Pathophysiology of antiphospholipid syndrome
Antiphospholipid syndrome (APS) is an autoimmune disorder characterised by the presence of antiphospholipid antibodies (aPL), which target phospholipid-binding proteins involved in coagulation. These antibodies disrupt normal endothelial function, leading to hypercoagulability and an increased risk of thrombosis.
1. Endothelial dysfunction and loss of anticoagulant protection
- Annexin V displacement: aPL antibodies interfere with the anticoagulant properties of annexin V, promoting clot formation.
- Reduced nitric oxide (NO) production: Impaired NO synthesis leads to vasoconstriction and platelet aggregation, increasing thrombosis risk.
- Tissue factor expression: Endothelial cells and monocytes upregulate tissue factor, activating the coagulation cascade.
2. Platelet activation and hypercoagulability
- Direct platelet stimulation: aPL antibodies bind to platelet membranes, enhancing aggregation.
- Increased thromboxane A₂ (TXA₂) levels: TXA₂ promotes vasoconstriction and clot formation.
- Interaction with β₂-glycoprotein I (β₂GPI): aPL antibodies neutralise β₂GPI, reducing its anticoagulant function.
3. Complement activation and vascular inflammation
- Complement-mediated damage: aPL antibodies activate the classical complement pathway, increasing thrombogenicity.
- Inflammation-driven thrombosis: Complement activation leads to endothelial injury and microvascular complications.
4. Disruption of fibrinolysis
- Impaired plasminogen activation: APS reduces fibrinolytic activity, leading to clot persistence.
- Increased plasminogen activator inhibitor-1 (PAI-1): PAI-1 inhibits fibrinolysis, increasing thrombotic burden.
Primary vs secondary APS
APS can be classified as primary or secondary, depending on its association with other autoimmune conditions:
- Primary APS: Occurs in isolation, without other autoimmune diseases. Patients may experience recurrent thrombosis or pregnancy complications without underlying connective tissue disorders.
- Secondary APS: Develops in the context of another autoimmune disease, most commonly systemic lupus erythematosus (SLE). Up to 50% of lupus patients test positive for aPL antibodies, increasing thrombotic risk.
The multi-system impact of APS thrombosis
Thrombosis in APS is not confined to a single vascular territory—it can affect arterial, venous, and microvascular beds, leading to complications across multiple organ systems:
1. Large-vessel thrombosis: Major systemic consequences
- Deep vein thrombosis (DVT): Often presenting with lower limb swelling, pain, and increased embolic risk.
- Pulmonary embolism (PE): Sudden breathlessness and chest pain due to a dislodged thrombus reaching the lungs.
- Ischaemic stroke and myocardial infarction (MI): APS increases risk of arterial thrombotic events, particularly in younger patients without traditional cardiovascular risk factors.
2. Microvascular thrombosis: Subtle but damaging
- APS nephropathy: Thrombotic microangiopathy leads to progressive kidney dysfunction and hypertension.
- Neurological complications: Chronic microvascular ischemia may contribute to cognitive impairment, migraines, or neuropsychiatric lupus features.
- Retinal thrombosis: APS may manifest as visual disturbances, including retinal vein occlusion, impacting eyesight.
3. Obstetric complications: The vascular nature of pregnancy loss
- Placental infarction: APS impairs placental circulation, causing fetal growth restriction or miscarriage.
- Pre-eclampsia risk: Increased vascular instability heightens the risk of hypertensive disorders in pregnancy.
- HELLP syndrome: APS may contribute to severe haemolysis, elevated liver enzymes, and low platelets, requiring urgent obstetric intervention.
4. Skin manifestations: Visible signs of vascular compromise
- Livedo reticularis: A lace-like vascular pattern caused by microvascular thrombosis, endothelial dysfunction and impaired perfusion. This finding can signal underlying vascular compromise and is frequently seen in APS patients.
- Digital ischaemia: Severe APS cases may progress to gangrenous necrosis in fingers or toes.
Clinical implications of widespread clotting risk
- Multi-organ involvement means APS is a systemic vascular disease, often requiring lifelong anticoagulation.
- Microvascular thrombosis may go unrecognised, leading to subtle organ dysfunction over time.
- Tailored management strategies must consider both arterial and venous thrombotic risks, guiding the choice of anticoagulant therapy.
Long-term complications
APS can lead to chronic damage in multiple organ systems due to repeated thrombotic events:
- Progressive organ damage from microvascular thrombosis, particularly affecting kidneys, lungs, and the CNS.
- Cognitive decline related to microvascular ischemia.
- Post-thrombotic syndrome following recurrent DVTs, leading to chronic venous insufficiency
- While APS can present with acute thrombotic events, it can also lead to subclinical clot formation that gradually impairs organ function.
Cardiovascular complications in APS
Patients with APS are at increased risk of cardiovascular disease, largely due to accelerated atherosclerosis, endothelial dysfunction, and thrombosis.
- Valvular heart disease: APS is associated with Libman-Sacks endocarditis, characterised by sterile, fibrin-rich vegetations on heart valves. These can lead to valvular insufficiency or embolic events.
- Coronary artery thrombosis: APS can cause myocardial infarction even in young patients without traditional risk factors. Microvascular involvement may contribute to ischemic cardiomyopathy.
- Pulmonary hypertension: Chronic thrombosis in pulmonary vasculature may lead to secondary pulmonary hypertension, affecting cardiac output.
- Arrhythmias: Some APS patients develop atrial fibrillation or conduction abnormalities, possibly linked to microvascular ischemia or inflammation.
APS and valvular heart disease
APS is linked to non-bacterial thrombotic endocarditis (NBTE), often seen as Libman-Sacks endocarditis, especially in patients with lupus-associated APS. This condition involves sterile fibrin-rich vegetations forming on heart valves due to immune-mediated endothelial dysfunction.
Mechanisms behind APS-associated valve pathology
- Endothelial injury and hypercoagulability
- aPL antibodies trigger endothelial activation, exposing subendothelial collagen and promoting platelet adhesion.
- Tissue factor upregulation further enhances coagulation, driving the formation of non-infectious fibrin-platelet aggregates.
- Inflammation and immune complex deposition
- Chronic immune activation in APS and lupus leads to immune complex deposition on valvular surfaces, contributing to fibrosis and thickening.
- Complement activation exacerbates endothelial dysfunction, promoting sterile inflammatory changes.
- Thrombotic vegetations and embolic risk
- The vegetations formed in Libman-Sacks - endocarditis are composed of platelets, fibrin, and immune complexes, rather than bacterial elements.
- Unlike infective endocarditis, these sterile thrombi may detach and embolise, leading to stroke or systemic embolic events.
Clinical consequences
- Mitral valve thickening is the most commonly affected site, leading to valvular insufficiency or stenosis.
- Some patients develop progressive valve dysfunction, requiring long-term monitoring or surgical intervention.
- Embolic strokes can occur due to vegetations dislodging into the circulation.
Management considerations
- Anticoagulation: Patients with APS and valvular involvement often require lifelong anticoagulation (warfarin or heparin) to reduce embolic risk.
- Immunosuppressive therapy: If significant valvular damage progresses in secondary APS with lupus, steroids or biologics (rituximab) may be considered.
- Surgical intervention: Valve replacement is rare but may be needed in severe regurgitation or stenotic lesions.
Diagnosis of APS: Clinical and laboratory criteria
The diagnosis of antiphospholipid syndrome (APS) requires both clinical features (such as thrombosis or pregnancy complications) and laboratory confirmation of antiphospholipid antibodies (aPL). A definitive diagnosis is made based on the revised Sydney criteria, which include:
1. Clinical criteria
- Thrombosis: One or more documented episodes of arterial, venous, or small-vessel thrombosis.
- Pregnancy morbidity:
- Three or more consecutive miscarriages before 10 weeks.
- One or more fetal losses beyond 10 weeks.
- Preterm birth before 34 weeks due to placental insufficiency, pre-eclampsia, or eclampsia.
2. Laboratory criteria
To meet diagnostic requirements, aPL must be present on two occasions at least 12 weeks apart, reducing the likelihood of transient elevations due to infections or medications.
Key antiphospholipid antibodies
- Lupus anticoagulant (LA) – Strongly associated with thrombosis, detected via clotting assays like the dilute Russell viper venom test (dRVVT) and activated partial thromboplastin time (aPTT).
- Anticardiolipin antibodies (aCL) – IgG and IgM types linked to both arterial and venous thrombosis, measured via ELISA.
- β₂-glycoprotein I (β₂GPI) antibodies – Often persistent in APS and strongly linked to thrombosis risk.
- Triple positivity (LA + aCL + β₂GPI) is associated with the highest risk of thrombosis, significantly increasing the likelihood of recurrent events.
Additional diagnostic considerations
- Thrombophilia screening: Other prothrombotic conditions, such as Factor V Leiden or protein C/S deficiencies, should be ruled out in unexplained thrombosis.
- Complement markers: Elevated C5b-9 (membrane attack complex) may indicate complement activation, particularly relevant in APS nephropathy.
- Imaging and biopsy: MRI for silent brain infarcts, echocardiography for valvular lesions, and renal biopsy for thrombotic microangiopathy may further clarify APS-related complications.
Fluctuating antibody levels and clinical relevance
- Antibody titres can vary over time, and not all patients with aPL develop APS or experience thrombosis.
- Some individuals may persistently test positive for aPL but remain asymptomatic, while others may have episodic elevations linked to thrombotic events.
- Transient aPL positivity can occur due to infections, medications, or inflammatory states, meaning repeat testing after 12 weeks is crucial for diagnosis.
Implications for disease monitoring
- Fluctuations do not always correlate with clinical symptoms, making APS a challenging condition to predict.
- Triple positivity (LA + aCL + β₂GPI) is associated with the highest risk of thrombosis, but isolated antibody findings should be interpreted within a broader clinical context.
- In patients with lupus, APS-related thrombotic risk is not solely dictated by antibody titres—complement activation, endothelial dysfunction, and additional thrombophilia factors contribute.
APS in lupus
APS frequently coexists with systemic lupus , (click to relevant blog post) leading to severe complications, including:
- Thrombosis: Increased risk of deep vein thrombosis (DVT), stroke, and myocardial infarction.
- Obstetric complications: APS is a major cause of recurrent pregnancy loss, pre-eclampsia, and fetal growth restriction.
- Neurological involvement: APS-related microvascular thrombosis contributes to cognitive dysfunction and neuropsychiatric lupus.
Linking APS and lupus pathophysiology
APS and lupus share overlapping immune mechanisms, particularly in autoantibody production and complement activation. While lupus primarily involves immune complex deposition and systemic inflammation, APS adds a prothrombotic component, increasing the risk of vascular complications.
- Loss of immune tolerance: Both conditions involve autoantibody production, driving sustained immune activation.
- Complement activation: APS exacerbates vascular inflammation, worsening lupus-related organ damage.
- Clinical implications: Patients with both APS and lupus require multidisciplinary management, balancing immunosuppression and anticoagulation.
Clinical examples of APS in lupus
Recurrent miscarriage: a vascular aetiology
A 32-year-old woman with known SLE presents with a history of three consecutive first-trimester miscarriages. Laboratory tests reveal positive antiphospholipid antibodies, including lupus anticoagulant and anticardiolipin antibodies. She is diagnosed with APS secondary to lupus.
- Pathophysiology: aPL antibodies disrupt placental blood flow, leading to fetal loss.
- Management: She is started on low-dose aspirin and heparin during pregnancy to reduce thrombotic risk.
- Takeaway: APS is a significant cause of recurrent pregnancy loss, necessitating targeted anticoagulation.
Stroke in lupus: thrombotic risks beyond traditional factors
A 28-year-old man with SLE develops sudden left-sided weakness and slurred speech. Imaging confirms an ischemic stroke despite no traditional cardiovascular
risk factors. Further testing reveals elevated antiphospholipid antibodies, confirming APS-related thrombosis.
- Pathophysiology: aPL antibodies promote endothelial dysfunction and platelet aggregation, increasing stroke risk.
- Management: He is placed on lifelong anticoagulation therapy with warfarin.
- Takeaway: APS should be considered in young patients with unexplained stroke, particularly in the context of lupus.
APS nephropathy: microvascular thrombosis and renal dysfunction
A 45-year-old woman with long-standing lupus nephritis presents with worsening renal function and hypertension. Renal biopsy shows thrombotic microangiopathy, consistent with APS nephropathy.
- Pathophysiology: APS-related microvascular thrombosis exacerbates renal damage in lupus nephritis.
- Management: She is treated with immunosuppressive therapy and anticoagulation to prevent further vascular injury.
- Takeaway: APS can significantly contribute to renal disease progression in lupus patients, warranting early intervention.
Catastrophic antiphospholipid syndrome (CAPS): A rapid, life-threatening form of APS
CAPS is a rare but severe variant of antiphospholipid syndrome (APS) characterised by widespread, rapid-onset thrombosis affecting multiple organ systems simultaneously. Unlike typical APS, which may present with isolated thrombotic events, CAPS leads to multi-organ failure due to extensive microvascular occlusion.
Pathophysiology:
- CAPS is driven by massive endothelial activation, leading to systemic inflammatory response syndrome (SIRS).
- Diffuse complement activation amplifies thrombosis, promoting microvascular ischemia in vital organs such as the kidneys, lungs, heart, and brain.
- The condition is often triggered by infections (like COVID!), surgery, trauma, or abrupt cessation of anticoagulation therapy.
Clinical presentation and management:
- Patients deteriorate rapidly, presenting with organ dysfunction, disseminated intravascular coagulation (DIC), and severe thrombocytopenia.
- High-dose anticoagulation (heparin), plasmapheresis, intravenous corticosteroids, and rituximab are key treatment strategies.
- Despite aggressive management, mortality rates remain high, necessitating early recognition and multidisciplinary intervention.
Treatment of APS
Management of APS depends on thrombotic history, pregnancy risk, and associated autoimmune conditions.
1. Anticoagulation therapy
- Low-dose aspirin: Used for primary prevention in patients with aPL antibodies but no prior thrombosis.
- Heparin: Preferred in pregnancy to prevent miscarriage, often combined with aspirin.
- Warfarin: Mainstay for long-term anticoagulation in secondary APS with lupus, especially after recurrent thrombosis.
2. Immunosuppressive therapy in lupus-associated APS
- Corticosteroids: Used in severe cases with immune-mediated vasculopathy.
- Rituximab: A B-cell-targeted therapy that may help reduce autoantibody production in refractory cases.
3. Emerging therapies
- Complement inhibitors: Novel approaches aim to mitigate complement-mediated vascular damage, particularly in APS nephropathy.
- Direct oral anticoagulants (DOACs): Mixed results in APS, but research continues into their efficacy compared to warfarin.
In summary
APS is an insidious condition—while some patients present with dramatic thrombotic events, others experience silent but progressive vascular compromise. Recognising the clinical and serological features of APS is critical for early intervention and prevention of devastating complications.
Managing APS requires a balance between anticoagulation and immunosuppression, especially in lupus patients. A multidisciplinary approach involving rheumatologists, haematologists, and obstetricians is crucial for optimising outcomes and preventing long-term damage.
While warfarin remains the mainstay of APS treatment, advances in targeted therapies—including complement inhibitors and B-cell-directed approaches—may offer new hope for reducing thrombotic risk and long-term complications.
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