Antiphospholipid Syndrome - APS | Choose the Right Test

Medical Experts

Contributor

Moser

Karen A. Moser, MD

Professor (Clinical), University of Utah

Medical Director, Hematopathology and Hemostasis/Thrombosis Laboratory, ARUP Laboratories

Contributor

Saadalla

Abdulrahman Saadalla, MBBCh

Assistant Professor (Clinical), University of Utah

Medical Director, Immunology Core Lab and Coagulation, ARUP Laboratories

Contributor

Smock

Kristi J. Smock, MD

Associate Division Chief of Clinical Pathology, Professor (Clinical), University of Utah

Medical Director, Hemostasis/Thrombosis Laboratory, ARUP Laboratories

Antiphospholipid syndrome (APS), also known as antiphospholipid antibody syndrome, is an autoimmune disorder in which autoantibodies are directed against phospholipid-protein complexes. APS is characterized by thromboses (arterial, venous, or small vessel) and/or pregnancy complications and persistently positive tests for antiphospholipid-protein (aPL) antibodies. Cytopenias, other hematologic disorders, and neurologic, dermatologic, or cardiopulmonary abnormalities may also be observed in patients with APS.^, An uncommon acute form of the syndrome, catastrophic APS, results in extensive microvascular thrombosis and multiorgan failure. Those at increased risk for APS include patients with systemic lupus erythematosus (SLE), infections, malignancy, and liver or vascular disease. Transient aPL antibodies may occur in association with infections, certain medications (e.g., procainamide and chlorpromazine), and malignancy.

Quick Answers for Clinicians

Are there any formal diagnostic criteria for antiphospholipid syndrome?

Currently, no formal diagnostic criteria exist for antiphospholipid syndrome (APS). However, there are published classification criteria intended for clinical research that have been used in clinical settings to inform diagnosis.

The most recent classification criteria for APS were released by the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR). Notably, the International Society on Thrombosis and Haemostasis (ISTH) has expressed hesitancy about the routine clinical use of these criteria as they were designed primarily to standardize patient cohorts for research studies. In addition, experts in laboratory medicine have pointed out that the ACR-EULAR’s recommendation to use enzyme-linked immunosorbent assay (ELISA)-only testing for antiphospholipid-protein (aPL) antibodies may present a challenge due to the prevalence and advantages of automated testing, as well as the lack of harmonization between the aPL ELISAs currently available.

Which lab tests are most useful for diagnosing antiphospholipid syndrome?

Three test groups, used together, are recommended for the diagnosis of antiphospholipid syndrome (APS). They include lupus anticoagulant (LA), anticardiolipin (aCL) antibodies (immunoglobulin G [IgG] and IgM), and anti-beta-2 glycoprotein 1 (anti-β₂GP1) antibodies (IgG and/or IgM). If one or more of these tests are positive, the test(s) should be repeated at least 12 weeks later to confirm persistent positivity.^,^, If the tests are negative but strong suspicion for APS remains, “noncriteria” tests may be indicated. Refer to the Noncriteria Tests section for additional information.

What factors are important in testing for antiphospholipid syndrome?

Testing during acute thrombotic episodes is not recommended, as the presence of acute phase reactants (e.g., factor VIII or C-reactive protein) can lead to false-positive and false-negative lupus anticoagulant (LA) test results. The presence of anticoagulant therapies can also produce spurious LA test results; therefore, whenever possible, testing should be performed when anticoagulants are not present. In some cases, testing in the absence of anticoagulants may not be feasible, in which case testing that includes anticoagulant measurement and neutralization (e.g., direct oral anticoagulant [DOAC] adsorption) may be useful.

Because antiphospholipid-protein (aPL) antibodies can occur transiently, persistent positivity on consecutive testing occasions is required for classification as antiphospholipid syndrome (APS). In addition, testing for LA, anticardiolipin (aCL) antibodies, and anti-beta-2 glycoprotein 1 (anti-β₂GP1) antibodies reduces the risk of false-negative findings and helps in assessing risk for complications such as thrombotic events.

Indications for Testing

Laboratory testing for APS is appropriate in individuals who have an increased likelihood of the disorder, including those with^,^,^,:

Arterial thrombosis, unprovoked venous thrombosis, or evidence of brain ischemia before 50 years of age
Unexplained recurrent thrombosis
Thrombosis at an unusual site
Extensive microvascular thrombi
Unexplained pregnancy loss, either prefetal or fetal (at or after 10 weeks of gestation)
Severe preeclampsia/eclampsia; hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome; or severe placental insufficiency
A diagnosis of SLE

Testing may also be considered in other specific clinical scenarios; for additional information, refer to the International Society on Thrombosis and Haemostasis (ISTH) guidelines.

Laboratory Testing

Diagnosis

First-Line or Criteria Tests

Recommended first-line testing for possible APS includes lupus anticoagulant (LA) clot-based assays, tests for anticardiolipin (aCL) antibodies (immunoglobulin G [IgG] and IgM), and tests for anti-beta-2 glycoprotein 1 (anti-β₂GP1) antibodies (IgG and/or IgM),^,^, which are available separately or as a panel. The combination of these three tests reduces the risk of false-negative findings and is important for estimating disease risk. Positivity for all three (LA as well as aCL and anti-β₂GP1 antibodies) is strongly associated with thromboembolism and pregnancy-related morbidity. Triple positivity also indicates a high risk of thrombotic recurrence in patients with APS.

If positive, laboratory tests should be repeated at least 12 weeks later to confirm persistent positivity.

Lupus Anticoagulant

At least two phospholipid-dependent clotting assays should be performed in parallel to identify LA.^, Assays should include appropriate reflexive steps (e.g., screening, mixing, confirmation) and should be based on different principles (e.g., activated partial thromboplastin time [aPTT] and dilute Russell viper venom time [dRVVT]). If either clotting assay produces positive results, LA should be considered present.

Because anticoagulant therapy can produce false-positive and false-negative LA test results, when possible, specimens should be collected from patients who are not taking anticoagulants. In patients able to tolerate a temporary pause in direct oral anticoagulant (DOAC) therapy, LA testing can be considered at least 48 hours postdose with concurrent measurement of DOAC concentration. DOAC or heparin neutralization may be used to minimize test interference when these anticoagulants are present.^,

Positivity for LA alone, apart from the other aPLs, has a strong association with thrombotic events and adverse outcomes in pregnancy.^,^, However, LA testing in pregnant individuals may produce false-positive or false-negative results. If LA testing is performed during pregnancy, testing should be repeated postdelivery to confirm aPL status. Testing 3 months postdelivery may be reasonable, but an exact time frame has not been fully established.

Anticardiolipin and Anti-Beta-2 Glycoprotein 1 Antibodies

A strong correlation has been observed between aCL and anti-β₂GP1 antibody concentrations, but testing for both antibody types in conjunction with LA is still recommended. Detecting aCL and anti-β₂GP1 antibodies of the same isotype (IgG or IgM) supports the likelihood of APS. Measurement of both IgG and IgM is advised.

Noncriteria Tests

In recent decades, “noncriteria” aPL tests have been investigated for their potential value in APS diagnosis or risk assessment. Although their role is still unclear and routine use is not recommended, when criteria tests are negative but a strong suspicion for APS remains, noncriteria tests can be considered. These include tests for phosphatidylserine/prothrombin antibodies (IgG and IgM), phosphatidylserine antibodies (IgG and IgM), prothrombin antibody (IgG), anti-β₂GP1 antibody (IgA), and aCL antibody (IgA), and anti-β₂GP1 domain 1 (IgG).

Noncriteria Antibody Testing in Obstetric Settings

Although LA has been considered the most predictive criteria test for adverse pregnancy outcomes, a recent study found that two noncriteria tests, anti-β₂GP1 domain 1 (IgG) and phosphatidylserine/prothrombin antibody (IgG), were the strongest independent predictors of obstetric complications. Using anti-β₂GP1 domain 1 (IgG) and phosphatidylserine/prothrombin antibody (IgG) together may offer another option for identifying patients at risk for obstetric complications that is not subject to interferences that affect clot-based LA testing.