What’s new?

C Antibodies directed against domain I of b2-GPI correlate better

with thromboembolic complications than antibodies directed

against other domains of b2-GPI

C Low titre antiphospholipid antibodies appear to be implicated

in recurrent miscarriage

C High-intensity anticoagulation is appropriate for some patients

e however, substantive evidence is lacking

C Low-dose aspirin is ineffective for the prevention of thrombosis

in patients with asymptomatic aPL

C Plasmapheresis, intravenous immunoglobulin and immuno-

suppression are non-evidence-based therapies gaining popu-

larity for the management of patients with resistant disease

C Statins and ACE inhibitors have been shown to possess anti-

inflammatory properties in vitro and may have a role in the

armamentarium of APS in the future

OTHER AUTOIMMUNE DISORDERS

Antiphospholipid syndromeSteven Austin

Hannah Cohen

AbstractAntiphospholipid syndrome (APS) is an autoimmune disorder in which

autoantibody production can lead to a hypercoagulable state, pregnancy

failure and/or a multitude of other systemic manifestations. In recent

times, research into the antiphospholipid antibodies has increased our

understanding of the pathogenic process and encouraged improved

detection of antiphospholipid antibodies. However, the precise nature

of the pathology of APS remains challenging, as does the management

of this disorder. This review outlines the key features of APS, including

the laboratory tests and their interpretation, and offers advice regarding

the management of patients with APS both in the medical and obstetric

settings.

Keywords anticardiolipin antibodies; anticoagulation; antiphospholipid

syndrome; b2-glycoprotein-I antibodies; lupus anticoagulant; obstetric

morbidity; thrombosis

Antiphospholipid syndrome (APS) is characterized by throm-

bosis (venous and/or arterial) and/or pregnancy failure in

association with the persistent production of a group of hetero-

geneous autoantibodies known as antiphospholipid antibodies

(aPL). The primary targets 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 Russell’s viper venom time

[DRVVT]); this effect is abolished by the addition of excess

phospholipid (e.g. from platelets)

� anticardiolipin antibodies (aCL) of immunoglobulin G (IgG)

and IgM class, which are determined by enzyme-linked

immunosorbent assay (ELISA)

� b2-glycoprotein-I (b2-GPI) antibodies of IgG and IgM class

detected by ELISA

The prevalence of aPL in the form of LA or aCL is 1e5% of

healthy individuals. The prevalence increases in the elderly and

in those with chronic disease. APS has conventionally been

divided into primary and secondary forms; the latter is associated

Steven Austin MBBS FRACP FRCPA is a Locum Consultant Haematologist at

St George’s Hospital, London, UK. Competing interests: none declared.

Hannah Cohen MD FRCP FRCPath is Consultant Haematologist at University

College London Hospitals NHS Foundation Trust, London, UK.

Competing interests: none declared.

MEDICINE 38:2 101

with chronic inflammatory conditions, mainly systemic lupus

erythematosus (SLE). However, this distinction was abandoned

in the Sydney classification on the basis that it is unknown

whether APS and SLE are two diseases coinciding in an indi-

vidual, underlying SLE offers a setting for the development of

APS, or APS and SLE represent two elements of the same process.

Several studies have shown that the prevalence of aPL in SLE

patients is variable (15e86%). The frequency of antibody posi-

tivity 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, whereas under 5% of patients with

APS will develop SLE.

Pathogenesis

Recent progress has furthered our understanding of the mecha-

nism behind the development of aPL. However, a precise path-

ophysiological 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

� ADAMTS13 (a disintegrin-like and metalloprotease with

thrombospondin type 1 motif, member 13) dysfunction.

Platelet and monocyte activation may also promote throm-

bosis. 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.

� 2009 Elsevier Ltd. All rights reserved.

OTHER AUTOIMMUNE DISORDERS

Bacterial peptides homologous to b2-GPI infused into mice

have been reported to induce antibodies to b2-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-immunological pro-

coagulant factors. The patient’s genetic background (in relation

to candidate genes of inflammatory mediators) may also be

a critical variable for the development of clinical APS manifes-

tations. It is now accepted that anti-b2-GPI are the major path-

ological 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 throm-

bosis (arterial or venous) and aCL are associated more with

arterial than venous thrombosis. Anti-b2-GPI may confer

a stronger thrombotic risk than do aCL especially for venous

thrombosis. Positivity in more than one assay and immuno-

globulin subclass (IgG being more significant for thrombosis) is

also important. Low-titre antibodies appear to be implicated in

recurrent miscarriage.

Clinical features

Thrombosis

Clinical associations of antiphospholipid antibodies

Conditions associated with production of aPL

C Systemic lupus erythematosus, rheumatoid arthritis, systemic

sclerosis, Behcet’s disease, temporal arteritis, Sjogren’s syndrome

C Infections e HIV, varicella, hepatitis C, syphilis, malaria, leprosy

C

APS is associated with venous and arterial thrombotic events.

Among patients with venous thromboembolism, 3e17% have

aCL, and 3e14% 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).

Drugs e phenothiazines, procainamide, phenytoin, quinidine,

hydralazine

Neurological features C Lymphoproliferative disease (lymphoma, paraproteinaemia)

Clinical manifestations in patients with aPL

C Cardiovascular e venous/arterial thromboembolic disease,

valvular heart disease, sterile endocarditis with embolism

C Obstetric e recurrent miscarriage, intrauterine foetal death

(IUFD), stillbirth, early severe pre-eclampsia, HELLP, placental

insufficiency, prematurity, intrauterine growth restriction (IUGR)

C Neurological e cerebral ischaemic events, chorea, dementia,

psychiatric disorders, transverse myelopathy, seizures,

GuillaineBarre syndrome, Sneddon’s syndrome

C Haematological e autoimmune thrombocytopenia, autoimmune

haemolytic anaemia

C Dermatological e livedo reticularis

Ischaemic stroke is the most common neurological feature

(>50% of CNS complications), and the commonest type of

arterial thrombosis in APS. Recurrent stroke can lead to multi-

infarct dementia. More subtle cognitive dysfunction has been

reported to be associated with aPL and may represent micro-

thrombotic 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

Sneddon’s syndrome (recurrent stroke and livedo reticularis).

Other reported, but unproven, neurological manifestations

include migraines, seizures, chorea, transverse myelitis and

a multiple sclerosis-like syndrome.

aPL, antiphospholipid antibodies; HELLP, haemolysis, elevated liver enzymes

Pregnancy morbidity

and low platelets.

Table 1

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 can be up to 90% without pharmacological

MEDICINE 38:2 102

treatment. Late fetal death or stillbirth can also occur. Other

possible obstetric complications of APS include placental insuf-

ficiency, 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 (CAPS)

Although most patients with APS suffer thrombosis in one area at

a time, they occasionally present with life-threatening acute

multiple organ failure from extensive microvascular thrombosis

(‘thrombotic storm’). Laboratory evidence of disseminated

intravascular coagulation can occur. Suggested precipitants of

CAPS include infection, oral contraceptives, surgery and with-

drawal of anticoagulation. The mortality rate is approximately

50%.

Seronegative antiphospholipid syndrome

A subset of patients has been identified who exhibit clinical

manifestations of APS, without any recognized aPL on labo-

ratory testing. These individuals are said to have SNAP

(seronegative antiphospholipid) syndrome and anticoagulation

may be warranted. Subsequent repeat aPL testing can be

positive.

Other clinical associations of aPL

These are listed in Table 1.

Diagnosis

APS patients present to a wide range of specialties. Two ques-

tions are of fundamental importance.

� 2009 Elsevier Ltd. All rights reserved.

OTHER AUTOIMMUNE DISORDERS

What criteria are used to make the diagnosis?

Indications for antiphospholipid antibody testing

Consider testing in all patients with

C Apparently spontaneous venous thromboembolism, especially in

the young or in those with thrombosis at unusual sites

C Recurrent thrombosis

C Stroke, myocardial infarction and peripheral arterial occlusive

events presenting at a young age (<40 years), or in selected older

patients with no obvious conventional cardiovascular risk factors

C Systemic lupus erythematosus or those with autoimmune disease

and thrombosis

C Recurrent pregnancy loss or pregnancy complications with

premature birth

C Unexplained thrombocytopenia

C

Table 2 illustrates the criteria for APS based on the 2006 Sydney

update of the 1999 Sapporo classification. Although useful as

a clinical tool, these criteria were devised primarily for research

purposes, and are tailored to a high diagnostic specificity (in

practice such criteria can exclude patients with features consis-

tent with APS). It is essential that persistent aPL positivity is

confirmed in two separate blood samples; the criteria recom-

mend an interval of at least 12 weeks between sampling. Given

that thrombotic disease, pregnancy loss and transient aPL posi-

tivity are common, it is important to address all other causes of

thrombosis and miscarriage during the initial evaluation of sus-

pected APS. A careful drug history is also needed: compounds

such as phenothiazines, phenytoin and hydralazine are associ-

ated with aPL positivity.

Livedo reticularis

Who should be tested for APS?

Table 3

Table 3 lists the indications. Testing for aPL should be performed

in a specialized haemostasis laboratory. Samples for LA should be

taken with minimal venous stasis, rapid draw and immediate

anticoagulation. Platelet-poor plasma should be prepared within 1

h of blood collection. Lack of adequate sampling and preparation

may result in a false-negative result for LA. Anticoagulation may

interfere with laboratory diagnosis of LA; however, in certain

specialized laboratories aPL testing can be performed whilst the

patient is taking anticoagulant treatment. Strategies include the

use of the DRVVT where the international normalized ratio (INR)

is only modestly elevated (<3.0) or the use of an alternative

coagulation test employing a reagent that is less sensitive to the

effects of warfarin (the Taipan snake venom time).

Management

The Haemostasis and Thrombosis Task Force of the British

Society for Haematology (BCSH) has published guidelines on the

management of APS and the American College of Chest

Diagnostic criteria for antiphospholipid syndrome

Clinical criteria

C Vascular thrombosis e one or more episodes of arterial, venous

or small vessel thrombosis in any tissue or organ (confirmed by

imaging or histopathology)

C Recurrent pregnancy loss (1 > 10 weeks’ gestation, or 3 < 10

weeks’ gestation) or one or more premature births due to preg-

nancy complications

Laboratory criteria

C Lupus anticoagulant in plasma on two occasions at least 12

weeks apart

C Anticardiolipin antibodies of IgG and/or IgM isotype on two

occasions at least 12 weeks apart

C Anti-b2-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.

Ig, immunoglobulin; GPI, glycoprotein-I.

Table 2

MEDICINE 38:2 103

Physicians (ACCP) guidelines include advice on the management

of patients with APS and a history of pregnancy morbidity. Use of

specialist referral centres is important. Decisions about the

commencement and duration of anticoagulant therapy rest on

the accurate diagnosis of such events, so appropriate assessment

and imaging are vital. The treatment of venous thromboembo-

lism must never be delayed whilst awaiting aPL test results. An

evidence-based approach to management is difficult because of

the limited number of randomized controlled trials involving the

APS population.

Asymptomatic aPL

Prophylactic intervention for the prevention of primary throm-

bosis 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 hormone replacement therapy) and give short-term heparin

prophylaxis during high-risk periods (surgery, periods of immo-

bilization and hospitalization). A recent prospective, randomized

clinical trial has shown that prophylactic low-dose aspirin is

ineffective for the prevention of thrombosis in individuals with

asymptomatic aPL. Whether primary prophylaxis with aspirin is

useful for some subsets of aPL patients at particularly high risk of

thrombosis, such as those with SLE or with specific patterns of

aPL positivity, remains to be established.

Venous thromboembolism and stroke

Initial management of venous thromboembolism involves stan-

dard therapy with low-molecular-weight heparin (LMWH) fol-

lowed by oral anticoagulation. The duration of therapy depends

on any additional risk factors, the location, severity and conse-

quences of previous thrombosis, patient age and the relative risk

of further thrombosis versus haemorrhage due to anti-

coagulation. 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 balance the risk of thrombosis against

that of bleeding (1% per year, 0.25% severe haemorrhage).

� 2009 Elsevier Ltd. All rights reserved.

OTHER AUTOIMMUNE DISORDERS

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

a target INR of 2.5 is insufficient. Although such a group is

difficult to define, further events occurring despite therapeutic

anticoagulation should alert one to the requirement for more

intensive anticoagulation with a target INR of 3.5 (3.0e4.0).

In patients with arteriothrombotic stroke associated with aPL,

management should involve long-term warfarin. The optimal

intensity remains disputed, as prospective studies have not

shown a benefit of high-intensity compared with moderate-

intensity anticoagulation (but the study population was not

representative of an APS population). The addition of aspirin

may also be of benefit, but with increased risk of bleeding. There

is interest in the use of hydroxychloroquine and statins to reduce

thrombotic risk in APS, but their use in this context remains

empirical. In view of the association between APS and arterial

thrombotic disease, every effort should be made to correct

conventional arteriopathic risk factors in all patients with APS.

Pregnancy morbidity

All pregnant women with APS should be managed within

a specialist obstetric unit with ready access to neonatal care.

Given the teratogenicity of warfarin (6.4%), which is the highest

in the first trimester, warfarinization is contraindicated in early

pregnancy. In addition, foetal intracerebral haemorrhage can

occur at any gestation. Women on long-term oral anticoagulation

must be advised that warfarin should be stopped as early as

possible and before 6 weeks’ gestation. The recommended

treatment in women who experience recurrent miscarriage (and

no history of thrombosis) 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. While 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 should also be considered), and LMWH

when foetal 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 it is reasonable to continue

therapy to 38 weeks’ gestation. Thrombotic risk is increased

during pregnancy, and women with APS with thrombotic mani-

festations require careful anticoagulation, which should be

individualized.

MEDICINE 38:2 104

Catastrophic antiphospholipid syndrome

Anecdotal reports suggest that the following agents may be

beneficial: anticoagulation, intravenous immunoglobulin,

plasma exchange and immunosuppressive therapy, including

high-dose corticosteroids, cyclophosphamide and rituximab.

Conclusions

In recent years there has been significant progress in the under-

standing 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 the

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 that warrant investigations for aPL, taking heed

of the possibility of transient aPL, and application of an appro-

priate 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. Antith-

rombotic agents e aspirin, LMWH and warfarin e are the main-

stay of therapy of APS. Further large-scale randomized clinical

trials using these agents are needed to increase the evidence base

and optimize management of APS. Novel approaches to eliminate

the autoantibody, which may offer the potential for cure in the

future, are under investigation. A

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� 2009 Elsevier Ltd. All rights reserved.