Symposium- Rheumatology

Antiphospholipid syndrome: A review

Varun Dhir, Benzeeta Pinto

Abstract
Antiphospholipid syndrome is being increasingly recognized as a disease with a myriad of clinical manifestations
ranging from recurrent thrombosis and pregnancy morbidity to valvular lesions, transverse myelitis,
thrombocytopenia and hemolytic anemia. It may be primary or secondary, i.e., associated with other autoimmune
diseases. The latest classification criteria (Sydney 2006) recognize just three tests to define this syndrome-lupus
anticoagulant, anticardiolipin antobodies and anti 2 glycoprotein 1 antibodies. Treatment of thrombotic events
involves lifelong anticoagulation with vitamin K antagonists like warfarin. Antiphospholipid antibody syndrome
(APS) with only pregnancy morbidity is treated with thromboprophylaxis using heparin during pregnancy
and postpartum for 6 weeks. Catastrophic APS occurs in approximately 1% of APS, and is characterized by
microvascular thrombosis (thrombotic storm) and organ dysfunction. In this review we discuss the pathogenesis,
diagnosis, treatment and prognosis of the APS.

Keywords: Antiphospholipid syndrome, autoimmune disease, treatment

Introduction
Antiphospholipid antibody syndrome (APS) is an
autoimmune thrombophilic syndrome characterized by
recurrent venous, arterial or small vessel thrombosis and
pregnancy morbidity in the presence of antiphospholipid
antibodies. APS may occur in association with other
autoimmune disorders called secondary APS or may be
primary in the absence of any underlying illness. The
discovery of this syndrome can be traced back to the
1950s with the finding of prolonged activated partial
thromboplastin time (aPTT) and even earlier with the
biologic false positive syphilis test. Subsequently, in the
1980s with the detection of antibodies against cardiolipin,
it was named the anticardiolipin syndrome, later revised
Access this article online
Quick Response Code:
Website:
www.jmgims.co.in

DOI:
10.4103/0971-9903.126231

to antiphospholipid syndrome.[1] This review synthesises

the current information on this syndrome. The search
strategy for this review included a search on Pubmed
using the term antiphospholipid or anticardiolipin
or lupus anticoagulant.

Pathogenesis of Antiphospholipid
Syndrome
As the name suggests antiphospholipid syndrome
is mediated through antibodies directed against
phospholipids or proteins associated with
phospholipids, the latter being more common.
Although many antiphospholipid antibodies have
been described, the three that are the best studied
and are part of the diagnostic criteria are lupus
anticoagulant, anticardiolipin and anti 2 glycoprotein
1. More than one antibody is associated with lupus
anticoagulant activity including antibodies to
cardiolipin (ACL), 2GP1, prothrombin and annexin
V. Several mechanism have been suggested to explain
the prothrombotic state induced by antibodies to the

Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Address for correspondence:
Dr. Varun Dhir, Department of Internal Medicine, Rheumatology Services, Postgraduate Institute
of Medical Education and Research, Chandigarh-160 012, India.
E-mail: varundhir@gmail.com

March 2014 | Vol 19 | Issue 1

Journal of Mahatma Gandhi Institute of Medical Sciences

20

aforementioned antigens. The primary mechanism

has been thought to be activation of endothelial
cells, monocytes and platelets by antiphospholipid
antibodies. This leads to increased expression
of adhesion molecules on endothelial cells and
upregulation of tissue factor. Activated platelets also
synthesize thromboxane A2 altering the prostacyclinthromboxane balance to favour thrombosis. In
addition, APL may also impair fibrinolysis and
interefere with the thrombomodulin-protein C-protein
S pathway. The pathogenesis of pregnancy loss in APS
is more complex, and apart from the hypercoagulable
state causing vasculopathy and thrombosis of spiral
arteries of the placenta causing uteroplacental
insufficiency, other mechanisms may also play a role.
These include interference with annexin V (placental
anticoagulant protein), complement activation, the
action of antiphospholipid antibodies directly on the
trophoblast affecting its differentiation and maturation
and finally immunomodulation by activation of toll
like receptor (TLR)4.[2-5]

Criteria for Diagnosis and Classification

of Antiphospholipid Syndrome
The diagnosis of APS is based on the occurrence of
the clinical features of APS in the context of persistent
positivity for antiphospholipid antibodies (APLA).
Classification criteria were initially proposed in 1998
in Sapporo (Japan) and have been widely referred
to as Sapporo criteria.[6] These were subsequently
revised in 2006 and are known as the revised or
Sydney criteria.[7] These were proposed to categorize
patients for research purposes; however, they are also
used to make a definite diagnosis. The presence of
one clinical criterion and one laboratory criterion

Dhir and Pinto: Antiphospholipid syndrome

is essential. [Table1] The revised criteria retain the

fundamental features of the original Sapporo criteria,
but are different in increasing the interval between
repeat testing to 12 weeks and adding antib2GP1 as a
laboratory criterion.

Clinical Features
Like other autoimmune diseases, there is a female
preponderance in APS as well (F:M = 4-5:1). APS
has an onset in the middle aged, i.e 30-40 years old,
although, the Euro-phospholipid cohort had around
10% patients who were older than 50 years and 2.5%
below 15 years of age. Antiphopholipid syndrome
can be a standalone entity (called primary APS)
or it may be associated with other connective tissue
diseases (called secondary APS). Primary APS was
most common (50%) followed by APS associated
with systemic lupus erythematosus (SLE;around
35%) in a large cohort of patients with APS.[8]
Thrombosis is characteristic of this syndrome with
venous thrombosis being most common. Common
manifestations (non-obstetric), at onset, in a large
cohort of 1000 patients (Euro-phospholipid cohort)
were deep venous thrombosis, thrombocytopenia,
livedo reticularis, stroke, pulmonary embolism,
fetal loss and hemolytic anemia. Less common
but nonetheless important clinical features were
pseudovasculitic skin lesions, skin ulcers, myocardial
infarction and digital gangrene.[8] Among the
cumulative manifestations during the evolution of the
disease (initial 5-6 years) the most common was deep
venous thrombosis (38.9%) [Table 2].[8]
Obstetric and fetal complications include early and
late pregnancy losses and pre-eclampsia. Other

Table 1: Revised Sapporo or Sidney criteria for classification of antiphospholipid antibody syndrome

Clinical criteria
The presence of either vascular thrombosisorpregnancy morbidity, is defined as follows:
Vascular thrombosis is defined as one or more episodes of venous, arterial, or small vessel thrombosis, with unequivocal imaging or histologic evidence of
thrombosis in any tissue or organ. Superficial venous thrombosis doesnotsatisfy the criteria for thrombosis for APS.
Pregnancy morbidity is defined as otherwise unexplained fetal death at 10 weeks gestation of a morphologically normal fetus,orone or more premature
births before 34 weeks of gestation because of eclampsia, pre-eclampsia, or placental insufficiency*,orthree or more embryonic (<10 week gestation)
pregnancy losses unexplained by maternal or paternal chromosomal abnormalities or by maternal anatomic or hormonal causes.
*Accepted features of placental insufficiency include: i) abnormal or non-reassuring fetal surveillance tests ii) abnormal Doppler flow velocimetry waveform
analysis suggestive of fetal hypoxemia iii) oligohydramnios iv) postnatal birth weight less than the tenth percentile for the gestational age.
Laboratory criteria
The presence of aPL, on two or more occasions at least 12 weeks apart and no more than five years prior to clinical manifestations, as demonstrated by one
or more of the following:
IgGand/orIgM aCL in moderate or high titer (>40 units GPL or MPL or >99th percentile for the testing laboratory)
Antibodies to 2-glycoprotein I (anti-2GPI) of IgG or IgM isotype at a titer >99th percentile for the testing laboratory when tested according to
recommended procedures
Lupus anticoagulant (LA) activity detected according to guidelines established by international society of Thrombosis and hemostasis.

Journal of Mahatma Gandhi Institute of Medical Sciences

March 2014 | Vol 19 | Issue 1

Dhir and Pinto: Antiphospholipid syndrome

Table 2: Major manifestations of antiphospholipid

syndrome as per the europhospholipid cohort study
Venous thrombosis

Arterial Thrombosis

Obstetric/fetal
manifestations
Deep vein thrombosis
Stroke (19.8%)
Early fetal loss
(38.9%)
(35.4%)
Pulmonary
Myocardial infarction
Late fetal loss
thromboembolism (14.1%) (5.5%)
(16.9%)
Arm vein thrombosis
Arterial thrombosis legs Preterm birth
(3.4%)
(4.3%)
(10.6%)
Subclavian vein thrombosis Arterial thrombosis arms Pre-eclampsia
(1.8%)
(2.7%)
(9.5%)
Jugular vein thrombosis
Digital gangrene (3.3%) Eclampsia (4.4%)
(0.9%)
Cerebral vein thrombosis
Skin gangrene (2.1%)
(0.7%)
Retinal vein thrombosis
(0.9%)

manifestations included premature births, abruptio

placentae and postpartum cardiopulmonary syndrome.
In the europhospholipid cohort, pre-eclampsia and early
fetal loss were the most common complications [Table
2].[8] This was also found in another cohort (EUROAPS)
on 211 women with APS (530 pregnancies) which
found the prevalence of early fetal loss and late fetal
loss to be 43.3% and 32.4%, respectively.[9] Recurrent
miscarriage syndrome (RMS) which is defined as three
or more consecutive miscarriages before mid second
trimester, is an important manifestation of APS. RMS
is not uncommon, occuring in 1 to 3% of women.
Although, the most common cause of RMS is fetal
chromosomal abnormalities,[10] APS is found in 10-15%
of RMS making it an important correctable cause of
the same.[11] APS is even more important for 2nd and 3rd
trimester losses, due to the limited number of causes, and
a study found lupus anticoagulant to be positive in 1/3rd
of the patients with pregnancy loss after 20 weeks.[12]
APS also causes intrauterine growth retardation (IUGR)
due to placental insufficiency and prematurity. Women
with only obstetric manifestations of APS are also at
risk for thrombotic events. In a prospective study, the
risk of thrombosis during pregnancy was 5 percent
among women with known APS (compared with
0.025 to 0.10 percent in the general).[13] The Nimes
Obstetricians and Hematologists study on ladies with
recurrent miscarriages (3 first trimester losses) or late
miscarriages (2nd and 3rd trimester), also found higher
annual incidence of deep vein thrombosis (1.46%) in the
APLA positive women compared to 0.43% in others.[14]
A minority of patients have catastrophic APS; which
is characterized by multiple simultaneous vascular
occlusions occurring in a small span of time, first
March 2014 | Vol 19 | Issue 1

21

described by Asherson in 1992 and hence the eponym

Ashersons syndrome.[15] Manifestations are usually
in the form of cutaneous (skin purpura, necrosis,
splinter hemorrhages), renal failure (requiring
dialysis in some), Pulmonary (ARDS) cardiac
failure and neurologic (seizures and stroke) and
gastrointestinal (mesenteric ischemia). Other unusual
manifestations include focal hepatic necrosis, bonemarrow necrosis, adrenal, splenic infarctions and
polyneuropathy. Large vessel involvement may also
occur concomitantly. Laboratory findings include
thrombocytopenia in a majority (3/4th) which is often
mild to moderate (unlike the severe thrombocytopenia
in thrombocytopenic thrombotic purpura), hemolytic
anemia (1/4th patients), disseminated intravascular
coagulation (1/4th) and occasionally schistocytes.[15]
An important clue in half the patients is the previous
history (in the form of unexplained DVT etc) or
diagnosis of the classical antiphospholipid syndrome
before they present with the catastrophic variant
of the same. The immediate precipitating factor in
catastrophic antiphospholipid syndrome (CAPS)
can be infections, surgery or sudden stoppage of
anticoagulation. Upto 6% of CAPS seems to be
associated with pregnancy and peupeurium; many
starting as HELLP syndrome (defined as hemolysis,
elevated aspartate aminotransferase and low platelets).
In one series, more than half the pregnancies had fetal
or neonatal demise.[16]

Laboratory Findings in
Anti-Phosholipid Syndrome
General

Unlike other autoimmune disease, where even in the

absence of autoantibodies, clinical features alone can be
used to diagnose the disease (like antinuclear antibody
negative SLE), anti-phospholipid syndrome requires
the detection of autoantibodies. However, similar to
other autoimmune diseases, even persistently positive
antibodies are not diagnostic without clinical features. In a
case control study in 73 such women who had persistently
positive antibodies, there was no difference with respect
to pregnancy outcomes compared to controls.[17] Indeed,
positivity of antiphospholipid antibodies may reach upto
10% in some populations and 50% in SLE, most not
manifesting the clinical features of the syndrome.[18]
The three tests included in the classification criteria
are anticardiolipin antibody, anti-b2GP1 antibody and
lupus anticoagulant. These tests are not equal, i.e., they
Journal of Mahatma Gandhi Institute of Medical Sciences

22

have different connotations with respect to prognosis.

A meta-analysis looked at the relationship of the test
positivity and the risk of late (<24 weeks) and early
(<13 weeks) recurrent fetal loss. They found that lupus
anticoagulant had the strongest association with late
recurrent fetal loss (odds ratio 7.8) followed by IgG
anticardiolipin antibody (odds ratio 3.6). There was no
association of fetal loss with anti-b2GP 1.[19]

Anticardiolipin antibody

The anticardiolipin antibody test is perhaps the

most commonly performed test for the detection
of this syndrome. It was first described in 1983 as
a radioimmunoassay and the ELISA format was
established in1985.[20,21] It detects antibodies against
cardiolipin (usually of bovine or human origin), and
is usually done in an ELISA format. It is now believed
that most of the antibodies that the assay actually
detects are those against anti-b2GP1 (a protein bound
to the cardiolipin) and not the cardiolipin itself.[22,23]
The b2GP1 protein is introduced during the procedure
of the ELISA (washing with bovine serum albumin as
a blocking agent). It is usually done for both the IgG
and the IgM subtypes, although in some cases IgA is
also done. The results are reported as GPL and MPL
units, which have been standardized with regard to
how much cardiolipin purified preparations of these
antibodies, will bind. The general trend found in a large
study (Europhospholipid cohort) is that of the total
cases of antiphospholipid syndrome, approximately
90% are anticardiolipin positive, with 45% being
IgG ACL alone, 30% being IgG and IgM ACL both
positive and 15% being IgM positive alone.[8]
Before the Sydney criteria,[6] most laboratories would
report results as low positive (<20 units MPL or GPL),
medium titers (above 20 upto 40 units) and high titers
(more than 40 units); with medium to high titers taken
as positive. However, the Sydney criteria has tried to
increase the specificity of the diagnosis by taking a cut
off of positive of more than 40 units (both MPL and
GPL).[7] However, at the same time, it is recommended
that every laboratory performing this test, defines their
own cutoffs using healthy samples. These tests are
considered positive only if they are persistently found
to be positive even after 12 weeks.

Lupus anticoagulant

The lupus anticoagulant is both a phenomenon and

a test! The phenomenon was the one first recognized
in patients with systemic lupus erythematosus, when
it was seen that they had increased aPTT values but a
Journal of Mahatma Gandhi Institute of Medical Sciences

Dhir and Pinto: Antiphospholipid syndrome

paradoxical thrombosis. The lupus anticoagulant effect

is due to antibodies against a variety of phospholipids
or phospholipid-protein complexex. The phospholipids
these antibodies are directed against include b2GP1,
cardiolipin, prothrombin, annexin V and others. Thus
unlike the anticardiolipin assay and anti-b2GP1
assays which detect the antibodies directly using an
immunoassay like ELISA, this test is a measure of
the functional effect of the antibodies on coagulation
tests. The usual trend in a large study was that 50%
of all patients of antiphopholipid syndrome had lupus
anticoagulant positivity; however, lupus anticoagulant
was the sole positive test in only 10% of these.[8] A
positive lupus anticoagulant as compared to a positive
ACL is associated with the highest risk for thrombosis.
Thus, despite having anti-cardiolipin positivity
satisfying the diagnosis of APS, it is still essential to
go ahead and do a LAC, as the chance of a recurrent
thrombosis goes up substantially if the latter is also
positive.[24]
The most common coagulation tests used to detect
the Lupus anticoagulant are the dilute aPTT and the
dilute Russel viper venom time. The blood sample of
the patient should be taken in an anticoagulant (citrate)
and then centrifuged with a high speed within 4 hours
to get platelet poor plasma. If the coagulation time is
prolonged, then a sequence of steps can help to confirm
the presence of LAC[25,26] [Table 3].

b2GP1 antibody test

The b2GP1 antibody test was a result of the realization

that actually the antibodies against cardiolipin were
recognizing a protein and not the phospholipid.[22,27]
This protein was b2 glycoprotein 1 (b2GP1) and hence
as a corollary to this, efforts were made to develop
tests which directly detected the specific antibody by
coating this protein in ELISA plates. Like the ACL,
here also both IgM and IgG subtypes are tested for
Table 3: The various steps to confirm the presence
ofLupus anticoagulant
Prolongation of a phospholipids-dependent clotting assay: Typically dilute
Russel Viper venom time (DRVVT) or dilute aPTT

Evidence of an inhibitor demonstrated by mixing studies: Typically mix

normal pooled plasma in a 1:1 or similar ratio with the patients sample

Confirmation of the phospholipids-dependent nature of the inhibitor:

Reversal of the prolongation by adding excess phospholipids, which
quench the antiphospholipid antibodies.

Lack of specific inhibition of any coagulation factor

March 2014 | Vol 19 | Issue 1

Dhir and Pinto: Antiphospholipid syndrome

Table 4: Treatment of Anti-phospholipid syndrome

Antiphospholipid syndrome only with obstetric manifestations

Start low dose aspirin before pregnancy
Injection heparin (prophylactic dose*) with low dose aspirin for the
duration of the pregnancy and postpartum till 6 weeks.
*Prophylactic dose = Either unfractionated heparin 5000 IU subcutaneous
BD or fractionated heparin (Inj Enoxaparin 40 mg subcutaneous OD or Inj
Dalteparin 5000 IU subcutaneous OD)
Antiphospholipid syndrome with thrombotic manifestations (Venous
or arterial)
Injection heparin (full anticoagulant dose**) for the initial few days (till
oral anticoagulant starts working)
Oral anticoagulant warfarin/acetocoumarin to achieve INR of 23 to be
continued lifelong***
Low dose aspirin may be added
**Either unfractionated heparin (UFH) or low molecular weight heparin
(LMWH)
UFH as intravenous continuous infusion (Bolus 80 IU followed by 18
Units/Kg/Hour to maintan aPTT to 1.5 to 2x control) or can substitute with
250 IU/kg subcutaneous BD (i.e. around 20-35,000 units of heparin per
day)
LMWH as enoxaparin 1mg/kg BD or dalteparin 100 IU/Kg BD
***warfarin is usually started at 5 mg OD and then adjusted as per INR.
Antiphospholipid syndrome with thrombotic manifestations who
becomes pregnant
Heparin (full dose) with low dose aspirin for pregnancy + postpartum 6
weeks
Shift back to oral anticoagulant warfarin/acetocoumarin to achieve INR
of 23 after pregnancy to be continued lifelong.
**Either unfractionated heparin 250 IU/kg subcutaneous BD (i.e.
around 2025,000 units of heparin per day) or enoxaparin 1mg/kg BD or
dalteparin 100 IU/Kg BD
Catastrophic Antiphospholipid syndrome
Control of inciting event antibiotics, removal of gangrene
Plasma exchange (daily)
Pulse steroids usually injection methylprednisolone 1gram OR
injection dexamethasone 100 mg intravenous in 100 mL normal saline
over 1 hour.
Intravenous immunoglobulins.
Further immunosuppression if there is concomitant active systemic lupus
erythematosus Injection cyclophosphamide 15 mg per Kg body weight
in 1 pint normal saline over 2 hours (at this dose premedication with
mesna may or may not be given). Similarly prehydration may or may not
be given.

and any of them if found to be positive on repeat

testing (at 12 weeks) will constitute a criteria for this
syndrome.
However, despite its initial promise, the test has not
replaced the anticardiolipin antibody test. This is
because of lack of standardization of the test and the
realization that the anticardiolipin test actually was
picking up many other pathogenic antibodies as well,
e.g., those that recognized the protein-phospholipid
complex. Indeed, it has been suggested that 25%
of the cases are picked up extra by anticardiolipin
antibodies that are not picked up using b2GP1 and
LAC.[24]
March 2014 | Vol 19 | Issue 1

23

Non-criteria antibodies

Testing for other antibodies against other

phospholipids namely phosphatidic acid (PA),
phosphatidylserine (PS), phosphatidylinositol (PI),
phosphatidylethanolamine or against phospholipidassociated proteins namely annexin V, prothrombin
etc is currently done in research laboratories and as
of now are not recommended to diagnose APS in the
clinic. Some authors refer to patients having clinical
manifestations with non-standardized antibody test
positive as seronegative APS.[28]

Treatment of Antiphospholipid syndrome

The treatment of antiphospholipid syndrome is
evolving. However, we will endeavour to give the
current treatment protocols along with the evidence for
them. It is important to differentiate a-priori patients
with thrombotic manifestations (venous or arterial)
from those with just obstetric manifestations of APS.

Treatment of a patient with venous or arterial

thrombosis

The treatment strategy consists of anticoagulation of the

patient for life. The patient is usually started on injection
heparin (unfractionated or low molecular weight)
for the initial few days (till oral anticoagulant starts
working) followed by oral anticoagulant (warfarin or
acenocoumarol) to achieve INR of 2-3 to be continued
lifelong. It must be noted that usually the INR is not
affected by APLA per se [Table 4]. This is true for
both venous and arterial thrombosis. Unfractionated
heparin can be given as an infusion or by subcutaneous
injections. Low molecular weight heparin is often
preferred, because of ease of administration, lack of
requirement to adjust aPTT and less risk of heparin
induced thrombocytopenia and osteoporosis.
The drug of choice for oral anticoagulation in APS
till date remains warfarin with dose adjustment to
achieve an INR of 2-3. There is as yet little evidence
that targeting a higher INR leads to better results in
the case of venous thrombosis. This was the subject
of two randomized controlled trials which did not find
targeting a higher INR (3-4) resulted in any better
outcomes, paradoxically there was higher thrombotic
episodes in the latter.[29] However, there has been a
recommendation, based on limited evidence, that in the
case of arterial APS, treatment with a higher INR (>3)
be preferred. However, this remains controversial, with
a difference of opinion among experts.[30] Similarly, the
role of the newer anticoagulants like direct thrombin
Journal of Mahatma Gandhi Institute of Medical Sciences

24

inhibitors (dabigatran etexilate) or direct Xa inhibitors

(rivaroxaban, Apixaban and Edoxaban) which have been
proven in most settings to be equal to warfarin, is still
under scrutiny and as of now cannot replace warfarin
in APS.[31] It is not certain that add-on low dose aspirin
gives any benefit over anticoagulation, however, it has
been recommended in the case of arterial thrombosis.[30]
In patients with ischemic stroke, the APL and stroke
study (APASS), looked at presence of antiphospholipid
antibodies in patients with stroke (single time not
repeated), and found in those with positive APLA, there
was no difference between those treated with aspirin or
warfarin.[32]
Unlike other autoimmune diseases immunomodulatory
drugs have very little role in APS except in catastrophic
APS. Basic research has shown that hydroxychloroquine
reverses platelet activation and directly reduces the
binding of antiphospholipid antibody-2-glycoprotein I
complexes to phospholipid bilayers.[33,34] Observational
studies have found that hydroxychloroquine use is
protective in preventing thrombosis in SLE patients with
aPL positivity.[35] However, its utility in primary APS is
unclear. Another drug that deserves mention is rituximab,
a chimeric monoclonal antibody directed against
CD20, which has been used in APS not responding
to conventional anticoagulation, thrombocytopenia
associated with APS and in catastrophic APS.[36,37] Finally,
risk factor modification in patients with traditional
cardiovascular risk factors should be undertaken. Statins
may have a direct benefit in antiphospholipid syndrome
by decreasing tissue factor production and endothelial
adhesiveness induced by aPL antibodies, however, they
are not currently part of the routine management.[38]

Treatment of antiphospholipid syndrome

inpregnancy

In patients with just obstetric complications (never had

thrombosis), the current recommendation is treatment
with heparin and low dose aspirin for the duration of the
pregnancy and postpartum till 6 weeks. Importantly, the
dose used in this case is equivalent to the prophylactic
doses of these agents. It has also been recommended
that low dose aspirin be started pre-conceptionally in
these women. Despite treatment, there remains a failure
rate of 20-30%.[39-41] The major trials looking therapy in
patients with just obstetric complications of APS have
been the subject of some criticism. Rai et al., compared
aspirin alone to aspirin with unfractionated heparin and
found the latter to be better in leading to a successful
pregnancy (71% versus 42%). However, a majority of
patients in this study had recurrent fetal losses before
Journal of Mahatma Gandhi Institute of Medical Sciences

Dhir and Pinto: Antiphospholipid syndrome

10 weeks (63%), and anticardiolipin positivity was

low.[42] In contrast, Farquharson et al., did not find any
difference in successful pregnancies comparing low
dose aspirin alone compared to dalteparin (fractionated
heparin) with low dose aspirin (72% versus 78%).[43]
Studies that have just looked at aspirin monotherapy
versus no therapy have found no benefit of aspirin
alone.[44,45]
In women who have already suffered a thrombotic
event (with or without an obstetric complication), the
therapeutic approach differs and includes full dose
anticoagulation with heparin during pregnancy.[46]
Warfarin although teratogenic has been tried in a small
study in women between 15-34 weeks period of
gestation without harm.[47] Another drug, which deserves
a mention, is steroids, which currently has no role
in the management of APS in pregnancy. Studies on
oral steroids did not find them to be efficacious in
addition to aspirin with or without heparin; on the
contrary, they were associated with more prematurity
and hypertension.[48,49] However, some recent reports
of low dose steroids have suggested benefit on
use in first trimester in refractory obstetric APS.[50]
Intravenous immunoglobulins have also been tried in
refractory patients with antiphospholipid syndrome.[51]
The role of newer anticoagulants like fondaparinux
(pentasaccharide which inhibits Xa) is unclear.

Treatment of asymptomatic aPL carriers

The role of aspirin to prevent thrombosis in

asymptomatic aPL positive patients and obstetric
complications is controversial. Only one randomized
trial examined the efficacy of aspirin in asymptomatic
APS carriers. This study used 81 mg of aspirin and
after a mean duration of followup of 2.30 0.95 years
found no benefit of aspirin. However, a recent metaanalysis which included 11 studies (10 observational
and 1 interventional) with 1208 patients found that
low dose aspirin reduced the risk of first thrombosis
in aPL positive asymptomatic subjects and those with
SLE.[52] It may be prudent to prescribe aspirin to those
with high risk such as patients with triple positivity and
with additional cardiovascular risk factors.

Treatment of the catastrophic

antiphospoholipid syndrome

The catastrophic antiphospholipid syndrome requires a

multi-pronged strategy that deals with the inciting event
(antibiotics for any infection), removal of the plasma
mediators of inflammation as well as antiphospholipid
antibodies (plasma exchange), pharmacologic control
March 2014 | Vol 19 | Issue 1

Dhir and Pinto: Antiphospholipid syndrome

of inflammatory cascade (pulse steroids or intravenous

immunoglobulins other immunosuppressants like
cyclophosphamide especially in case of associated
systemic lupus), and finally anticoagulation. The
removal of necrotic tissues (like finger/toe amputations)
may help to quell thrombotic storm. Plasma exchange
(daily) is widely considered to be the most effective
treatment. In one study, the survival of patients using
the multimodal therapy was 70%, indicating that
early aggressive intervention may lead to reasonable
outcomes.[15]

Prognosis
Most patients of APS with thrombosis do well on
anticoagulation. In the five year follow up of the
europhosholipid cohort in which patients were on oral
anticoagulation, only 2.1% developed new DVT, 2.4%
developed new strokes and 2.3% developed new transient
ischemic attacks.[53] However, untreated, a majority of
patients with APS will have recurrent thrombosis in the
next 5 years. The prognosis of patients with pregnancy
morbidity was also fairly good in the europhospholipid
cohort with 74% having successful pregnancies at study
entry which increased to 81.8% in the five year followup. The overall mortality was 5.3%.[53]

Conclusions
The antiphospholipid syndrome is an enigmatic
autoimmune disease with newer manifestations
being recognized on an ongoing basis. The current
classification criteria (Sydney 2006) which require
the presence of one clinical and one laboratory criteria
are used in diagnosis. Treatment includes lifelong
anticoagulation in a case of thrombosis, whereas for
isolated obstetric APS, prophylactic heparin is given
in pregnancy. Low dose aspirin is often added to both
regimens. APS remains an exciting area for research
and encompasses all areas of medicine presenting as
young stroke to a neurologist, venous thrombosis to
an internist, poor obstetric history to an obstetrician,
valvular disease or myocardial infarctions to a
cardiologist.

References
1. Hughes GR, Asherson RA, Khamashta MA. Antiphospholipid
syndrome: Linking many specialties. Ann Rheum Dis
1989;48:355-6.
2. Giannakopoulos B, Passam F, Rahgozar S, Krilis SA. Current
concepts on the pathogenesis of the antiphospholipid
syndrome. Blood 2007;109:422-30.

March 2014 | Vol 19 | Issue 1

25
3. de Laat B, Mertens K, de Groot PG. Mechanisms of disease:
Antiphospholipid antibodies-from clinical association to
pathologic mechanism. Nat Clin Pract Rheumatol 2008;4:1929.
4. Baker WF Jr, Bick RL, Fareed J. Controversies and unresolved
issues in antiphospholipid syndrome pathogenesis and
management. Hematol Oncol Clin North Am 2008;22:155-74,
viii.
5. Kwak-Kim J, Agcaoili MS, Aleta L, Liao A, Ota K, Dambaeva S,
etal. Management of women with recurrent pregnancy losses
and antiphospholipid antibody syndrome. Am J Reprod
Immunol 2013;69:596-607.
6. Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch
DW, Piette JC, et al. International consensus statement on
preliminary classification criteria for definite antiphospholipid
syndrome: Report of an international workshop. Arthritis
Rheum 1999;42:1309-11.
7. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey
RL, CerveraR, et al. International consensus statement
on an update of the classification criteria for definite
antiphospholipid syndrome (APS). J Thromb Haemost
2006;4:295-306.
8. Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld
Y, CampsMT, et al. Euro-Phospholipid Project Group.
Antiphospholipid syndrome: Clinical and immunologic
manifestations and patterns of disease expression in a cohort
of 1,000 patients. Arthritis Rheum 2002;46:1019-27.
9. Alijotas-Reig J, Ferrer-Oliveras R. EUROAPS Study Group.
The European Registry on Obstetric Antiphospholipid
Syndrome (EUROAPS): A preliminary first year report. Lupus
2012;21:766-8.
10. Alijotas-Reig J, Garrido-Gimenez C. Current concepts and
new trends in the diagnosis and management of recurrent
miscarriage. Obstet Gynecol Surv 2013;68:445-66.
11. Rai RS, Regan L, Clifford K, Pickering W, Dave M, Mackie I,
et al. Antiphospholipid antibodies and beta 2-glycoprotein-I
in 500 women with recurrent miscarriage: Results of
a comprehensive screening approach. Hum Reprod
1995;10:2001-5.
12. Drakeley AJ, Quenby S, Farquharson RG. Mid-trimester loss
appraisal of a screening protocol. Hum Reprod 1998;13:197580.
13. Branch DW, Silver RM, Blackwell JL, Reading JC, Scott
JR. Outcome of treated pregnancies in women with
antiphospholipid syndrome: An update of the Utah
experience. Obstet Gynecol 1992;80:614-20.
14. Gris JC, Bouvier S, Molinari N, Galanaud JP, CocheryNouvellon E, Mercier E, et al. Comparative incidence of a
first thrombotic event in purely obstetric antiphospholipid
syndrome with pregnancy loss: The NOH-APS observational
study. Blood 2012;119:2624-32.
15. Merrill JT, Asherson RA. Catastrophic antiphospholipid
syndrome. Nat Clin Pract Rheumatol 2006;2:81-9.
16. Hanouna G, Morel N, Le Thi Huong D, Josselin L, VauthierBrouzesD, Saadoun D, et al. Catastrophic antiphospholipid
syndrome and pregnancy: An experience of 13 cases.
Rheumatology (Oxford) 2013;52:1635-41.
17. Soh MC, Pasupathy D, Gray G, Nelson-Piercy C. Persistent
antiphospholipid antibodies do not contribute to
adverse pregnancy outcomes. Rheumatology (Oxford)
2013;52:1642-7.

Journal of Mahatma Gandhi Institute of Medical Sciences

26
18. Vila P, Hernandez MC, Lopez-Fernandez MF, Batlle J.
Prevalence, follow-up and clinical significance of the
anticardiolipin antibodies in normal subjects. Thromb
Haemost 1994;72:209-13.
19. Opatrny L, David M, Kahn SR, Shrier I, Rey E. Association
between antiphospholipid antibodies and recurrent fetal
loss in women without autoimmune disease: A metaanalysis.
J Rheumatol 2006;33:2214-21.
20. Harris EN, Gharavi AE, Boey ML, Patel BM, MackworthYoungCG, Loizou S, et al. Anticardiolipin antibodies: Detection
by radioimmunoassay and association with thrombosis in
systemic lupus erythematosus. Lancet 1983;2:1211-4.
21. Harris EN, Gharavi AE, Wasley GD, Hughes GR. Use of an
enzyme-linked immunosorbent assay and of inhibition
studies to distinguish between antibodies to cardiolipin from
patients with syphilis or autoimmune disorders. J Infect Dis
1988;157:23-31.
22. Galli M, Comfurius P, Maassen C, Hemker HC, de Baets MH,
van Breda-Vriesman PJ, et al. Anticardiolipin antibodies
(ACA) directed not to cardiolipin but to a plasma protein
cofactor. Lancet 1990;335:1544-7.
23. Matsuura E, Igarashi Y, Fujimoto M, Ichikawa K, Koike T.
Anticardiolipin cofactor(s) and differential diagnosis of
autoimmune disease. Lancet 1990;336:177-8.
24. Tincani A, Filippini M, Scarsi M, Galli M, Meroni PL. European
attempts for the standardisation of the antiphospholipid
antibodies. Lupus 2009;18:913-9.
25. Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, et al.
Update of the guidelines for lupus anticoagulant detection.
Subcommittee on Lupus Anticoagulant/Antiphospholipid
Antibody of the Scientific and Standardisation Committee
of the International Society on Thrombosis and
Haemostasis. J tThromb Haemost 2009;7:1737-40.
26. Hoppensteadt DA, Fabbrini N, Bick RL, Messmore HL, Adiguzel
C, Fareed J. Laboratory evaluation of the antiphospholipid
syndrome. Hematol Oncol Clin North Am 2008;22:19-32.
27. McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Antiphospholipid antibodies are directed against a complex
antigen that includes a lipid-binding inhibitor of coagulation:
Beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U
S A 1990;87:4120-4.
28. Nayfe R, Uthman I, Aoun J, Saad Aldin E, Merashli M,
Khamashta MA. Seronegative antiphospholipid syndrome.
Rheumatology (Oxford) 2013;52:1358-67.
29. Pengo V, Denas G, Banzato A, Bison E, Bracco A, Facchinetti M,
et al. Secondary prevention in thrombotic antiphospholipid
syndrome. Lupus 2012;21:734-5.
30. Les I, Ruiz-Irastorza G, Khamashta MA. Intensity and duration
of anticoagulation therapy in antiphospholipid syndrome.
Semin Thromb Hemost 2012;38:339-47.
31. Arachchillage DJ, Cohen H. Use of new oral anticoagulants
in antiphospholipid syndrome. Curr Rheumatol Rep
2013;15:331.
32. Levine SR, Brey RL, Tilley BC, Thompson JL, Sacco RL, Sciacca
RR, et al. APASS Investigators. Antiphospholipid antibodies
and subsequent thrombo-occlusive events in patients with
ischemic stroke. JAMA 2004;291:576-84.
33. Rand JH, Wu XX, Quinn AS, Chen PP, Hathcock JJ, Taatjes
DJ. Hydroxychloroquine directly reduces the binding of
antiphospholipid antibody-beta2-glycoprotein I complexes
to phospholipid bilayers. Blood 2008;112:1687-95.

Journal of Mahatma Gandhi Institute of Medical Sciences

Dhir and Pinto: Antiphospholipid syndrome

34. Espinola RG, Pierangeli SS, Gharavi AE, Harris EN.
Hydroxychloroquine reverses platelet activation induced by
human IgG antiphospholipid antibodies. Thromb Haemost
2002;87:518-22.
35. Tektonidou MG, Laskari K, Panagiotakos DB, Moutsopoulos
HM. Risk factors for thrombosis and primary thrombosis
prevention in patients with systemic lupus erythematosus
with or without antiphospholipid antibodies. Arthritis
Rheum 2009;61:29-36.
36. Kumar D, Roubey RA. Use of rituximab in the antiphospholipid
syndrome. Curr Rheumatol Rep 2010;12:40-4.
37. Erkan D, Vega J, Ramon G, Kozora E, Lockshin MD. A pilot
open-label phase II trial of rituximab for non-criteria
manifestations of antiphospholipid syndrome. Arthritis
Rheum 2013;65:464-71.
38. Lopez-Pedrera C, Ruiz-Limon P, Aguirre MA, RodriguezAriza A, Cuadrado MJ. Potential use of statins in the
treatment of antiphospholipid syndrome. Curr Rheumatol
Rep 2012;14:87-94.
39. Ruiz-Irastorza G, Khamashta MA. Antiphospholipid syndrome
in pregnancy. Rheum Dis Clin North Am 2007;33:287-97.
40. Petri M, Qazi U. Management of antiphospholipid syndrome
in pregnancy. Rheum Dis Clin North Am 2006;32:591-607.
41. Empson M, Lassere M, Craig J, Scott J. Prevention of
recurrent miscarriage for women with antiphospholipid
antibody or lupus anticoagulant. Cochrane Database Syst Rev
2005:CD002859.
42. Rai R, Cohen H, Dave M, Regan L. Randomised controlled
trial of aspirin and aspirin plus heparin in pregnant women
with recurrent miscarriage associated with phospholipid
antibodies (or antiphospholipid antibodies). BMJ
1997;314:253-7.
43. Farquharson RG, Quenby S, Greaves M. Antiphospholipid
syndrome in pregnancy: A randomized, controlled trial of
treatment. Obstet Gynecol 2002;100:408-13.
44. Cowchock S, Reece EA. Do low-risk pregnant women with
antiphospholipid antibodies need to be treated? Organizing
Group of the Antiphospholipid Antibody Treatment Trial. Am
J Obstet Gynecol 1997;176:1099-100.
45. Pattison NS, Chamley LW, Birdsall M, Zanderigo AM, Liddell
HS, McDougall J. Does aspirin have a role in improving
pregnancy outcome for women with the antiphospholipid
syndrome? A randomized controlled trial. Am J Obstet
Gynecol 2000;183:1008-12.
46. Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J. Venous
thromboembolism, thrombophilia, antithrombotic therapy,
and pregnancy: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines, 8th ed. Chest
2008;133(6 Suppl):844-86S.
47. Pauzner R, Dulitzki M, Langevitz P, Livneh A, Kenett R,
Many A. Low molecular weight heparin and warfarin in
the treatment of patients with antiphospholipid syndrome
during pregnancy. Thromb Haemost 2001;86:1379-84.
48. Silver RK, MacGregor SN, Sholl JS, Hobart JM, Neerhof
MG, Ragin A. Comparative trial of prednisone plus aspirin
versus aspirin alone in the treatment of anticardiolipin
antibody-positive obstetric patients. Am J Obstet Gynecol
1993;169:1411-7.
49. Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L.
Repeated fetal losses associated with antiphospholipid
antibodies: A collaborative randomized trial comparing

March 2014 | Vol 19 | Issue 1

Dhir and Pinto: Antiphospholipid syndrome

prednisone with low-dose heparin treatment. Am J Obstet
Gynecol 1992;166:1318-23.
50. Bramham K, Thomas M, Nelson-Piercy C, Khamashta M,
Hunt BJ. First-trimester low-dose prednisolone in refractory
antiphospholipid antibody-related pregnancy loss. Blood
2011;117:6948-51.
51. Kwak JY, Quilty EA, Gilman-Sachs A, Beaman KD, Beer AE.
Intravenous immunoglobulin infusion therapy in women
with recurrent spontaneous abortions of immune etiologies.
J Reprod Immunol 1995;28:175-88.
52. Arnaud L, Mathian A, Ruffatti A, Erkan D, Tektonidou M,
Cervera R, et al. Efficacy of aspirin for the primary prevention

27
of thrombosis in patients with antiphospholipid antibodies:
An international and collaborative meta-analysis. Autoimmun
Rev 2013.
53. Cervera R, Boffa MC, Khamashta MA, Hughes GR. The EuroPhospholipid project: Epidemiology of the antiphospholipid
syndrome in Europe. Lupus 2009;18:889-93.

How to cite this article: Dhir V, Pinto B. Antiphospholipid syndrome:

A review. J Mahatma Gandhi Inst Med Sci 2014;19:19-27.
Source of Support: Nil, Conflict of Interest: None declared.

Author Help: Online submission of the manuscripts

Articles can be submitted online from http://www.journalonweb.com. For online submission, the articles should be prepared in two files (first
page file and article file). Images should be submitted separately.
1) First Page File:

Prepare the title page, covering letter, acknowledgement etc. using a word processor program. All information related to your identity should
be included here. Use text/rtf/doc/pdf files. Do not zip the files.
2) Article File:

The main text of the article, beginning with the Abstract to References (including tables) should be in this file. Do not include any information
(such as acknowledgement, your names in page headers etc.) in this file. Use text/rtf/doc/pdf files. Do not zip the files. Limit the file size
to 1024 kb. Do not incorporate images in the file. If file size is large, graphs can be submitted separately as images, without their being
incorporated in the article file. This will reduce the size of the file.
3) Images:

Submit good quality color images. Each image should be less than 4096 kb (4 MB) in size. The size of the image can be reduced by decreasing
the actual height and width of the images (keep up to about 6 inches and up to about 1800 x 1200 pixels). JPEG is the most suitable file
format. The image quality should be good enough to judge the scientific value of the image. For the purpose of printing, always retain a good
quality, high resolution image. This high resolution image should be sent to the editorial office at the time of sending a revised article.
4) Legends:

Legends for the figures/images should be included at the end of the article file.

March 2014 | Vol 19 | Issue 1

Journal of Mahatma Gandhi Institute of Medical Sciences