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CLINIcAL REVIEW

Diagnosis and management of the antiphospholipid syndrome

Danielle Cohen,1 Stefan P Berger,2 Gerda M Steup-Beekman,3 Kitty W M Bloemenkamp,4 Ingeborg M Bajema1
1

Department of Pathology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, Netherlands 2 Department of Nephrology, Leiden University Medical Centre and Department of Internal Medicine, Haga Teaching Hospital, PO Box 40551, 2504 LN the Hague, Netherlands 3 Department of Rheumatology, Leiden University Medical Centre and Bronovo Hospital, PO Box 96900, 2509 JH the Hague 4 Department of Obstetrics, Leiden University Medical Centre Correspondence to: D Cohen d.cohen@lumc.nl
Cite this as: BMJ 2010;340:c2541 doi: 10.1136/bmj.c2541

Antiphospholipid syndrome was rst described 27 years ago in patients with systemic lupus erythematosus (SLE) and positive anticardiolipin antibodies, who presented with a clotting syndrome that affected arteries and veins.1 Female patients had a high risk of recurrent miscarriage and late fetal loss. The international classication criteria for this syndrome used today are based on those initial clinical observations.2 The syndrome is under-recognised and underdiagnosed and can have devastating consequences if untreated, mainly because of uncontrolled thrombosis. Difficulties in diagnosis are compounded by a lack of standardisation of diagnostic tests. Early recognition is crucial, because treatment can reduce mortality and morbidity in relatively young people who often present with diseases such as stroke, myocardial infarction, and deep vein thro mbosis. Because of its variable clinical presentation, patients with antiphospholipid syndrome present to a variety of medical practitioners. Here, we introduce this complicated and intriguing syndrome, and provide basic guiding principles for the recognition, diagnosis, and management of affected patients.

SOURCES AND SELECTION CRITERIA We searched the following databases for evidence from systematic reviews, clinical trials, and prospective cohort studies: PubMed (1949 to January 2010), Embase (1980 to January 2010), Web of Science (1945 to January 2010), Cochrane Library (1990 to January 2010), CINAHL (1982 to January 2010), and Academic Search Premier (1865 to January 2010). All relevant keyword variations were used. In general, the search consisted of the combination of the following terms: antiphospholipid syndrome, Hughes syndrome, antiphospholipid antibodies, lupus anticoagulant, anticardiolipin antibodies, anti-2 glycoprotein I antibodies, and catastrophic antiphospholipid syndrome. Results were limited to articles written in English.

most c ommon20-35% of patients with SLE develop secondary antiphospholipid syndrome.3 An acute variant of the syndromecatastrophic antiphospholipid syndromeresults in widespread thrombotic microangiopathy and multiple organ failure (box 1).4 Classication criteria were last updated in 2006 (box 2). A combination of clinical and laboratory ndings is needed to conrm the diagnosis.2
Box 1 | Catastrophic antiphospholipid syndrome Catastrophic antiphospholipid syndrome is a rare life threatening condition, characterised by the rapid development of multiple microthrombi in various organ systems, typically the brain (fig 1A), kidneys (fig 1B), lungs, and skin.w1 Thrombocytopenia, haemolysis, schistocytes (fig 1C) and activation of the coagulation system are common laboratory findings, so thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome, and disseminated intravascular coagulation are important differential diagnoses. Mortality in this syndrome approaches 50%.w2 Data on treatment are limited, but current treatment regimens have reduced mortality when compared with historical case series.w2 Successful treatment regimens include anticoagulation, high dose corticosteroids, and plasma exchange, with or without intravenous immunoglobulins. Plasma exchange seems to be particularly useful in thrombotic microangiopathy. Precipitating disorders such as infection should be treated promptly.
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What is antiphospholipid syndrome? Antiphospholipid syndrome is a systemic autoimmune disorder characterised by arterial and venous thrombosis, adverse outcomes in pregnancy (for mother and fetus), and raised titres of antiphospholipid antibodies. It occurs in isolation (primary antiphospholipid sy ndrome) in more than 50% of patients, but it can be associated with other autoimmune diseases. SLE is the

SUMMArY POINTs
If untreated, antiphospholipid syndrome can lead to permanent disability, severe maternal or perinatal morbidity, or even death Symptoms can occur in virtually all organ systems Venous thrombosis and stroke are the most common thrombotic manifestations In pregnancy the syndrome is associated with adverse maternal and fetal outcomes The lupus anticoagulant test is the most useful because positivity correlates most strongly with clinical manifestations Cardiac valvular disease is an important clinical manifestation and may contribute to the risk of stroke
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rimary or secondary antiphospholipid syndrome develop p the catastrophic form, and in almost half of them it appears de novo, without previous thrombotic events.3

Fig 1 | Classic histological findings in a patient with catastrophic antiphospholipid syndrome. (A) Cerebral microthrombi (arrows); the fibrin thrombi are stained blue by phosphotungstic acid haematoxylin. (B) Renal microthrombi, prominently present in a glomerulus (arrow). (C) Blood smear showing schistocytes (fragmented red blood cells), which are formed by fibrin strands that sever red blood cells as they try to move past a (micro)thrombus (arrows), and are indicative of microangiopathic haemolytic anaemia

Who gets it? SLE affects one to 20 in every 100000 women (depending on ethnic origin), and around 30% of those develop secondary antiphospholipid syndrome. The population prevalence of primary antiphospholipid syndrome is unknown, although it is estimated that it affects 0.5% of the population. Antiphopholipid syndrome occurs mainly in young women of fertile age, rarely occurs in children, and only 12% of patients present after age 50. In a large international cohort, mean age at diagnosis was 34 (standard deviation 13) years. The male:female ratio was 1:3.5 for primary disease and 1:7 for secondary diagnosis associated with SLE.3 A recently reported, unique cohort of 122 paediatric cases (primary and secondary) had a mean age of 10.7 at disease onset (range 1.0-17.9) and a male:female ratio of almost 1:1.7 Patients who present after 50 are more often male and present more often with stroke and coronary heart disease.2 Fewer than 1% of patients with
Box 2 | Classification criteria for the antiphospholipid syndrome2 Antiphospholipid syndrome is present if at least one of the clinical criteria and one of the laboratory criteria below are met. Clinical criteria Vascular thrombosis One or more episodes of arterial, venous, or small vessel thrombosis in any tissue or organ. Thrombosis must be confirmed by objective validated criteria (unequivocal findings on appropriate imaging studies or histopathology). For histopathological confirmation, thrombosis should be present without evidence of inflammation in the vessel wall. Morbidity in pregnancy One or more unexplained death of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus. One or more premature birth of a morphologically normal neonate before the 34th week of gestation because of eclampsia or severe pre-eclampsia defined according to standard definitions, or recognised features of placental insufficiency. Three or more unexplained consecutive spontaneous miscarriages before the 10th week of gestation, with maternal anatomical or hormonal abnormalities excluded and paternal and maternal chromosomal causes excluded. Laboratory criteria Lupus anticoagulant present in plasma on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Haemostasis.5 Medium or high titre (>40 IgG or IgM phospholipid units (1 unit is 1 g of antibody), or >99th centile) of IgG or IgM anticardiolipin antibody in serum or plasma on two or more occasions, a least 12 weeks apart, measured by standardised enzyme linked immunosorbent assay (ELISA).6 Medium or high titre (>40 IgG or IgM phospholipid units, or >99th centile) of IgG or IgM anti-2 glycoprotein I antibody in serum or plasma on two or more occasions, a least 12 weeks apart, measured by standardised ELISA, according to recommended procedures.
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What are antiphospholipid antibodies and how might they cause symptoms? Antiphospholipid antibodies form a heterogeneous group of autoantibodies directed at plasma proteins that bind to phospholipids.8 Some antibodies from the antiphospholipid family have a paradoxical effect on coagulation: in vivo they are associated with recurrent thrombosis, but in vitro they increase phospholipid dependent clotting times, a phenomenon known as lupus anticoagulant activity.w3 The lupus anticoagulant assay is a functional assay based on a combination of several clotting tests. Two other antibodies are useful for diagnosing antiphospholipid syndrome: anticardiolipin antibodies and anti-2 glycoprotein I antibodies (box 1),2 both of which can be detected by enzyme linked immunosorbent assays (ELISAs). Antibodies with lupus anticoagulant activity are important clinicallytwo systematic reviews found them to be strongly correlated with thrombotic and obstetric complications of the syndrome.910 Table 1 describes assays for lupus anticoagulant, anticardiolipin antibodies, and anti-2 glycoprotein I antibodies. Unfortunately, agreement between laboratories for all of these assays is poor. A recent survey that evaluated lupus anticoagulant positive plasma samples found a false positive rate of 24%.w4 This highlights the importance of good communication between the laboratory and the clinician when making a diagnosis and of ensuring that guidelines are followed.5 Antiphospholipid antibodies are found in 1-5% of apparently healthy subjects. Prevalence increases with age and may be inuenced by chronic disease, infections, malignancies, and the use of certain drugs. Positivity in these conditions usually arises from IgM antibodies at low titres and is not associated with thrombosis or adverse pregnancy outcome.11 Persistent positivity is rare. In a cross sectional study of 552 healthy blood donors, 6.5% had anticardiolipin IgG, but fewer than 2% still had increased titres nine months later.w5 A denitive diagnosis of antiphospholipid syndrome requires the presence of clinical criteria and positive results for at least one of the three assays on at least two separate occasions 12 weeks apart because only persistent antiphospholipid antibodies are clinically relevant.2 w6 The correlation between current antiphospholipid antibody and clinical symptoms is variable. Well designed prospective diagnostic studies are scarce. Difficulties in interpreting clinical-serological studies arise from nonstandardised assays, variable inclusion criteria, and broad denitions for case selection. Overall, the evidence supports the following: Lupus anticoagulant is strongly associated with venous thrombosis, in SLE and in the general population (odds ratio 11).9 This effect is stronger in younger age groups (<50).w7 Lupus anticoagulant is strongly associated with stroke, in SLE and the general population (odds ratio 8.1, 95% condence interval 2.4 to 27.5). This effect is stronger in young age groups (<50).9 w8 w9
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Table 1 |Antiphospholipid antibodies

Antibody type Test details Test Test guidelines Which antibodies are detected? Relevant isotypes What titres are considered positive? Is the test influenced by anticoagulation therapy? Is there overlap with other tests? Anticardiolipin antibodies Anticardiolipin ELISA Pierangeli et al (2008)6 Antibodies against cardiolipin and cardiolipin bound 2 glycoprotein I IgG, IgM Medium to high: >99th centile, or >40 IgG or IgM phospholipid units No Lupus anticoagulant The lupus anticoagulant assay* Pengo et al (2009)5 Detects immunoglobulins that cause prolonged clotting times in vitro but are associated with thrombosis in vivo IgG, IgM Not applicable Medium to high: >99th centile, or IgG or Not applicable IgM phospholipid units No Yes. Both heparin and warfarin influence the test results, so testing during treatment is controversial Yes, this test overlaps with that for lupus Yes, this test overlaps with that for Yes, anti-2 glycoprotein I and anticardiolipin antibodies can have an anticoagulant lupus anticoagulant anticoagulant effect, but other antibodies, such as antiprothrombin and antiannexin V, can contribute to this effect Anti-2 glycoprotein I antibodies Anti-2 glycoprotein I ELISA None yet Antibodies against 2 glycoprotein I

*A set of coagulation assays in three steps: screening (identification of a prolonged clotting time), mixing (confirmation of an inhibitor and exclusion of factor deficiencies), and confirmation (confirmation of phospholipid dependence of the inhibitor). 1 unit=1 g of antibody.

Lupus anticoagulant is strongly associated with fetal loss at greater than 10 weeks gestation (7.8, 2.30 to 26.45).10 Lupus anticoagulant predicts venous thrombosis and fetal loss more strongly than do anticardiolipin antibodies (odds ratio 1.6-3.5).910 The anticardiolipin ELISA is thought to have high sensitivity but low specicity. A positive result has a stronger association with morbidity in pregnancy than with thrombosis.10 w10 w11 Studies that have investigated the relation between anti-2 glycoprotein I antibodies and clinical symptoms have shown contradictory ndings.10 w6 w12 The clinical relevance of isolated anti-2 glycoprotein I antibodies is uncertain. Patients with positivity for all three antibodies have a particularly high risk for pregnancy morbidity or thromboembolism (34.4, 3.5 to 335).w13 w14 Risk factors for thrombosis such as smoking (arterial disease) and oral contraception (venous thrombosis) further increase the risk of thrombosis in the presence of antiphospholipid antibodies.w8 The risk of apparently healthy people with persistently positive antiphospholipid antibodies eventually developing a clinical event, such as thrombosis or adverse pregnancy outcome, is unknown. A PATIENTS PERSPECTIVE From the age of 16, I had frequent headaches, sometimes with double vision, and I occasionally had pins and needles in one hand. My general practitioner never found an obvious cause. At 21 I was diagnosed with a deep vein thrombosis in my left leg, after a minor car accident. I was treated with heparin and aspirin for a few months. A year later I had a miscarriage at 9 weeks gestation. My platelets were low and did not improve. My gynaecologist sent me to a haematologist, who thought of the antiphospholipid syndrome. The blood test was positive. It was a double feeling: on the one hand I felt relieved to have a diagnosis that explained all my medical problems, but I suddenly had a disease that I had never heard of. My friends and family have difficulty understanding when I try to explain what antiphospholipid syndrome is. The most frustrating thing is that even some of the doctors I talk to have never heard of it. Two years ago they found out that two of my heart valves are leaking. I have had surgery for one valve recently, and one more operation is needed for the other. It is scary to think that if my anticoagulation therapy is stopped I will be at risk of developing things like a stroke. It is surreal to have to think about these things in your early 30s. Because of the heart valves I had to postpone further pregnancies. I hope for the best, and hope that with heparin treatment Ill have a fair chance of becoming a mother one day. A Meijer-Bezema, Stadskanaal, Netherlands
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What is known about its aetiology and pathophysiology? The cause of the production of autoantibodies to phospholipid binding proteins such as anti-2 glycoprotein I is largely unknown.8 12 Effect on coagulation and inflammatory pathways Antiphospholipid antibodies affect the coagulation cascade and inammation. In a process mediated by 2 glycoprotein I, antiphospholipid antibodies bind to platelets and endothelial cells, activating endothelial cells and inducing a procoagulant state. Antibody binding also activates complement,w15 resulting in recruitment of other inammatory cells, activation of tissue factor, endothelial damage, and nally thrombosis.w16 Although cerebral involvement is thought to be mainly thrombotic in nature, evidence now suggests that antiphospholipid antibodies may have more direct effects, causing neurological impairment unrelated to thrombosis through antibody-cellular interactions, possibly because of complement activationw17 or a disrupted blood-brain barrier.w18 w19 Is there an additional trigger? Most patients develop a discrete thrombotic event at a certain site in the body, suggesting that an additional trigger or risk factora second hitis needed for the development of thrombosis. Infection, local endothelial damage, and pregnancy are possible candidates. Pregnancy Thrombosis in the placental vasculature was initially thought to be the main cause of adverse outcomes in pregnancy. However, placental thrombosis and infarction are not specic to antiphospholipid syndrome but occur in other conditions, such as non-antiphospholipid syndrome pre-eclampsia.w20 In vitro and animal studies showing that antiphospholipid antibodies can bind directly to trophoblast cells and cause direct cellular injury, defective invasiveness, and a local inammatory response as a result of activation of the classical and alternative pathways of complement provided important insights into the pathophysiology of pregnancy loss.w16 w21 Moreover, they showed that the protective effect of heparin resulted from its anti-complement activity and not only from its effects on coagulation.w22 Antiphospholipid antibodies seem to cause direct dysfunction of the trophoblast as well as activation
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Migraine Stroke Transient ischaemic attack Pulmonary embolism Cardiac valve pathology Coronary artery disease Renal vein thrombosis Renal infarction Thrombotic microangiopathy Antiphospholipid syndrome nephropathy Recurrent early miscarriage Intrauterine fetal death Early or severe pre-eclampsia (or both) Intrauterine growth restriction Raynauds phenomenon Livedo reticularis Deep vein thrombosis

overview of the most common clinical ndings. Venous thrombosis, along with its complications, is more common than arterial thrombosis. In a cohort of 1000 patients, the rst symptom was deep vein thrombosis in the leg in 32% and pulmonary embolism in 14%.3 Other vessels such as renal, hepatic, subclavian, and retinal veins; cerebral sinuses; and vena cava are more often affected than in thrombosis not related to antiphospholipid syndrome.3 The most common arterial thrombotic events are stroke and transient ischaemic attack, which are the initial clinical manifestation in 13% and in 7% of patients, respectively.3 Recurrent thrombotic events are common. The vascular pattern of recurrent thrombosis is fairly consistent for venous thrombosis (70% venous recurrence) and arterial thrombosis (90% arterial recurrence).w23

Fig 2 | Clinical manifestations of antiphospholipid syndrome

of complement at the fetomaternal interface, resulting in an impaired exchange of blood components between mother and fetus, which can lead to early miscarriage, pre-eclampsia, intrauterine growth restriction, or even intrauterine fetal death.

Cerebral involvement Cerebral involvement is common in antiphospholipid syndrome and was highlighted in the original description of the syndrome.1 w24 Cerebral ischaemia, migraine, cognitive dysfunction, seizures, chorea, transverse myelitis, psychosis, depression, and Guillain-Barr syndrome have all been associated with the presence of antiphospholipid antibodies.w19 Despite a strong observed association between chronic headache, including migraine, and antiphospholipid syndrome,w25 studies have shown contradictory results.w26 An association has been reported between valvular heart disease and central nervous system manifestations of the syndrome, which suggests that c erebral emboli from valvular lesions may be a risk.w27 Involvement of other organs The most common cardiac abnormality in patients with antiphospholipid syndrome is non-bacterial thrombotic endocarditis characterised by adherent platelet-brin thrombi on the endocardial surface of valves, which has been reported in 11.6% of patients during the evolution of disease.3 w28 Myocardial infarction is the presenting symptom of the syndrome in 2.8% of patients.3
Box 4 | Situations when you should test for antiphospholipid antibodies Thrombosis Arterial thrombosis before the age of 50 Unprovoked venous thrombosis before the age of 50 Recurrent thrombosis Thrombosis at an unusual site Patients with both arterial and venous thrombotic events Any patient admitted with thrombotic microangiopathy of unknown aetiology Obstetric manifestations One or more unexplained fetal loss after 10 weeks gestation Unexplained severe intrauterine growth restriction Early or severe pre-eclampsia Three or more spontaneous miscarriages before 10 weeks gestation Patients with systemic lupus erythematosus At baseline Repeat testing before pregnancy, surgery, transplantation, and use of oestrogen containing treatments, or in the presence of a new neurological, vascular, or obstetric event
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How do patients with antiphospholipid syndrome present? The clinical features of antiphospholipid syndrome are diverse and can affect all organ systems. Figure 2 gives an
Box 3 | Conditions that point to antiphospholipid syndrome Red flags Unexplained deep vein thrombosis or pulmonary embolism in patients under 50 Stroke in patients under 50 Transient ischaemic attack in patients under 50 Recurrent thrombosis Thrombosis at an unusual site Unexplained fetal loss after 10 weeks gestation Severe or early pre-eclampsia Severe intrauterine growth restriction Pre-eclampsia with severe thrombocytopenia Cardiac valve disease (in combination with other symptoms in this box) A new diagnosis of systemic lupus erythematosus Yellow flags Livedo reticularis Raynauds phenomenon Unexplained persistent thrombocytopenia Recurrent early pregnancy loss
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rospective studies have shown that antiphospholipid P anti bodies are associated with an increased risk of myocardial infarction.w8 w10 Thrombosis can occur anywhere in the renal vasculature. Occlusion of the renal veins and arterial trunk can occur, and microthrombi in glomerular capillaries can cause rapid decline of renal function.3 In secondary antiphospholipid syndrome, no prospective studies have looked at whether antiphospholipid antibodies worsen the outcome for traditional lupus, but retrospective analyses provide good evidence for this.w29 Haematological manifestations, such as thrombocytopenia and haemolytic anaemia, and dermal symptoms, such as livedo reticularis, occur in 10-30% of patients, although these features are not included in the classication criteria.3 Box 3 lists red ag and yellow ag conditions that indicate when antiphospholipid syndrome should be included in a differential diagnosis.

TIPS FOR NON-SPECIALISTS Early recognition of antiphospholipid syndrome helps prevent recurrent thrombosis and recurrent maternal and fetal morbidity A delayed diagnosis can cause permanent disability, as a result of uncontrolled thrombosis formation, or even death When testing for this syndrome, perform all three laboratory tests in box 1 Try to obtain the first test results before starting anticoagulants, which influence the results the lupus anticoagulant test Refer patients with a positive test result to a specialist Pregnancy carries a high risk, and women should be managed at specialised centres Traditional risk factors for cardiovascular disease increase the risk of thrombosis in this syndrome, even at young age. Provide support for patients to stop smoking, lose weight, and avoid oral contraception and hormone replacement therapy

Maternal and fetal effects in pregnancy Obstetric criteria used to define antiphospholipid syndrome are fetal loss after 10 weeks gestation, three or more unexplained consecutive embryonic losses before the 10th week of gestation, and pre-eclampsia or features of placental insufficiency associated with the premature birth of a morphologically normal neonate before the 34th week of gestation.3 Other manifestations that are not stated in the criteria, but are sequelae of the syndrome, are pregnancy related maternal thrombosis and unexplained intrauterine growth restriction. Late fetal loss is strongly associated with the presence of antiphospholipid antibodies, particularly lupus anticoagulant. Prospective studies have shown that positive lupus anticoagulant or high titres of cardiolipin IgG increase the risk of recurrent adverse outcome in a subsequent pregnancy.w30 w31 Evidence for a causal association between antiphospholipid antibodies and early miscarriage is limited.10 Early miscarriage is relatively common and has many causes, of which fetal chromosomal abnormalities are the most likely. Observational studies of the association between antiphospholipid syndrome and recurrent early miscarriage are likely to be heavily confounded, especially by inclusion of women with sporadic rather than recurrent miscarriage. International guidelines therefore advise screening for antiphospholipid an tibodies only in women with more than three early miscarriages.1314
ONGOING RESEARCH AND FUTURE CHALLENGES To clarify the relation between inflammation and thrombosis in antiphospholipid syndrome To unravel the effects of different antiphospholipid antibodies on haemostasis, endothelial activation, and placental invasiveness To find more specific tests for antiphospholipid antibodies that correlate better with clinical symptoms. Lupus anticoagulant inducing anti-2 glycoprotein I antibodies and anti-2 glycoprotein I domain I antibodies are promising new binding targets8 To identify the role of newer, preferably oral, anticoagulants in treatment To identify the role of anti-inflammatory drugs (rituximab, anticomplement agents, statins) To perform well designed randomised controlled trials in pregnancy related settings

Women with antiphospholipid syndrome have an increased incidence of early or severe pre-eclampsia, which often leads to iatrogenic preterm birth due to termination of pregnancy for maternal or fetal reasons. Preeclampsia with severe thrombocytopenia may also point towards the presence of the syndrome, and is a red ag condition (box 3).15

Who should be tested for antiphospholipid antibodies? Box 4 lists the indications for testing for antiphospholipid antibodies.16 Systemic lupus erythematosus Testing for antiphospholipid antibodies is recommended in the initial evaluation of patients with SLE and should be re-evaluated if new risk factors for thromboembolic events emerge.17 Lupus anticoagulant and persistent anticardiolipin antibodies increase the risk of thromboembolic events in patients with SLE.w32 w33 Data on antiphospholipid antibodies can help when interpreting new symptoms in these patients and may inuence therapeutic decisions in situations with increased thromboembolic risk, such as surgery, pregnancy, puerperium, or the use of oestrogen containing drugs. Pregnancy A recent prospective study of pregnant women with only one previous spontaneous abortion before the 10th week of gestation reported that the presence of antiphospholipid antibodies signicantly increased the risk of embryonic loss, pre-eclampsia, and intrauterine growth restriction in the next pregnancy.w30 However, after single pregnancy loss, most subsequent pregnancies are u neventful without treatment. Therefore, testing after one early miscarriage, or even testing all women who plan to become pregnant, is not advised.16 How can antiphospholipid syndrome be treated? Antithrombotic agents aim to reduce the risk of recurrent thromboembolism and are the mainstay of treatment.
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Previous thrombosis Yes No

Proximal deep vein thrombosis or pulmonary embolism Warfarin (INR 2.0-3.0) No transient risk factor: long term anticoagulation Transient/reversible risk factor: 3-6 months

Arterial thrombosis

Pregnant Therapeutic low molecular weight heparin monitor anti-FX Change to warfarin (INR 2.0-3.0) postpartum Yes

Pregnant No No treatment

Cerebral

Non-cerebral

Previous pregnancy morbidity satisfying antiphospholipid syndrome classification criteria Yes Unfractionated heparin or low molecular weight heparin plus aspirin

Cardioembolic Warfarin (INR 2.0-3.0)

Noncardioembolic Warfarin (INR 2.0-3.0) or clopidogrel or aspirin dipyridamole

No No treatment

Cardiac Aspirin + clopidogrel stent

Non-cardiac Warfarin (INR 2.0-3.0)

Recurrent episode while receiving warfarin Warfarin (INR 3.0-4.0) or warfarin (INR 2.0-3.0) + low dose aspirin or if unstable INR low molecular weight heparin

Fig 3 | Treatment algorithm for antiphospholipid syndrome. Adapted, with permission, from Giannakopoulos et al18

Recent guidelines on treating the syndrome subdivide patients into those with venous thrombosis, those with arterial thrombosis, and those with obstetric anti phospholipid syndrome.18 Figure 3 shows a treatment algorithm containing an overview of these guidelines.

First episode For a first episode of unprovoked venous thrombosis or thromboembolism associated with persistent positive antiphospholipid antibodies, long term anticoagulation with vitamin K antagonists, such as warfarin, is recommended to reduce the risk of recurrence of a
ADDITIONAL EDUCATIONAL RESOURCES Resources for healthcare professionals References 16 and 18 in the main reference list provide excellent reviews on recent developments in the diagnosis and treatment of antiphospholipid syndrome References 13, 14, 19, and 24 all provide international guidelines on various aspects of the antiphospholipid syndrome Garcia D, Crowther MA, Ageno W. Practical management of coagulopathy associated with warfarin. BMJ 2010;340:c1813. Useful strategies for patients being treated with a vitamin K antagonist who present with an international normalised ratio outside the therapeutic range Resources for patients Thackray K. Sticky blood explained. Braiswick, 2003. A personal account of dealing with the condition. Holden T. Positive options for antiphospholipid antibody syndrome. Hunter House, 2003. UpToDate (www.uptodate.com/patients/content/topic.do?topicKey=~CQUbGyAA8 E5yqH&selectedTitle=1%7E150&source=search_result)Patient information about antiphospholipid syndrome Agency for Healthcare Research and Quality (www.healthcare411.ahrq.gov/videocast. aspx?id=555)A video with general information for patients on anticoagulants YouTube (www.youtube.com/watch?v=V3J8BLkZyhU)Video in which Dr Hughes of the London Lupus Centre explains the antiphospholipid syndrome and two patients relate their experiences with recurrent miscarriages and stroke
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thrombotic event.19 However, if a reversible risk factor for thr omboembolismsuch as surgery, immobilisation, oestrogen therapy, or pregnancyis reliably eliminated indenite anticoagulation may not be justied.18 The only prospective study focusing on arterial cerebral events showed similar rates of recurrent thromboembolism and risk of major bleeding in patients treated with warfarin or low dose aspirin.20 However, inappropriate criteria for dening antiphospholipid antibody positivity limit the generalisability of this study.21 In patients with antiphospholipid syndrome and stroke, long term anticoagulation with warfarin or low dose aspirin is advised. Two randomised controlled trials compared high intensity anticoagulation (aimed at an international normalised ratio (INR) of 3.1-4) with moderate intensity anticoagulation (INR 2-3) for the prevention of recurrent venous and arterial thrombotic events in non-pregnant adults with antiphospholipid syndrome. Both trials used oral warfa rin and found that high intensity treatment was no better at preventing thrombotic events.2223 When results were pooled, the risk of bleeding was slightly increased in patients on high intensity treatment.w34 The limitations of these trials (patients with arterial events were in the minority and many patients randomised to a target INR >3 did not achieve this target), and the fact that the results contradict those of observational st udies, mean that treatment aims are still a point of ongoing debate.21 International guidelines and systematic reviews currently recommend aiming for an INR between 2 and 3.18192425

Preventing obstetric complications Several strategies have been proposed to prevent maternal thrombotic complications and improve the outcome of pregnancy in women with antiphospholipid syndrome.
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Table 2 |Treatment of patients with persistent positive antiphospholipid antibodies in pregnancy*

Clinical presentation Women (including patients with SLE) with previous thrombosis Women with late fetal loss (>10 weeks) Women with recurrent miscarriage (<10 weeks) Women with history of early or severe pre-eclampsia or intrauterine growth restriction Women with persistently positive antiphospholipid antibodies without clinical symptoms Women with SLE without previous obstetric or thrombotic complications Women with SLE with previous obstetric complications Treatment regimen in pregnancy Graduated elastic compression stockings; weight adjusted, full dose LMWH from <6 weeks gestation Low dose aspirin or LMWH Low dose aspirin plus LMWH Low dose aspirin. Consider additional LMWH Treatment regimen postpartum Graduated elastic compression stockings; 6 weeks LMWH or warfarin At least 7 days LMWH or warfarin At least 7 days LMWH or warfarin At least 7 days LMWH or warfarin Evidence level C C A C

Close surveillance

At least 7 days LMWH or warfarin

Low dose aspirin Low dose aspirin plus LMWH

At least 7 days LMWH or warfarin At least 7 days LMWH or warfarin

C C

*Abbreviations: LMWH=low molecular weight heparin; SLE=systemic lupus erythematosus. A=consistent randomised controlled trials or cohort studies (or both); B=consistent retrospective cohort, exploratory cohort, or case control studies or extrapolations from level A studies; C=case series or extrapolations from level B studies; D=expert opinion without explicit critical appraisal. Warfarin crosses the placenta, is teratogenic, and must be avoided in pregnancy. If possible try to enrol patients in a randomised controlled trial.

Few well designed trials have been carried out and studied populations are heterogeneous, so the level of evidence for all treatment options is low. Table 2 gives suggestions for primary and secondary prevention of thrombosis and adverse pregnancy outcome; these are based on the l imited available evidence and our own experience.

ntagonists is effective for secondary prevention of throma bosis. In pregnant patients with SLE and antiphospholipid syndrome, combined unfractionated heparin or low molecular weight heparin and aspirin reduce pregnancy loss and thrombosis and should be considered.28

Preventing maternal thrombotic complications Warfarin crosses the placenta and is teratogenic in the rst trimester of pregnancy so low molecular weight heparins are the agents of choice for antenatal thromboprophylaxis.1426 Observational studies have shown that low molecular weight heparin is at least as effective as unfractionated heparin and safer.1426 Women who are on long term warfarin because of previous thrombosis should switch to heparin when trying to conceive or on conrmation of conception. The dose of heparin will depend on the womans clinical history and should be discussed with a haematologist. Preventing adverse pregnancy outcome A meta-analysis of intervention trials for recurrent (early) miscarriage have concluded that heparin with low dose aspirin reduces pregnancy loss by 54%.27 No randomised controlled trials have investigated prevention in patients with a history of late miscarriage, fetal death, and intra uterine growth restriction. Most clinicians would consider treatment with low dose aspirin and heparin (mostly low molecular weight heparin) in such cases. In patients with antiphospholipid antibodies and a history of severe preeclampsia at least low dose aspirin (75-80 mg once daily) is recommended.18 Glucocorticoids, cytotoxic agents, and intravenous immunoglobulin have no conrmed benet and may even be teratogenic.18 Systemic lupus erythematosus In patients with SLE and antiphospholipid antibodies, low dose aspirin may be considered for primary pr evention of thrombosis and pregnancy loss.28 In non-pregnant patients with SLE and antiphospholipid syndrome associated thrombosis, long term anticoagulation with vitamin K
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Catastrophic antiphospholipid syndrome Box 2 summarises the management and characteristics of this rare manifestation of the syndrome. Future challenges for management A reliable diagnostic test is still needed. Antiphospholipid syndrome mimics many other conditions, which leads to misdiagnosis and thwarts efforts to perform studies of sufcient size to give unequivocal support for diagnostic and treatment strategies. However, left untreated the syndrome can have serious sequelae. We advise that any patient with a suspected antiphospholipid syndrome should be seen by a multidisciplinary team of specialists that ideally includes a rheumatologist, haematologist, neurologist, nephrologist, and obstetrician for diagnosis, treatment, and education.
Thanks to L A van Es, J P Vandenbroucke, A P van Rossum, and F J M van der Meer for advice and critical manuscript review; JW Schoones for help with the literature search; and F van Meurs for producing fig 2. Contributors: DC and IMB had the idea for the article. DC did the literature search. DC, GMS-B, KWMB, and SPB wrote and revised sections with which they were most familiar. IMB was involved throughout with the process and provided histological images. DC is guarantor. Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: (1) No financial support for the submitted work from anyone other than their employer; (2) No financial relationships with commercial entities that might have an interest in the submitted work; (3) No spouses, partners, or children with relationships with commercial entities that might have an interest in the submitted work; (4) No non-financial interests that may be relevant to the submitted work. Provenance and peer review: Commissioned; externally peer reviewed. Patient consent obtained.
1 2 Hughes GR. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. BMJ 1983;287:1088-9. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295-306. 1131

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Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1000 patients. Arthritis Rheum 2002;46:1019-27. Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, Piette JC, et al. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 2003;12:530-4. Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, et al. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost 2009;7:1737-40. Pierangeli SS, Harris EN. A protocol for determination of anticardiolipin antibodies by ELISA. Nat Protoc 2008;3:840-8. Avcin T, Cimaz R, Silverman ED, Cervera R, Gattorno M, Garay S, et al. Pediatric antiphospholipid syndrome: clinical and immunologic features of 121 patients in an international registry. Pediatrics 2008;122:e1100-7. De Laat B, Mertens K, de Groot PG. Mechanisms of disease: antiphospholipid antibodies-from clinical association to pathological mechanism. Nat Clin Pract Rheumatol 2008;4:192-9. Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003;101:1827-32. 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. Petri M. Epidemiology of the antiphospholipid antibody syndrome. J Autoimmun 2000;15:145-51. Pierangeli SS, Chen PP, Raschi E, Scurati S, Grossi C, Borghi MO, et al. Antiphospholipid antibodies and the antiphospholipid syndrome: pathogenic mechanisms. Semin Thromb Hemost 2008;34:236-50. Jauniaux E, Farquharson RG, Christiansen OB, Exalto N. Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod 2006;21:2216-22. Royal College of Gynaecologists. Reducing the risk of thrombosis and embolism in pregnancy and the puerperium. Green-top guideline. 2009. www.rcog.org.uk/womens-health/clinical-guidance/reducing-risk-ofthrombosis-greentop37. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 2005;330:565. Giannakopoulos B, Passam F, Ioannou Y, Krilis SA. How we diagnose the antiphospholipid syndrome. Blood 2009;113:985-94.

17 Mosca M, Tani C, Aringer M, Bombardieri S, Boumpas D, Brey R, et al. European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies. Ann Rheum Dis 2010; published online 21 April. 18 Giannakopoulos B, Krilis SA. How I treat the antiphospholipid syndrome. Blood 2009;114:2020-30. 19 Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed). Chest 2008;133(6 suppl):454S-545S. 20 Levine SR, Brey RL, Tilley BC, Thompson JL, Sacco RL, Sciacca RR, et al. Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. JAMA 2004;291:576-84. 21 Ruiz-Irastorza G, Hunt BJ, Khamashta MA. A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum 2007;57:1487-95. 22 Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003;349:1133-8. 23 Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, et al. A randomized clinical trial of high-intensity warfarin vs conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 2005;3:848-53. 24 Hirsh J, Guyatt G, Albers GW, Harrington R, Schunemann HJ; American College of Chest Physician. Antithrombotic and thrombolytic therapy: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed). Chest 2008;133(6 suppl):110S-2S. 25 Lim W, Crowther MA, Eikelboom JW. Management of antiphospholipid antibody syndrome: a systematic review. JAMA 2006;295:1050-7. 26 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 edition). Chest 2008;133(6 suppl):844S-86S. 27 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;2:CD002859. 28 Bertsias G, Ioannidis JP, Boletis J, Bombardieri S, Cervera R, Dostal C, et al. EULAR recommendations for the management of systemic lupus erythematosus. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. Ann Rheum Dis 2008;67:195-205.

ANSWERS TO ENDGAMES, p 1145. For long answers go to the Education channel on bmj.com Statistical Question Nested case-control studies
Answers a and b are true; c and d are false.

case report An elderly woman with recurrent episodes of confusion

1 The most likely diagnosis is a hypoglycaemic disorder, although further investigations are warranted to look for an insulinoma. 2 The diagnosis could be conrmed by instigating a supervised 72 hour fast, with measurement of plasma insulin, C-peptide, proinsulin, and -hydroxybutyrate concentrations if the patient develops hypoglycaemia (plasma glucose <3 mmol/l) during the fast. 3 The initial investigation to localise the underlying pathology of the hypoglycaemia symptoms is computed tomography or magnetic resonance imaging of the pancreas. 4 The best treatment for insulinomas is surgical resection of the tumour.

Chest radiograph showing cardiomegaly (orange arrow) and pulmonary plethora (yellow arrow). Wrist radiograph showing widening (yellow arrows), cupping (red arrow), and fraying (orange arrow) of the epiphysis of the right radius and ulna

Picture QuiZ An infant with respiratory distress

1 The chest radiograph shows cardiomegaly and pulmonary plethora. The wrist radiograph shows widening, cupping, and fraying of the epiphysis of the right radius and ulna suggestive of rickets. 2 Electrocardiography, echocardiography, and measurement of vitamin D and parathyroid hormone concentrations. 3 Cardiomyopathy secondary to vitamin D deciency. 4 Vitamin D and calcium supplementation for the rickets and anti-heart failure drugs.

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