Introduction 

Antiphospholipid syndrome (APS) is considered as an autoimmune blood disorder that generates abnormal blood clots. Autoimmune disorders will occur when the body attacks its own cells or tissues. This syndrome leads to serious health issues such as blood clot formation in the arteries, veins and pregnancy complications such as fetal death, miscarriage or premature birth. APS is due to the presence of antiphospholipid antibodies, that is considered as an multisystemic autoimmune disorder.¹,²,³ It is associated with 7-15% of individuals with systemic lupus erythematosus (SLE) and may also be linked with other autoimmune disorders. Giving that is a relatively rare condition, affecting about one in every 2,000 people in the general population.⁴

Types of antiphospholipid antibodies 

• Lupus anticoagulants (LA)
• Anti-beta-2-glycoprotein-I (anti-β2GPI) antibodies IgG or IgM
• Anticardiolipin antibodies(aCL) IgG or IgM¹ 

What are the causes of antiphospholipid syndrome (APS)

In 40 % of the cases APS is considered to be primary when there is no evidence of any associated other autoimmune conditions. In secondary APS there is evidence of clinical conditions such as autoimmune diseases, drugs, infections, or cancer. It occurs when associated with conditions such as hemolytic anemia, arthritis in children, rheumatoid arthritis, systemic sclerosis, psoriatic arthritis, Sjögren syndrome, dermatoses, systemic lupus erythematosus, vasculitis, polymyositis, Behçet disease, rheumatic polymyalgia, and autoimmune thyroid diseases in which there is presence of LA and aCL is reported. When aPL production is triggered by infections, secondary APS may occur, which can occasionally result in conditions such as catastrophic antiphospholipid syndrome.

Drugs associated with APS 

• Chlorpromazine
• Hydralazine 
• Amoxicillin
• Quinidine
• Interferon alpha
• Phenytoin
• Cysteamine
• Oral contraceptives
• Propranolol

These drugs can induce the production of antiphospholipids that leads to the development of APS. Tumor necrosis factor alpha inhibitors are also associated with the production of antiphospholipid antibodies.¹

Other types of APS

Thrombotic antiphospholipid syndrome: in the individuals diagnosed with APS, the common sign is the involvement of deep vein thrombosis (DVT). These individuals are diagnosed based on thrombosis in the arteries or veins and continuous laboratory requirement for the diagnosis of antiphospholipid antibodies.

Obstetrics APS: APS is diagnosed based on pregnancy complications like severe preeclampsia, fetal loss, placental insufficiency, or recurrent miscarriages, along with specific laboratory criteria for APLA. Patients with both clotting issues and pregnancy-related complications are classified as having thrombotic and obstetric APS.

Catastrophic APS: Catastrophic antiphospholipid syndrome (CAPS) is a rare but severe complication of APS, affecting fewer than 1% of patients and carrying a high mortality rate, especially in those with lupus or major organ involvement. It causes widespread blood clots in multiple organs within days, leading to complications in the lungs, kidneys, heart, brain, skin, and digestive system.

Common triggers for CAPS include stopping anticoagulation, infections, and surgery. Managing infections and maintaining some level of anticoagulation can help reduce risk.

CAPS is mainly diagnosed based on four criteria: Involvement of at least three organs, symptoms appearing within a week, lab confirmation of APLA, and biopsy evidence of small blood vessel blockages. Meeting all four criteria confirms CAPS, while three indicate probable CAPS. Early diagnosis and treatment are critical for better outcomes.³

What are the clinical features of APS

The signs and symptoms of APS may differ from mild asymptomatic presence of APLA and CAPS. Thrombosis of arteries, and veins, and complications due to pregnancy are the distinctive features for the diagnosis of APS. Also, various other organ systems may be involved. Main clinical features include:

• Vascular thrombosis: Blood clots are formed in the arteries and veins can involve one or multiple organ systems. Deep vein thrombosis is the most frequent cause of venous thrombosis and this can result in pulmonary embolism ( blood clots are formed in the pulmonary arteries in the lungs) leading to pulmonary hypertension ( raise in blood pressure in the arteries of lungs). Other sites such as hepatic, portal, axillary, pelvic, ocular, renal, sagittal and inferior vena cava can be involved in the formation of venous thrombosis

Arterial thrombosis can be seen in any arteries ranging from largest artery aorta to the smallest capillaries. The frequent signs of APS in arterial thrombosis is ischaemic stroke or transient ischaemic events. If transient ischaemic events occur without any of the risk factors for the atherosclerosis in young individuals, we can suspect APS. Various other sites such as brachial, mesenteric, retinal, and peripheral arteries are involved in the arterial thrombosis and this has low prognosis due to its high recurrence risk.

• Complications during pregnancy: APS individuals frequently lose their pregnancies, and early losses are influenced by hereditary factors. A 10% APLA positive incidence is associated with late pregnancy loss. The risk is increased by APLA-positive tests, prior pregnancy loss, thrombosis, or SLE. To ensure a safe pregnancy, careful observation is essential
• Valvular involvement is frequent in APS, affecting up to 80% of patients. The mitral and aortic valves are most commonly impacted, showing thickening, nodules, and vegetations, which may lead to regurgitation or stenosis
• Hematological conditions: Thrombocytopenia affects over 15% of APS cases, though severe haemorrhage is rare. A positive Coombs test is common, but hemolytic anaemia is uncommon
• Neurological condition: APS commonly causes transient ischaemic events (TIEs) and recurrent strokes, leading to cognitive impairment, seizures, and multi-infarct dementia. It can also result in blindness from retinal occlusion and sudden deafness due to sensorineural hearing loss
•  APS can lead to myocardial infarction and cardiac emboli. A non-ST segment elevation myocardial infarction with a normal angiogram but abnormal cardiac MRI may suggest APS
• Pulmonary artery thromboembolism from DVT is common in APS and can lead to pulmonary hypertension. Diffuse pulmonary haemorrhage due to capillaritis (A harmless skin condition that causes reddish-brown patches due to tiny leaking blood vessels under the skin) has also been reported
• APS can affect the kidneys, causing high blood pressure, protein in the urine, and kidney failure due to small blood vessel clots. It may also lead to renal artery blockages, making hypertension difficult to control, and areas of kidney tissue loss³

How to diagnose APS

When the individual presents with the clinical manifestations of APS, the antiphospholipid antibody test should be done. APS diagnosis requires persistent aPL detected at least 12 weeks apart. Testing LA, aCL, and aβ2GP1 is essential, as the aPL profile influences thrombotic risk. Triple aPL positivity carries the highest thrombosis risk, with medium to high titres being clinically significant, while low titres are mainly relevant for pregnancy complications.⁴

People with APS often experience low platelet counts or anaemia. Kidney problems, like protein in the urine or failure, may signal small blood vessel clots. Inflammation markers are usually normal, though sedimentation rates may rise during a clotting event. Those with SLE may have specific antibodies, while low complement levels with kidney issues could suggest lupus nephritis rather than APS.³

Treatment of APS

Managing thrombosis and bleeding risks

• Vitamin K-antagonist (VKA) is recommended for patients with known aPL
• Single or double aPL-positive patients on direct oral anticoagulants (DOAC) for their first venous thromboembolism (VTE) may continue with shared decision-making
• Triple aPL-positive patients on DOAC should switch to VKA, but if they choose to stay on DOAC, regular monitoring, including brain MRI, is crucial to detect ischaemic lesions and reassess treatment

Managing arterial risk 

To lower the risk of recurrent arterial clots, it's important to manage factors like high blood pressure, high cholesterol, excess weight, poor blood sugar control, and smoking. Patients with aPL should start anticoagulation, with VKA being the standard treatment for APS-related arterial clots. The choice of INR target (2.0 – 3.0 with or without low-dose aspirin, or 3.0 – 4.0) should be personalised, balancing the risk of stroke and cognitive decline against the risk of bleeding.

Small vessel thrombosis management

Anticoagulation is often used as a precaution, with VKA being the main option and low-molecule-weight Heparin (LMWH) preferred if platelet levels are low. DOACs should be avoided unless part of a clinical trial. If lupus nephritis is present, it should be actively treated. In severe cases, additional treatments like rituximab, IV immunoglobulins, plasma exchange, eculizumab, vasodilators, certain surgeries, or hyperbaric oxygen therapy may be considered.⁴

Summary 

Antiphospholipid syndrome (APS) is an autoimmune disorder that disrupts normal blood clotting, potentially leading to organ damage, deep vein thrombosis (DVT), strokes, and pregnancy loss. It can occur independently or alongside other conditions. Diagnosis involves repeated testing for antiphospholipid antibodies (aPL), with higher levels increasing the risk of clot formation. Treatment primarily includes anticoagulants such as VKA, and lifestyle adjustments, while severe cases may require immune therapy or plasma exchange.