VOLUME 47 : NUMBER 6 : DECEMBER 2024

ARTICLE

Diagnosis and management of

antiphospholipid syndrome
Yeri Ahn
SUMMARY Staff Specialist in
Immunopathology and
Antiphospholipid syndrome is an autoimmune disease characterised by thrombotic and/or Clinical Immunology1
obstetric manifestations with persistent antiphospholipid antibodies. Clinical Lecturer2

Diagnosis involves confirming the persistence of antiphospholipid antibodies in symptomatic Carolyn Hawkins
patients, using validated classification criteria as a guide. The likelihood of obtaining false- Senior Staff Specialist in
Immunopathology and
positive or false-negative test results in certain settings, and the lack of standardisation between
Clinical Immunology1
laboratory methods, are important considerations.
Clinical Associate Professor2
Patients who have had thrombotic manifestations require lifelong anticoagulation from the first Eliza Pearson
thrombotic event, typically with warfarin. Patients with a history of thrombotic and/or obstetric Chief Medical Registrar and
manifestations who become pregnant should receive low-molecular-weight heparin and low-dose Rheumatology Advanced
aspirin during pregnancy and postpartum. Trainee3
Paul Kubler
Testing asymptomatic people is not recommended, except in the context of systemic lupus
Director of Rheumatology3
erythematosus. Management of asymptomatic people with persistent antiphospholipid antibodies
Senior Lecturer4
depends on their individual antibody profile and risk factors.
1
Canberra Hospital
2
School of Medicine and
Introduction interpreting these results in the context of the
Psychology, Australian
patient’s clinical presentation, using validated
Antiphospholipid syndrome (APS) is a rare, National University,
classification criteria as a guide. Canberra
multisystem autoimmune disorder that is
characterised by thrombotic and/or obstetric Clinical manifestations
3
Royal Brisbane and
manifestations with persistent antiphospholipid Women’s Hospital
antibodies. It has an estimated prevalence of 17 to Thrombotic manifestations 4
Faculty of Medicine, The
50 per 100,000 population.1,2 Venous thromboembolism resulting in deep University of Queensland,
Brisbane
APS may occur as a primary autoimmune disorder vein thrombosis is the most common presenting
(53 to 59% of people with APS),3,4 or as a secondary manifestation of APS, affecting approximately 32%
of people with APS. Pulmonary embolism occurs in Keywords
condition in association with an autoimmune
anticoagulants,
connective tissue disease, most commonly systemic approximately 9% of people with APS.5
antiphospholipid antibodies,
lupus erythematosus (SLE), but also systemic Arterial thromboembolism secondary to APS antiphospholipid syndrome,
sclerosis, primary Sjögren syndrome and rheumatoid most commonly presents as stroke, representing fetal death, thrombosis
arthritis.3 Patients with APS usually require tertiary around 13% of first presentations of APS. Transient
care as part of a multidisciplinary team to optimise ischaemic attack is also a common first presentation Aust Prescr 2024;47:179–85
patient management. (approximately 7%).5 APS may also be associated with https://doi.org/10.18773/
This article aims to provide an overview of APS rare stroke syndromes, such as cerebral venous sinus austprescr.2024.055
diagnosis, including common clinical manifestations, thrombosis. Other possible arterial thromboembolic
the role and limitations of antiphospholipid manifestations are acute myocardial infarction, acute
lower limb ischaemia, avascular necrosis of bone,
antibody testing, and the updated APS classification
mesenteric infarction and renal vessel occlusion.6
criteria. Management of clinical manifestations and
asymptomatic people with persistent antiphospholipid Microvascular thrombosis secondary to APS can
antibodies is also discussed. result in acute and chronic antiphospholipid antibody
nephropathy, adrenal and pulmonary haemorrhage,
Diagnosis and myocardial disease. Cutaneous manifestations
Patients are usually investigated for APS following including lower limb ulceration, subungual splinter
the occurrence of a suggestive clinical manifestation. haemorrhages and livedo racemosa (a violaceous
Confirming the diagnosis involves testing for the branching and non-continuous discolouration of the
persistence of antiphospholipid antibodies and skin) can also occur.7,8

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ARTICLE Diagnosis and management of antiphospholipid syndrome

Catastrophic APS is a rare, life-threatening and anti-beta2-glycoprotein I, the immunoglobulin G

presentation in people with thrombotic manifestations (IgG) isotype confers a higher risk than the
of APS, whereby microvascular or small-vessel immunoglobulin M (IgM) isotype.14
thrombosis leads to concurrent multiorgan Some people may test positive for more than one
dysfunction (e.g. acute kidney injury, mesenteric antibody. Individuals with double antibody positivity
ischaemia, myocardial infarction). It should be are considered to have a high-risk antibody profile.
suspected in patients with thrombosis with 2 or Triple-positive APS, defined as the persistence of all 3
more organs concurrently involved; involvement of antibodies, confers the highest risk for development
3 organs concurrently is diagnostic. Catastrophic of thrombotic and obstetric manifestations.21,22
APS most commonly occurs when there has
been an interruption to or a change in long-term Indications for testing
anticoagulation in patients with known APS (e.g. in Testing for antiphospholipid antibodies should be
the perioperative period; in concomitant inflammatory limited to patients in whom there is a high clinical
states such as infection, surgery or malignancy).4 suspicion of APS. Testing may be warranted
in younger individuals (especially those under
Obstetric manifestations
50 years) who present with unexplained venous
Early and late obstetric manifestations, such as thromboembolism or arterial thrombosis (e.g.
fetal loss, pre-eclampsia or placental insufficiency, ischaemic stroke, transient ischaemic attack, acute
are possible sequelae of APS. In a study among myocardial infarction). Testing may also be indicated
pregnant women with APS-related complications, in those with adverse pregnancy outcomes such
the most common complication in the mother was as recurrent early fetal losses, or one or more fetal
pre-eclampsia (9.5%). Early fetal loss occurred in deaths later in pregnancy.23
approximately 35% of pregnancies and late fetal loss
Screening for antiphospholipid antibodies in
in 17% of pregnancies. Approximately 11% of live births
asymptomatic individuals is not recommended,
were premature.5 There is also an increased risk of
including in those with a family history of APS, or
maternal venous thromboembolism in APS.
who are pregnant or planning pregnancy. This is to
Other clinical manifestations avoid incidental findings which can lead to patient
anxiety and unnecessary treatment.23 The exception
Valvular heart disease with cardiac valve thickening
to this is people with SLE. Antiphospholipid antibodies
(with occasional significant valve masses) resulting in
are present in 20 to 30% of patients with SLE and
regurgitation (Libman–Sacks endocarditis) is the most
may lead to increased risk of thrombotic or obstetric
common cardiac manifestation.9
manifestations. Antibody testing in patients with
Mild to moderately severe thrombocytopenia is the
SLE can be considered, especially in those who are
most common haematological manifestation of APS.
pregnant or planning pregnancy, and in the context of
An uncommon manifestation is haemolytic anaemia,
other factors that increase the risk of thrombosis such
which can occur either secondary to thrombotic
as commencing estrogen-containing contraception.3,24
microangiopathy or with an autoimmune association.5
Potential pitfalls of testing
Antiphospholipid antibodies
When ordering antiphospholipid antibody tests or
As thrombotic and obstetric manifestations are not
interpreting test results, there are potential pitfalls
unique to APS, reliable confirmation of persistent
that should be considered (Table 2).
antiphospholipid antibodies is crucial for accurate
diagnosis. Antiphospholipid antibodies encompass Classification criteria
a heterogeneous group of immunoglobulins that Classification criteria for APS were developed to
bind phospholipids, phospholipid-binding plasma identify homogeneous patient cohorts for clinical
proteins and phospholipid–protein complexes at cell studies; however, they can be helpful in practice
surfaces. They activate the endothelium, platelets to guide diagnosis. Classification criteria outlining
and leucocytes, which promotes thrombotic and clinical manifestations and laboratory criteria were
inflammatory complications.10-12 initially proposed in 1998, then updated in 2006.30 The
The 3 commonly tested antiphospholipid antibodies American College of Rheumatology and European
are anticardiolipin, anti‑beta2-glycoprotein I and Alliance of Associations for Rheumatology published
lupus anticoagulant (Table 1). Of all 3 antibodies, a further update in 2023 to capture advancements in
a persistently positive lupus anticoagulant carries the understanding of APS and address limitations of
the highest risk for developing future clinical the 2006 criteria, such as the lack of evidence-based
manifestations.19,20 With regard to anticardiolipin definitions for individual manifestations.7

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The 2023 classification criteria apply weighting to

Table 1 Description of commonly tested antiphospholipid
individual criteria and have a higher specificity (99%)
antibodies
but lower sensitivity (86%) compared with the 2006
criteria. According to the 2023 criteria, patients can Antiphospholipid Description
be classified as having APS if they score at least antibody
3 points from the clinical criteria and 3 points from the Anticardiolipin These antibodies target cardiolipin, an anionic phospholipid
laboratory criteria, with at least one clinical criterion antibodies component of the inner mitochondrial membrane.
and one laboratory criterion present within 3 years of (IgG or IgM) Nonpathological anticardiolipin antibodies (associated with a
each other (Table 3).7 lower risk of thrombosis) can be transiently produced at low
titres in response to infection, some autoimmune diseases
The 2023 classification criteria specify anticardiolipin and
and malignancy.13
anti-beta2-glycoprotein I antibody titres as measured
IgG antibodies are more strongly correlated with thrombosis
by enzyme-linked immunosorbent assay; however, in
than IgM antibodies.14
practice, many laboratories in Australia employ other
analytical methods with differing cut-off values. Given Anti-beta2- These antibodies target beta2-glycoprotein I, a phospholipid-
glycoprotein I binding protein that acts as a naturally occurring inhibitor of
this, there are challenges in directly applying the
antibodies platelet aggregation in plasma and inhibits contact activation
laboratory classification criteria to all test results and (IgG or IgM) of the coagulation cascade.15
results may be incomparable between laboratories. IgG antibodies have been strongly associated with thrombotic
events; IgM antibodies have less clinical relevance.14,16,17
Management
Lupus Lupus anticoagulant is not a single antibody itself, but refers
Patients with thrombotic manifestations anticoagulant to a collection of antibodies that interfere with phospholipid-
In patients with persistent antiphospholipid dependent coagulation.18
antibodies, the first thrombotic episode would confirm A persistently positive lupus anticoagulant carries the highest
the diagnosis of APS. These patients should be initially risk for developing future clinical manifestations compared with
anticardiolipin and anti-beta2-glycoprotein I antibodies.19,20
treated with standard therapeutic anticoagulation
(i.e. subcutaneous low-molecular-weight heparin or
IgG = immunoglobulin G; IgM = immunoglobulin M
intravenous unfractionated heparin).31
Secondary prophylaxis with warfarin is required
lifelong from the first thrombotic episode, with a
target INR of 2 to 3. Some patients may require Table 2 Potential pitfalls of antiphospholipid antibody
a higher target INR (e.g. recurrent venous testing and practical considerations
thromboembolism despite an INR of 2 to 3).31
Potential pitfall of testing Practical considerations
Direct-acting oral anticoagulants (DOACs)
Non-persistence of Antiphospholipid antibodies may be transiently present
(e.g. rivaroxaban, apixaban) are not appropriate
antiphospholipid antibodies in individuals without APS. 25 To reduce the likelihood
for secondary prophylaxis as the rate of recurrent of a false-positive result, a follow-up test should be
thromboembolism with DOACs is significantly higher performed at least 12 weeks after the initial test to
than with warfarin in patients with APS.32,33 However, confirm persistence of antibody positivity.
DOACs may be considered in patients who are unable False-negative and false- False-positive results can occur because of transient
to achieve target INR, unable to adhere to regular positive results anticardiolipin antibodies during infection, some
INR monitoring, or who have contraindications to autoimmune diseases and malignancy. 26
warfarin.31 In patients with a low risk of APS (e.g. low- Immunoglobulin infusions, plasmapheresis or
titre antibody positivity with single thrombotic event antibody‑depleting therapy can interfere with
in the context of provoking factors), it is unclear if antibody titres. 23

warfarin remains superior to DOACs. Vitamin K antagonists (e.g. warfarin) have been
associated with both false-positive and false-negative
If subsequent thrombotic episodes occur despite results for lupus anticoagulant. 23
therapeutic anticoagulation with warfarin, the addition Direct-acting oral anticoagulants can interfere with
of an antiplatelet drug such as low-dose aspirin or lupus anticoagulant testing and produce false-positive
dipyridamole should be considered.34 results, even at low doses. 23
For management of a patient with thrombotic Lack of standardisation of Methods for detection of antiphospholipid antibodies
manifestations who becomes pregnant, see below. antibody tests (in particular anticardiolipin and anti-beta2-
glycoprotein I antibodies), diagnostic cut-offs and
Patients with obstetric manifestations normal reference ranges differ between laboratories.
People with APS who plan to conceive are Therefore, it can be difficult to apply titre cut-offs
specified in classification criteria and inaccurate to
recommended to receive preconception assessment,
compare results from different laboratories. 27-29
including counselling on the increased risk of adverse

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Table 3 Summary of 2023 classification criteria for antiphospholipid syndrome7 [NB1]

Clinical criteria Points

Macrovascular manifestations [NB2]
Venous thromboembolism:
• with high-risk venous thromboembolism profile 1
• without high-risk venous thromboembolism profile 3

Arterial thrombosis:
• with high-risk cardiovascular disease profile 2
• without high-risk cardiovascular disease profile 4

Microvascular manifestations
One or more of the following suspected: 2
• livedo racemosa (examination)
• livedoid vasculopathy lesions (examination)
• acute or chronic antiphospholipid antibody nephropathy (examination or laboratory results)
• pulmonary haemorrhage (symptoms or imaging)

One or more of the following established: 5

• livedoid vasculopathy (pathology)
• acute or chronic antiphospholipid antibody nephropathy (pathology)
• pulmonary haemorrhage (bronchoalveolar lavage or pathology)
• myocardial disease (imaging or pathology)
• adrenal haemorrhage (imaging or pathology)

Obstetric manifestations
• 3 or more consecutive prefetal (less than 10 weeks) and/or early (from 10 weeks to 15 weeks and 6 days) fetal deaths 1
• fetal death (from 16 weeks to 33 weeks and 6 days) without pre-eclampsia or placental insufficiency with 1
severe features
• pre-eclampsia or placental insufficiency with severe features (less than 34 weeks) with or without fetal death 3
• pre-eclampsia and placental insufficiency with severe features (less than 34 weeks) with or without fetal death 4

Other clinical manifestations

• cardiac valve thickening 2
• cardiac valve vegetation 4
• thrombocytopenia 2

Laboratory criteria [NB3][NB4]

• positive lupus anticoagulant (single, one time) 1
• positive lupus anticoagulant (persistent) 5
• moderate or high positive IgM antibodies to anticardiolipin and/or anti-beta2-glycoprotein I (persistent) 1
• moderate positive IgG antibodies to anticardiolipin and/or anti-beta2-glycoprotein I (persistent) 4
• high positive IgG antibodies to anticardiolipin or anti-beta2-glycoprotein I (persistent) 5
• high positive IgG antibodies to anticardiolipin and anti-beta2-glycoprotein I (persistent) 7

IgG = immunoglobulin G; IgM = immunoglobulin M

NB1: A person is classified as having antiphospholipid syndrome if they score at least 3 points from the clinical criteria
and at least 3 points from the laboratory criteria, with at least one clinical criterion and one laboratory criterion present
within 3 years of each other.
NB2: Determination of the risk of venous thromboembolism and cardiovascular disease is based on general population
guidelines – refer to full classification criteria.7
NB3: Persistence of antiphospholipid antibodies is defined as positive laboratory results on 2 occasions, at least
12 weeks apart.
NB4: The classification criteria specify antibody titres as measured by coagulation-based functional assay (for lupus
anticoagulant) and enzyme-linked immunosorbent assay (for anticardiolipin and anti-beta2-glycoprotein I antibodies).
Adapted from Barbhaiya M, Zuily S, Naden R, Hendry A, Manneville F, Amigo MC, et al. The 2023 ACR/EULAR
Antiphospholipid Syndrome Classification Criteria. Arthritis Rheumatol 2023;75:1687-702. https://doi.org/10.1002/art.42624

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maternal and fetal outcomes and how these risks antibody positive on the initial test, a follow-up test is
may impact the perceived benefits of having a child. recommended to confirm antibody persistence.
After pregnancy is confirmed, these patients should Asymptomatic people with persistent
be referred to an obstetrician or obstetric medicine antiphospholipid antibodies do not have a diagnosis
physician as their situation would be considered a of APS; however, management may be required
high-risk pregnancy. All patients with SLE, especially based on an assessment of the individual’s risk of
those with persistent antiphospholipid antibodies, developing future clinical manifestations. Their risk
should also be encouraged to discuss plans for is informed by their individual antibody profile,
conception with their treating specialist. coexistence of other systemic autoimmune diseases
If a patient with a history of obstetric manifestations such as SLE, and the presence of thromboembolic
(but no history of thrombotic manifestations) becomes and cardiovascular risk factors.31 All people with
pregnant, both prophylactic-dose low-molecular- persistent antiphospholipid antibodies should be
weight heparin and low-dose aspirin are recommended educated on the relevance of antiphospholipid
for the duration of the pregnancy and postpartum for antibodies and supported to address their modifiable
6 to 12 weeks.31,35 As low-molecular-weight heparin thromboembolic and cardiovascular risk factors, such
is associated with an increased risk of osteoporosis, as smoking and obesity.31
it is important to minimise the treatment duration of There is uncertainty surrounding the role of primary
this drug to a maximum of 12 weeks. Patients should prophylaxis with aspirin for asymptomatic people
be checked for, and advised on, appropriate dietary with persistent antiphospholipid antibodies.36,37
intake of calcium and vitamin D. If there are recurrent The benefits and harms of using low-dose aspirin
obstetric complications despite treatment, increasing should be considered on an individual basis.
the heparin dose to a therapeutic dose or adding Thromboprophylaxis with low-dose aspirin may be
hydroxychloroquine may be considered.31 considered in asymptomatic people with a high-risk
If a patient with a history of thrombotic manifestations antibody profile (e.g. persistent lupus anticoagulant,
(but no history of obstetric manifestations) becomes triple antibody positivity) who are trying to conceive
pregnant, therapeutic-dose low-molecular-weight and have strong unmodifiable risk factors for
heparin and low-dose aspirin are recommended for thrombosis.31,33 Short-term thromboprophylaxis
the duration of the pregnancy and for 6 to 12 weeks (e.g. with low-molecular-weight heparin) may also be
postpartum.35 Patients previously on warfarin should considered in situations with a high risk of developing
be switched to low-molecular-weight heparin because venous thromboembolism (e.g. peripartum period,
of the risk of birth defects with warfarin.31 surgery, flights).
Long-term thromboprophylaxis for patients with In patients with SLE and a high-risk antibody profile,
a history of obstetric manifestations who are not prophylactic low-dose aspirin is recommended.31
pregnant or hoping to conceive is not recommended; Hydroxychloroquine is the mainstay treatment
however, low-dose aspirin may be considered for people with SLE and may have additional
short term in high-risk situations (e.g. long-haul benefits for people with SLE who have persistent
flights, surgery). antiphospholipid antibodies.3
People with a history of obstetric manifestations who All patients with SLE who are hoping to conceive
develop a thrombotic episode should be managed should receive preconception counselling. In
as per patients with APS-associated thrombosis (i.e. asymptomatic pregnant women with persistent
lifelong secondary prophylaxis with warfarin).31 antibodies (with or without SLE), prophylactic low-
dose aspirin before 16 weeks gestation has been
Catastrophic antiphospholipid syndrome
recommended with careful monitoring of the fetus
If catastrophic APS is suspected, the patient should
and the mother.31,35
be immediately referred to a hospital for assessment
and management. Initial treatment involves
anticoagulation and high-dose corticosteroids, and is
Conclusion
often followed by plasma exchange and/or rituximab
or cyclophosphamide.4 Testing for antiphospholipid antibodies should only
be initiated in patients in whom there is a high clinical
Asymptomatic people with persistent suspicion of APS or with SLE. The detection of
antiphospholipid antibodies persistent antiphospholipid antibodies is key to the
Investigating for antiphospholipid antibodies is not diagnosis and risk stratification of patients with APS.
recommended in asymptomatic individuals, except However, there are challenges with the interpretation
in patients with SLE. If an asymptomatic person is of test results.

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ARTICLE Diagnosis and management of antiphospholipid syndrome

Patients with thrombotic manifestations of APS should This article was finalised on 14 November 2024.
be initially treated with therapeutic heparin, followed
by warfarin for long-term secondary prophylaxis. Conflicts of interest: Paul Kubler has received funding
from AbbVie for trials of upadacitinib for systemic lupus
Pregnant patients with APS require low-dose
erythematosus. Paul was a member of the expert group
aspirin and low-molecular-weight heparin at either a
for Therapeutic Guidelines: Rheumatology Version 4
therapeutic or prophylactic dose, depending on prior
(under review).
manifestations, during pregnancy and postpartum.
Asymptomatic people with persistent antiphospholipid Yeri Ahn, Carolyn Hawkins and Eliza Pearson have no
antibodies do not have a clinical diagnosis of APS. The conflicts of interest to declare.
decision to initiate thromboprophylaxis in this group
is based on their individual antiphospholipid antibody
profile and other risk factors.

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