What are phosphatidylserine antibodies?

Phosphatidylserine Antibodies: Role in Antiphospholipid Syndrome

Phosphatidylserine antibodies are autoantibodies that target phosphatidylserine, a negatively charged phospholipid, and are considered non-criteria antiphospholipid antibodies that may have diagnostic value in antiphospholipid syndrome (APS), particularly when conventional tests are negative. 1

Definition and Types

• Phosphatidylserine antibodies can be detected as isolated anti-phosphatidylserine antibodies (aPS) or more commonly as anti-phosphatidylserine/prothrombin complex antibodies (aPS/PT), where prothrombin binds to phosphatidylserine in the presence of calcium ions 1
• These antibodies belong to the broader category of antiphospholipid antibodies (aPL), but are not included in the current classification criteria for APS 1
• They are typically measured using enzyme-linked immunosorbent assays (ELISA), as non-ELISA systems are not yet available for their detection 1

Diagnostic Value

• aPS/PT antibodies show a strong correlation with lupus anticoagulant (LA) activity, with approximately two-thirds of LA activity apparently due to antibodies against prothrombin 2
• These antibodies have high specificity (87%) for APS, with 70% of aPS-positive patients being confirmed APS cases 3
• Among confirmed primary APS cases, 75% of patients may be positive for aPS, suggesting significant diagnostic value 3
• aPS/PT testing may be particularly valuable in detecting APS in patients who are negative for conventional criteria aPL tests (lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein I antibodies) 3, 2

Clinical Significance

• aPS/PT antibodies are highly associated with thrombotic APS patients who are triple-positive for conventional aPL tests 1
• Patients with thrombotic manifestations display significantly higher IgG aPS/PT titers compared to asymptomatic aPL carriers 2
• aPS/PT closely correlates with activated protein C resistance and might identify patients at higher risk of thrombosis 1
• The association of LA and aPS/PT might confer an increased risk for cerebrovascular events, even when β2GPI-dependent tests are negative 1
• aPS antibodies are significantly more often associated with thromboembolic episodes, livedo reticularis, or both, compared to autoimmune diseases 4

Testing Methodology

• aPS/PT is commonly measured by ELISA, with prothrombin bound to plastic wells precoated with phosphatidylserine in the presence of calcium ions 1
• Detection of aPS/PT has proven difficult to standardize, and reference material is lacking 1
• Commercial ELISA assays for aPS/PT show reproducible and accurate results with shorter running times compared to in-house methods 1
• Other non-criteria aPL tests, including those for phosphatidylserine antibodies, are often detected by alternative nonstandardized solid phase assays such as multiline dot assays, line immunoassays, and thin layer chromatography 1

Limitations and Considerations

• aPS/PT has not been included as an additional laboratory criterion in the 2023 ACR/EULAR classification criteria for APS 1
• Study results on non-criteria aPL tests, including aPS, are inconsistent and show no definite added value according to some guidelines 1
• There is a distinction between using aPS/PT as a diagnostic biomarker versus a marker for thrombotic risk assessment 1
• aPS/PT antibodies appear to be a distinct antibody population in APS, not cross-reacting with anti-β2-glycoprotein I antibodies 2

Clinical Applications

• In second-line testing, aPS/PT can consolidate the APS diagnosis in high-risk patients 1
• When the aPL profile shows double aPL positivity, positive aPS/PT may suggest a false negative LA 1
• When aPS/PT are negative in double-positive patients, this may suggest a lower thrombotic risk 1
• The good correlation between aPS/PT ELISA and LA may support its use as a surrogate test for LA, particularly useful to overcome technical limitations of functional assays 2
• Patients with isolated LA (negative for other conventional aPL) frequently have aPS/PT antibodies, especially when LA is detected by two positive coagulation tests 5

Emerging Research

• Beyond autoimmune contexts, phosphatidylserine-targeting antibodies are being investigated for potential therapeutic applications in cancer immunology, as phosphatidylserine externalization on tumor cells may serve as an immune modulatory signal driving tolerance and immune escape 6