QuestionSBA
QuestionChoice
While aCL antibodies can be found in Behçet's syndrome, there would likely also be a history of recurrent aphthous ulcers and uveitis. With positive LA antibodies, this points to antiphospholipid syndrome
33029
b
Behçet's syndrome
QuestionChoice
Protein C deficiency is a rare cause of thrombosis, which can present with recurrent miscarriages. It is not, however, associated with LA, aCL, or anti-b2-glycoprotein I antibodies
33032
e
Protein C deficiency
QuestionChoice
The name lupus anticoagulant is a misnomer and has only a weak association with SLE. It is a prothrombotic antibody where most patients with positive antibodies do not have SLE, and only a small proportion proceeds to develop the disease. The patient is otherwise well with no other systemic features and so makes the diagnosis of SLE unlikely
33031
d
Systemic lupus erythematosus (SLE)
QuestionChoice
All three of the antibodies above can be present in antiphospholipid syndrome, resulting in thrombophilia. This can often present as either unexplained recurrent miscarriages or vascular thrombosis
33028
a
Antiphospholipid syndrome
QuestionChoice
Factor V Leiden is a common cause of thrombosis, which can present with recurrent miscarriages. It is not, however, associated with LA, aCL, or anti-b2-glycoprotein I antibodies
33030
c
Factor V Leiden
Concept
Chapter
# Summary

Antiphospholipid syndrome (APS) is a systemic autoimmune disease that occurs in patients with antiphospholipid antibodies, causing thrombosis of veins, arteries and small vessels. It may occur alone or in association with another condition such as systemic lupus erythematosus. Common manifestations include thrombosis of peripheral arteries or veins, adverse pregnancy outcomes including recurrent miscarriage and intrauterine growth restriction, pulmonary embolism, stroke, retinal thrombosis and valvular disease. Key investigations include a full blood count, clotting screen (aPTT is typically paradoxically raised) and testing for anti-cardiolipin, anti-beta2-glycoprotein I and lupus anticoagulant antibodies. Management involves treating thrombotic episodes with anticoagulation, with warfarin being the preferred option. Asymptomatic APS does not require treatment. Pregnant women with recurrent pregnancy loss require low molecular weight heparin and aspirin throughout pregnancy.

# Definition

Antiphospholipid syndrome (APS) is an autoimmune condition characterised by the presence of antiphospholipid antibodies with clinical manifestations of venous or arterial thrombosis and adverse pregnancy outcomes. 

# Epidemiology

- Prevalence of APS in the UK is 50 per 100,000 in women and 9.8 per 100,000 in men
- Onset is typically between the ages of 20 and 50
- Antiphospholipid antibodies are found in 1-5% of the healthy population, and in 30% of people with systemic lupus erythematosus
- Approximately 1 in 6 people under the age of 50 with strokes, deep vein thrombosis, myocardial infarct or recurrent miscarriages have APS 

# Aetiology

APS occurs due to antiphospholipid antibodies which cross-react with cell membrane phospholipids, leading to a hypercoagulable state that predisposes patients to vascular thrombosis.

APS can occur in isolation (primary APS), or in association with another autoimmune disease such as:

- Systemic lupus erythematosus (SLE)
- Rheumatoid arthritis
- Sjogren's syndrome
- Systemic sclerosis
- Dermatomyositis

More rarely, cases may be associated with malignancies (e.g. lymphoma) or infections (e.g. HIV).

# Diagnostic Criteria

APS is diagnosed using the **revised Sapporo criteria** - patients need at least one clinical and one laboratory criteria.

**Clinical criteria:**

- Vascular thrombosis 
- At least 1 episode of venous/arterial/small vessel thrombosis
- Not including superficial thrombophlebitis
- This should be unprovoked or provoked by a minor risk factor only
- Pregnancy morbidity with any of:
- 3 miscarriages < 10 weeks
- 1 miscarriage _<_10 weeks
- Premature birth < 34 weeks

**Laboratory criteria:**

- On at least 2 occasions at least 12 weeks apart, any of the following are positive:
- Anticardiolipin antibodies
- Anti-beta2-glycoprotein I antibodies
- Lupus anticoagulant

# Signs and Symptoms

Clinical manifestations are due to thrombosis of arteries, veins or small vessels which may affect a variety of organ systems:

- Cerebral involvement e.g. ischaemic stroke, central venous sinus thrombosis (signs and symptoms include focal neurology such as weakness, sensory changes, dysphasia)
- Rashes e.g. livedo reticularis, skin ulceration
- Lung involvement e.g. pulmonary embolism, pulmonary hypertension (shortness of breath, haemoptysis, presyncope, tachycardia may occur)
- Cardiac involvement e.g. myocardial infarction, valvular disease (mitral regurgitation is most common), may have chest pain, peripheral oedema, shortness of breath
- Thrombosis of peripheral arteries leading to acute limb ischaemia (affected area will be cool; pallor, pulselessness, paraesthesia, paralysis and pain may be seen)
- Deep vein thrombosis, causing swelling, erythema and pain of the affected limb
- Obstetric complications including recurrent miscarriage, stillbirth, pre-eclampsia and intrauterine growth restriction
- Retinal thrombosis (either arterial or venous) leading to blurred vision and painless visual loss in one eye
- Adrenal infarction which may cause flank pain, as well as hypotension, fatigue and confusion
- Budd-Chiari syndrome (due to hepatic vein thrombosis) causing abdominal pain, ascites and hepatomegaly
- Mesenteric ischaemia causing abdominal pain, diarrhoea, nausea and vomiting
- Avascular necrosis of bone leading to localised severe pain
- Nephropathy which may present with nephrotic syndrome (e.g. oedema), hypertension or with flank pain and haematuria

[lightgallery] 

# Differential Diagnosis

- **Factor V Leiden** which is the commonest genetic thrombophilia and increases the risk of venous but not arterial thrombosis
- **Protein C or S deficiency** are also genetic conditions that increase the risk of venous thrombosis (and possibly arterial thrombosis to a small extent)
- **Antithrombin III deficiency** may be inherited or acquired (e.g. due to liver dysfunction, disseminated intravascular coagulation or nephrotic syndrome), causes venous thrombosis (and may also increase the risk of arterial thrombosis)
- **Malignancy** is a prothrombotic state for a multitude of reasons, including tumour cells activating the coagulation system, cancer treatments causing immobility and venous stasis and disrupting the endothelium (e.g. indwelling lines); risk of both arterial and venous thrombosis is increased 
- **Polycythaemia** may be primary (polycythaemia vera) or secondary (usually due to chronic hypoxia, e.g. in chronic obstructive pulmonary disease); causes an increase in blood viscosity that is associated with both arterial and venous thrombosis
- **Other causes of recurrent miscarriage** e.g. chromosomal abnormalities, uterine anomalies, cervical incompetence
- **Multiple sclerosis** may cause similar symptoms to repeated cerebral infarctions in APS, e.g. decline in mobility, visual loss, dysphasia and cognitive impairment

# Investigations

**Bedside tests:**

- Urine dip for proteinuria (which may occur in renal involvement, or indicate nephrotic syndrome as a differential)

**Blood tests:**

- Patients need to have at least one of the following antiphospholipid antibodies present on testing on two occasions at least 12 weeks apart:
- Lupus anticoagulant
- Anticardiolipin antibody
- Anti-beta2-glycoprotein I antibody
- Full blood count - may show thrombocytopenia and/or haemolytic anaemia
- Clotting screen - may show paradoxical prolongation of the aPTT
- U&Es looking for renal involvement
- Testing for SLE if secondary APS is suspected (e.g. antinuclear, anti-double-stranded DNA and anti-smith antibodies)
- Testing for other hypercoagulable states (e.g. factor V Leiden, protein C and S or antithrombin III deficiency) to rule out differentials

**Imaging tests:**

- Doppler ultrasound for suspected deep vein thrombosis
- CT or MRI of the brain for suspected stroke
- CT abdomen for suspected Budd-Chiari syndrome
- CT pulmonary angiography for suspected pulmonary embolism
- Transthoracic echocardiography for valvular disease and vegetations (Libman-Sacks endocarditis in SLE), and for pulmonary hypertension

# Management 

**Conservative management:**

- Asymptomatic APS does not require any specific treatment
- All patients should be advised on measures to reduce risk of cardiovascular disease
- Smoking cessation
- Regular exercise
- Maintaining a healthy diet and weight
- Avoiding alcohol excess
- Effective management of comorbid hypertension, diabetes and dyslipidemia
- Patients should avoid oestrogen-containing contraceptive and hormone replacement therapy as this further increases thrombosis risk 
- Joint management with other services (e.g. stroke, cardiology) is important after stroke, myocardial infarction etc.

**Medical management:**

- Anticoagulation is the mainstay of treatment for patients after a thrombotic event, which is usually given lifelong
- Warfarin is the anticoagulant of choice, with a target INR of 2-3 
- DOACs are not recommended
- A higher target INR should be considered in patients with recurrent thrombosis on warfarin (e.g. 3-4)
- If thrombotic episodes continue, immunomodulatory treatments (e.g. hydroxychloroquine) can be considered
- Adding an antiplatelet (e.g. aspirin) to warfarin treatment should be considered in patients after a stroke if they have additional vascular risk factors
- All patients with stroke should be started on statins
- Miscarriage prevention in APS is with low-dose aspirin and low molecular weight heparin (LMWH)
- Pregnant patients with APS should take 75-150 mg aspirin daily from 12 weeks gestation until delivery
- Warfarin is teratogenic and so should be switched to treatment dose LMWH during pregnancy; it is safe in breastfeeding and so can be switched back after birth

# Complications

- Catastrophic antiphospholipid syndrome is characterised by rapid-onset widespread small vessel thrombosis
- It causes multiorgan dysfunction, often with a systemic inflammatory response syndrome
- There may be an identifiable trigger, e.g. infection, surgery, pregnancy or subtherapeutic anticoagulation
- Unregulated complement activation occurs and reduced C3 and C4 levels are often seen
- Management involves triple therapy with treatment dose heparin, high-dose steroids and either IVIG or plasma exchange
- Recurrent cerebral infarction can cause cognitive impairment, seizures and vascular dementia
- Retinal artery or vein occlusion can lead to visual loss
- Chronic pulmonary emboli or thrombosis may lead to pulmonary hypertension
- Renal failure due to thrombosis may occur
- Cardiac valvular disease may be severe enough to require replacement

# Prognosis

- Prognosis of APS varies widely
- Overall survival is good - approximately 90-94% over 10 years
- However, significant disability may result from complications such as stroke and pulmonary hypertension
- With treatment, pregnant women have an 80% chance of a successful birth
- Catastrophic APS occurs in only 1% of patients, however mortality is approximately 50%

# References

[British Society of Haematology Guidelines](https://b-s-h.org.uk/guidelines/guidelines/guidelines-on-the-investigation-and-management-of-antiphospholipid-syndrome)

[Patient UK - Antiphospholipid syndrome](https://patient.info/doctor/antiphospholipid-syndrome-pro)

[Radiopaedia - Antiphospholipid syndrome](https://radiopaedia.org/articles/antiphospholipid-syndrome)

[StatPearls - Antiphospholipid syndrome](https://www.ncbi.nlm.nih.gov/books/NBK430980)
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The typical appearance of livedio reticularis.
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Antiphospholipid syndrome
Topic
54
Rheumatology
6606
Lupus anticoagulant, anticardiolipin antibody, and anti-β2-glycoprotein I antibody are autoantibodies linked to antiphospholipid syndrome, which increases the risk of blood clots and pregnancy complications, indicating a higher risk of thrombotic events.
A 32-year-old woman has presented to the GP for advice about fertility. She has had four miscarriages prior to 20 weeks gestation, following which tests revealed no anatomical, hormonal, or chromosomal precipitating causes. She is otherwise well. Tests are requested to screen for thrombophilia with the results shown below:

| Serum                           | Result   | Result at 12 weeks |
| ------------------------------- | -------- | ------------------ |
| Lupus anticoagulant (LA)        | positive | positive           |
| Anticardiolipin (aCL) antibody  | positive | positive           |
| Anti-b2-glycoprotein I antibody | negative | negative           |

Which of the following is the most likely diagnosis?
a