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Current Vascular Pharmacology, 2017, 15, 313-326

REVIEW ARTICLE
ISSN: 1570-1611
eISSN: 1875-6212

Current Vascular
Pharmacology
Thrombotic Management of Antiphospholipid Syndrome: The journal for current and in-depth reviews on Vascular Pharmacology

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Towards Novel Targeted Therapies

BENTHAM
SCIENCE

Md. Asiful Islam1,#,*, Fahmida Alam1,#, Kah Keng Wong2, Mohammad Amjad Kamal3,4,5 and Siew Hua Gan1,*

1
Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan,
Malaysia; 2Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian,
Kelantan, Malaysia; 3King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah, Saudi
Arabia; 4Enzymoics; 5Novel Global Community Educational Foundation, 7 Peterlee Place, Hebersham, NSW 2770,
Australia

Abstract: Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by throm-

bosis and/or pregnancy morbidity with persistent levels of antiphospholipid antibodies (aPLs). The
development of thrombosis in APS is mediated by aPLs and contributes to the high mortality rate in
APS patients. However, although APS has been reported for more than 30 years, there has been no op-
ARTICLE HISTORY
timal regimen for its prevention or for the management of thrombosis, mainly because the mainstay
Received: May 30, 2016 treatment strategies for managing APS are not targeted towards aPL-mediated thrombotic pathophysiol-
Revised: December 07, 2016
Accepted: December 07, 2016
ogy. Instead, the treatments commonly used are aimed at general thrombotic disorders. Warfarin is the
most commonly used vitamin K antagonist (VKA), in addition to anti-platelet medications, such as aspi-
DOI:
Current Vascular Pharmacology

10.2174/1570161115666170105120931 rin and clopidogrel. Over the last decade, novel non-VKA oral anticoagulants, including rivaroxaban,
apixaban and dabigatran, as well as immunomodulatory agents, such as rituximab, eculizumab, hy-
droxychloroquine, statins and sirolimus, have also been used. In this review, we discuss the current
treatment strategies and future treatment outlook for thrombotic APS.

Keywords: Antiphospholipid syndrome, antiphospholipid antibodies, thrombosis, treatment, anticoagulant, anti-platelet agents.

1. INTRODUCTION thrombotic events in a study published in 1985 [5]. However,

Antiphospholipid syndrome (APS) is a systemic autoim-
mune disease characterized by recurrent vascular thrombosis
(venous and/or arterial) and/or pregnancy morbidity, in addi-
tion to the presence of serum antiphospholipid antibodies
(aPLs) [lupus anticoagulant (LA) antibody, anticardiolipin
antibody (aCL) and anti-
2 glycoprotein I (anti-
2GPI) anti-
body] as laboratory features [1]. APS is classified into the
following categories: 1) primary APS (at least one clinical
and one laboratory feature present), 2) APS associated with
other diseases (for this category, an autoimmune disease,
usually systemic lupus erythematosus (SLE), should be pre-
sent in addition to the clinical and laboratory features of
APS), and, 3) catastrophic APS (the most aggressive form,
characterized by multiple organ failure) [2-4].
Thrombosis is one of the major clinical features of APS,
and 30% of patients were documented to experience
*Address correspondence to these authors at the Human Genome Centre,
School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang
Kerian, Kelantan, Malaysia; Tel: +6097676797; Fax: +6097658914;
E-mails: ayoncx70@yahoo.com, shgan@usm.my
#
These authors contributed equally to this work.
in 2002, Asherson [6] reported that 55% of the APS patients
experienced deep vein thrombosis (DVT) and 40% experi-
enced pulmonary embolism (PE). According to the Euro-
Phospholipid project (involving 13 European countries with
1,000 participants), thrombosis was the most frequently
(28.1%) observed clinical manifestation [7].
To date, there is still no optimal treatment strategy to
combat thrombotic APS. Although the pathogenesis of
thrombi is mainly mediated by aPLs, most of the current
regimens are focused on preventing the recurrence of throm-
bosis in such a way that they are more appropriate for gen-
eral, non-APS thrombotic patients, rather than targeting dis-
ease-specific pathophysiology [8]. Anticoagulant drugs such
as warfarin and anti-platelet agents, including aspirin or
clopidogrel, are most commonly used alone in patients with
thrombotic APS or in combination with other drugs (ster-
oids, other anticoagulants, anti-platelet agents or immuno-
suppressive agents), based on the characteristics and degree
of thrombosis [9-11]. In addition to the mainstay regimens, a
substantial number of drugs, such as new non-vitamin K
antagonist (non-VKA) oral anticoagulants (NOAC) and im-

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314 Current Vascular Pharmacology, 2017, Vol. 15, No. 4
munomodulatory agents, have been used in the last decade
for the treatment of thrombosis in APS patients.
To date, there is a lack of comprehensive reviews ad-
dressing the updates on all the current thrombotic treatment
strategies used in patients with APS. Therefore, in this re-
view, treatment strategies for managing thrombotic APS
patients with vitamin K antagonists (VKAs) as conventional
anticoagulants (warfarin), anti-platelet agents (aspirin and
clopidogrel), novel NOACs (rivaroxaban, apixaban and
dabigatran) and immunomodulatory agents [rituximab, ecu-
lizumab, hydroxychloroquine (HCQ), statins and sirolimus]
are discussed, based on both experimental and clinical evi-
dence.
2. THROMBOSIS AND APS
According to the latest Sydney classification criteria [1],
thrombosis is one of the two clinical manifestations observed
in patients with APS. Among the other thrombophilic disor-
ders, both arterial and venous thromboses are observed in
APS patients, which contribute to the high mortality rate [10,
12]. A 10-year multicenter prospective study (n=1,000)
revealed that the most frequent causes of death in patients
with APS were severe thrombosis (36.5%) and thrombotic
events (21.4%), including DVT, myocardial infarction (MI),
transient ischemic attacks (TIAs), stroke, PEs and superficial
thrombophlebitis, thus indicating that there is a strong
clinical impact and economic burden worldwide [7, 9].
A thrombus can develop in any tissue and/or organ in
patients with APS, as confirmed by imaging, ultrasound or
histopathology studies, except in the case of superficial ve-
nous thrombosis [1]. In cases of catastrophic APS, the fre-
quently reported cause of death is multiple organ failure due
to the formation of acute thrombi in the organs, which is
believed to be the major cause of death (55.6%) [7].
3. PATHOGENESIS OF THROMBOSIS IN APS
Although the complete thrombotic pathophysiology of
APS is still unclear, generally, the formation of thrombi in
APS is mediated by aPL-induced dysregulation of cell acti-
vation, coagulation, the fibrinolytic pathway, the immune
system, genetics and some other factors [8]. Activation of
platelet markers, such as CD63, procaspase activating com-
pound-1 (PAC-1) [13], CD62 [14], and CD62P [15], the
formation of a thrombogenic complex between homo-
tetrameric platelet factor 4 (PF4) and two dimerized mole-
cules of 2GPI [16], activation and elevation of the von
Willebrand factor (vWF) levels [17, 18], dysfunction of
ADAMTS13 (a protease enzyme) [19, 20], dysregulation of
prostaglandins [prostacyclin (PGI2) and thromboxane A 2
(TXA2)] [17, 21, 22], and annexin A2 [23] and toll-like re-
ceptors (TLRs) [24] are involved in platelet activation, adhe-
sion and aggregation, leading to the generation of thrombi in
APS patients. In addition to impaired fibrinolysis [25] in the
coagulation pathway, the involvement of tissue factors (TFs)
[26], annexin A5 [27], proteins C and S [28, 29], factor XI
[30], tissue factor pathway inhibitor (TFPI) [31] was also
observed in patients with thrombotic APS. The activation of
the complement system [32, 33] and the involvement of B
and T cells [34, 35] and tissue necrosis factor alpha (TNF-
)
Islam et al.
[36, 37] were reported to be the major immune-mediated
phenomena contributing to thrombosis in APS patients.
4. TREATMENT STRATEGIES
To date, there is no single drug or recommended dosage
for the ideal management of thrombosis in patients with
APS. Single medications or combined therapeutic strategies
with different intensities and dosages have both been suc-
cessful and unsuccessful for managing thrombosis in APS.
In addition to the use of conventional anticoagulants and
anti-platelets, novel NOACs (Table 1) and targeted immu-
nomodulatory agents have recently been incorporated in the
management of thrombotic APS (Fig. 1). The experimental
and clinical evidence indicating both the advantages and
pitfalls of the current treatment strategies for treating throm-
bosis in APS patients are considered in the subsequent sec-
tions.
5. ANTICOAGULANTS
5.1. Warfarin
Warfarin (Coumadin®) is the most widely used oral anti-
coagulant for the prevention of thrombosis and thromboem-
bolism. Following its administration, warfarin is rapidly ab-
sorbed from the gastrointestinal (GI) tract and reaches its
maximal blood concentrations in healthy adults after 90 min
[38, 39]. The half-lives of warfarin components, which con-
sists of a racemic mixture containing two active stereoi-
somers (R and S), are 36 and 42 h, respectively. Warfarin
binds to the plasma proteins for circulation and accumulates
in the liver before being metabolically transformed via the
cytochrome P450 enzymes [40]. Warfarin acts by inhibiting
the vitamin K-dependent synthesis of calcium-dependent
blood clotting factors II, VII, IX and X, as well as some
regulatory factors, including proteins C, S and Z [41].
Warfarin therapy is monitored based on the international
normalized ratio (INR). The INR is a mathematical conver-
sion of the prothrombin time (PT) that is used to normalize
the results, irrespective of the different PT reagents (throm-
boplastins) [42]. Usually, the targeted INR following war-
farin administration is between 2.0 and 3.0 [43]. A high INR
value is associated with increased risk of bleeding, whereas
INRs below the therapeutic values are indicative of an in-
adequate warfarin dose to confer protection against throm-
boembolism. The risk of bleeding is greatly increased when
the INR exceeds 4.5 [44].
With the increased use of warfarin, the number of cases
with bleeding has also increased and has contributed to a
significant number of deaths. It was reported that the fre-
quency of major bleeding due to the use of warfarin was as
high as 16%. Therefore, in 2006, a ‘black box’ warning re-
garding the bleeding risk caused by warfarin was added to
the United States (US) product labels [45]. The warfarin
dosage is complex because of the drug and food interactions
[46]. Drugs that are largely protein-bound compete with war-
farin for protein binding, contributing to the increased INR
[47]. Since foods containing vitamin K1, such as green leafy
vegetables (i.e. lettuce and spinach), are reported to interact
with warfarin, it is recommended that its activity be
Thrombotic Management of Antiphospholipid Syndrome Current Vascular Pharmacology, 2017, Vol. 15, No. 4 315

Table 1. Characteristics of the new non-vitamin K antagonist oral anticoagulants (NOACs) used for the treatment of thrombosis
in APS patients.

New NOACs Incorporated in the Treatment of Thrombotic APS

Characteristics Rivaroxaban Apixaban Dabigatran
(Xarelto®) (Eliquis ®) (Pradaxa®)

Bristol-Myers Squibb Company Boehringer Ingelheim

Manufacturer Janssen Pharmaceuticals Inc.
and Pfizer Inc. Pharmaceuticals Inc.

First FDA approval 2011 2012 2010

Yes
Any ongoing clinical trials with APS? Yes
(NCT02116036; No
(ClinicalTrials.govIdentifier) (NCT02295475)
NCT02157272)

Yes
Is this a prodrug? No No
(Dabigatran etexilate)

Required routine INR monitoring? No No No

Target Factor Xa Factor Xa Thrombin

Approved doses Fixed, once daily Fixed, once daily Fixed, twice daily
(mg) 10, 15, and 20 2.5 and 5 75 and 150

Molecular weight (g/mol) 435.9 459.5 627.8

10 mg dose: 80-100
Bioavailability (%) 50 3-7
20 mg dose: 66

Time to peak maximum

2-4 3-4 1-2
concentration (hours)

Protein binding (%) 92-95 87 35

Volume of distribution (L) 50 21 50-70

Half-life (hours) 5-9 Approximately 12 12-17

Major: CYP3A4;
CYP3A4/5, CYP2J2,
Metabolism Minor: CYP1A2, CYP2C8, Conjugation
and hydrolysis
CYP2C19, and CYP2J2

66% (Renal) 25% (Renal)

Elimination 80% (Renal)
33% (Fecal) 55% (Fecal)

References [166, 167] [168, 169] [170, 171]

monitored using the INR by conducting blood tests so that an
adequate and safe dose can be maintained [48].
In APS patients, thrombosis leads to more deaths than
bleeding. In fact, according to a systematic review [49], 18
deaths among APS patients were reported to occur due to
recurrent thrombosis compared with only a single death due
to hemorrhage. According to the Euro-Phospholipid cohort
study on APS patients (n=1,000), 36.5% of the total deaths
occurred due to thrombotic events during the follow-up pe-
riod, whereas only 10.7% patients died due to hemorrhage
[7].
A higher targeted INR (>2.0-3.0) may be required for
warfarin [43] in APS patients. According to a retrospective
study, anticoagulation therapy with a targeted INR of >3.0 is
more protective in preventing recurrent thrombosis in APS
patients compared with anti-platelet therapy or standard anti-
coagulation therapy that targets a lower INR (2.0-3.0) [50].
However, Erkan et al. (2014) recommended the incorpora-
tion of a longer duration of anticoagulation therapy to pre-
vent recurrent thrombosis among APS patients [51]. In an-
other study, a low dose of warfarin, when given in combina-
tion with aspirin, successfully prevented recurrent thrombo-
sis in an APS patient suffering from livedoid vasculitis [52].
According to a randomized, double-blind clinical trial of
APS patients (n=114), a moderate-intensity warfarin treat-
ment with a targeted INR between 2.0 and 3.0 was more
effective at thromboprophylaxis than a high-intensity war-
farin treatment (INR 3.0-4.0). Recurrent thrombosis was
observed in 10.7% of patients receiving the high-intensity
warfarin treatment compared with patients receiving a mod-
erate-intensity treatment, which reported only a 3.4% inci-
dence [53]. Another randomized trial with APS patients
(n=109) also reported that the incidences of recurrent throm-
bosis were 11.1% and 5.5% among patients receiving war-
316 Current Vascular Pharmacology, 2017, Vol. 15, No. 4 Islam et al.

Antithrombotic Therapy in Antiphospholipid Syndrome

Anticoagulant Drugs Anti-platelet Drugs Immunomodulatory Drugs

Inhibits clotting Binds to the widely

Warfarin Rituximab expressed CD20
factors II, VII, IX, X Aspirin Clopidogrel
and regulatory protein on the B cell
proteins C and S surface
Inhibits both Inhibits the ADP
COX1 and COX2, receptor on Eculizumab
Directly inhibits Apixaban platelet Inhibits the cleavage
which produce
free or clot-bound membranes of C5 to C5a and C5b
inflammatory PGs
factor Xa

Directly inhibits Inhibits TLR9 and

Rivaroxaban HCQ reduces inflammatory
free or bound factor
Xa (prothrombinase processes
complex)
Statins Blocks cholesterol
synthesis by
Directly inhibits Dabigatran
inhibiting HMG-CoA
thrombin (factor IIa) reductase

Sirolimus Blocks B and T cell

activation by
inhibiting mTOR

Fig. (1). Summary of the types of antithrombotic therapy used to treat antiphospholipid syndrome and their protein targets or mechanisms of
actions.
COX: Cyclooxygenase; PGs: Prostaglandins; ADP: Adenosine diphosphate; C5: Complement 5; TLR: Toll-like receptor; HCQ: Hydroxy-
chloroquine; HMG-CoA: 3-hydroxy-3-methylglutaryl-coenzyme A; mTOR: Mammalian target of rapamycin.

farin at high (INR 3.0-4.5) and moderate intensities (INR
2.0-3.0), respectively [54].
A meta-analysis combining the results of these two ran-
domized control trials did not establish any significant dif-
ference in the rate of thrombosis recurrence between the two
regimens, although a higher thrombotic risk was observed
following the use of a higher dose of warfarin [54]. A retro-
spective study reported that higher doses of warfarin were
more effective in preventing recurrent thrombosis among
APS patients compared with either low doses of aspirin or
warfarin [55]. According to a familial case, the levels of
aPLs were decreased in three patients with thrombotic APS
from the same family following prolonged warfarin interven-
tion that targeted moderate INR values (2.0-3.0) [56]. Taken
together, these results suggest that moderate-intensity war-
farin treatments might be more effective than high-intensity
warfarin treatments in preventing thrombosis recurrence in
APS patients.
In APS patients, the variable sensitivity of throm-
boplastin reagents to LA may lead to an overestimated INR.
This overestimation may pose challenges in both the moni-
toring and management of warfarin anticoagulation. In
addition, the lack of information on PT measurements at
baseline before starting the anticoagulation therapy may
complicate the situation further [57]. A cross-sectional study
suggested that a thrombin generation (TG) test should be
incorporated in future prospective studies to determine the
appropriate anticoagulant intensity and address this chal-
lenge, including achieving
3.5 INRs in APS patients to im-
prove their anticoagulation treatment [58]. According to a
recent (2016) prospective observational study [59] assessing
the quality of anticoagulation therapy in APS patients,
warfarin was shown to be an inferior anticoagulation
therapy, due to the tendency to resist VKAs, in addition to
the lower therapeutic range (TTR) (<60%), indicating that a
considerable proportion of time is spent below the
therapeutic range. The authors have recommended that pa-
tients with APS need a significantly higher weekly dosage of
warfarin to maintain their targeted INR values. However,
higher intensity anticoagulation therapy is associated with
INR fluctuations and bleeding risk. Therefore, a larger num-
ber of prospective studies with larger sample sizes are re-
quired to confirm these findings.
5.2. Rivaroxaban
Rivaroxaban (Xarelto®) is the first NOAC that directly
inhibits factor Xa (FXa). The absorption of rivaroxaban is
rapid, and food does not have any effects on its absorption or
pharmacokinetic properties. Rivaroxaban reaches its maxi-
mum plasma peak concentration at 1 to 4 h [60]. A bioavail-
ability of approximately 80% can be achieved from a 10 mg
rivaroxaban tablet [61]. The half-life of plasma elimination is
5 to 9 h in young people and 11 to 13 h in aged people [60,
62].
In 2011, rivaroxaban was initially approved by the US
Food and Drug Administration (FDA) and European
Medicines Agency (EMA) for the treatment of DVT, which
was later extended to use for the prevention of strokes
(2011), reduction of blood clot recurrences (2012), and
inhibition of stent thromboses (2013) [63]. Rivaroxaban is
Thrombotic Management of Antiphospholipid Syndrome
superior to the VKAs, as it has a fixed dose and does not
require routine monitoring of its coagulation profile, in addi-
tion to fewer interactions with food, alcohol and drugs [64].
In a Polish cohort of APS patients (n=12), only two APS
patients (associated with SLE in the presence of LA, aCL
and anti-
2GPI) were reported to develop recurrent DVT
during treatment with rivaroxaban, although DVT, PE,
stroke or miscarriage were reported as the initial clinical
manifestations [65]. In a French cohort of APS patients
(n=26, duration of APS between 0 and 22 years), rivaroxa-
ban was suggested (15-20 mg/day) for use in 15 patients who
were suffering from vascular thrombotic events, such as
DVT, stroke, PE and arterial thrombosis. After 1 to 27
months of follow-up, a recurrence of thrombosis was not
observed in 14 patients; however, three patients discontinued
rivaroxaban treatment due to severe migraines, rectal bleed-
ing and the recurrence of microthromboses [66]. In another
APS cohort (n=18, disease duration 8.8 ± 6.7 years) from the
UK, none of the patients exhibited vascular thromboem-
bolisms after a mean of 12.9 months of rivaroxaban treat-
ment, although 13 patients had a previous history of DVT
and five had a history of both DVT and PE [67].
However, a controversial scenario was observed in
Brazilian APS patients (n=8) where all of the patients
developed thrombi (DVT/PE/renal infarction/stroke) as the
initial manifestations; six patients developed thrombotic
events (MI/DVT/stroke/arterial ischemia), and two patients
exhibited refractory migraines and headaches while being
treated with rivaroxaban [68]. According to a case report on
an American patient with primary APS (female, 59 years
old), rivaroxaban failed to prevent recurrent thrombosis at a
dose of 20 mg/day [69]. In another case report (male, 28
years old) of a patient with primary APS [70], thrombi
occurred in the right internal saphenous vein below the knee
(120 mm in length), in the middle of the thigh (30 mm), and
in the left internal vein (50 mm), in addition to the
presentation of relapsing superficial thrombophlebitis. When
rivaroxaban was administered (20 mg/day), the relapsing
superficial thrombophlebitis was resolved in that patient.
Therefore, rivaroxaban could be an effective treatment
choice for APS patients suffering from superficial thrombo-
phlebitis or vascular thrombosis. However, there are contra-
dictory results regarding the use of rivaroxaban in preventing
thrombosis in patients with APS. The development of
thrombotic events and side-effects, as well as the failure of
rivaroxaban to prevent recurrent thrombosis, has raised ques-
tions about its safety and effectiveness. Currently, two clini-
cal trials are ongoing (recruiting patients) in Canada [71] and
Italy [72], in addition to one published protocol from the UK
[73], to systematically assess the safety and efficacy of ri-
varoxaban use in thrombotic patients with APS. Therefore,
before the results of the clinical trials are published, it is not
recommended that rivaroxaban is used to treat thrombotic
patients with APS; however, this drug could be an option for
exceptional cases only. In addition, if patients show moder-
ate renal impairment (creatinine clearance: 30-49 mL/min),
the dose should be reduced from 20 mg/day to 15 mg/day,
and rivaroxaban is not recommended in cases of severe renal
impairment (creatinine clearance: <15 mL/min) [74].
Current Vascular Pharmacology, 2017, Vol. 15, No. 4 317
5.3. Apixaban
Apixaban (Eliquis®) is another direct FXa-inhibiting
NOAC. After administration, the oral absorption of apixaban
is rapid, and it achieves the maximum plasma peak concen-
tration within 1 to 3 h [75]. The bioavailability is approxi-
mately 66%, and the elimination half-life is 8 to 15 h in
young people [75, 76]. Apixaban was reported to have a few
drug interactions; however, it does not interact with food and
alcohol, as it is partially metabolized by cytochrome P450.
Because of its reduced interactions with foods, alcohol or
drugs compared with VKA antagonists, such as warfarin,
apixaban exerts a more persistent anticoagulant intensities in
thrombotic patients, without the need for regular INR moni-
toring [9, 63]. Apixaban was licensed by the EMA and first
approved by the FDA in 2012. It is currently used to reduce
the risk of cerebrovascular accidents and peripheral vascular
embolisms, including recurrent DVT, which can lead to PE
[77], as superior efficacy of different doses (2.5 and 5.0 mg,
twice daily) of apixaban was observed compared to the
placebo or low-molecular-weight heparin (LMWH) (1.0
mg/Kg every 12 h) [78, 79].
A recent (2016) case report [80] did not observe a
recurrence of thrombosis in a patient (female, 28 years old)
with primary APS [presenting venous thromboembolism
(VTE) in the presence of LA and aCL (both IgG and IgM)]
following treatment with 5 mg of apixaban (3 times a day).
Currently, a prospective, randomized, open-label, blinded
event pilot study is ongoing to assess the efficacy, effective-
ness and safety of apixaban (2.5 mg twice a day) for the sec-
ondary prevention of thrombosis in patients with APS
(n=668) compared with warfarin [81]. Therefore, before the
results of this clinical trial are available, the usability of
apixaban as a secondary preventative measure for thrombosis
in APS patients will remain unclear, and it is not
recommended for use in patients with APS.
5.4. Dabigatran
Dabigatran (Pradaxa®) is a prodrug that is rapidly ab-
sorbed after oral administration, followed by direct binding
and thrombin (factor IIa) inhibition. It is completely
converted into the active form in the plasma and the liver.
Dabigatran has a half-life of 12 to 14 h, and it achieves the
maximum peak plasma concentration within 2 h after oral
administration [82]. It is reported to have a low bioavailabil-
ity of approximately 6 to 7% [83].
Dabigatran is not metabolized by the CYP enzymes.
However, it is a substrate for the P-glycoprotein transporter
and is mainly excreted by the kidneys [84, 85]. Dabigatran
was licensed by the EMA in 2008 for the treatment of pa-
tients with VTE, and the FDA initially approved its used for
the prevention of stroke in 2010 [73].
In a French cohort of APS patients (n=26, duration of
APS from 0 to 23 years) with an initial thrombotic history
(DVT, stroke, PE and arterial thrombosis), dabigatran was
administered and followed up between 6 and 39 months (150
mg/twice daily) in 11 patients. Neither the recurrence of
thrombotic events nor bleeding were observed in any of the
patients [66]. Dabigatran was reported to be a successful
prolonged anticoagulation therapy that prevented the recur-
318 Current Vascular Pharmacology, 2017, Vol. 15, No. 4
rence of thrombosis after orthotopic liver transplantation in a
22-year-old Russian male with primary APS co-existing with
Budd-Chiari syndrome [86].
A 43-year-old female with primary APS was initially
managed with warfarin; however, due to heavy menstrual
bleeding and difficulty in managing her INR, she was di-
rected to take dabigatran at a dose of 150 mg/day. Eventu-
ally, it failed to prevent the recurrence of vascular thrombo-
sis [69]. Win et al. [87] reported a study of a 53-year-old
female patient with severe APS and a history of multiple
thrombotic complications [recurrent DVT and TIA]. It was
suggested that she switch from warfarin to dabigatran (150
mg twice daily) because of her uncontrollable INR due to
genetic limitations in warfarin metabolism (heterozygous for
CYP2C9 and homozygous for the vitamin K epoxide
reductase complex subunit 1). Although a recurrence of
thrombotic events was not observed later, neurologic abnor-
malities, such as memory loss, transient weakness, acute
vision changes and presyncopal events, were apparent. Be-
cause existing studies are not conclusive in regards to the
safety and efficacy of dabigatran, larger cohort studies are
needed to obtain a clear picture of the usage of dabigatran in
APS patients with thrombotic manifestations.
5.5. Anti-Platelet Drugs
5.5.1. Aspirin
Aspirin (acetylsalicylic acid) is a platelet aggregation
inhibiting agent that is usually used to prevent thrombosis. In
addition, aspirin has a substantial role in the treatment of
other health conditions, such as fever, rheumatic fever, colo-
rectal, breast and prostate cancers, pain, neuropsychiatric
disorders, cardiovascular disease and inflammation-related
diseases, including rheumatoid arthritis and pericarditis [88].
Aspirin is administered via the oral route. After inges-
tion, aspirin takes approximately 30 to 40 min to reach to its
peak plasma level. It has been reported to be rapidly ab-
sorbed in the stomach and upper GI tract [89]. The half-life
of aspirin in the plasma is only 20 min. Over a wide range of
doses, approximately 40% to 50% bioavailability is reported
for regular aspirin tablets [90].
Aspirin exerts its anti-platelet activity by permanently
inactivating the key platelet enzyme cyclooxygenase (COX)
[91], although nascent platelet generation can reverse this
effect. It has been reported that platelet turnover helps to
recover COX activity by approximately 10% per day after
ingestion of a single dose of aspirin [92]. Aspirin-mediated
inhibition of platelet function is measurable within 60 min of
administration [93]. However, enteric-coated aspirin requires
3 to 4 h to achieve the peak plasma effect [94]. Randomized
controlled trials (RCTs) reported that aspirin doses between
50 and 100 mg/day effectively act as an antithrombotic
agent, although dosages as low as 30 mg/day are suggested
to be highly effective [93].
Aspirin administration is reported to be adversely
associated with an increased risk of bleeding, specifically, GI
tract bleeding [93]. The combined administration of aspirin
with other non-steroidal anti-inflammatory drugs (NSAIDs),
clopidogrel or warfarin has reported to further increase the
bleeding risk in the upper GI tract [95]. Co-administration of
Islam et al.
aspirin with other nonselective, reversible COX inhibitors,
such as ibuprofen and naproxen, impairs its efficacy, as other
drugs compete with aspirin for a common docking site (ar-
ginine 120) within the COX channel [96].
Several clinical studies have reported the efficacy of aspi-
rin for managing thrombosis in patients with APS. In 2001,
Erkan et al. reported that APS patients who had pregnancy
loss as the only APS manifestation were at high risk of de-
veloping subsequent vascular thrombosis and suggested that
aspirin treatment would be an effective prophylaxis against
thrombosis [97]. In 2005, an open-label RCT with APS
patients (n=109) reported that the standard treatment (aspirin
alone at a dose of 100 mg/day or warfarin at doses adjusted
to an INR range 2.0-3.0) was superior to high-intensity
warfarin (INR range 3.0-4.5) for preventing recurrent
thrombosis, where warfarin was also found to be linked with
an increase in minor hemorrhagic complications [54]. In
2008, a retrospective study by Hereng et al. on asymptomatic
aPL-positive carriers (n=103) associated with different dis-
eases reported that SLE patients (4/10) who were not taking
aspirin developed thrombosis compared to those SLE pa-
tients (3/27) who were taking aspirin. Patients with autoim-
mune thrombocytopenia (4/6) who were not taking aspirin
developed thrombotic events compared with patients who
were taking aspirin (1/10). The study results supported the
use of aspirin to prevent thrombotic events as APS manifes-
tation in aPL-positive patients with SLE and autoimmune
thrombocytopenia [98].
Based on the data from a randomized, double-blind, pla-
cebo-controlled trial in 2007, Erkan et al. suggested that low-
dose aspirin (81 mg/day) did not protect against primary
thrombosis in asymptomatic, persistently aPL-positive indi-
viduals (without any vascular and/or pregnancy events) [99].
However, a recent (2014) meta-analysis reported that low-
dose aspirin treatment had a protective effect on the risk of
primary arterial thrombosis in SLE patients and asympto-
matic aPL individuals compared to HCQ [100]. A prospec-
tive, open RCT also reported the efficacy of low-dose aspirin
alone in comparison with the combination of low-intensity
warfarin plus low-dose aspirin in causing fewer thrombotic
and bleeding episodes in aPL-positive patients with SLE
and/or obstetric morbidity [101].
Combination treatments consisting of aspirin with other
anticoagulants have been reported to have positive outcomes
in several clinical studies. In 2004, a prospective study re-
ported that aspirin (325 mg/day) and heparin (1 mg/kg
enoxaparin once daily) treatment of asymptomatic aPL-
carriers (n=178) who were at high risk of thrombosis re-
sulted in no episodes of thrombosis in any of the carriers
during the follow-up period of 36 months. On the other hand,
APS patients (n=226) who received the dicumarin treatment
exhibited a recurrence of venous and arterial thrombosis,
indicating that this treatment was an insufficient anticoagula-
tion therapy [102].
From our observations, most of the existing evidence
supports the use of aspirin alone, rather than in combination
with other drugs. It is also observed that the combination of
aspirin with other COX inhibitors leads to competition for
the common binding sites, whereas combinations with anti-
coagulants increase the bleeding risk, although controversial
Thrombotic Management of Antiphospholipid Syndrome
results are also reported. The selection of an effective dose of
aspirin is also a controversial issue. Therefore, more investi-
gations are required to make a conclusive decision about the
effective dose and efficacy of aspirin either alone or in com-
bination with other anti-thrombotic drugs.
5.5.2. Clopidogrel
Clopidogrel (Plavix®) is a thienopyridine class anti-
platelet drug. Oral administration of 75 mg clopidogrel
reaches to its maximum peripheral blood concentration
within 1.5 h which declines to undetectable values in most
cases within 6 h [103]. Age and food do not significantly
influence its bioavailability [104]. However, interindividual
differences may affect the peak plasma concentration and the
time to peak plasma concentration [105]. Clopidogrel is rap-
idly absorbed in the intestine and is then activated in the liver
by cytochrome P450 enzymes, mainly the CYP2C19 [106].
Mechanistically, clopidogrel irreversibly inhibits the P2Y12
subtype of adenosine diphosphate (ADP) chemoreceptors
(present on platelet cell membranes) by forming a disulfide
bridge. Inhibition of P2Y12 by clopidogrel further inhibits
platelet activation, which thereby inhibits fibrin-mediated
cross-linking and prevents the formation of blood clots [44].
It is mainly used to treat peripheral vascular, cerebrovascular
and coronary arterial diseases [107]. Clopidogrel is also very
effective in preventing MI and stroke [108]. However, a
3.58-fold greater risk of major cardiovascular events (stroke
and heart attack) has been reported in patients who express a
variant allele of CYP2C19 [109]. In these patients, lower
levels of the active metabolite of clopidogrel were observed,
which failed to inhibit a sufficient number of platelets. The
risk of adverse events is greatest in CYP2C19 poor metabo-
lizers [110]. In 2010, the US FDA alerted consumers about
the reduced effectiveness of clopidogrel in people with a
poor capacity to metabolize the drug [111, 112].
Bleeding is considered as one of the most common ad-
verse effects caused by clopidogrel [113]. In addition to
bleeding, thrombotic thrombocytopenic purpura is also
reported as an adverse effect [114]. Co-administration of
aspirin has been reported to increase the rate of hemorrhage
[115]. In 2009, the FDA announced that patients who use
proton pump inhibitors, such as omeprazole or esomepra-
zole, should use caution when they are already taking clopi-
dogrel [116] as these drugs can completely inhibit the
CYP2C19 isoenzyme preventing the active metabolite for-
mation of clopidogrel [117].
In previous years, several clinical reports revealed the
efficacy of clopidogrel in combination with other agents in
APS or non-APS patients. According to a recent (2014) case
report, clopidogrel in combination with rivaroxaban signifi-
cantly reduced the symptoms and improved the prognosis of
a 55-year-old female (diagnosed with acute PE, acute MI and
a cerebral infarction) patient who did not have any major
bleeding episodes [118].
According to a case report published in 2003, a 31-year-
old male APS (associated with SLE) patient developed
erythematous purpuric plaques. Biopsies of the lesioned skin
showed intravascular EC proliferation associated with the
formation of microthrombi, which failed to be resolved by
warfarin treatment, although the therapeutic INR and protein
Current Vascular Pharmacology, 2017, Vol. 15, No. 4 319
C levels were adequate. However, the oral administration of
clopidogrel in association with subcutaneous LMWH
(enoxaparin) and oral aspirin induced the rapid and remark-
able resolution of the skin lesions and improved the clinical
condition [119].
In 2009, another 35-year-old male APS patient was diag-
nosed with MI and exhibited a recanalized thrombus in the
left anterior descending artery. Treatment with aspirin,
clopidogrel and enoxaparin for 2 months managed the clini-
cal state of the patient [120]. In 2010, a male patient (59
years old) who was suspected to have APS and presented MI
developed multiple recurrent stent thrombosis. The patient
showed mildly elevated titers [12 IgG phospholipid (GPL)
unit] of the aCL antibody and resistance to clopidogrel.
However, a 6-week combination treatment with LMWH,
clopidogrel and aspirin effectively resolved the chest pain
and thrombosis. Undetectable titers of IgG, IgA, IgM aCL
and LA were present [121]. In 2011, a female APS patient
with SLE who had a past history of PE reported a sudden
onset of chest pain and shortness of breath. The patient was
diagnosed with a thrombus in the proximal left anterior de-
scending artery. However, daily treatment with full-dose
aspirin, clopidogrel (75 mg), continuous heparin infusions,
and a 24-h continuous eptifibatide infusion resolved the
chest pain and breathing problems and showed effective re-
gression of the thrombus [122]. In 2012, a retrospective
single-center study of APS patients (n=81) with arterial
thromboses revealed that a dual anti-platelet treatment
(n=13) with aspirin and ticlopidine/clopidogrel prevented the
recurrence of arterial thrombosis in 54% of APS patients
[123]. In 2013, an 18-year-old female APS patient was re-
ported to develop recurrent DVT and was treated with long-
term warfarin therapy. However, the combination of clopi-
dogrel and HCQ instead of warfarin succeeded in preventing
the recurrence of thrombotic or bleeding events in that pa-
tient [124].
To the best of our knowledge, most of the evidence
mentioned above is confined to case reports in which clopi-
dogrel was effective in combination with other anti-
thrombotic drugs. Therefore, more prospective studies with
larger sample sizes and in vivo studies are required to evalu-
ate the safety and efficacy of clopidogrel in APS patients,
and its synergistic interaction with other well-documented
anti-thrombotic medications, respectively.
5.6. Immunomodulatory Drugs
5.6.1. Rituximab
Rituximab is a chimeric monoclonal antibody that binds
to the B cell surface protein CD20 (anti-CD20 antibody) and
induces apoptosis [125]. Initially, rituximab was approved
for the treatment of B-cell lymphomas, and it has since been
successfully used to treat systemic autoimmune diseases,
including APS, with a consistent safety profile [126]. In
APS, the pathogenic role of B cells in the generation of
thrombi is assumed [8]. Therefore, rituximab is used to at-
tenuate the titer of aPLs and ultimately prevent aPL-
mediated thromboses in patients with APS, although the ef-
ficiencies were heterogeneous [127, 128]. For the first time,
Ahn et al. [129] reported the use of rituximab in an APS
320 Current Vascular Pharmacology, 2017, Vol. 15, No. 4
patient (female, 30 years old) with a thrombotic history of
over 10 years (recurrent and spontaneous DVT, PE and
stroke) and the persistent presence of aPLs (LA, aCL and
anti-
2GPI). Following four weekly infusions of rituximab
(375 mg/m2), the LA titers became persistently negative, and
the aCL IgM titer was temporarily negative and later
reverted to a positive, low titer. Although there was no sig-
nificant change in the aCL (IgG) and anti-
2GPI (IgM) lev-
els, an improvement of her thrombocytopenic condition was
observed, as well as a remission from thrombosis. Rituximab
(375 mg/m2 weekly x 4 doses) was successful in resolving
cerebral venous sinus thrombosis and in a complete visual
recovery in an APS patient, with no side effects [130]. Stud-
ies reported a reduction in the aPL levels and a reduced fre-
quency of recurrent thrombotic events in patients with APS
who were treated with rituximab and followed for as long as
41 months [131, 132]. According to a recent (2014) system-
atic analysis of the literature [133], the clinical manifesta-
tions were improved and/or no recurrence of thrombosis was
observed in 23 pediatric APS patients (13 ± 4.6 years) who
were treated with rituximab in combination with immuno-
suppressive regimens, anticoagulants and/or steroids. How-
ever, none of the patients who were positive for aPLs (LA,
aCL and anti-
2GPI) became negative for these antibodies
after the rituximab treatment.
According to Berman et al. [134], among the 20
refractory catastrophic APS patients from the “European
CAPS registry”, 16 recovered (80%) from acute episodes of
catastrophic APS after treatment with different dosages of
rituximab [8 (40%) and 12 (60%) patients received rituximab
as the first-line and second-line treatments, respectively], but
4 (20%) patients died during the follow-up. Rituximab was
also used to treat APS patients who exhibited ‘non-criteria’
manifestations, including thrombocytopenia, skin ulcers and
hemolytic anemia with persistent levels of aPLs [127, 135].
Recently (2016), a 43-year-old triple aPL-positive (with high
titers) woman was treated with rivaroxaban, tinzaparin (a
LMWH), warfarin and aspirin for her recurrent DVT and
multifocal cerebral ischemic symptoms. Despite the use of
these regimens, she experienced recurrent transient stroke
episodes. Therefore, in addition to her existing medications,
HCQ, methylprednisolone and rituximab were added. After 3
months of follow-up, she did not experience further throm-
botic events [136]. Therefore, rituximab may be another
emerging regimen that can be used in combination with other
anticoagulants, anti-platelets, anti-inflammatory drugs and
appropriate steroids to restrain the recurrence of thrombosis
in APS patients.
The abovementioned evidence is from case reports/series
and pilot clinical studies; therefore, large, well-designed,
prospective RCTs should be conducted to evaluate the effi-
cacy and safety of rituximab as a secondary thromboprophy-
laxis and for the treatment of ‘non-criteria’ manifestations in
patients with APS.
Based on our observations, rituximab is more effective in
combination with other regimens than alone. Therefore,
more studies of rituximab are warranted to evaluate its effi-
cacy in combination with anticoagulants, anti-platelet drugs,
anti-inflammatory drugs and appropriate steroids to restrain
the recurrence of thrombosis in APS patients. Currently, all
Islam et al.
the evidence us from case reports/series and pilot clinical
studies; hence, large, well-designed, prospective RCTs
should be conducted to evaluate the efficacy and safety of
rituximab as a secondary thromboprophylaxis and for the
treatment of ‘non-criteria’ manifestations in patients with
APS.
5.6.2. Eculizumab
Eculizumab (Soliris®) is a humanized monoclonal
antibody (IgG2/4k) that inhibits the activation of C5
complement by preventing the cleavage of C5 into C5a and
C5b, followed by inhibiting the generation of the membrane
attack complex (MAC) [137, 138], which plays a major role
in the pathogenesis of thrombi formation in APS [8]. Eculi-
zumab was approved by the FDA and the EMA in 2007 for
the treatment of paroxysmal nocturnal hemoglobinuria
(PHN) and was later approved in 2011 for the treatment of
atypical hemolytic uremic syndrome (aHUS) [139].
To date, eculizumab has mainly been used in refractory
patients with catastrophic APS [140]. In 2012, eculizumab
was administered (six doses of 600 mg approximately every
week) to a 28-year-old young man suffering from cata-
strophic APS and during the more than three-year follow-up
period, no recurrence of any forms of thrombotic events was
observed in addition to the reversal of his thrombocytopenia
[141]. Eculizumab was also successful in another cata-
strophic APS patient with thrombotic microangiopathy
(male, 51 years old) who underwent renal transplantation
[142]. Recently (2015), a 47-year-old primary catastrophic
male APS patient was treated with eculizumab, which pro-
gressively improved both the clinical and laboratory features
during the over 16-month follow-up period [143].
To date, histories of success for eculizumab treatments in
APS patients are very limited and are only confined to case
reports. Currently, a clinical trial investigating the efficacy of
eculizumab in kidney-transplanted patients with catastrophic
APS is ongoing (ClinicalTrials.gov Identifier: NCT01029587)
[144]. In addition, large prospective cohort studies are war-
ranted to investigate the safety and efficacy of eculizumab in
patients with thrombotic APS.
5.6.3. Hydroxychloroquine (HCQ)
HCQ (Plaquenil®) is mainly an antimalarial regimen that
possesses anti-inflammatory, immunomodulatory and anti-
thrombotic activities. It is widely used for the treatment of
rheumatoid arthritis, SLE and APS [145].
According to in vitro studies, a significant reduction of
binding between anti-
2GPI and the phospholipid bilayer
[146], inhibition of GPIIb/IIIa on aPL-activated platelets
[147] and prevention of aPL-induced disruption of the
annexin A5 shield [148] were observed upon treatment with
effective concentrations of HCQ as low as 1, 25 and 1
μg/mL, respectively. HCQ significantly diminished the sizes
of the thrombi in male CD-1 mice that were injected with
human IgG aCL, possibly by reversing the thrombogenic
properties of aPLs [149]. A cross-sectional study observed a
possible role of HCQ in protecting asymptomatic aPL-
positive subjects from thrombosis [150].
Thrombotic Management of Antiphospholipid Syndrome
According to the first prospective, non-randomized study
of patients with primary APS, co-administration of oral anti-
coagulants and HCQ protected against recurrent thrombosis
[151]; however, a recent meta-analysis (2015) found that
there was no substantial protective effect of HCQ on throm-
bosis [100]. According to a recent (2015) observational
study, 26 patients with thrombotic APS were treated with
NOACs, rivaroxaban or dabigatran, and HCQ was
administered to 50% of the patients (n=13) as an adjunct
regiment [66]. Among the 13 patients, a recurrence of
thrombosis was not observed in 11 subjects, whereas 2 dis-
continued the treatment due to severe migraines and recur-
rent rectal bleeding (no information was available about their
recurrence of thrombosis). Therefore, concurrent treatment
strategies with NOACs and HCQ could be an interesting
clinical aspect of determining whether HCQ exerts any
synergistic effect on preventing the recurrence of thrombosis
in APS patients.
As the results of existing studies are contradictory, it
would be interesting to investigate the effects of concurrent
treatment strategies using NOACs and HCQ to observe
whether HCQ exerts any synergistic effect on preventing
recurrence of thrombosis in APS patients. Currently, a clini-
cal trial investigating the efficacy of HCQ on the endothelial
dysfunction in patients with APS is ongoing (ClinicalTri-
als.gov Identifier: NCT02595346) [152], and the results of
this trial are expected to clarify the contradiction regarding
the efficiency of using HCQ to treat thrombotic patients with
APS.
5.6.4. Statins
Statins are a class of lipid-lowering drugs that regulate
cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl-
coenzyme A (HMG-CoA) reductase [153]. A meta-analysis
revealed that use of statins is significantly associated with
reduced frequencies of VTE [154]. Based on in vitro studies,
statins (fluvastatin, simvastatin and rosuvastatin) diminished
the aPL-mediated upregulation of TFs and adhesion mole-
cules in ECs [155, 156]. A similar type of ameliorating effect
was observed in an in vivo study of aPL-induced throm-
bogenic and proinflammatory biomarkers [157], indicating
that statins have the potential to regulate inflammation and
thrombosis.
According to a recent (2014) 3 month, open-label,
prospective pilot intervention trial (ClinicalTrials.gov
identifier: NCT00674297) with aPL-positive subjects (n=41,
39 had history of thrombotic events) [158], 40 mg/day
fluvastatin significantly (p<0.05) diminishes 50% of the
proinflammatory and prothrombotic biomarkers [interleukin
(IL)-1, vascular endothelial growth factor (VEGF), TNF-
,
inducible protein-10 (IP-10), soluble CD40 ligand (sCD40L)
and soluble TF] that are generally upregulated in patients
with APS. A case-control study with APS patients (n=42)
observed that upon administration of 20 mg of
fluvastatin/day for 30 days, a significant reduction (p<0.05)
in the levels of several monocyte-mediated inflammatory
molecules [TF, protein activator receptors (PAR) 1, 2 and
VEGF] and altered expression of some thrombogenic
biomarkers (annexin A2, RhoA and protein disulfide
Current Vascular Pharmacology, 2017, Vol. 15, No. 4 321
isomerase (PDI)] that were responsible for the induction of
thrombosis in patients with APS were observed [159].
Although the use of statins to prevent the recurrence of
thrombosis in APS patients might be beneficial (because of
the lipid-lowering activity of statins), clinical evidence of the
effects of statins on APS patients is substantively limited.
Therefore, RCTs are warranted to determine the safety and
efficacy of using statins to prevent thrombosis in patients
with APS.
5.6.5. Sirolimus
Sirolimus (Rapamune®), also known as rapamycin, is an
immunosuppressor that acts on the mammalian target of
rapamycin (mTOR, a kinase that integrates a variety of
signaling pathways to regulate cellular growth, proliferation
and survival) and thereby inhibits the activation of B and T
cells by inhibiting IL-2 [160, 161]. Sirolimus has success-
fully been used to prevent rejection in organ transplantation,
especially renal transplantations [162]. In 2014, Canaud
et al. [163] reported that patients with APS nephropathy who
required renal transplantation were treated with sirolimus
and did not show a recurrence of vascular lesions compared
with patients who were not treated with sirolimus. In
addition, 70% of transplanted patients who were treated with
sirolimus had a functioning renal allograft (144-month fol-
low-up) compared with 11% of patients who were not re-
ceiving sirolimus. Therefore, sirolimus could be a potential
immunosuppressive drug for renal transplanted patients with
APS; however, well-designed RCTs are required to confirm
these findings.
6. FUTURE DIRECTIONS AND CONCLUSION
Although the thrombotic pathogenesis of APS has been
studied extensively, further studies are required to identify
novel molecular targets and develop precise treatment strate-
gies for thrombotic APS.
As the mechanism of thrombi generation in APS is
unique compared to general thrombi formation, new thera-
peutic approaches targeting pathogenic molecules are en-
couraged for the management of thrombosis in APS. In addi-
tion to the existing VKA anticoagulants and anti-platelet
agents, new NOACs and immunomodulatory agents seem to
have the potential to prevent thrombosis or manage the re-
currence of thrombosis. However, firm clinical safety and
efficacy data are required before wide therapeutic use is
practiced (except for exceptional refractory cases in which
all the currently approved drugs are ineffective). Upon the
completion of current, ongoing clinical trials investigating
APS and newer drugs in the thrombotic management of
APS, novel information is expected to add guidance for gov-
erning the thrombotic management of APS in a better direc-
tion. Currently, our Cochrane systematic review and meta-
analysis [164] assessing the efficacy and safety of anti-
platelet and anticoagulant agents at preventing the recurrence
of any peripheral vascular thrombosis (arterial or venous, or
both) in patients with APS is ongoing and is expected to
clarify the appropriate type of regimens to use in the
thrombotic management of APS patients. Combined thera-
peutic approaches targeting different unregulated thrombotic
pathways in APS can be a potential management strategy;
322 Current Vascular Pharmacology, 2017, Vol. 15, No. 4
therefore, well-designed RCTs are required to investigate the
efficacy and safety of combined therapy compared with pla-
cebo or other currently used individual antithrombotic regi-
mens. In addition to the current antithrombotic regimens, the
development of new antithrombotic drugs from natural com-
pounds is encouraged [165], which can be another potential
treatment for APS patients in the future.
LIST OF ABBREVIATIONS
APS = Antiphospholipid Syndrome
aPL = Antiphospholipid Antibody
DVT = Deep Vein Thrombosis
HCQ = Hydroxychloroquine
MI = Myocardial Infarction
PE = Pulmonary Embolism
SLE = Systemic Lupus Erythematosus
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
We would like to acknowledge the Universiti Sains Ma-
laysia (USM) Vice-Chancellor Award (2015/2016) and the
USM Global Fellowship (2014/2015) awarded to Md. Asiful
Islam and Fahmida Alam, respectively, to pursue their PhD
degrees.
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