Antiphospholipid Syndrome - APS

Antiphospholipid syndrome (APS), also called 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 or other hematologic disorders, and neurologic, dermatologic, or cardiopulmonary abnormalities, may also be seen in patients with APS.   Catastrophic APS is an uncommon acute form of the syndrome that results in extensive thrombotic microangiopathy and multiorgan failure.  Those at increased risk for APS include patients with systemic lupus erythematosus (SLE), infections, malignancy, and liver or vascular disease. Some medications are also associated with increased risk. Transient aPL antibodies may occur in association with infections, certain medications (procainamide, chlorpromazine), and malignancy. 

Quick Answers for Clinicians

Who should be tested for antiphospholipid syndrome?

Individuals with arterial thrombosis or unprovoked venous thrombosis before 50 years of age, recurrent thrombosis or thrombosis at an unusual site, or thrombotic microangiopathy of unknown etiology should be screened for antibodies associated with antiphospholipid syndrome.    Testing should also be considered for patients with certain obstetric manifestations, such as one or more unexplained fetal losses after week 10 of gestation, unexplained severe intrauterine growth restriction, severe or early preeclampsia, or three or more spontaneous miscarriages before week 10 of gestation (after exclusion of maternal anatomic or hormonal abnormalities or paternal/maternal chromosomal causes).    Patients with systemic lupus erythematosus (SLE) should have a baseline test performed for antiphospholipid syndrome (APS), and testing should be repeated before surgery, transplantation, pregnancy, and use of treatments containing estrogen, or if the patient presents with a new vascular, neurologic, or obstetric event. 

Which lab tests are most useful for diagnosing antiphospholipid syndrome?

Three test groups, used together, are recommended for antiphospholipid syndrome (APS) diagnosis. They include lupus anticoagulant (LA), anticardiolipin (aCL) antibodies (immunoglobulin G [IgG] and IgM), and anti-beta-2 glycoprotein (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 are indicated. See Noncriteria Tests.

What issues are important in antiphospholipid syndrome testing?

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

Which testing algorithms are related to this topic?

Indications for Testing

Testing for APS is appropriate for individuals with indications of APS, such as venous or arterial thromboses or pregnancy-related morbidity (see Quick Answers for complete list of indications).

Criteria for Diagnosis

Current Classification Criteria for APSa
Clinical Criteria
Vascular thrombosis ≥1 clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ, validated by imaging studies or histopathology
Pregnancy morbidity ≥1 unexplained deaths of a morphologically normal fetus after the 10th week of gestation

≥1 premature births of a morphologically normal neonate before the 34th week of gestation due to preeclampsia, eclampsia, or placental insufficiency

≥3 unexplained, consecutive, spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded

Laboratory Criteria
Positive for LA, aCL, or anti-β2GP1 (according to specified criteria) on ≥2 occasions at least 12 weeks apart LA: detected in plasma according to ISTH guidelines

aCL: IgG and/or IgM isotype present in a medium or high titer (>40 GPL or MPL units or >99th percentile), as measured by standardized ELISA

Anti-β2GP1: IgG and/or IgM isotype in high titer (>99th percentile), measured by standardized ELISA

aAt least 1 clinical and 1 laboratory criterion must be met.

aCL, anticardiolipin; anti-β2GP1, anti-beta-2 glycoprotein 1; ELISA, enzyme-linked immunosorbent assay; GPL, immunoglobulin G (IgG) phospholipid antibody; ISTH, International Society on Thrombosis and Haemostasis; MPL, IgM phospholipid antibody

Sources: Miyakis, 2006 ; Bertolaccini, 2014 ; Devreese, 2018 

Laboratory Testing

Diagnosis

First-Line or Criteria Tests

Current recommendations for first-line testing in APS include lupus anticoagulant (LA) clot-based assays, aCL IgG and IgM antibodies, and anti-β2GP1 IgG and IgM antibodies    (available together in an APS panel test in some labs). The combination of the 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 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 with appropriate reflexive steps to satisfy detection guidelines, based on different principles (such as activated partial thromboplastin time [aPTT] and dilute Russell viper venom testing [dRVVT]), should be performed to identify LA.  Positivity for LA alone, apart from the other aPLs, has a strong association with thrombotic events and adverse outcomes in pregnancy.  

Anticardiolipin and Anti-Beta-2 Glycoprotein 1 Antibodies

A strong correlation has been observed between aCL and anti-β2GP1 levels, but performing both of these tests in conjunction with LA is still recommended.  Detecting aCL and anti-β2GP1 of the same isotype supports the likelihood of APS.  Measurement of both IgG and IgM is advised. 

Noncriteria Tests

If tests for the antibodies relevant to APS criteria are negative, but there is strong suspicion for APS, “noncriteria” aPL tests may be indicated. 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). 

ARUP Lab Tests

First-Line or Criteria Tests

Preferred initial panel when APS is strongly suspectedimportant information

Components: anti-β2GP1 antibodies, IgG and IgM; aCL antibodies, IgG and IgM; and LA reflexive panel

For patients with significant probability of having APS; LA, aCL, and anti-β2GP1 should all be tested

Note: These tests are available singly or as part of the APS reflexive panel (2003222)

Acceptable alternative to aCL IgG and IgM antibody tests. May be more specific than aCL IgG and IgM antibodies in patients with underlying infectious disease.

Acceptable initial tests when APS is strongly suspected, but IgG-IgM panel test is preferred; in addition to aCL, LA and anti-β2GP1 should be tested

Second-Line or Noncriteria Tests

For APS risk estimation when aPL criteria tests are negative or equivocal

Components: phosphatidylserine antibody, IgG and IgM; phosphatidylserine and prothrombin antibody, IgG and IgM; and prothrombin antibody, IgG

Second-line tests; use with other noncriteria aPL tests when APS is strongly suspected but patient is seronegative

  

Related Tests

Method

Chromogenic Assay/Electromagnetic Mechanical Clot Detection/Quantitative Enzymatic/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Polymerase Chain Reaction/Fluorescence Monitoring/Microlatex Particle Mediated Immunoassay

Medical Experts

Contributor

Moser

Karen A. Moser, MD
Assistant Professor of Clinical Pathology, University of Utah
Medical Director, Hemostasis/Thrombosis, ARUP Laboratories
Contributor
Contributor

Smock

Kristi J. Smock, MD
Associate Professor of Clinical Pathology, University of Utah
Medical Director, Hemostasis/Thrombosis, ARUP Laboratories
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®