Antiphospholipid syndrome

01Definition and overview

Antiphospholipid syndrome (APS) is an autoimmune disease in which persistent antiphospholipid antibodies cause thrombosis in arteries, veins or small vessels, or complications of pregnancy. The antibodies are directed mostly not at phospholipids themselves but at proteins that bind them, above all β2-glycoprotein I, and prothrombin.

It is described by its setting and its form:

• primary APS, on its own, in about half of patients;
• APS with another autoimmune disease, mostly systemic lupus erythematosus, in about a third;
• thrombotic APS and obstetric APS, which can occur alone or together;
• catastrophic APS, a rare storm of small-vessel thrombosis in many organs.

The names can mislead. Lupus anticoagulant is not a test for lupus, and in the body it is procoagulant: it prolongs clotting in the test tube, because the antibodies compete with clotting factors for the phospholipid in the reagent, but in the body it promotes thrombosis. A patient with the antibodies but no clinical event is an antiphospholipid antibody carrier, not a patient with the syndrome.

02Etiology and pathophysiology

Where the antibodies come from

Antiphospholipid antibodies, like those of lupus, are thought to arise against phospholipids and β2-glycoprotein I exposed on apoptotic cells, in people with a genetic tendency, linked to several HLA class II genes. Infections, notably syphilis, hepatitis C, HIV, Epstein–Barr virus and many acute infections, and drugs such as chlorpromazine and procainamide can induce antibodies too, but these are usually transient, low in titre, IgM and not directed at β2-glycoprotein I, and they rarely cause thrombosis.

How they cause thrombosis

1. 1

   Binding

   β2-glycoprotein I opens up when it binds negatively charged phospholipid on cell surfaces, exposing an epitope on its first domain (domain I). Pathogenic antibodies bind there.
2. 2

   Activated cells

   The antibody–β2-glycoprotein I complex signals through receptors on endothelial cells, monocytes and platelets. Endothelium and monocytes express tissue factor and adhesion molecules, platelets aggregate, and neutrophils release extracellular traps.
3. 3

   Lost protection

   The antibodies disrupt natural anticoagulants: they displace annexin A5, which shields phospholipid surfaces, and impair protein C and fibrinolysis.
4. 4

   Complement

   Complement is activated; C5a amplifies the attack on endothelium and, in pregnancy, on the placenta.

Antibodies alone are often not enough: a "second hit" such as surgery, immobility, pregnancy, oestrogen, smoking or infection usually triggers the clot, which is why risk factors matter so much.

In pregnancy

The antibodies bind trophoblast, impairing its invasion of the maternal spiral arteries and its hormone production, and they cause inflammation and complement activation in the placenta. Thrombosis plays a smaller part than once thought. The result is early miscarriage, fetal death, early severe pre-eclampsia and placental insufficiency with growth restriction. Heparin probably helps partly by blocking complement and antibody binding, not only clotting.

03Clinical features

Thrombosis

APS is one of the few causes of thrombophilia that causes both venous and arterial thrombosis.

• Venous: deep vein thrombosis of the legs is the commonest event, in about a third of patients, with or without pulmonary embolism; thrombosis in unusual sites (cerebral venous sinuses, hepatic, portal, mesenteric, renal or adrenal veins) should raise the question.
• Arterial: stroke and transient ischaemic attack, the commonest arterial events, often in young people; myocardial infarction; limb, retinal, renal and mesenteric arterial occlusion. Stroke or myocardial infarction in a person under 50 without obvious cause calls for antiphospholipid tests.
• Microvascular: antiphospholipid nephropathy, a thrombotic microangiopathy with hypertension, proteinuria and kidney failure; diffuse alveolar haemorrhage; skin necrosis and livedoid vasculopathy; myocardial microvascular disease; adrenal haemorrhage with adrenal failure.

Pregnancy morbidity

• three or more unexplained consecutive miscarriages before 10 weeks;
• one or more unexplained fetal deaths at 10 weeks or later with a normal fetus;
• birth before 34 weeks because of severe pre-eclampsia, eclampsia or placental insufficiency.

Other features

These are not thromboses but are typical, and the 2023 criteria count some of them:

• livedo racemosa, a broken, irregular violaceous network on the skin, more specific than the regular livedo reticularis;
• thrombocytopenia, usually mild (above 50 × 10⁹/L), which does not protect from thrombosis;
• valve disease: thickening and sterile vegetations (Libman–Sacks), mostly mitral and aortic, which can embolise or leak;
• neurological: migraine-like headache, cognitive impairment, white-matter lesions, chorea, seizures;
• autoimmune haemolytic anaemia.

Catastrophic APS

Catastrophic antiphospholipid syndrome (CAPS) affects under 1 per cent of patients. Small-vessel thrombosis strikes three or more organs within a week, typically kidneys, lungs, brain, heart, skin and gut, with a systemic inflammatory response, and often thrombocytopenia and haemolysis that mimic thrombotic thrombocytopenic purpura or disseminated intravascular coagulation. Infection is the commonest trigger; surgery, stopping anticoagulation, pregnancy and the puerperium, and cancer are others. It can be the first presentation.

All four make definite CAPS. Probable CAPS is the same picture with one part incomplete: only two organs, no biopsy, the third organ affected within a month rather than a week, or no repeat antibody test because the patient died early.

04Diagnosis and management

Who to test

Testing is targeted, because antibodies without events are common and low-titre results mislead. It is done after an unprovoked venous thrombosis in a young person, thrombosis at an unusual site, arterial thrombosis under about 50, recurrent thrombosis, the pregnancy morbidity above, and in every patient with lupus. It is also done in unexplained prolonged aPTT, livedo racemosa, thrombocytopenia or valve vegetations.

The three tests

The detail of the antibodies is in humoral immunity in rheumatic diseases; in brief:

The risk profile:

• high-risk profile: lupus anticoagulant, positivity in two or all three tests, or persistently high titres;
• low-risk profile: isolated anticardiolipin or anti-β2-glycoprotein I at low to moderate titre, particularly if transient.

Pitfalls of testing

• Persistence: antibodies rise for a few weeks with infections and acute illness, so a positive test is repeated at least 12 weeks later.
• Anticoagulants distort the lupus anticoagulant test. Direct oral anticoagulants (rivaroxaban, apixaban, edoxaban, dabigatran) cause false positives, especially in the dilute Russell viper venom time. Warfarin prolongs both clotting tests, so they are hard to read unless the INR is low or the sample is mixed with normal plasma; heparin is neutralised by most reagents only up to a limit. Ideally the test is done before anticoagulation starts or after it stops; DOAC-removing agents or venom-based tests (Taipan and ecarin) help in specialised laboratories.
• The ELISAs for anticardiolipin and anti-β2-glycoprotein I are not affected by anticoagulants, and can be done at any time.
• The acute phase changes clotting: a raised factor VIII can shorten the aPTT and hide a lupus anticoagulant, and CRP can interfere with some reagents, so results near a thrombosis are confirmed later.
• Antibodies against prothrombin and phosphatidylserine, and IgA antibodies, are not part of the criteria but may help in patients with typical events and negative tests (sometimes called seronegative APS).
• Lupus anticoagulant can also raise the INR measured by point-of-care machines, overestimating anticoagulation; a laboratory INR, or a chromogenic factor X assay, checks it.

Classification: from Sydney 2006 to ACR/EULAR 2023

The revised Sapporo criteria of Sydney 2006 needed one clinical criterion (an objectively confirmed thrombosis, or the pregnancy morbidity above) and one laboratory criterion (lupus anticoagulant, or anticardiolipin or anti-β2-glycoprotein I IgG or IgM at medium or high titre) present twice at least 12 weeks apart, with no more than five years between test and event. They were sensitive but treated a provoked clot like an unprovoked one.

The 2023 ACR/EULAR criteria replaced them for research. After an entry criterion, a positive antiphospholipid test within three years of a clinical event, they add weighted points:

Only the highest item in each domain counts, and a clinical item counts only if no other cause is at least as likely. At least 3 clinical points and at least 3 laboratory points classify APS. The new criteria are more specific (99 against 86 per cent) and less sensitive (84 against 99 per cent) than the Sydney criteria. They are built for studies: a clinician can treat a patient with a typical picture who falls short, and UK haematology guidance keeps them for research rather than routine diagnosis.

Management

Every patient has their other risk factors addressed: stopping smoking, treating hypertension, lipids and diabetes, avoiding oestrogen-containing contraception and hormone replacement, and thromboprophylaxis in high-risk situations such as surgery, immobility and the puerperium.

Why not a direct oral anticoagulant

Direct oral anticoagulants are not recommended in antiphospholipid syndrome, above all in triple-positive patients and after arterial thrombosis. In the TRAPS trial of triple-positive patients, rivaroxaban was stopped early after 12 per cent had a stroke or myocardial infarction, against none on warfarin. In a smaller trial of apixaban, 6 of 23 patients had a stroke against none on warfarin, and the trial ended early. A meta-analysis of the randomised trials found about five times the odds of arterial events, strokes above all, with no fewer bleeds. In 2019 the European Medicines Agency's safety committee had the product information of all four changed to advise against them in APS with a history of thrombosis, particularly in triple-positive patients. European recommendations say rivaroxaban should not be used with triple positivity and prefer a vitamin K antagonist after arterial events; they allow a DOAC to be considered only after venous thrombosis, in a patient who cannot reach the target INR despite good adherence or cannot take a vitamin K antagonist. UK guidance does not recommend DOACs after arterial events and recommends against starting them in triple-positive patients.

Pregnancy

Pregnancy is planned with a specialist team. Warfarin is teratogenic between about 6 and 12 weeks, so women on it are switched to heparin as soon as pregnancy is confirmed, and direct oral anticoagulants are not used. Aspirin starts before conception or early in pregnancy and heparin when the pregnancy is confirmed, both continued until delivery, with heparin for about six weeks after. Uterine artery Doppler and fetal growth scans watch for placental insufficiency. When losses recur despite this, therapeutic-dose heparin, hydroxychloroquine or low-dose prednisolone in the first trimester may be added. Warfarin and heparin are both compatible with breastfeeding.

Catastrophic APS

CAPS is managed in intensive care with triple therapy:

1. 1

   Anticoagulation

   Intravenous unfractionated heparin, which can be stopped quickly if bleeding or a procedure demands it.
2. 2

   Glucocorticoids

   High doses, often intravenous methylprednisolone pulses, to damp the inflammatory response.
3. 3

   Antibody removal

   Plasma exchange and/or intravenous immunoglobulin.

The trigger, usually infection, is treated at the same time. In refractory disease rituximab or the complement C5 inhibitor eculizumab have been used, and cyclophosphamide is added when CAPS complicates active lupus.

05Epidemiology

APS is estimated to affect about 2 people per 100,000 a year and about 50 per 100,000 in all, though it is underdiagnosed. Most patients are young or middle-aged adults, and women predominate, mainly because of obstetric APS and lupus; in a European cohort of 1,000 patients, 82 per cent were women. Antiphospholipid antibodies are found in about 1 to 5 per cent of healthy people, more in older people, mostly at low titre and transiently. They are found in about 1 in 10 people with deep vein thrombosis, about 1 in 7 with stroke and 1 in 9 with myocardial infarction (more under 50), and about 1 in 16 with pregnancy morbidity. About a third of patients with lupus have the antibodies, and a smaller share develops the syndrome.

06Prognosis

Without anticoagulation the risk of recurrent thrombosis after a first event is high, and a recurrence tends to repeat the type of the first: arterial after arterial, venous after venous. Warfarin lowers the risk greatly but does not abolish it; in a European cohort of 1,000 patients, about 1 in 6 had a thrombosis within five years despite treatment, and 9 per cent died within ten years, mostly from severe thrombosis and infection. Catastrophic APS still kills more than a third of patients: 37 per cent of episodes in the international registry, more with lupus.

Asymptomatic carriers with a triple-positive profile have a first thrombosis at about 5 per cent a year; those with a single low-titre antibody have a much lower risk. Men, other thrombotic risk factors and lupus raise it. Under treatment, about seven in ten pregnancies in women with APS end in a live birth, but prematurity and growth restriction remain common.

Patients need lifelong review: INR control, bleeding, new manifestations such as valve disease, kidney involvement or cognitive decline, signs of lupus developing in primary APS, and their cardiovascular risk factors.