Topics

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z #

Antiphospholipid Syndrome - APS

Clinical Background

Antiphospholipid syndrome (APS) is an autoimmune disorder in which autoantibodies are directed against phospholipid-protein complexes. APS is characterized by thrombosis (arterial, venous, or small vessel) and/or pregnancy complications and persistently positive tests for antiphospholipid-protein (aPL) antibodies. aPL antibodies are often classified as either lupus anticoagulant (LA), or anticardiolipin antibodies (aCL), or anti-beta-2 glycoprotein I (β2GP1) antibodies.

Epidemiology

Prevalence
- aPL antibodies are an acquired thrombotic risk factor
- aPL antibodies are present in a low percentage of young healthy subjects (1-5%) and up to 10% of patients with venous thrombosis
  - Estimates of prevalence are hampered by the variety of test systems that can be used for diagnosis
- Higher prevalence in patients with autoimmune disease such as systemic lupus erythematosus (up to 50%), malignancy, liver disease, and vascular disease
- Most patients with aPL antibodies do not have an underlying autoimmune disease

Pathophysiology and Basis for Laboratory Tests

Proposed mechanisms for thrombosis include endothelial cell damage or activation, platelet activation, and interference with the function of anticoagulant proteins
LAs are autoantibodies that target complexes of phospholipids with either β2GP1 or other plasma proteins such as prothrombin
- LAs usually demonstrate an inhibitor effect in laboratory clotting tests by interfering with phospholipid-dependent clotting reactions
- Prolongation of clotting times (apparent anticoagulation) is an in vitro laboratory phenomenon; in vivo thrombosis is much more common than bleeding
ELISA assays to detect aCL and β2GP1 IgG and IgM antibodies
- In the aCL assay, antibodies recognize a complex of phospholipid-binding protein (often β2GP1) and cardiolipin (an anionic phospholipid)
- Assays evaluating antibody specificity for protein cofactors such as β2GP1 are also used
APS patients may have LA activity, positivity to aCL and/or β2GP1 IgG and IgM antibodies
- Thrombosis appears to be more common in patients with LA activity
- Positivity for all 3 (LA, aCL antibodies, and β2GP1 antibodies) is a strong independent risk factor for thrombosis
Transient aPL antibodies may occur in association with infections and certain medications (procainamide, hydralazine, quinidine, chlorpromazine, penicillin)

Clinical Presentation

Venous, arterial, or small vessel thrombosis, and/or obstetric complications
Other potential abnormalities include cytopenias or other hematologic disorders, and neurologic, dermatologic, or cardiopulmonary abnormalities
Catastrophic antiphospholipid-antibody syndrome (CAPS) is a multi-organ illness caused by diffuse small vessel thrombosis and tissue ischemia

Treatment

Treatment decisions depend on the extent of clinical symptoms and may range from no treatment to long-term anticoagulation

Diagnosis

Indications for testing – recurrent vascular thromboses, recurrent pregnancy loss
- Additional indications for testing may also include the presence of endocarditis, livedo reticularis, thrombocytopenia, hemolytic anemia, and thrombotic microangiopathy
Laboratory testing
- Both clinical and laboratory criteria must be met (see below)
- Current recommendations for laboratory testing include testing for LA (liquid-based clotting assays), IgG and IgM aCL antibodies (ELISA) and IgG and IgM β2GP1 antibodies (ELISA)
  - The presence of IgA antibodies alone is not diagnostic
  - At least 2 phospholipid-dependent clotting assays, based on different principles, should be performed to identify LA
  - Positive laboratory tests should be repeated after 12 weeks to confirm persistent positivity
  - Repeat testing may be needed if there is strong clinical suspicion for APS but laboratory tests are negative
  - If results are negative and strong suspicion persists, the following tests could be considered:
    - Cardiolipin antibody, IgA
    - Beta-2 glycoprotein 1 antibody, IgA
    - Phosphatidylserine antibodies, IgG, IgM, & IgA
    - Prothrombin antibody, IgG
    - Prothrombin antibody, IgM

Revised Classification Criteria for the Antiphospholipid Antibody Syndrome
At least 1 clinical and 1 laboratory criterion must be met
Clinical criteria Vascular thrombosis: One or more clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ that have been validated by imaging studies or histopathology Pregnancy morbidity: One or more unexplained deaths of a morphologically normal fetus beyond the 10th week of gestation One or more premature births of a morphologically normal neonate before the 34th week of gestation due to preeclampsia, eclampsia, or placental insufficiency Three or more 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 test must be present on 2 or more occasions at least 12 weeks apart Lupus anticoagulant: detected in plasma according to the guidelines of the International Society on Thrombosis and Hemostasis Anticardiolipin antibody: IgG and/or IgM isotype present in a medium or high titer (>40 GPL or MPL or >99th percentile), measured by a standardized ELISA Anti-β2 glycoprotein I antibody: IgG and/or IgM isotype in high titer (>99th percentile), measured by a standardized ELISA
GPL: IgG phospholipid antibody; MPL: IgM phospholipid antibody; ELISA: enzyme-linked immunosorbent assay

Revised Classification Criteria for the Antiphospholipid Antibody Syndrome

At least 1 clinical and 1 laboratory criterion must be met

Clinical criteria

Vascular thrombosis: One or more clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ that have been validated by imaging studies or histopathology

Pregnancy morbidity:

One or more unexplained deaths of a morphologically normal fetus beyond the 10th week of gestation
One or more premature births of a morphologically normal neonate before the 34th week of gestation due to preeclampsia, eclampsia, or placental insufficiency
Three or more 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 test must be present on 2 or more occasions at least 12 weeks apart

Lupus anticoagulant: detected in plasma according to the guidelines of the International Society on Thrombosis and Hemostasis
Anticardiolipin antibody: IgG and/or IgM isotype present in a medium or high titer (>40 GPL or MPL or >99th percentile), measured by a standardized ELISA
Anti-β2 glycoprotein I antibody: IgG and/or IgM isotype in high titer (>99th percentile), measured by a standardized ELISA

GPL: IgG phospholipid antibody; MPL: IgM phospholipid antibody; ELISA: enzyme-linked immunosorbent assay

Differential Diagnosis

Inherited thrombophilia
Connective tissue disorder
- Systemic lupus erythematosus (SLE)
Malignancy

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations
Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Recommended Use	Limitations	Follow Up
Lupus Anticoagulant Reflexive Panel 0030181 Method: Clotting	Identify lupus anticoagulant in a patient with clinical features of APS or unexpected prolonged partial thromboplastin time results For suspected APA, order along with Cardiolipin Antibodies, IgG & IgM Beta-2 Glycoprotein 1 Antibodies, IgG & IgM Panel includes LA-sensitive PTT and dilute Russell Viper Venom (dRVVT) for screening, followed by mixing studies and confirmatory assays if indicated First-line test in the evaluation of APS	No single testing system will identify 100% of LA antibodies Anticoagulant therapy may interfere with test results	Negative results – consider repeat testing if clinical suspicion is high Positive results – confirm at least 12 weeks apart
Cardiolipin Antibodies, IgG & IgM 0099344 Method: Enzyme-Linked Immunosorbent Assay	APS diagnosis Order along with Lupus Anticoagulant Reflexive Panel Beta-2 Glycoprotein 1 Antibodies, IgG & IgM	False-positive results may occur with infectious and autoimmune diseases	Inconclusive results – consider repeat testing Positive results – confirm at least 12 weeks apart
Beta-2 Glycoprotein 1 Antibodies, IgG & IgM 0050321 Method: Enzyme-Linked Immunosorbent Assay	APS diagnosis Order along with Lupus Anticoagulant Reflexive Panel Cardiolipin Antibodies, IgG & IgM		Inconclusive results – consider repeat testing Positive results – confirm at least 12 weeks apart

Test Name and Number

Recommended Use

Limitations

Follow Up

Lupus Anticoagulant Reflexive Panel 0030181

Method: Clotting

Identify lupus anticoagulant in a patient with clinical features of APS or unexpected prolonged partial thromboplastin time results

For suspected APA, order along with

Cardiolipin Antibodies, IgG & IgM
Beta-2 Glycoprotein 1 Antibodies, IgG & IgM

Panel includes LA-sensitive PTT and dilute Russell Viper Venom (dRVVT) for screening, followed by mixing studies and confirmatory assays if indicated

First-line test in the evaluation of APS

No single testing system will identify 100% of LA antibodies

Anticoagulant therapy may interfere with test results

Negative results – consider repeat testing if clinical suspicion is high

Positive results – confirm at least 12 weeks apart

Cardiolipin Antibodies, IgG & IgM 0099344

Method: Enzyme-Linked Immunosorbent Assay

APS diagnosis

Order along with

Lupus Anticoagulant Reflexive Panel
Beta-2 Glycoprotein 1 Antibodies, IgG & IgM

False-positive results may occur with infectious and autoimmune diseases

Inconclusive results – consider repeat testing

Positive results – confirm at least 12 weeks apart

Beta-2 Glycoprotein 1 Antibodies, IgG & IgM 0050321

Method: Enzyme-Linked Immunosorbent Assay

APS diagnosis

Order along with

Lupus Anticoagulant Reflexive Panel
Cardiolipin Antibodies, IgG & IgM

Inconclusive results – consider repeat testing

Positive results – confirm at least 12 weeks apart

Additional Tests Available

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Beta-2 Glycoprotein 1 Antibody, IgA 0050324 Method: Enzyme-Linked Immunosorbent Assay	Not recommended
Cardiolipin Antibodies, IgG, IgM, & IgA 0051162 Method: Enzyme-Linked Immunoassay	IgG and IgM panel test preferred
Cardiolipin Antibody, IgG 0050901 Method: Enzyme-Linked Immunosorbent Assay	IgG and IgM panel test preferred
Cardiolipin Antibody, IgM 0050902 Method: Enzyme-Linked Immunosorbent Assay	IgG and IgM panel test preferred
Cardiolipin Antibody, IgA 0098358 Method: Enzyme-Linked Immunosorbent Assay	Not recommended
Phosphatidylcholine Antibodies, IgG, IgM & IgA 0051590 Method: Enzyme Immunoassay	Not recommended
Phosphatidylethanolamine Antibodies, IgG, IgM & IgA 0051622 Method: Enzyme Immunoassay	Not recommended
Phospholipid Antibodies, IgG, IgM, & IgA 0051600 Method: Enzyme Immunoassay	Not recommended
Phosphatidylinositol Antibodies, IgG, IgM & IgA 0051624 Method: Enzyme Immunoassay	Not recommended
Phosphatidylglycerol Antibodies, IgG, IgM & IgA 0051623 Method: Enzyme Immunoassay	Not recommended
Phosphatidylserine Antibodies, IgG, IgM, & IgA 0050905 Method: Enzyme Immunoassay	Not recommended
Prothrombin Antibody, IgG 0051302 Method: Enzyme-Linked Immunosorbent Assay	Not recommended
Prothrombin Antibody, IgM 0051303 Method: Enzyme-Linked Immunosorbent Assay	Not recommended
Dilute Russell Viper Venom Time (dRVVT) with Reflex to dRVVT 1:1 Mix & Confirmation 0030461 Method: Clotting	Preferred test is the lupus anticoagulant reflexive panel which includes Hexagonal Phospholipid Neutralization and Dilute Russell Viper Venom (dRVVT)
Thrombotic Risk (Acquired) Reflexive Panel 0030268 Method: Refer to individual components
Hexagonal Phospholipid Neutralization 0030064 Method: Clotting	Preferred test is the lupus anticoagulant reflexive panel which includes Hexagonal Phospholipid Neutralization and Dilute Russell Viper Venom (dRVVT)