Other autoimmune disorders

Antiphospholipid syndrome

Whats new?

Steven Austin

B2GP-1 Antibodies are now known to be important

pathogenic antibodies which confer a strong risk of
thrombosis, and consequently anti-B2GP-1 detection
is now required for a comprehensive assessment of
patients suspected of APS.

Hannah Cohen

Animal studies into the development of autoimmune

disease and APS suggest that molecular mimicry may
be important in the development of antiphospholipid
antibodies.

Abstract
Antiphospholipid syndrome (APS) is an autoimmune disorder in which
autoantibody production may lead to a hypercoagulable state, pregnancy
failure and/or a multitude of other systemic manifestations. In recent
times, research into the antiphospholipid antibodies has strengthened
our understanding of the pathogenic process, and encouraged improved
detection of antiphospholipid antibodies. However, the precise nature
of the pathology of APS, as well as the management of this disorder,
remain challenging. This review outlines the key features of APS, including the laboratory tests and interpretation, and offers advice regarding
management of patients with APS both in the medical and obstetric
settings.

Many new antibody targets have been demonstrated in

vitro to play a role in APS, but any strong association
with clinical manifestations has not been shown
Anticoagulation remains the mainstay of therapy,
with adjuvant antiplatelet agents potentially offering
additional protection from morbidity in certain patient
groups.
For the majority of APS patients high intensity
anticoagulation is not considered superior to moderate
intensity (for details please see text below).

Keywords antiphospholipid syndrome; anticardiolipin antibody; -2glycoprotein-I antibody; lupus anticoagulant; thrombosis; recurrent
miscarriage; anticoagulation

chronic disease. Clinically, APS is divided into primary and secondary forms; the latter is associated with chronic inflammatory conditions, mainly systemic lupus erythematosus (SLE). Several studies
have shown that the prevalence of aPL in SLE patients is variable
(1586%). The frequency of antibody positivity is likely to be around
30%, with the wide variation found in the literature explained by
study variations, ethnicity, and extent of autoimmune disease activity. Up to an estimated 40% of patients with SLE and aPL will eventually develop clinical features consistent with APS.

Antiphospholipid syndrome (APS) is characterized by thrombosis (venous and/or arterial) and/or pregnancy failure in association with the persistent production of a group of heterogeneous
autoantibodies known as antiphospholipid antibodies (aPL).
The primary target of aPL are phospholipid binding proteins,
although antibodies directed against phospholipids and other
proteins also occur. Additional features, particularly thrombocytopenia, are variably present. In the laboratory, the usual diagnostic tests for aPL are:
lupus anticoagulants (LA), which cause prolongation of
phospholipid-dependent clotting assays (e.g. activated partial
thromboplastin time, dilute Russells viper venom time); this
effect is abolished by the addition of excess phospholipid (e.g.
from platelets)
anticardiolipin antibodies (aCL) of IgG and IgM class, which
are determined by enzyme-linked immunosorbent assay
(ELISA)
2-glycoprotein-I (2-GPI) of IgG and IgM class detected by
ELISA.
The prevalence of aPL in the form of LA or aCL is 15% of healthy
individuals. The prevalence increases in the elderly and those with

Pathogenesis
Recent progress has furthered our understanding of the mechanism behind the development of aPL. However, a precise pathophysiological mechanism for the clinical features of APS remains
elusive. Proposed prothrombotic mechanisms, all of which can
result in a prothrombotic state, include:
acquired resistance to activated protein C
endothelial cell activation
up-regulation of tissue factor
reduced fibrinolysis
oxidant mediated endothelial injury.
Platelet and monocyte activation may also promote thrombosis.
Additional mechanisms of displacement of annexin V and complement activation have been linked with direct cellular damage and
abnormal placentation leading to implantation failure and foetal loss.
The clinical significance of any one (or more) of these hypotheses
remains unclear and reflects the likely multifactorial complex nature
of this condition, as is generally the case in acute thrombosis.
Animal studies have suggested that the mechanism of molecular mimicry plays an important role in experimental APS.

Steven Austin MBBS FRACP FRCPA is a Clinical research Fellow at University

College London, UK. Competing interests: none declared.
Hannah Cohen MD FRCP FRCPath is Consultant Haematologist at University
College London Hospitals NHS Trust, London, UK. Competing interests:
none declared.

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Other autoimmune disorders

Recently, bacterial peptides homologous to 2-GPI infused into

mice have been reported to induce antibodies to 2-GPI along
with APS manifestations. The development of aPL is probably
only one step towards the development of APS, and it is likely
that other factors play a role. Such second hits or triggers may
tip haemostasis in favour of a prothrombotic state and include
infection, endothelial injury, and other non-immunologic procoagulant factors. It is now accepted that anti- 2-GPI are the major
pathological antibodies in APS, although there is no clear consensus on how the occurrence of these antibodies is associated
with the various clinical features.
Systematic review of published data suggests that LA are a
stronger risk factor than aCL for thrombosis (arterial or venous)
and aCL are associated more with arterial than venous thrombosis. Anti-2-GPI confer a stronger thrombotic risk than do aCL,
especially for venous thrombosis. Positivity in more than one
assay, titre level and immunoglobulin subclass (IgG being more
significant for thrombosis) are also important.

Clinical associations of antiphospholipid antibodies

Conditions associated with production of aPL
Idiopathic (primary antiphospholipid syndrome)
Secondary antiphospholipid syndrome - systemic lupus
erythematosus, rheumatoid arthritis, systemic sclerosis,
Behets disease, temporal arteritis, Sjgrens syndrome
Other conditions
Infections - HIV, varicella, hepatitis C, syphilis, malaria,
leprosy
Drugs - phenothiazines, procainamide, phenytoin, quinidine,
hydralazine
Lymphoproliferative disease (lymphoma, paraproteinaemia)
Clinical manifestations in patients with aPL
Cardiovascular - venous/arterial thromboembolic disease,
valvular heart disease, sterile endocarditis with embolism
Obstetric - recurrent miscarriage, intrauterine fetal death
(IUFD), stillbirth, early severe pre-eclampsia, HELLP, placental
insufficiency, prematurity, intrauterine growth restriction
(IUGR)
Neurological - cerebral ischaemic events, chorea, dementia,
psychiatric disorders, transverse myelopathy, seizures,
Guillain-Barr syndrome, Sneddons syndrome
Haematological - autoimmune thrombocytopenia,
autoimmune haemolytic anaemia
Dermatological - livedo reticularis

Clinical features
Thrombosis APS is associated with venous and arterial
thrombotic events. Of patients with venous thromboembolism,
317% have aCL, and 314% have LA. Well-established risk
factors for thrombosis (e.g. pregnancy and surgery) also increase
the risk of thrombosis in APS patients as do coexistent inherited thrombophilias such as factor V Leiden. The most common
venous thrombotic manifestation of APS is lower limb deep
venous thrombosis, which occurs in up to 55% of patients, half
of whom also have pulmonary embolism. Occasionally, venous
thromboses occur in unusual sites (e.g. cerebral venous sinuses),
and indeed any part of the venous system can be involved (superficial, mesenteric, portal, intracranial, retinal).
Neurological features ischaemic stroke is the most common neurological feature (>50% of CNS complications), and the
commonest type of arterial thrombosis in APS. Recurrent stroke
may lead to multi-infarct dementia. More subtle cognitive dysfunction has been reported to be associated with aPL and may
represent microthrombotic change in the cerebral vasculature
or a direct effect of aPL on neuronal tissue. Some studies suggest a high rate of recurrent stroke in aPL-positive patients and a
younger age of onset of symptomatic events. aPL have also been
linked with Sneddons syndrome (recurrent stroke and livedo
reticularis). Other reported, but unproven, neurological manifestations include migraines, seizures, chorea, transverse myelitis
and multiple sclerosis like syndrome.
Pregnancy persistent aPL are seen in about 15% of women
with recurrent miscarriage in the first or second trimester. In
these women, the fetal loss rate may be up to 90% without pharmacological treatment. Late fetal death or stillbirth may also
occur. Other possible obstetric complications of APS include
placental insufficiency, HELLP syndrome (haemolysis, elevated
liver enzymes and low platelets) and severe early pre-eclampsia.
Fetal and neonatal complications include intrauterine growth
restriction, prematurity and rarely thrombosis.
Catastrophic APS although most patients with APS suffer
thrombosis in one area at a time, rarely they present with acute
multiple organ failure from extensive microvascular thrombosis.
Other clinical associations of aPL are listed in Table 1.

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Table 1

Diagnosis
APS patients present to a wide range of specialties. Two questions are of fundamental importance.
What criteria are used to make the diagnosis? Table 2 illustrates the criteria for APS based on a recently published revised
international consensus statement. Although useful as a clinical
tool, these criteria were devised primarily for research purposes.
It is essential that persistent aPL positivity is confirmed in two
separate blood samples; the criteria recommend an interval of at
least 12 weeks between sampling. Given that thrombotic disease,
pregnancy loss and transient aPL positivity are common, it is
important to address all other causes of thrombosis and miscarriage during the initial evaluation of suspected APS. A careful
drug history is also needed; compounds such as phenothiazines,
phenytoin and hydralazine are associated with aPL positivity.
Who should be tested for APS? Table 3 lists the indications.
Testing for aPL should be performed in a specialized haemostasis
laboratory. Samples should be taken with minimal venous stasis,
rapid draw and immediate anticoagulation. Platelet-poor plasma
should be prepared within 1 hour of blood collection. Lack of
adequate sampling and preparation may result in a false negative
result for LA.

Management
The Haemostasis and Thrombosis Task Force of the British
Society for Haematology has published guidelines on the management of APS. Use of specialist referral centres is important.
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(surgery, periods of immobilization). Empirical low-dose aspirin therapy is often undertaken in patients with SLE who have
aPL but have not suffered thrombosis. In addition, aspirin is also
often prescribed in primary APS patients, but its efficacy is not
proven.
Anticoagulation initial management of venous thromboembolism involves standard therapy with low molecular weight
heparin (LMWH) followed by oral anticoagulation. The duration of therapy depends on any additional risk factors, the
location, severity and consequences of previous thrombosis,
patient age and the relative risk of further thrombosis versus
haemorrhage due to anticoagulation. In other words, therapeutic decisions must be individualized. Recurrent venous thromboembolic events are managed using long-term warfarin. The
optimal intensity of long-term anticoagulation must be determined balancing the risk of thrombosis against that of bleeding
(1% per year, 0.25% severe haemorrhage). Recent prospective
randomized controlled trials suggest that high intensity warfarin
is not superior to moderate intensity. However, patients with a
high risk of recurrent thrombosis were not included in these trials, and it is likely that for some patients (those with recurrent
events on standard therapeutic anticoagulation) a target INR of
2.5 is insufficient. Although such a group is difficult to define,
further events on therapeutic anticoagulation would alert to the
requirement for more intensive anticoagulation with a target of
3.5 (3.04.0).
In patients with arteriothrombotic stroke associated with aPL,
management should involve long-term warfarin. The optimal
intensity remains disputed, but in the absence of adequate data
most adopt a conventional target INR of 2.5, reserving higher
intensity therapy for those with recurrent events. The addition of
aspirin may also be of benefit, but with increased risk of bleeding. In stroke patients, every effort should be made to correct
conventional arteriopathic risk factors.
Pregnancy loss all pregnant women with APS should be
managed within a specialist obstetric unit with ready access to
neonatal care. The recommended treatment in women who experience recurrent miscarriage associated with aPL is a combination of low-dose aspirin and heparin. However, the evidence for
this is driven primarily by the results of a single randomized
controlled trial in which aspirin was used as the control. Whilst
some studies suggest aspirin alone or even supportive care only,
in vitro data support an adjunctive role for heparin in this situation. At our institution we administer aspirin (75 mg daily) and
low dose LMWH therapy (dalteparin 2500 units daily subcutaneously (SC) to patients with APS associated with recurrent miscarriage, and, on a pragmatic basis, dalteparin 5000 units daily SC
to patients with aPL and late obstetric complications). Aspirin
should be started as soon as the urine pregnancy test becomes
positive (preconceptual aspirin may also be considered), and
heparin when fetal heart activity is established. The ideal duration of such therapy has not been determined, but in women
with miscarriage, about 25% of treated pregnancies are associated with late obstetric complications. In these patients, a thrombotic basis may be contributory, and, therefore it is reasonable
to continue therapy to 38 weeks gestation. Thrombotic risk is
increased during pregnancy, and, therefore, women with APS
with thrombotic manifestations require careful anticoagulation
which should be individualized.

Diagnostic criteria for antiphospholipid syndrome

Clinical criteria
Vascular thrombosis - one or more episodes of arterial,
venous or small vessel thrombosis in any tissue or organ
(confirmed by imaging or histopathology)
Recurrent pregnancy loss (1 > 10 weeks gestation, or 3 <10
weeks gestation) or one or more premature births due to
pregnancy complications
Laboratory criteria
Lupus anticoagulant in plasma on two occasions at least 12
weeks apart
Anticardiolipin antibodies of IgG and/or IgM isotype on two
occasions at least 12 weeks apart
Anti-2-GPI antibody of IgG or IgM isotype on two occasions
at least 12 weeks apart.
Antiphospholipid syndrome is considered to be definitely
present when at least one clinical criterion and one laboratory
criterion are met
Table 2

Decisions about the commencement and duration of anticoagulant therapy rest on the accurate diagnosis of such events, so
appropriate assessment and imaging is vital. The treatment of
venous thromboembolism must never be delayed whilst awaiting aPL test results. If necessary, tests can be undertaken later,
although in certain specialized laboratories aPL testing can be
performed whilst receiving anticoagulant treatment. An evidence based approach to management is difficult due to the limited number of randomized controlled trials involving the APS
population.
Prophylactic intervention for the prevention of primary
thrombosis in asymptomatic individuals with persistent aPL is
not supported by available evidence. However, it is prudent to
observe general thrombotic risk reduction measures (e.g. avoidance of smoking, oestrogen-containing oral contraception) and
give short-term heparin prophylaxis during high-risk periods

Indications for antiphospholipid antibody testing

Consider testing in all patients with apparently spontaneous
venous thromboembolism especially in the young or in the
case of unusual thrombosis sites
Recurrent thrombosis
Stroke and peripheral arterial occlusive events presenting at
a young age (< 50 years), or older patients with no obvious
other risk factors
In assessment of patients with systemic lupus erythematosus
or patients with autoimmune disease and thrombosis
Recurrent pregnancy loss or pregnancy complications with
premature birth
Unexplained thrombocytopenia
Table 3

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management of APS. Novel approaches to eliminate the autoantibody, which may offer the potential for cure in the future,
merit investigation.

Conclusion
In recent years there has been significant progress in the understanding of the aetiology, pathophysiology and diagnosis of
APS. However, the precise mechanism of action of aPL remains
elusive and more clarification is needed, particularly with regard
to certain clinical features of APS, namely neurological manifestations and late obstetric complications. Furthermore, we lack a
solid evidence base to guide optimal management. Current therapy relies on a logical approach based on available evidence. Of
paramount importance is recognition of clinical scenarios which
warrant investigations for aPL, taking heed of the possibility of
transient aPL, and application of an appropriate protocol for
laboratory testing. Interpretation of test results must occur in
concert with the clinical history, paying particular attention to
any additional thrombotic risk factors. Antithrombotic agents
aspirin, LMWH and warfarin are the mainstay of therapy of
APS. Further large scale randomised clinical trials using these
agents are needed to increase the evidence base and optimise

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Further reading
International consensus statement on an update of the classification
criteria for definite antiphospholipid syndrome (APS). J Thromb
Haemost 2006; 4: 295306.
De Groot P G, Derksen R M. Pathophysiology of the antiphospholipid
syndrome. J Thromb Haemost 2005; 3: 185460.
Robertson B A, Greaves M. Antiphospholipid syndrome: an evolving
story. Blood Rev 2006; in press.
Greaves M, Cohen H, Machin S, Mackie I J. Guidelines on the
investigation and management of the antiphospholipid syndrome.
Br J Haematol 2000; 109: 70415.
Khamashta M A, ed. Hughes syndrome, antiphospholipid syndrome.
Berlin: Springer-Verlag, 2000.

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2006 Published by Elsevier Ltd.