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REVIEW

Antiphospholipid syndrome in children:

review of pathogenesis, diagnosis
and treatment
Emma J MacDermott &
Antiphospholipid syndrome in children is a complex problem. Active investigation continues
Thomas JA Lehman†
into its pathogenesis and the role of anticardiolipin antibodies, anti-β2glycoprotein1
†Author for correspondence antibodies and other autoantigens. Despite these ongoing questions, there is substantial
Hospital for Special Surgery,
new information available regarding the differential diagnosis, clinical features and current
Division of Pediatric
Rheumatology, Department of and potential treatment options.
Pediatrics, 535 East 70th
Street, New York, Antiphospholipid syndrome (APS) is characterized Updated Sapporo criteria summary
NY 10021, USA,
and,
by venous, arterial thrombosis and/or recurrent Clinical criteria
Weill Cornell Medical Center pregnancy loss, associated with a distinct autoanti- • Vascular thrombosis: one or more arterial,
USA body profile. The association of recurrent clotting venous or small-vessel thrombosis in any
Tel.: +1 212 606 1151; abnormalities with autoantibodies arose from rec-
Fax: +1 212 606 1938; organ or tissue.
[email protected] ognition that these problems were associated with
false-positive biologic tests for syphilis. In the early Pregnancy morbidity
1950s, the association was expanded with recogni- • One or more unexplained deaths of a mor-
tion of the increased prevalence in patients with phologically normal fetus at or beyond the
systemic lupus erythematosus (SLE). Studies of the tenth week of gestation;
false-positive biologic test for syphilis established • One or more premature births of a morpho-
the association of thromboembolic events with the logically normal neonate before the 34th week
presence of antiphospholipid antibodies (aPL). of gestation because of eclampsia, severe
Key to understanding this syndrome was recog- pre-eclampsia or recognized features of
nition that lupus patients with clotting abnormal- placental insufficiency;
ities were not simply deficient in one of the
clotting factors, but in fact possessed a circulating • Three or more unexplained consecutive spon-
factor that slowed the clotting of normal serum. In taneous abortions before the tenth week of
1972, Rapaport and Feinstein proposed the term gestation, with maternal anatomic or hormo-
‘lupus anticoagulant’ [1]. The earliest use of the nal abnormalities and paternal and maternal
chromosomal causes excluded.
term APS was proposed by Harris in 1987 [2,3].
The first pediatric description in the literature was Laboratory criteria
made by Olive in 1979 [4]. • Anticardiolipin antibody (aCL) of immuno-
Historically, patients with APS have been dis- globulin (Ig)G or IgM isotype in serum or
tinguished as having primary or secondary dis- plasma, present in medium or high titer
ease on the basis of the presence or absence of (i.e., >40 IgG phospholipid units or IgM
concomitant illness. The international consenus phospholipid units, or more than the
statement on classification of APS advises against 99th percentile) measured by a standardized
the use of the term ‘secondary APS’. They were enzyme-linked immunosorbent assay
unable to find differences on the clinical conse- (ELISA);
quences of aPL in these groups. Most patients,
• Lupus anticoagulant present in plasma on two
including children with ‘secondary’ disease, have
or more occasions at least 12 weeks apart,
an underlying diagnosis of SLE. The unknown is
detected according to the guidelines of the
if APS and SLE occur together coincidentally, as
Intenational Society on Thrombosis and
two elements of the same disease process, or if
Hemostasis;
SLE provides a setting for APS to develop [5].
• Anti-β2 glycoprotein (GP)1 antibody of IgG
Keywords: antibodies, or IgM isotype in serum or plasma (in titer
antiphospholipid, children,
Definition of APS
systemic lupus erythematosus It is important to recognize that the presence of more than the 99th percentile), measured by a
aPL does not define APS. The updated Sapporo standardized ELISA;
part of
criteria for the classification of patients with APS • Laboratory criteria must be positive on two or
were proposed in 1998 and recently revised. more occasions, at least 12 weeks apart;

10.2217/17460816.2.2.203 © 2007 Future Medicine Ltd ISSN 1746-0816 Future Rheumatol. (2007) 2(2), 203–211 203
REVIEW – MacDermott & Lehman

• At least one clinical and one laboratory criteria LA. However, the kaolin clotting time is a more
must be met. Since recurrent pregnancy fail- sensitive measure (it does not require the addi-
ure is not a usual feature of pediatrics, diagno- tion of exogenous phospholipids, thus maximiz-
sis of APS in childhood requires the child to ing the effect of the LA if present). The dilute
have had documented thrombosis and not Russell viper venom test may detect additional
simply laboratory abnormalities. cases [8]. Failure to correct a prolonged clotting
time in mixing studies with normal plasma is key
Although they are important, the nonthrom- to the definition of the LA even in the absence of
botic features of the disease do not define its aPL detected by routine ELISA.
presence. These features include livido reticula- aCL and anti-β2GP1 antibodies are measured
ris, cardiac involvement (including valvulo- using conventional ELISA techniques. The most
pathy), chorea, seizures and a multiple-sclerosis- common aPL isotype is IgG. IgA and IgM isotype
like condition. Associated laboratory findings antibodies are less common. Approximately a
include: antibodies in low titer that do not fulfill third of patients have aPL of more than one
the updated Sapporo criteria, thrombocytopenia isotype [8].
and hemolytic anemia [6]. Antibodies to annexin, The anticoagulant, β2GP1 binds to negatively
prothrombin and neutral phospholipids have charged phospholipids, inhibiting platelet aggre-
been detected in patients with APS [7]. The clin- gation via an adenosine diphosphate-dependant
ical significance of their presence is as yet pathway. β2GP1 also inhibits prothrombinase.
unclear. A false-positive venereal disease research Paradoxically, antibodies to this glycoprotein may
laboratory was the finding that gave rise to the accelerate clotting or decrease platelet inhibition
discovery of the condition; however, it is no and prolong the coagulation cascade [8].
longer a criterion for classification. Although
consensus criteria were developed for adult Pathogenesis of APS
patients, they apply equally to children as to The mechanism(s) by which aPL increase the
adults. As with adults, children may present with incidence of thrombosis is uncertain. The proba-
a nonclassical aPL-related manifestation and bility is that development of clinical APS is
then go on to develop APS with thrombosis. dependent on the multiple-hit hypothesis, with
both genetic susceptibility and environmental
Antiphospholipid antibodies triggers playing a role. Potential mechanisms are
aPL are heterogeneous and different antibodies discussed below.
react against different phospholipids or serum
phospholipid-binding proteins. There are three Interference with the
main groups of aPL: lupus anticoagulants (LAs), coagulation cascade
aCL and other antibodies against specific phos- aPL may induce a procoagulant state by altering
pholipid-binding proteins. Specific phospholipid the interaction of phospholipid-binding proteins
binding protein targets include, most importantly throughout the coagulation cascade. This may
β2GP1, but also protein C, protein S, pro- include inhibition of protein S or the thrombo-
thrombin and annexin V. These aPL occur in var- modulin–thrombin complex. Alternatively, aPL
ied titers and frequencies in different populations may cause downstream inhibition of protein C
and circumstances. In general, APS is more com- substrates or annexin V. Additionally, aPL may
mon in patients with anti-β2GP1 antibodies than act by disrupting activation of platelets, leading
in those with other laboratory findings [8]. to increased thromboxane production and
LAs are hexagonal immunoglobulins that platelet adhesion.
interfere with the conversion of prothrombin to
thrombin. The resultant laboratory abnormalities Activation of endothelial cells
may include altered activated partial thrombo- Endothelial cell activation stimulates coagula-
plastin time, kaolin clotting time and/or the Rus- tion via cytokine secretion, increased surface
sell viper venom time. Because of their adhesion molecule expression and increased
heterogeneity, the detection of LA is by a three- tissue factor production. Binding of aPL, to
step functional assay, and no single functional β2GP1 expressed on the endothelial cell surface
assay is adequate to reliably detect their presence. has been shown to increase cellular activation
Routine coagulation studies – specifically the in vitro. An alternative mechanism of activation
activated partial thromboplastin time, are the may relate to the development of antibodies to
most commonly used method of screening for low-density lipoprotein (LDL), which results in

204 Future Rheumatol. (2007) 2(2) future science group

 Antiphospholipid syndrome in children – REVIEW

macrophage activation. In the presence of aCL, atherosclerotic damage. Thrombosis in children

autoantibodies to oxidized LDL develop. Anti- with aPL is rare over the relatively short periods
body-linked oxidized LDLs are taken up by for which they have been followed.
macrophages at the endothelial surface. Subse- In childhood, deep vein thrombosis occurs
quent activation of these macrophages may lead more frequently than superficial. Pulmonary
to endothelial cell activation and damage [9,10]. emboli and pulmonary artery hypertension
resulting from multiple microthromboemboli
Clinical features of APS & aPL have been reported [14]. Additional complica-
in childhood tions reported include infarction of the adrenal
APS and aPL have a broad spectrum of clinical glands resulting in Addison’s disease [15], as well
manifestations. Many children with aPL anti- as thrombosis of the inferior vena cava, renal,
bodies are picked up coincidentally and do not hepatic and mesenteric veins. The retinal vein
fulfill criteria for APS. Even if a child is docu- thrombosis with visual loss and cavernous sinus
mented to have circulating LA, by definition, thrombosis may also occur.
they do not have APS if there has never been a The CNS is the most common site of arterial
thrombotic episode (see aforementioned thrombosis in childhood, with stroke being the
updated Sapporo criteria). However, careful most commonly reported event. aPL are a risk
attention to the history and physical examina- factor for pediatric stroke. Of 58 children with
tion are required to ensure that an episode of ischemic stroke, 53% had at least one marker of
thrombosis has not been overlooked. Addition- thrombophilia compared with 25% of controls [16].
ally, catastrophic APS (Asherson’s syndrome) As well as an increased stroke risk [16], an increase
may occur in children with no antecedent in transient ischemic events has been reported in
events. Nonetheless, in the absence of a throm- children with aPL [17]. Any child presenting with
botic episode, these children should be noted to thrombosis in the absence of other recognized
have aPL, but not diagnosed with APS. The predispositions should be evaluated for APS.
long-term prognosis of such children is
under study. Nonthrombotic
A number of studies have attempted to assess Although thrombosis is the causative pathological
the prevalence of aCL in healthy children, but mechanism in most cases, there is increasing evi-
they have reported widely divergent results [11]. dence that there are several nonthrombotic mech-
In a group of 61 children tested at well visits, anisms at play in the etiology of the various
aPL were detected in 11%, with anti-β2GP1 symptoms of APS. A direct role for autoantibodies
antibodies in 7%. Blood was drawn at a single is postulated in the development of transverse
time point for each child, giving a prevalence of myelitis and of the chorea and epilepsy observed
aPL positivity, but not fulfilling laboratory crite- in APS patients [18]. It has been suggested that a
ria for APS [12]. Levels of β2GP1 antibodies were vasculopathy of the major vessels may have a caus-
highest in babies. Some have questioned ative role in avascular necrosis [18]. Subendothelial
whether oral food items may induce a transient immune complex deposition has been demon-
production of anti-β2GP1 antibodies [12]. strated in APS valve disease [19]. The mechanism
of recurrent fetal loss, although infrequently a
Thrombosis problem in pediatrics, has been demonstrated to
Ravelli and Martin suggest that APS in the pedi- have a complement-driven component [20].
atric age group is more common in females [13].
APS occurring in the context of another auto- Other CNS manifestations
immune condition, usually SLE, is recognized Multiple neurological symptoms not clearly
more commonly than primary APS in childhood. linked to thrombosis have been reported in chil-
Associated thrombotic events may occur in any dren with aPL. aPL interact directly with cells of
vascular bed. However, the relative frequency of the neurological system or cause deposition of
arterial thrombosis in children appears to be immune complexes on the cell surface, leading
greater. Children have few underlying thrombo- to cellular activation. Reported clinical presenta-
embolic risk factors. In general, they are tions include seizures, Gullian–Barre syndrome,
nonsmokers, do not use the oral contraceptive pill chorea, psychosis and migraine [14]. aPL may also
and, although an increasing number have cause transverse myelitis [17]. A potential role for
sedentary lifestyles and are overweight, their aPL in Tourette’s syndrome has also been
vasculature has incurred fewer years of cumulative postulated, but not yet established [21].

future science group www.futuremedicine.com 205

REVIEW – MacDermott & Lehman

Cardiac children who fulfill adult criteria with rapid onset

A valvulopathy similar to Libman–Sacs endo- of organ failure in the setting of positive aPL.
carditis has been reported in adults with aPL. The Most often reported is acute renal failure, but car-
vegetations are composed of platelets and fibrin. diopulumonary embolism, cerebral infarction
Most commonly the mitral and aortic valves are and deep vein thrombosis are also suffered [26–28].
affected. This valvulitis is more diffuse than that Asherson’s syndrome may occur in the setting of
seen in other rheumatic diseases and often infection, surgery, lupus flare or other events.
involves the chordae tendinae. Other cardiac Lupus vasculitis, sepsis, disseminated intravascu-
pathology associated with aPL includes ventri- lar coagulation (DIC) and macrophage-activa-
cular hypertrophy and dysfunction, intracardiac tion syndrome should be considered in the
thrombosis and pulmonary hypertension [22]. differential diagnosis [29–31].

Dermatologic Neonatal
Livido reticularis is the most common dermato- Infants delivered to aPL-positive mothers often
logic manifestation in children. Digital gan- have detectable antibodies resulting from trans-
grene, purpura, skin ulceration and necrosis have placental passage. The most common perinatal
all been reported [14]. Pretibial lesions are more complications are intrauterine growth retarda-
common in childhood, perhaps because of the tion (IUGR) and prematurity. As expected, aPL
nature of their activities. Healing can be slow diminish over the first 6 months of life. Throm-
and painful with extensive scarring. botic complications are rare. Renal vein throm-
boses in association with in-dwelling catheters
Hematologic and cerebral ischemia have been reported.
Thrombocytopenia is common in patients with It is postulated that thrombotic complications
APS, with up to a third of children affected. are rare in aPL-positive neonates because their
Platelet counts are usually in the 100–150 ×109/l vessel walls lack atherosclerotic or other antecedent
range, rarely dropping to less than 50 × 109. This damage to serve as a point of initiation. Alterna-
may occur because aPL (particularly anti-β2GP1 tively, the antiphospholipid IgG subclasses trans-
antibodies) interact with platelet membrane ferred transplacentally may be less effective [32].
phospholipids [14]. Hemolytic anemia occurs and Nonetheless, children of aPL-positive mothers
up to 20% of patients may be Coombs-positive. should be monitored for thrombosis at least until
Evans syndrome (hemolytic anemia and the aPL titers have diminished. Recent work con-
thrombocytopenia) is reported [14]. firms a low rate of aPL transplacental passage for
The acquired hypothrombinemia–lupus anti- mothers with aPL-positive autoimmune disease,
coagulant syndrome occurs when antibodies to with none of 22 infants testing positive for aCL
prothrombin lead to profound hypoprothrom- IgG or IgM. There was a high percentage of posi-
binemia and severe bleeding [23]. Becton and col- tivity for anti-β2GP1 antibodies (15 out of
leagues have reported on six children, in whom 22 infants) at 1 year of age. It is postulated that the
the most common presentation was epistaxis. antibody may be stimulated by infection or nutri-
The children responded to corticosteroids [24]. tional exposure. The authors conclude that meas-
uring aCL is the more reliable assay for monitoring
Catastrophic antiphospholipid the disappearance of maternal antibody [33].
syndrome (Asherson’s Syndrome)
The catastrophic antiphospholipid syndrome APS associated with other
(CAPS) is now referred to as Asherson’s syndrome autoimmune conditions
[25]. It is defined as the clinical involvement of at The clinical manifestations of the APS in these
least three organ systems with histopathologic children are similar to those with primary dis-
evidence of multiple thrombi occurring over a ease. In a recent, well-conducted study of long-
period of days to weeks. Acute microangiopathy term outcomes in 14 children with primary
in the small vessels is more common than large- APS, fulfilling updated Sapporo criteria fol-
vessel involvement. The kidneys are affected most lowed for a median of 6 years, two had devel-
frequently, but CNS, lung, heart and skin may oped SLE, one lupus-like syndrome and one
also be affected. Multiorgan failure results in a non-Hodgkin’s lymphoma [34]. In 12 combined
mortality rate of 50%. Disseminated intravascu- series of children with SLE, 48% were positive
lar coagulopathy occurs in approximately 25%. for aCL and 23% for lupus anticoagulant. How-
Although rare, reported cases have occurred in ever, the reported positive percentage varied

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 Antiphospholipid syndrome in children – REVIEW

widely between studies [11]. Children with SLE The varicella-autoantibody syndrome occurs
and aPL may be at a greater risk of thrombosis rarely in children following varicella infection.
than those with either alone [35]. The relation- DIC, purpura fulimans or thrombosis may occur
ship of specific aPL subsets to risk of thrombosis as the result of a transient reduction in protein S.
and specific disease manifestations remains Levels are decreased when autoantibodies to pro-
uncertain, although symptoms of APS occur tein S bind, forming immune complexes that are
more commonly in patients with positive anti- rapidly cleared. The autoantibodies aCL and LA
β2GP1 antibodies [8]. Associations between aPL have been seen in many children with this condi-
and cerebrovascular disease, chorea and micro- tion, although their specificity has not been
angiopathic nephropathy have been reported in defined [43].
childhood. A study of 137 children with lupus, More recently, Kurugol and colleagues have
of whom 26% (22 out of 84) had LA and 65% demonstrated the presence of LA along with
(23 out of 137) had aCL, demonstrated a statis- decreased protein S in children with typical
tically significant association between the pres- varicella infection, suggesting that this virus
ence of aPL and that of cerebrovascular disease. mediates a transient hypercoagulable state [44].
They also showed an association between per-
sistently positive aCL and chorea [36]. An associ- Differential diagnosis
ation has also been observed between aCL Because thrombotic events occur rarely in chil-
positivity in patients with SLE and ischemic dren without heart disease or arteriovenous mal-
microangiopathic nephropathy [37]. formations, thorough search for the cause is
aPL can be found in children with a variety of necessary. In addition to testing for aPL, one
other autoimmune conditions, including juve- should consider deficiency of protein C or S,
nile idiopathic arthritis (JIA), dermatomyositis, Factor V, Leiden or antithrombin III. Other
diabetes and rheumatic fever. In JIA, APS has known risk factors, such as homocystine levels,
been reported to occur in anything from 7 to should also be assessed.
53% [14]. Serra and colleagues report a prevalence A careful history and physical examination are
of aPL in JIA of 32.5%, similar to the percentage essential to the detection of unrecognized rheu-
of antibody-positive juvenile SLE patients matic disease, heart defects or atrio-ventricular
(37.5%). However, no association between the (AV) malformation. A family history of recurrent
presence of antibodies and clinical manifesta- thromboses may be associated with inherited
tions was observed [38]. Only two reports appear deficiencies or predisposition to rheumatic
in the literature of thrombosis occurring in disease. A family history of recurrent pregnancy
aPL-positive JIA patients. One of these patients loss or rheumatic disease increases the likelihood
developed a bilateral femuropopliteal vein of APS. Medication use, including contraceptives
thrombosis but had the additional risk factor of a and anticoagulants, and illicit drug use must be
prolonged immobilization in plaster for a tibial evaluated. The presence of thrombocytopenia
fracture. The second patient had a central retinal and leucopenia suggests rheumatic disease, but
vein occlusion [39,40]. An association has been may also occur in children with malignancies.
observed between the presence of aPL and the Infections may both cause thrombosis and be
development of persistent parvovirus B19 associated with the appearance of aPL. A schema
infection in children with JIA [41]. for the detection and confirmation of the
aPL often occur following infections, for presence of aPL is suggested in Figure 1.
example HIV and Epstein–Barr virus (EBV) and
the use of some medications. These aPL differ by Treatment
binding to negatively charged phospholipids. The treatment of children with aPL or APS
They are less often associated with complica- is controversial.
tions, but are not distinguished from pathogenic
aPL by normal testing. Children who test Asymptomatic children with aPL
positive for aPL following an infection should aPL are found in a significant percentage of the
have repeated positive tests before a definitive healthy population. Their presence alone may not
aPL-positive label is applied [14]. There is some be associated with an increased risk of thrombosis
evidence in murine models to suggest that the in the absence of secondary factors [45]. In children
presence of viral or bacterial peptides may induce with persistent positive tests for aPL, consideration
the presence of aCL’s through a molecular may be given to treatment with an antiplatelet dose
mimicry model [42]. of aspirin. Some clinicians argue that no therapy is

future science group www.futuremedicine.com 207

REVIEW – MacDermott & Lehman

Figure 1. A schema for the detection and confirmation of the presence of

antiphospholipid antibodies.

Suspected antiphospholipid syndrome

Perform coagulation Anticardiolipin IgG,

screen/aPTT IgA and IgM by ELISA

Prolonged

Perform mixing Perform Kaolin

study 1:1 with clotting time
normal plasma or dRVVT Normal results but
clinical suspician
remains high
Normalizes Partial correction

B2IgG, IgA and IgM

Screen for Inhibitor
by ELISA
factor present =
deficiencies incubate

Normalizes No change

Specific factor Lupus anticoagulant

aPTT: Activated partial thromboplastin time; dRVVT: dilute Russell viper venom test; ELISA: Enzyme-linked
immunosorbent assay; Ig: Immunoglobulin.

necessary as the risk is low and the reduction in risk degree of anticoagulation did not appear more
associated with aspirin use is unproven. Large-scale effective at preventing recurrence [47]. Since chil-
studies evaluating the use of aspirin in adults with dren are at lower risk of recurrence and a higher
aPL are ongoing. In our practice, children with sig- risk of trauma with athletic activity, moderate
nificant aPL titers are advised to take 81 mg of anticoagulation may be best for pediatric APS
aspirin daily. While there is a suggestion that aspi- patients. However, the severity of the problem
rin may have a protective role in APS, substantive and degree of risk must be considered for each
data are needed [46]. In addition, we advise strongly child individually.
against other known risk factors, such as tobacco
use and oral contraceptives. Thrombocytopenia
Although commonly present, thrombocytopenia
Children with APS is usually mild. Thrombocytopenia in the pres-
Significant thrombosis in children with aPL ence of aPL is not treated differently from idio-
requires initial treatment with heparin followed pathic thrombocytopenic purpura (ITP) or
by oral anticoagulation. There is no consensus thrombocytopenia associated with any recognized
regarding duration of therapy or the appropriate underlying condition, unless there has been an
degree of anticoagulation. Thrombosis in APS episode of thrombosis. Use of aspirin in patients
patients tends to reoccur, hence treatment with low platelets may increase the risk of bleed-
should be maintained at least until aPL are ing. Splenectomy is not advised in patients with
undetectable, and many authorities recommend APS as the subsequent thrombocytosis may
continued anticoagulation. In adults, a higher increase the risk of thrombosis [14].

208 Future Rheumatol. (2007) 2(2) future science group

 Antiphospholipid syndrome in children – REVIEW

Catastrophic antiphospholipid syndrome platelets. Aspirin or HCQ may have a protective

(Asherson’s syndrome) role in a cross-sectional review of asymptomatic
CAPS (Asherson’s syndrome) is an emergency aPL-positive patients [46].
that must be aggressively treated. The treatment Statins are known to downregulate cytokines,
regimen for adults is based on the consensus inhibit platelet function and interfere with the
statement from the international congress [48]. interaction between leukocytes and the
No independent pediatric recommendations endothelium [51]. They may benefit patients
exist. Key steps in treating a child with Asher- with aPL through any of these mechanisms or
son’s syndrome are identification of precipitating simply by reducing the severity of athero-
factors and control of ongoing thrombosis. sclerotic damage. The lupus Atherosclerosis
Intravenous anticoagulation may be combined Prevention in Pediatric Lupus Erythematosus
with corticosteroids, intravenous immuno- (APPLE) study investigating the effects of statin
globulin, plasma exchange and, in children with use in these children is currently ongoing; this
rheumatic diseases, additional immunosuppres- will give us safety and efficacy data in a group of
sion [49,50]. Any child with CAPS should be children with autoimmune disease.
anticoagulated indefinitely. Protaglandin E1 and prostacyclin infusions
have been used in patients with CAPS. These
Future perspective drugs act as potent vasodilators and inhibit
Optimal therapy for adults and children with platelet aggregation. The risk of rebound
aPL, APS or CAPS remains to be determined. thrombosis must be carefully evaluated when
Many treatments have been used in uncon- considering their use [52].
trolled studies with reported success. These Reports of rituximab (anti-CD20 mono-
include hydroxycholoquine (HCQ), which has clonal antibody) use in aPL-positive patients
not only anti-inflammatory, but immuno- have shown some positive results, particularly
modulatory effects, and an inhibitory effect on in patients with thrombocytopenia [53].

Executive summary
Antiphospholipid syndrome
• Antiphospholipid syndrome (APS) is characterized by venous, arterial thrombosis and/or recurrent
pregnancy loss, and is associated with a distinct autoantibody profile.
• APS may occur alone or as a clinically identical sydrome seen in association with concomitant
autoimmune disease.
• In children, as in adults, the most common concomitantly occurring autoimmune condition is systemic
lupus erythematosus.
Definition of APS
• The Sapporo criteria for the classification of patients with APS were proposed in 1998 and recently revised.
• Diagnosis of APS in childhood requires the child to have had documented thrombosis and not simply
laboratory abnormalities, since recurrent pregnancy failure is not a usual feature in pediatric patients.
• Nonthrombotic features of the disease are important but do not define the presence of APS.
• Consensus criteria were developed for adult patients, but they may be equally applied to children.
Children may present with a nonclassical manifestation and then go on to develop APS with thrombosis.
Pathogenesis of APS
• The mechanism(s) by which antiphospholipid antibodies (aPL) increase the incidence of thrombosis
are uncertain.
• The probability is that development of clinical APS is dependant on the multiple-hit hypotheses, with
both genetic susceptibility and environmental triggers playing a role.
• aPL may induce a procoagulant state by altering the interaction of phospholipid-binding proteins
throughout the coagulation cascade.
• Antibody-linked oxidized low-density lipoproteins are taken up by macrophages at the endothelial
surface. Subsequent activation of these macrophages may lead to endothelial cell activation and damage.
Future perspective
• Optimal therapy for adults and children with aPL, APS or catastrophic APS remains to be determined.
• Many treatments have been used in uncontrolled studies with reported success, these include
hydroxycholoquine and rituximab (anti-CD20 monoclonal antibody).
• Current areas of research include complement inhibition, the inhibition of protein kinases in the
platelet and inhibition of tissue-factor expression.
future science group www.futuremedicine.com 209
REVIEW – MacDermott & Lehman

Many additional therapeutic avenues are Conclusion

undergoing exploration as the molecular basis aPL are surprisingly common in children with-
of aPL and APS becomes more clearly under- out manifestations of disease and their signifi-
stood. Current areas of research include cance is uncertain. By contrast, APS in
complement inhibition, the inhibition of childhood is rare but potentially devastating.
protein kinases in the platelet and inhibition of Both APS and aPL are more commonly seen in
tissue-factor expression. In a murine model children with rheumatic diseases, but occur in
system, tumor necrosis factor-α blockade con- isolation. Any child presenting with LA or unex-
fers protection against pregnancy loss in mice plained thrombosis should be vigorously evalu-
with aCLs. This has not been explored in ated for aPL, and children with APS should be
humans [54]. vigorously treated.
Synthetic proteins that mimic regions
of β2GP1 and block its thrombogenic pro- Disclosure
perties are under investigation, as is a β2GP1 Thomas JA Lehman, MD, is a member of the speakers’
toleragen [55]. bureau for Genentech.

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