The Antiphospholipid Syndrome in Pregnancy: A Review
Article
Cacciola Rossella,
Gentilini Cacciola Elio, Cacciola Emma
Cacciola
Rossella, Gentilini Cacciola Elio, Hemostasis Unit, Department of
Clinical and Experimental Medicine, University of Catania, Ferrarotto Hospital,
Via S. Citelli 6, 95124 Catania, Italy
Cacciola
Emma,
Department of Medical, Surgical and
Advanced Technologies Sciences G.F., Ingrassia, University of Catania, Italy
Correspondence to: Cacciola
Rossella, MD, PhD, Hemostasis Unit, Department of Clinical and Experimental Medicine,
University of Catania, Ferrarotto Hospital, Via S. Citelli 6, 95124 Catania,
Italy
Email:
rcacciol@unict.it
Telephone: +39-95-7435963
Received: February 1, 2015
Revised: February 16, 2015
Accepted: February 18, 2015
Published online: November 18, 2015
ABSTRACT
The antiphospholipid syndrome is an autoimmune
thrombophilic disease characterized by occurrence of vascular events (arterial,
venous, or small vessel thrombosis) and/or pregnancy complications, in
association with persistently positive antiphoshpolipid antibodies such as
lupus anticoagulant, anticardiolipid antibodies, and/or anti-2-glycoprotein I antibodies. The
international consensus (revised Sapporo) criteria for antiphospholipid
syndrome-related pregnancy morbidity include a) one or more unexplained deaths
of a morphologically normal fetus at or beyond the 10th week of gestation, with
normal fetal morphology documented by ultrasound or by direct examination of
the fetus; or b) one or more premature births of a morphologically normal
neonate before 34th week of gestation because of eclampsia or severe
pre-eclampsia (PE); or c) three or more unexplained consecutive spontaneous
miscarriages before the 10th week of gestation. The recognition of aPLAbs by
endothelial cells, monocyte and platelets is one of the pathogenic mechanisms
contributing to antiphospholipid syndrome. The mandatory laboratory criteria
for antiphospholipid syndrome are repeated positive tests for the antiphopsholipid
antibodies on 2 or more occasions al least 12 weeks apart. Lupus anticoagulant
is clinically the most relevant among all tests. Recently, two coagulometric
tests have been recommended by recent guidelines for lupus anticoagulant
detection: activated partial thromboplastin time and/or diluited prothrombin
time. Obstetric antiphospholipid syndrome is currently managed by administering
low-dose aspirin and either low-dose unfractioned heparin (twice daily) or
low-molecular-weight heparin (once daily).
© 2015 ACT. All rights reserved.
Key words: Pregnancy;
Antiphospholipid antibodies; Thrombosis
Cacciola R, Elio GC, Emma C. The Antiphospholipid
Syndrome in Pregnancy: A Review Article. International
Journal of Hematology Research 2015; 1(1): 12-19 Available from: URL:
http://www.ghrnet.org/index.php/ijhr/article/view/1053
Introduction
The antiphospholipid syndrome (APS) is an autoimmune thrombophilic
disease characterized by occurrence of vascular events (arterial, venous, or
small vessel thrombosis) and/or pregnancy complications, in association with
persistently positive antiphoshpolipid antibodies (aPLAbs) such as lupus
anticoagulant (LA or LAC), anticardiolipid antibodies (aCL), and/or anti-2-glycoprotein I antibodies (a2-GPI)[1]. In the absence of other associated autoimmune
disorders, such as lupus erythematosus, the disease is classified as primary
APS (PAPS). In association with other disease processes, including connective
tissue diseases, the APS is defined secondary (SAPS)[1]. The
international consensus (revised Sapporo) criteria for APS-related pregnancy
morbidity, which may occur in women with no history of vascular thrombosis and
who present APS during pregnancy (purely obstetric APS), include a) one or more
unexplained deaths of a morphologically normal fetus at or beyond the 10th week
of gestation, with normal fetal morphology documented by ultrasound or by
direct examination of the fetus; or b) one or more premature births of a
morphologically normal neonate before 34th week of gestation because of
eclampsia or severe pre-eclampsia (PE) defined according to standard
definitions or recognised features of placental insufficiency; or c) three or
more unexplained consecutive spontaneous miscarriages before the 10th week of
gestation (i.e. recurrent miscarriages), with maternal anatomic or hormonal
abnormalities and paternal and maternal chromosomal causes excluded[2-5].
The recognition of aPLAbs by endothelial cells (EC), monocyte and platelets is
one of the pathogenic mechanisms contributing to APS. LA is clinically the most
relevant among all aPLAbs tests. LA belongs to a group of autoantibodies direct
against proteins with affinity for negatively charged phospholipid (PLs)[1,5].
The in vitro anticoagulant effect of LA is explained by the assumption that
this antibody competes with clotting factors for anionic PLs acting as
catalytic surface for coagulation reactions[1,5]. Since 2GP-I-dependent LAs are antibodies directed against 2GP-I, such competition can only be explained by an increased affinity
of 2GP-I for PLs upon antibody binding
to this protein[5]. It has been shown that 2-GPI-dependent LAs are better predictors of thrombotic comlications
than LAs directed against prothrombin[1,5]. The mandatory laboratory
criteria for APS are repeated positive tests for the aPLAbs on 2 or more
occasions al least 12 weeks apart[1,4]. The 3 tests exploring aPLAbs
are LA, aCL, and a2-GPI detected by standardized
ELISA[1,4]. ELISA-detected positive Abs must be of IgG and/or IgM
isotype present in medium or high titer (Table 1). Recently, two coagulometric
tests have been recommended by recent guidelines for LA detection: activated
partial thromboplastin time (aPTT) and/or diluited prothrombin time (dRVVT)[1,6].
Obstetric APS is currently managed
by administering low-dose aspirin (LDA) and either low-dose unfractioned
heparin molecular-weight heparin (twice daily) or low-molecular-weight heparin
(LMWH, once daily)[7].
Natural
history and pathogenesis of APS pregnancy
Women who carriers aPLAbs (LA, aCL, a2-GPI) are at higher risk of obstetric complications and general
thrombotic risk including venous thromboembolism (VTE) and cerebrovascular
thrombosis (Figure 1 from
Giannakopoulos et al with permission)[2,8].
The pregnancy
morbidity include fetal loss (early is defined as before 10 weeks gestation,
late as miscarriage at or beyond 10 weeks according APS classification
criteria), recurrent spontaneous abortions, abruptio placentae, intrauterin
growth restriction (IUGR), PE, eclampsia, small gestational age (SGA),
premature delivery[2,8,9,7,10]. The vascular morbidity during
pregnancy is clinically characterized by the occurrence of venous, arterial or
microvascular thrombosis in any tissue or organ. The episodes of venous and
arterial thrombosis include proximal unprovoked deep vein thrombosis, distal
unprovoked vein thrombosis (DVT), superficial vein thrombosis (SVT), transient
ischaemic attach (TIA) or stroke, respectively[2].
The obstetric
and/or vascular morbidity is associated with disturbance of hemostasis leading
abnormal placental development and thrombosis[9,11]. Transvaginal
ultrasonography has shown that the arterial signals in the yolk sac circulation
disappear, and the umbilicoplacental circulation increases between the
beginning of the eighth and the 10th weeks of gestation, indicating that the
placenta replaces the yolk sac as an essential source of blood supply to the
embryo at the time. During these 2 crucial weeks, in such an early placental
circulation, hypercoagulability in the mother may induce pregnancy termination[12].
aPLAbs are heterogeneous autoantibodies that recognize PL-binding proteins such
as 2-GPI and prothrombin, protein C
(PC), protein S (PS), annexin V, complement factor H, high- and low-
molecular-weight kininogen, prekallikrein, Factor IX, tissue factor pathway
inhibitor (TFPI), Factor VII/VIIa, platelet factor 4 (PF4)[1,13,14].
Animal studies have shown that the most prominent antigen target in APS is 2-GPI[15]. The potential binding site for autoantibodies
against β2-GPI is located in domain I. This epitope includes Arg39 and Arg43
(Figure 2 from Giannakopoulos et al with permission)[15].
The
pathogenetic mechanism underlying pregnancy complications in women with APS
differ from that in thrombotic APS, where thrombosis is neither a universal nor
a specific feature. There is an association between LA positivity and adverse
pregnancy outcomes[7]. LA is a heterogeneous group of antibodies,
and its activity can be 2-GPI dependent or independent; 2-GPI dependent LA is strongly correlated with thrombosis[7].
LA may be associated with extensive placental necrosis, infarction and
thrombosis in women with recurrent pregnancy loss. These abnormalities may
result from thrombosis during the development of the normal materno-placental
circulation, perhaps via interference with trophoblastic annexin V[3].
It has been reported that pregnant women with aPLAbs show decreased levels of
annexin V on the placental villi[9]. The human placental
syncytiothrophoblast is a rich source of annexin V, a protein that displays a
strong in vitro anticoagulant activity due to its high affinity binding to
negatively charged phospholipids and to its capacity to displace coagulation
factors from phospholipid membranes, creating a protective shield against
procoagulant reactions[9]. The anatomic location of annexin V on the
apical surface of placental villi facing the maternal slow-moving blood in the
intervillous circulation might, therefore, play an antithrombotic role by
inhibiting intervillous thrombosis and maintaining blood fluidity, so that
nutrition exchange functions in the placenta result unimpaired[9].
During
differentiation syncytium, trophoblasts express cell membrane anionic
phospholipid that can bind 2-GPI. aPLAbs
which are 2-GPI-dependent
may recognise their own antigen on trophoblast and decidual cells as a “planted
antigen” and it has been suggested that the binding to this antigen affects
several trophoblast cell functions, leading to defective placentation[3].
In addition, the 2-GPI/anti-2-GPI complex formation may
activate complement and thereby induce local inflammatory damage[3].
Complement activation by aPLAbs appears to play a major role in the
pathogenesis of recurrent pregnancy loss, and there is evidence that complement
activation may also have a role in the pathogenesis of thrombosis in APS[3].
Ruffatti et
al[16] reported that there is a strong association with
recurrent late fetal loss (>10 weeks gestation) in women who are positive on
all 3 assays (LA, a-β2-GPI, aCL), compared with women who are either dual or
single assay positive. In particular, a-β2-GPI with LA activity may mediate a
more prominent effect in late gestation miscarriage via distinct mechanism,
perhaps by inducing intrauterine placental thrombosis, in view of the strong
association of this class of antibodies with thrombosis (predominantly the IgG
isotype, particularly IgG2 subclasses)[16]. In vivo
observations raises the possibility that non-β2-GPI antibodies may be
particularly relevant in early miscarriages, perhaps via the induction of an
inflammatory mechanism[16].
The mechanism
by which aPLAbs lead to thromboembolic events is unknown[15]. The
most popular theory to explain why APS patients have an increased thrombotic
risk is that these autoantibodies can cause activation of different cell types
involved in regulation of the hemostatic balance, such as EC, monocytes,
platelets, neuthrophils, fibroblasts and trophoblasts[15,17-19].
Activation of these cells results in a shift toward a prothrombotic state.
One mechanism by which aPLAbs/antiβ2-GPI may promote activation of EC is
that these autoantibodies are thought to interfere with “anticoagulant”
surface-mediated processes. One anticoagulant pathway involves PC, activated by
thrombin on endothelial thrombomodulin, and PS. Activated PC in association
with PS cleaves factor Va and factor VIIIa on the PL surface and thereby
inactivates the intrinsic tenase and prothrombinase reactions. Occupancy of the
surface by immune complexes could impede these interactions and thereby promote
coagulative activation[1,5]. Indeed, LAs can induce “activated
protein C resistance”. A second anticoagulant mechanism involves TFPI. This
protein binds to negatively charged PL and to factor Xa on PL. This protein
complex then links to the TF-factor VIIa complex, and shuts off further
TF-mediated clotting. Occupancy of the PL surface by immune complexes may
impede this interaction, leading to prolonged thrombin generation[1,5].
Recent studies have demonstrated that the aPLAbs/antiβ2-GPI cross-link a
receptorial multiprotein signaling complex consisting of annexin A2, TLR4,
calreticulin, and nucleolin that is present on the EC surface and mediates the
EC activation[20]. EC activation leads to increased expression of
adhesion molecules (E-selectin, ICAM-1, VCAM-1), inflammatory cytokines and
chemokines as well as procoagulant activity and the release of microparticles
expressing anionic phospholipid that is a site for assembly of coagulation
complex and TF[19-21].
Toll like
receptor 2 (TLR2) and TLR1 or TLR6, and CD14 contribute to monocyte activation
of aPLAb. In particular, TLR2, TLR1, and TLR6 are involved in aPLAb recognition
by human monocytes. The CD14-dependent internalization of TLR2 by aPLAb in
monocytes triggers NF-kB activation inducing TF expression and upregulating TF
activity[1,15,18,22]. In addition, aPLAbs induce TLR8 expression and
signaling in monocytes leading to the secretion of inflammtory cytokines[22].
Proteomic analysis has identified the vimentin (VIM) as a key antigen in the
APS. VIM is an intermediate filament cytoskeletal protein, which is expressed
by neuthrophils, T cells, monocytes and EC. Anti-VIM/CL antibodies were found
in 92% of patients with APS[1,19]. The 2-GPI antibody/2-GPI complex binding
apolipoprotein E2 receptor and GPIb is responsible for platelet
activation/adhesion[14]. Other target proteins are plasminogen
activator inhibitor type-1 (PAI-1) linked to APS thrombogenesis. Immunoglobulin
G isotype activates p38 mitogen-activated protein kinase (MAPK) causing the
upregulation of TF activity and inducing the expression of vascular endothelial
gowth factor (VEGF)[1,19].
Among all
aPLAbs, LA is the unique risk factor independent for vascular thrombotic
disease, including proximal unprovoked deep vein thrombosis, distal unprovoked
deep vein thrombosis, and SVT. Surprisingly, no single aPLAb is an independent
risk factor for cerebrovascular events[2]. LA is considered to be
the most powerful predictor of thrombosis[8]. Strong risk factors
for thrombosis are generally associated with spontaneous, rather than provoked,
thrombotic events, which fits with the Rosendaal thrombosis potential model[8].
Non-criteria
obstetric APS: clinical manifestations and laboratory
Several obstetric manifestations additional to those in the
international consensus criteria have been proposed as ‘obstetric morbidity
associated with APS (OMAPS)’[3]. These include two unexplained
miscarriages, three non-consecutive miscarriages, late pre-eclampsia, placental
abruption, late premature birth, or two or more unexplained in vitro
fertilisation failures (Table 2 from Arachillage et al with permission). The
preliminary first report from the European Registry on Obstetric
Antiphospholipid Syndrome (EUROAPS) suggested that there were no statistically
significant differences in pregnancy outcome between women with obstetric APS,
as defined by the International consensus criteria, or OMAPS[2].
There are women who are strongly suspected of having obstetric APS, showing the
classical clinical features but persistently negative for currently recommended
laboratory tests for aPLAbs. It has been proposed that autoantibodies directed
against negatively charged phospholipids other than cardiolipin; other proteins
of coagulation cascade; specific domains of 2-GPI, or those interfere with the anticoagulant activity of annexin
A5; may be relevant to APS and defined as non-criteria aPL. Some authors have
described this phenomenon as ‘seronegative APS’. These patients were often
positive for antibodies to zwitterionic phospholipid (e.g.
phoshpatidylethanolamine); various phospholipid-binding plasma
proteins/phospholipid-protein complexes; and anionic phospholipids other than
cardiolipin[3]. It has been reported that women with non-criteria
clinical and/or laboratory obstetric APS may benefit from standard treatment
for obstetric APS with LMWH plus LDA with good pregnancy outcomes[3].
However, prospective multicentre studies are required to investigate the
diagnostic validity, management implications and long-term outcomes of
non-criteria clinical and/or laboratory manifestations of obstetric APS. In
meantime, decisions about the use of antithrombotic therapy during pregnancy in
women with non-criteria clinical and/or laboratory manifestations of obstetric
APS, should be based on an individual risk/benefit assessment. Management
should ideally be within a high risk antenatal clinic setting and treatment
decisions discussed with the patient and documented[3]. Interestingly,
Comellas–Kirkerup and collaborators[23] report that thrombocytopenia
and autoimmune hemolytic anemia (“hematologic APS”) may antedate thrombosis or
pregnancy morbidity. Even more, some authors have proposed that these
hematologic manifestations might represent a prethrombotic state preceding the
onset of APS.
Diagnostic
criteria for APS
The presence of aPLAb alone does not constitute APS. Definitive APS is
defined by the simultaneous presence of clinical and laboratory criteria as
agreed upon International criteria for APS (Sapporo criteria) in 1998 and
revised in 2006[1,4]. The clinical criteria are one or more
objectively confirmed episodes of pregnancy morbidity and/or vascular
thrombosis at any site defined as more than one unexplained death of a morphologically
normal foetus, more than one premature birth of a morphologically normal
neonate, or more than 3 unexplained consecutive spontaneous abortions before
the 10th week of gestation[1,4]. The laboratory criteria are the
presence of aPL. i.e. LA; and/or moderate or high positive IgG or IgM aCL (i.e.
>40 GPL or MPL or >99th centile); and/or a2-GPI (IgG and/or IgM) antibodies >99th centile. Persistently
positive aPL is defined on two or more consecutive occasions at least 12 weeks
apart (Table 3 from Arachchillage
et al with permission)[1,4,6].
Laboratory
Diagnosis of aPLAb
According to the last revison of the “Sapporo” criteria and the
recommendations published in 2009 by the Subcommittee for the detection of LA[24,25],
laboratory diagnosis for APS is based on the detection of aPLAbs on 2 or more
occasions at least 12 weeks apart. The 3 tests exploring aPLAbs are LA detected
by coagulation assays, aCL and a2-GPI antibody detected by standardized ELISA.
APS requires
the presence of at least one of the three aPLAbs (i.e. LA, IgG and/or IgM aCL
and IgG and/or IgM a2-GPI antibodies)[3].
The revised criteria provided details about the titres: >40 GPL or MPL or
> the 99th percentile for aCL and > the 99th percentile for a2-GPI[4,26]. Interestingly, LA is the strongest risk factor
for thrombosis and recurrent fetal loss whereas aCL antibodies show some
significant associations only at high titres. The G rather than the M isotype
is significantly associated with the clinical events for both aCL and aβ2-GPI
antibodies[26-28]. It has been reported that “triple
LA positivity”, defined by the presence of LA and high titres of aCL and aβ2-GPI
antibodies, correlated with both thrombosis and pregnancy morbidity more
strongly that single or double positivities[1,26].
Overview of
the assays
The Lupus Anticoagulant/Phospholipid-Dependent Antibodies Subcommittee of the Scientific and Standardization Committee of the ISTH has recommended criteria for the diagnosis of LA[27]. The recommendation is to perform two different tests, such as the activated partial thromboplastin time (aPTT) and the diluite Russel’s viper venom time (dRVVT)[27]. The LA is an assay that detects imunoglobulins that associate with thrombosis. The LA assay system chosen has to comply with the 3-step strategy defined in the International Society of Thrombosis and Haemostasis criteria[29]: (1) screening test: demonstration of the prolungation of a phospholipid-dependent clotting time beyond the upper limit of the reference interval; (2) mixing test: confirmation of the presence of a an inhibitor and the exclusion of a coagulation factor deficiency; and (3) confirmation that the inhibitor is phospholipid-dependent and no directed against a specific coagulation factor. The mixing test involve combining the patient’s plasma with normal plasma (1:1) and assessing the influence of this procedure on clotting time, the theoretical underpinning being that if prolongation of clotting time is the result of a coagulation factor deficiency, it will correct to normal, whereas with LA, correction requires larger volumes of normal plasma[29] (Table 4 from Rand with permission). Although ELISA-based methods were developed to detect aPLAb, LA detected by coagulometric tests has been shown to be strongly associated with thrombosis[6]. There is growing belief that 2-GPI-dependent aPLAbs are strongly associated with thrombosis[5,6]. For this reason, various attempts have been made to specifically detect β2-GPI-dependent LAs. Two methods of β2-GPI-dependent LA identification were described[30,31]. The aβ2-GPI antibodies may be divided into high and low avidity and the former is associate with thrombosis[29]. In the obstetric APS, testing positive on all 3 assays (LA, β2-GPI, and aCL-ELISAs) is associated with a greater risk for thrombosis[7,6]. In the update criteria, it is recommended that patients be divided into classes according to the type and number of antibodies. Patients are classified as class I when they posses more than one type of antibody. The group with all three types of antibodies (LA, aCL, and aβ2-GPI) were connected with the highest risk of pregancy loss[31]. The IgG rather the IgM isotype is significantly associated with the clinical events for both aCL and aβ2-GPI antibodies[28]. Patients with both LA and aβ2-GPI IgG or LA and aCL IgG positivity may represent the subgroups at the highest risk of thrombotic complications[28]. These observations support the suggestion to simplify the laboratory work-up of aPLAbs, excluding IgM from the ELISA mesurement of aCL and aβ2-GPI antibodies[27]. Conversely, both retrospective and prospective studies of women with pregnancy morbidity, particulary pregnancy loss, suggest that elimination of aCL and IgM aβ2-GPI from APS laboratory diagnostic criteria would lead to a failure to diagnose the syndrome in a significant proportion of women who could be regarded to have obstetric APS[3].
Treatment of
obstetric APS
In three meta-analyses of randomized trials in women with APS, the
combination of LDA plus LMWH reduced pregnancy loss (RR 0.46)[32] or
first-trimester loss (OR 0.39)[33] and increased live births than
with aspirin alone (RR2.3)[34]. The British Committee for Standards
in Hematology (BCSH)[35] and American College of Chest Physicians
(ACCP)[36] guidelines provide recommendations on the management of
women who fulfil the clinical and laboratory international consensus criteria
for obstetric APS, based on a history of recurrent miscarriages. The BCHS
guidance recommendes antenatal administration of heparin combined with LDA
throughout pregnancy, in general starting as soon as pregnancy is confirmed and
continuing until six weeks post-partum. The ACCP guidelines also recommend that
women with obstetric APS should be treated with prophylactic or intermediate
dose unfractionated heparin (UHF) or prophylactic dose LMWH combined with LDA
(75 to 100 mg/daily) in the antepartum period as soon as pregnancy is confirmed[37]
(Table 5). Although direct comparison studies are lacking, LMWH has superseded
the use of UHF in pregnancy (ACCP 2012) because of safety and convenience[3,7].
LMWH may promote extravillous trophoblast development, being able to stimulate
their invasive properties[38]. The classic complement pathway
inhibition in pregnant women treated with LMWH may also be relevant, altered
complement regulation being the role in PE[38]. The ACCP guidelines
recommend LDA alone throughout pregnancy, starting from the second trimester
for women considered at risk for PE. The BCSH guidelines also recommend LDA
alone for women with APS and a history of PE[3]. Despite the use of
aspirin and heparin treatment for women with obstetric APS, live birth rates
remain suboptimal[7]. This suggest that the antithrombotic treatment
may be inadequate: higher dose of LMWH and/or aspirin might be more effective,
and indeed, the optimal doses have not been established[7].
Theoretically, women with recurrent pregnancy loss refractory to treatment with
aspirin and heparin may benefit from immunosuppression, because of the
complement-mediate placental damage, to maintain a viable pregnancy[39].
Bramham et al[39] suggest that low-dose prednisolone (10 mg
daily) taken until 14 weeks’gestation in addition to aspirin and heparin may be
benefit in women with APS refractory to standard treatment[39].
Prednisolone such as heparin inhibits activation of complement allowing
adequate trophoblast invasion and placentation[39]. This study is
worthy of further assessment because prednisolone is associated with
significant side effects such as increased risk of gestational diabetes,
elevations in blood pressure during pregnancy, asymptomatic infections, and
preterm deliveries[38].
Treatment of
non-criteria obstetric APS
Prospective[40] and retrospective[41-43] cohort
studies in patients with non-criteria laboratory manifestations of obstetric
APS (OMAPS) suggest that they may have similar pregnancy outcomes with standard
treatment for obstetric APS as women who fulfil international consensus
criteria for obstetric APS. Such studies also suggest that women with OMAPS may
benefit from standard treatment for obstetric APS with LMWH plus LDA, with good
pregnancy outcomes. The role of post-partum thromboprophylaxis in this patient
group is not etsablished.
Treatment of
thrombotic APS
APS is an important predictor of subsequent VTE[8].
Management currently depends on expert opinion and on the perception of the
physician. According to the sixth ACCP guidelines for antithrombotic therapy
for the prevention and treatment of thrombosis, the mainstay of treatment of
arterial or venous thrombosis in patients with established APS is LMWH followed
by oral anticoagulation with a targeted INR of 2-3[5]. The use of
long term LDA is often applied in clinical practice. LDA has no effects on the
prevention of subsequent VTE whereas there may be a potential beneficial effect
on the prevention of TIA or stroke[2]. However, the risk-benefit
ratio in the prevention of arterial thrombosis should be evaluated by
randomized clinical trials. Given the higher risk of venous and arterial
thrombosis in women with purely obstetric APS, should we use long-term
anticoagulants for primary prophylaxis? At present there are no data on the
risk-to-benefit ratio of this approach[2]. Whether administration of
continuous primary prophylaxis can be considered in the presence of high-titer
LA (or triple aPLAbs positivity) and of additional risk factors for thrombosis
including inherited thrombophilia as well as what optimal regimen is for
on-demand prophylaxis in situations at risk for women with purely obstetric
APS, are still open questions. In the meantime, the decisions up to the
treating physicians and the patients based on a careful evaluation and counseling
on the thrombosis risk according to available data from the literature[2].
Interestingly, Schmidt-Tanguy et al[44] assessed the efficacy
of hydroxychloroquine (HCQ) as a new therapeutic approach in primary thrombotic
APS for secondary venous thrombosis prophylaxis in a small cohort of patients.
HCQ is an antimalarial drug that has several antithrombotic effects[45-47]
and its administration is associated with increased survival. The results are
encouraging but should be confirmed in a randomized controlled trial of HCQ for
thrombosis prevention in primary APS. (Table 5 from Soch MC et al with
permission).
Conclusion
APS probably constituites the single most recognisable risk factor in
the majority of cases of recurrent pregnancy loss and late placenta-mediated
obstetric morbidity. The pathogenetic mechanisms underlying pregnancy
complications in women with APS may differ from those in thrombotic APS. The
BCSH[35] and ACCP[36] recommendations support that women
with obstetric APS who meet International consensus criteria should be treated
with prophylactic or intermediate dose UHF or prophylactic LMWH combined with
LDA, in the antepartum period as soon as pregnancy is confirmed. Women with
non-criteria clinical and/or laboratory onstetric APS (OMAPS) may benefit from
standard treatment for obstetric APS with LMWH plus LDA, with good pregnancy
outcomes. Women with obstetric APS appear to be at higher risk than other women
of PE, placenta-mediated complications and neonatal morbidity. Accurate
diagnosis of obstetric APS is a prerequisite for optimal clinical management,
and thereby, the potential prevention of long-term disability as a result of
placenta-mediated obstetric complications. Women with obstetric APS also appear
to be at increased long-term risk of thrombotic events.
CONFLICT OF INTERESTS
The Authors have no conflicts of
interest to declare.
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Peer reviewer: Raul Hector Morales-Borges, American Red Cross, Puerto Rico
Region, PO Box 366046, San Juan, PR 00936-6046, USA.
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