Antiphosphatidylserine, IgA, IgG, IgM

Serum

1 mL

0.5 mL

Red-top tube or gel-barrier tube

As an aid in the diagnosis of certain autoimmune thrombotic disorders, such as antiphospholipid syndrome (aPS). Antibodies to PS/PT correlate with the presence of lupus anticoagulants (LA) and this test may be useful in cases with difficult LA test interpretation. This assay may also assist in the determination of risk for thrombosis as well as obstetric complications in patients with antiphospholipid antibodies.

• The pathogenic mechanism of aPS-PT antibody morbidity is substantially undefined, although under investigation.¹ To date, aPS/PT antibodies are not included among the formal laboratory classification criteria for APS but are suggested as supplemental assays.

• The clinical significance of PS/PT IgG or IgM antibodies in diseases other than SLE or APS is currently under investigation.

• When negative PS/PT IgG or IgM titers are found in the presence of clinical indications, a lupus anticoagulant, anticardiolipin, anti-β2 or other additional testing is indicated.

• Diagnosis cannot be made on the basis of PS/PT IgG or IgM results alone. These results must be interpreted in conjunction with physical findings.

• Treatment must not be initiated on the basis of a positive PS/PT IgG or IgM titer alone. Supportive clinical indications must also be present.

• It is to be expected that some samples can be anticardiolipin positive and/or anti-β2 GPI positive yet PS/PT IgG or IgM negative. The anti-β2 GPI test is a specific marker of thrombotic risk.

• Patients with APS can be PS/PT positive yet lupus anticoagulant, anticardiolipin or anti-β2 negative.

Enzyme-linked immunosorbent assay (ELISA)

• IgG = 0–30 Units

• IgM = 0–30 Units

• IgA = 0–19 APS Units

The antiphospholipid syndrome (APS) is a unique form of acquired autoimmune thrombophilia characterized by recurrent arterial and/or venous thrombosis, pregnancy-related complications (including miscarriages, fetal deaths, premature births, and preeclampsia), and the persistent presence of antiphospholipid antibodies (aPL).² The original APS classification criteria required positivity for any one of 1) anticardiolipin (aCL) IgG or IgM antibodies or 2) lupus anticoagulant (LA) as diagnostic laboratory criteria.³ In 2006, the sensitivity of the classification criteria was improved by the including positivity for 3) β2-glycoprotein 1 (β2GPI) IgG or IgM antibodies as additional laboratory criteria for APS and the specificity of diagnosis was improved by extending the requirement of persistent presence of aPL to 12 weeks.⁴ At least one clinical (vascular thrombosis or pregnancy morbidity) and one lab-based (positive test result for LA, aCL IgG/IgM or β2GPI IgG/IgM) criterion have to be met for a patient to be classified as having APS.

The antibodies associated with APS are known to react with phospholipids and/or with their binding proteins, either independently or in phospholipid–protein complexes. Early assays for antibodies to the lipid anticardiolipin were quite non-specific and were eventually replaced with assays employing complexes of cardiolipin with the protein β2GPI.^2,5 Assays for antibodies to β2GPI have been shown to be more specific for APS albeit with somewhat lower sensitivity. Antibodies to prothrombin (aPT), have also been shown to occur in patients with APS.^6-12 A large amount of data obtained mainly from retrospective studies provides contrasting evidence concerning the clinical significance of aPT antibodies.^13-16 It has been shown that aPT associated with LA activity or APS clinical manifestations can be detected only using assays employing purified PT antigen immobilized on irradiated plates or as a complex with the lipid phosphatidylserine (aPS/PT).^{10,11,14,17,18}

A systematic review and meta-analysis of 10 studies performed before 2014 found that aPS/PT antibody positivity is a strong risk factor for thrombosis and venous events independent from sites and type of thrombosis.⁶ A more recent meta-analysis, published in 2020,¹⁹ reviewing 15 studies published since the 2014 analysis^20-34 further confirmed the association between aPS/PT antibodies and thrombosis. Pooled analysis revealed a significant association between aPS/PT-IgG/IgM^{21-23,31,32,34} and thrombotic events with mean Odds Ratio (mOR = 6.8) relative to controls. Pooled analysis further found an association between thrombotic events and aPS/PT-IgG^{6,20,22-29,31-34} positivity (mOR = 6.7) and aPS/PT-IgM^{20-23,25,28-32,34} positivity (mOR = 4.35). A subset of studies,^{21,24,26,27,31-33} including 1,388 patients, evaluated the association between aPS/PT antibodies and pregnancy morbidity (PM) as defined by the 2006 criteria for the definition of APS.⁴ Pooled analysis of the results from these studies found a statistically significant association between any PM and aPS/PT IgG/IgM positivity (mOR = 10.6) and, specifically, aPS/PT IgG positivity (mOR = 6.7).¹⁹

While the tests currently included in the classification criteria for APS are able to detect the great majority of the cases, some patients present clinical manifestations highly suggestive of APS while being persistently negative for the aPL tests included in the guidelines.^1,35-39 These patients have been termed to have seronegative APS (SNAPS).^36,37,40 Testing for aPS/PT antibodies has been proposed as an additional tool to be considered when investigating a patient suspected of having APS, particularly in the absence of guideline aPL positivity^{9,26,28,32,36,37,40-48} or as a part of risk assessment strategies.⁴⁹ A number of studies have found that approximately 50 percent of patients with SNAPS were positive for IgG and/or IgM aPS/PT.^{33,35,37,39,50,51}

The addition of aPS/PT to current criteria aPL assays has been reported to contribute to the identification of patients with a history of thrombosis and/or pregnancy-related morbidity that would go undiagnosed using current criteria aPL assays.^{21,23,32,36,37,42,45,52-56} In a number of studies, aPS/PT positivity was reported to be an independent risk factor for LA activity and to occur in LA-negative SLE or APS patients with thrombosis and pregnancy loss.^23,54,56 Other investigators comparing different aPL combinations in patients with systemic lupus erythematosus observed that aPS/PT antibodies were significantly associated with both LA and pregnancy-related morbidity, while the combination of LA, anti-β2GPI and aPS/PT had superior diagnostic accuracy for thrombosis and pregnancy loss in APS.^57,58 These studies suggest that aPS/PT and LA are, at least in part, independent risk factors for clinical manifestations of APS. A recent study demonstrated that determination of aPS/PT antibodies in concert with β2GPI antibodies in patients positive for LA might be useful for identifying patients at different risk of thromboembolic events.⁵⁹ In addition, patients with triple positivity for LA, β2GPI and aPS/PT have been shown to be at a higher risk of developing thromboembolic events, risk even higher than that seen for the “classical” aCL, β2GPI and LA triple positivity.^52,58 aPS/PT have been shown to be associated with recurrent early or late abortions and with premature delivery irrespective of other aPL.⁵¹ aPS/PT positivity also has been found to be predicative of non-criteria clinical symptoms⁴ including thrombocytopenia or hemolytic anemia.³⁴

In addition to diagnosis, use of biomarkers to help predict risk of thrombosis has been addressed by the development of the anti-PhosphoLipid-Score (aPL-S) and the Global APS Score (GAPSS), Both these scoring systems include levels of aPS/PT antibodies (and not PS or PT) as components of the scoring system.^{19,48,49,60,61}