically,
confers an increased risk of haemorrhagic compli-
cations following renal biopsy, most likely due to
renal vasculopathy.51
Eculizumab
Eculizumab is a humanized monoclonal antibody
against the C5 complement component. It is
licensed for the treatment of paroxysmal noctur-
nal haemoglobinuria and atypical haemolytic
uraemic syndrome. It has also been used success-
fully to prevent thrombotic microangiopathy fol-
lowing renal transplantation for APS nephropathy
in several case reports52,53 and a phase II trial of
eculizumab for the prevention and treatment of
kidney graft reperfusion injury is currently ongo-
ing [ClinicalTrials.gov identifier: NCT01756508].
Eculizumab has also been used in patients with
CAPS and one patient during pregnancy. In the
latter patient, only small traces of the drug were
found to cross the placenta,54 suggesting potential
safety in pregnancy. Another phase II trial which
aimed to examine the use of another C5a inhibitor
in the treatment of noncriteria APS manifestations
was unfortunately terminated prematurely due to
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slow recruitment [ClinicalTrials.gov identifier:
NCT02128269]. Given the high cost of C5 inhib-
itors, their role may be limited to off-label use in
severe cases of CAPS in which mortality is high
despite conventional treatment, and RCTs are
near impossible to conduct.
Sirolimus
Sirolimus kinase also known rapamycin, inhibits
neointimal proliferation after endovascular injury
through inhibition of mammalian target of rapamy-
cin complex (mTORC) signalling. It is used in
coronary artery stents to prevent restenosis and
thrombosis. Canaud and colleagues examined vas-
cular specimens from patients with APS nephropa-
thy and CAPS and found increased mTORC
expression. In vitro it was shown that aPL activate
the mTORC signalling pathway and thereby induce
vascular intimal hyperplasia.55 Patients treated with
sirolimus following renal transplantation for APS
nephropathy had a higher graft survival and func-
tion. Biopsy specimens also showed a reduction of
vascular proliferation on histology.55
Defibrotide
Defibrotide is a mixture of single (90%) and
double-stranded (10%) phosphodiester oligo-
nucleotides which has antithrombotic, anti-
inflammatory and anti-ischaemic properties. It
is currently approved for the treatment of
hepatic veno-occlusive disease in patients fol-
lowing stem-cell transplant.56 Richardson and
coworkers reported its successful use in the
treatment of one patient with CAPS. In the
same patient, markers of vascular endothelial
cell stress, such as antitumour necrosis factor
alpha, also were reduced.57
Statins
Statins are widely used for the treatment of hyper-
cholesterolaemia and in secondary prevention of
atherosclerotic disease. There is extensive in vitro
evidence of the pleiotropic effects of these drugs
including the inhibition of vascular adhesion mol-
ecules, interleukin 6 and tissue factor in endothe-
lial cells.58 In humans, fluvastatin has been shown
to significantly reduce pro-inflammatory and pro-
thrombotic markers in APS patients. Follow up
was limited to 3 months and one patient (1/41)
with SLE-APS suffered a deep vein thrombosis;
but the study was not designed to assess clinical
outcomes.59 The reduction in pro-inflammatory
markers was independent of whether the patient
had primary or APS with an associated rheumatic
disease, or was an asymptomatic aPL carrier.
Another small study administered pravastatin to
pregnant individuals with APS who had developed
pre-eclampsia or intrauterine growth restriction
despite treatment with LDA and LMWH.
Pravastatin was associated with improved placen-
tal blood flow and a longer gestation compared
with those who did not receive the drug.60
There is a clear need for clinical trials examining
the effect of statins on thrombosis and pregnancy
morbidity in APS. In the meantime, it seems
appropriate to offer APS patients with hypercho-
lesterolaemia, other cardiovascular risk factors or
thrombotic disease resistant to conventional anti-
coagulation, treatment with a statin.
Conclusion
The Euro-Phospholipid study has demonstrated
that conventional anticoagulant treatment has
improved the life expectancy of APS patients.
Thrombosis, however, remains the most com-
mon cause of death and further study is required
to elucidate the optimal means of secondary pre-
vention. VKAs are the drug of choice for most
patients and the improved availability of point of
care INR testing may offer patients more auton-
omy, better quality of life, and therefore, better
compliance with VKA treatment.
APS is a heterogeneous condition, and this must
be carefully considered in the design of clinical
trials. In particular, adequate numbers of
patients who are at high risk of thrombosis must
be included. Further work and continued inter-
national collaboration are required to guide evi-
dence-based treatments for conventional and
noncriteria APS manifestations. Our increasing
recognition and understanding of the disease as
a vasculopathy may lead to the development of
new antiproliferative agents or increasing use of
existing drugs such as sirolimus and defibrotide
for which further study is required.
Funding
The authors received no financial support for the
research, authorship, and/or publication of this
article.
Conflict of interest statement
Professor David D’Cruz is a trustee of APS
Support UK.
Therapeutic Advances in Musculoskeletal Disease 12
8 journals.sagepub.com/home/tab
ORCID iD
Mia Rodziewicz https://orcid.org/0000-0003-
2797-8829
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... At this time, results are not yet available for these two mutations. The hematology department recommended continuing Eliquis after discharge for single-positive APLS studies and splenic infarcts [10][11][12]. He was also prescribed Bactrim® given the high-dose steroid taper received at discharge and a proton pump inhibitor. ...
... The team opted for direct oral anticoagulants (DOACs) instead of warfarin because the lab tests were significant only for B2GP1 IgM ( Table 2). In these cases, it is acceptable to continue with DOAC alone unless complications arise, such as failure to respond to treatment [10][11][12]. ...
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VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a rare genetic disorder originating from a somatic mutation in the hematopoietic stem cells. This syndrome was first described in 2020 and carries many clinical features that other conditions cannot explain. Widespread autoinflammation is the primary process the disease presents, with high morbidity and mortality in those who show signs of bone marrow failure. Treatment is complex, and response to current therapies is poor. Long-term prognosis carries a mortality of 50%. In addition, the advancement of new-generation messenger ribonucleic acid (mRNA) vaccines raises concerns about their safety in this population since it could trigger a vaccine-related autoimmune response. This case describes the hospital course of a male in his 50s exhibiting an unexplained cutaneous reaction to an mRNA COVID-19 vaccine. He was later diagnosed with VEXAS syndrome based on symptoms presentation and diagnostic workup.
... According to the Euro-Phospholipid cohort study of APS, researchers demonstrated a decrease in mortality from 5.3 percent in the initial five years of follow-up to 4.5 percent in the latter five years. In addition, treatment with anticoagulants in patients with obstetric APS had improved live births with an increase from 40 percent to 85 percent [16]. As a result, patients with asymptomatic elevated antiphospholipid antibody titers, pregnant women, and those with co-existent SLE should receive aspirin monotherapy [17]. ...
... In a recent study of another autoimmune condition, researchers studied the effects of disease-modifying antirheumatic drug (DMARD) therapy on the effects of cardiovascular disease in patients with early rheumatoid arthritis (RA) [16,20]. RA is associated with an almost three-fold increase in mortality compared to the general population and is largely due to an increased association with cardiovascular disease (CVD). ...
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Background: Kidney involvement is a frequent complication of systemic lupus erythematosus (SLE) and kidney biopsy is essential in differentiating lupus nephritis (LN) from thrombotic microangiopathy (TMA) secondary to antiphospholipid autoantibodies (aPL). Association between antiphospholipid syndrome (APS) and acquired hemophilia due to inhibitors was very rarely described in SLE patients. Case presentation: We present the case of a 61-year-old male diagnosed with SLE who acquired deficiency of clotting factor VIII due to circulating inhibitors, admitted for acute kidney injury (AKI), microangiopathic hemolytic anemia, thrombocytopenia, and diplopia. Kidney biopsy showed TMA due to APS, but no signs of LN. Head computed tomography identified low dense areas in the white matter, suggesting small blood vessels' involvement. A diagnosis of probable catastrophic antiphospholipid syndrome (CAPS) was established and treatment with low molecular weight heparin, intravenous methylprednisolone, plasmapheresis, and rituximab was initiated, followed by resolution of AKI, diplopia, and TMA with complete depletion of CD19+B-lymphocytes (CD19+B-Ly) after one month. We further review the current knowledge regarding pathogenesis and management of CAPS in SLE patients. Conclusions: Targeted therapy was possible after kidney biopsy, improving renal and general prognosis. CD19+B-Ly repopulation preceded biological relapse, so monitoring of CD19+B-Ly may serve as a tool to predict relapses and guide rituximab therapy.
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Objective: To assess the effect of statins on the prevention of recurrent thrombosis in patients with thrombotic antiphospholipid syndrome (APS). Methods: This retrospective cohort study included 184 patients with thrombotic APS. The effect of statins on recurrent thrombosis was investigated in the total study population and in an inverse probability of treatment weighting (IPTW)-adjusted population. Multivariable and IPTW-adjusted Cox proportional hazard regression analyses were performed on the total study population and the IPTW-adjusted population, respectively, to estimate the hazard ratios (HRs) with 95% confidence intervals (95% CIs) for recurrent thrombosis, according to the use of statins. Results: Of the 184 patients, 103 (56.0%) received statins, while the other 81 (44.0%) did not. Recurrent thrombosis occurred in 22 (12.0%) patients during the mean observation period of 48.5 (±34.9) months. In the multivariable Cox regression analyses, the use of statins was associated with a lower risk of recurrent thrombosis: (1) model 1 adjusted for risk factors of arterial and venous thrombosis, HR 0.24, 95% CI 0.09-0.63, p= 0.004; (2) model 2 adjusted for the use of anticoagulants, antiplatelets, and hydroxychloroquine, HR 0.28, 95% CI 0.10-0.76, p= 0.012; and (3) model 3 adjusted for the antiphospholipid autoantibody profile, HR 0.26, 95% CI 0.10-0.67, p= 0.005. The IPTW-adjusted Cox regression analysis also showed a lower risk of recurrent thrombosis with the use of statins (HR 0.28; 95% CI, 0.12-0.65; p= 0.003). Conclusion: Our data suggest that statins could be effective in reducing the risk of recurrent thrombosis in patients with thrombotic APS.
Article
Systemic lupus erythematosus is a multisystemic autoimmune disorder that predominantly affects women in reproductive years. Pregnancy in women with SLE is still considered a high-risk condition although several strategies may improve maternal and fetal outcomes. Preconception counseling is fundamental and should include identification of risk factors for adverse pregnancy outcomes, explanation of potential maternal and obstetric complications and timely planning of pregnancy. Risk stratification must consider end-organ damage, comorbidities, disease activity and autoantibodies profile in order to implement an individual-risk pregnancy monitoring plan by a multidisciplinary team. Hydroxychloroquine and low dose aspirin have shown to lower the risk of disease flares and preeclampsia with a good safety profile, so its use during pregnancy in all SLE patients is recommended. Lupus nephritis and preeclampsia share clinical and laboratory features hindering differentiation between both entities. Novel angiogenic markers and fetal ultrasound findings could be helpful in the differential diagnosis, especially after 20 weeks of gestation. Antiphospholipid antibodies, particularly lupus anticoagulant, are closely associated with obstetric complications. Therapy with low dose aspirin and heparin, according to risk profile, may improve live birth rates. Anti-Ro/La antibodies confer risk for neonatal lupus, and therefore preventive therapy and special fetal surveillance should be instituted.
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The objective was to develop evidence-based recommendations for the management of antiphospholipid syndrome (APS) in adults. Based on evidence from a systematic literature review and expert opinion, overarching principles and recommendations were formulated and voted. High-risk antiphospholipid antibody (aPL) profile is associated with greater risk for thrombotic and obstetric APS. Risk modification includes screening for and management of cardiovascular and venous thrombosis risk factors, patient education about treatment adherence, and lifestyle counselling. Low-dose aspirin (LDA) is recommended for asymptomatic aPL carriers, patients with systemic lupus erythematosus without prior thrombotic or obstetric APS, and non-pregnant women with a history of obstetric APS only, all with high-risk aPL profiles. Patients with APS and first unprovoked venous thrombosis should receive long-term treatment with vitamin K antagonists (VKA) with a target international normalised ratio (INR) of 2–3. In patients with APS with first arterial thrombosis, treatment with VKA with INR 2–3 or INR 3–4 is recommended, considering the individual’s bleeding/thrombosis risk. Rivaroxaban should not be used in patients with APS with triple aPL positivity. For patients with recurrent arterial or venous thrombosis despite adequate treatment, addition of LDA, increase of INR target to 3–4 or switch to low molecular weight heparin may be considered. In women with prior obstetric APS, combination treatment with LDA and prophylactic dosage heparin during pregnancy is recommended. In patients with recurrent pregnancy complications, increase of heparin to therapeutic dose, addition of hydroxychloroquine or addition of low-dose prednisolone in the first trimester may be considered. These recommendations aim to guide treatment in adults with APS. High-quality evidence is limited, indicating a need for more research.
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Objective To perform a systematic literature review (SLR) informing the European Lmmendations for the management of antiphospholipid syndrome (APS) in adults. Methods A SLR through January 2018 was performed. Research questions were constructed using the Patient, Intervention, Comparator, Outcome (PICO) format. We included data from articles that reported on each relevant intervention. Summary effect estimates were calculated for direct comparison studies that matched the PICO question exactly, and for studies with the relevant intervention and comparator. When meta-analyses were available, we used these estimates. Results From 7534 retrieved articles (+15 from hand searches), 188 articles were included in the review. In individuals with high-risk antiphospholipid antibody (aPL) profile without prior thrombotic or obstetric APS, two meta-analyses showed a protective effect of low-dose aspirin (LDA) against thrombosis. Two randomised controlled trials (RCTs) and three cohort studies showed no additional benefit of treatment with vitamin K antagonists at target international normalised ratio (INR) 3–4 versus INR 2–3 in patients with venous thrombosis. In patients with arterial thrombosis, two RCTs and two cohort studies showed no difference in risk of recurrent thrombosis between the two target INR groups. One open-label trial showed higher rates of thrombosis recurrences in triple aPL-positive patients treated with rivaroxaban than those treated with warfarin. RCTs and cohort studies showed that combination treatment with LDA and heparin was more effective than LDA alone in several types of obstetric APS. SLR results were limited by the indirect evidence and the heterogeneity of patient groups for some treatments, and only a few high-quality RCTs. Conclusion Well-designed studies of homogeneous APS patient populations are needed.
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Stroke and venous thromboembolism continues to be a major cause of morbidity and mortality worldwide. The use of anticoagulation therapy has proven effective in the prevention of stroke and management of thromboembolism; however, initiating treatment may bear clinical burden given the capacity of these agents to cause bleeding. Originally, warfarin has been primarily used, but with the approval of direct oral anticoagulants, therapeutic recommendations have shifted to direct oral anticoagulants for first line therapy for venous thromboembolism for patients without cancer. As compared to warfarin, direct oral anticoagulants are associated with predictable pharmacokinetic profiles, lower bleeding risks, and minimal drug interactions. Complexities in the medication use process can however heighten the risks of causing adverse events. The purpose of this article is to describe common medication errors associated with direct oral anticoagulants, provide practical guidance on the management of direct oral anticoagulants, and suggest strategies to reduce errors. Efforts to minimize medication errors involve the participation of an interdisciplinary team that has standardized policies, risk reduction strategies, and guiding principles to achieve optimal therapeutic outcomes. Current primary literature is not robust in assessment of clinical impact of medication errors associated with DOACs but reports of adverse drug events have been noted. Future studies should be guided to assess clinical outcomes associated with medication errors and identify potential clinical interventions to optimize therapy.
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Objective: To evaluate subsequent rate of thrombosis among obstetric antiphospholipid syndrome (Ob-APS) women in a multicenter database of antiphospholipid antibody (aPL)-positive patients; and clinical utility of adjusted Global Antiphospholipid Syndrome Score (aGAPSS), a validated tool to assess the likelihood of developing new thrombosis, in this group of patients. Design: Retrospective study. Setting: APS Alliance For Clinical Trials & International Networking (APS ACTION) Clinical Database And Repository. Population: Women with Ob-APS. Methods: Comparison of clinical and laboratory characteristics; measurement of aGAPSS of Ob-APS women with or without thrombosis after initial pregnancy morbidity (PM). Main outcome measures: Risk factors for thrombosis, aGAPSS. Results: Of 550 patients, 126 had Ob-APS; 74/126 (59%) presented thrombosis, and 47 (63%) of them developed thrombosis after initial PM, in a mean time of 7.6 ± 8.2 years (4.9/100 patient years). Younger age of Ob-APS, additional cardiovascular risk factors, superficial vein thrombosis, heart valve disease, and multiple aPL positivity increased the risk of first thrombosis after PM. Women with thrombosis after PM had higher aGAPSS compared to those with Ob-APS alone ([median 11.5 [4-16] vs 9 [4-13], P = 0.0089]). Conclusion: Based on retrospective analysis of our multicenter aPL database, 63% of Ob-APS women developed thrombosis after initial obstetric morbidity; additional thrombosis risk factors, selected clinical manifestations, and high-risk aPL profile increased risk. Women with subsequent thrombosis after Ob-APS had higher aGAPSS score at registry entry. We believe that aGAPSS is a valid tool to improve risk stratification in aPL-positive women. There was no funding for this study. This article is protected by copyright. All rights reserved.
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Thrombotic microangiopathy (TMA), characterized by organ injury occurring consequent to severe endothelial damage, can manifest in a diverse range of diseases. In complement-mediated atypical haemolytic uraemic syndrome (aHUS) a primary defect in complement, such as a mutation or autoantibody leading to over activation of the alternative pathway, predisposes to the development of disease, usually following exposure to an environmental trigger. The elucidation of the pathogenesis of aHUS resulted in the successful introduction of the complement inhibitor eculizumab into clinical practice. In other TMAs, although complement activation may be seen, its role in the pathogenesis remains to be confirmed by an interventional trial. Although many case reports in TMAs other than complement-mediated aHUS hint at efficacy, publication bias, concurrent therapies and in some cases the self-limiting nature of disease make broader interpretation difficult. In this article, we will review the evidence for the role of complement inhibition in complement-mediated aHUS and other TMAs.
Article
The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%–21% at 5 years in thrombotic APS and 20–28% in obstetrical APS [2, 3]. Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4–16]. Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency. Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial. This trial consists in two parts: a retrospective and a prospective study. The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS.
Article
Rivaroxaban is an effective and safe alternative to warfarin in patients with atrial fibrillation and venous thromboembolism. We tested the efficacy and safety of rivaroxaban as compared to warfarin in high-risk patients with thrombotic Antiphospholipid Syndrome. This is a randomized, open-label, multicenter, non-inferiority study with blinded end-point adjudication. Rivaroxaban 20 mg once daily (15 mg once daily based on kidney function) was compared to warfarin (INR target 2.5), for the prevention of thromboembolic events, major bleeding and vascular death in patients with Antiphospholipid Syndrome. Only high-risk patients triple positive for Lupus Anticoagulant, anti-cardiolipin and anti-β2-glycoprotein I antibodies of the same isotype (triple-positivity) were included in the study. The trial was terminated prematurely after the enrollment of 120 patients (59 randomized to rivaroxaban and 61 to warfarin) because of an excess of events among patients in the rivaroxaban arm. Mean follow up was 569 days. There were 11 (19%) events in the rivaroxaban group and 2 (3%) in the warfarin group. Thromboembolic events occurred in 7 (12%) patients randomized to rivaroxaban (4 ischemic stroke and 3 myocardial infarction) while no event was recorded in those randomized to warfarin. Major bleeding occurred in 6 patients, 4 (7%) in the rivaroxaban and 2 (3%) in the warfarin group. No death was reported. The use of rivaroxaban in high-risk patients with Antiphospholipid Syndrome was associated with an increased rate of events as compared with warfarin, thus showing no benefit and excess risk. (ClinicalTrials.gov Identifier: NCT02157272).
Article
The effect of additional treatments combined with conventional therapy on pregnancy outcomes was examined in high-risk primary antiphospholipid syndrome (PAPS) patients to identify the most effective treatment strategy. The study's inclusion criteria were (1) positivity to lupus anticoagulant alone or associated with anticardiolipin and/or anti-β2 glycoprotein I antibodies; (2) a history of severe maternal–foetal complications (Group I) or a history of one or more pregnancies refractory to conventional therapy leading to unexplained foetal deaths not associated with severe maternal–foetal complications (Group II). Two different additional treatments were considered: oral—low-dose steroids (10–20 mg prednisone daily) and/or 200 to 400 mg daily doses of hydroxychloroquine and parenteral—intravenous immunoglobulins at 2 g/kg per month and/or plasma exchange. The study's primary outcomes were live birth rates and pregnancy complications. A total of 194 pregnant PAPS patients attending 20 tertiary centres were retrospectively enrolled. Hydroxychloroquine was found to be linked to a significantly higher live birth rate with respect to the other oral treatments in the Group II patients. The high (400 mg) versus low (200 mg) doses of hydroxychloroquine (p = 0.036) and its administration before versus during pregnancy (p = 0.021) were associated with a significantly higher live birth rate. Hydroxychloroquine therapy appeared particularly efficacious in the PAPS patients without previous thrombosis. Parenteral treatments were associated with a significantly higher live birth rate with respect to the oral ones (p = 0.037), particularly in the Group I patients. In conclusion, some additional treatments were found to be safe and efficacious in high-risk PAPS pregnant women.
Article
Objective The objective of this study was to determine the efficacy of hydroxychloroquine (HCQ) in the primary thrombosis prevention of antiphospholipid antibody (aPL)-positive patients with no other systemic autoimmune diseases. Methods Under the auspices of Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking, a multicenter, international, randomized controlled trial (RCT) was initiated, in which persistently aPL-positive but thrombosis-free patients without systemic autoimmune diseases were randomized to receive HCQ or no treatment in addition to their standard regimen. The primary objective was the efficacy of HCQ in preventing the first thrombosis. The secondary objectives were the thrombosis incidence rate, and the effects of HCQ on aPL profile and mortality rate. Patients were risk-stratified based on antiplatelet agent use. The goal was to follow patients every 6 months for 5 years. Results We recruited 20 persistently aPL-positive patients (female: 19, mean age: 46.6 ± 9.9 years, and baseline antiplatelet medication: 14); 9/20 were randomized to HCQ. During the mean follow-up of 1.7 years, no patients developed thrombosis or a serious adverse event. The study was terminated early due to the low recruitment rate, exacerbated by the prolonged manufacturing shortage and significant price increase of HCQ in the United States. Conclusion Given that a small number of patients with a relatively short follow-up were enrolled in our RCT, and no patients developed thrombosis, we cannot accurately assess the effectiveness of HCQ for primary thrombosis prevention in persistently aPL-positive patients with no other systemic autoimmune diseases. Our experience suggests that conducting an international RCT, especially without pharmaceutical support, is an extremely challenging undertaking.