Indications for Testing
Individuals with venous or arterial thromboses or pregnancy-related morbidity may warrant testing for APS. Additional indications for testing may include systemic autoimmune diseases such as SLE or the presence of cardiac valve disease, livedo reticularis, thrombocytopenia, hemolytic anemia, thrombotic microangiopathy, cognitive dysfunction without stroke, or aPL antibody-related nephropathy.
Criteria for Diagnosis
Current Classification Criteria for APSa
- 1 or more clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ validated by imaging studies or histopathology
|Positive for 1 of the following tests on 2 or more occasions at least 12 weeks apart
- Lupus anticoagulant: 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), measured by standardized ELISA
- Anti-β2GP1: IgG and/or IgM isotype in high titer (>99th percentile), measured by standardized ELISA
- 1 or more unexplained deaths of a morphologically normal fetus after the 10th week of gestation
- 1 or more premature births of a morphologically normal neonate before the 34th week of gestation due to preeclampsia, eclampsia, or placental insufficiency
- 3 or more unexplained, consecutive, spontaneous abortions before the 10th week of gestation, and with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded
|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, IgG phospholipid antibody; ISTH, International Society on Thrombosis and Haemostasis; MPL, IgM phospholipid antibody
Sources: Miyakis, 2006 ; Bertolaccini, 2014 ; Devreese 2018
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.
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.
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).
Patients who experience one of the following should be screened for antibodies associated with APS :
- Arterial thrombosis or unprovoked venous thrombosis before 50 years of age
- Recurrent thrombosis
- Thrombosis at an unusual site
- Thrombotic microangiopathy of unknown etiology
Screening tests should also be considered for patients with certain obstetric manifestations, such as the following :
- One or more unexplained fetal losses after the 10th week of gestation
- Unexplained severe intrauterine growth restriction
- Early or severe preeclampsia
- Three or more spontaneous miscarriages before the 10th week of gestation (with no maternal anatomic or hormonal abnormalities or paternal/maternal chromosomal causes)
Patients with SLE warrant testing for APS and should have a baseline test performed. 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.