Antiphospholipid Syndrome

Algorithm(s)

PDF algorithm(s) available at www.arupconsult.com.

Antiphospholipid Syndrome Testing Algorithm

Clinical Background

Antiphospholipid syndrome (APS) is an autoimmune disorder in which the body makes antibodies against its own phospholipids or plasma proteins. APS is characterized by thrombosis, fetal loss or both and associated with persistent levels of antiphospholipid (aPL) antibodies.

Epidemiology

Prevalence
- Unknown in general population for APS
- Lupus anticoagulant (LA) antibodies affect 2-4% of the population and also occur in numerous conditions, particularly autoimmune diseases, thrombocytopenia and neurological disorders
Age - 20s-50s most commonly
Sex - female predominance

Risk Factors

Presence of an autoimmune disease

Pathophysiology

The presence of antiphospholipid (aPL) antibodies is a risk factor for vascular thrombosis and pregnancy-related morbidity
- Antiphospholipid antibodies represent a heterogeneous group of autoantibodies that recognize various phospholipids (PL), PL-binding plasma proteins, and/or PL-protein complexes
APL antibodies are present in as many as 50% of people with systemic lupus erythematosus (SLE) and in varying prevalences in the rest of the population
Lupus anticoagulants (LA) are autoantibodies that target complexes of phospholipids with either Beta-2 glycoprotein 1 (ß2GP1) or clotting factors such as prothrombin
- LA are also a risk factor for vascular thrombosis
- Thrombosis occurs in about 5-20% of all patients with LA
  - Recurrent thrombotic episodes can occur

Clinical Presentation

Recurrent thrombosis, pregnancy loss or prematurity
May also include endocarditis, stroke, heart attack, livedo reticularis, thrombocytopenia and hemolytic anemia

Treatment

Treatment of lupus anticoagulants reduces recurrent pregnancy loss

See Also

Hypercoagulable States - Thrombophilia

Infertility

Venous Thromboembolism

Algorithm(s)

PDF algorithm(s) available at www.arupconsult.com.

Antiphospholipid Syndrome Testing Algorithm

Diagnosis

Indications for testing - recurrent vascular thromboses, recurrent pregnancy loss or morbidity
Laboratory testing
- Some of the antibodies detected in the following tests may be present in APS but occur in association with either LA or aCL or ß2GP1 (IgG and/or IgM) antibodies
  - The presence of IgA antibodies alone are non-diagnostic and are not recommended in the workup of APS
  - Assays not recommended for the definitive diagnosis of APS
    - Cardiolipin IgA antibody
    - Beta-2 glycoprotein 1 antibody, IgA
    - Phosphatidylserine antibodies, IgG, IgM, and IgA
    - Prothrombin antibody, IgG and IgM

Revised Classification Criteria for the Antiphospholipid Antibody Syndrome

For antiphospholipid antibody syndrome to be discussed, 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, which must be validated by imaging studies or histopathology.

Pregnancy morbidity:

One or more unexplained deaths of a morphologically normal fetus beyond the 10th week of gestation or
One or more premature births of a morphologically normal neonate before the 34th week of gestation due to preeclampsia, eclampsia, or placental insufficiency or
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

(Each 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 > the 99th percentile), measured by a standardized ELISA.

Anti-ß2 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.

Adapted from Miyakis S et al. J Thromb Haemost. 2006.

Differential Diagnosis

Hypercoagulable state
Pregnancy loss
Autoimmune disease (systemic lupus erythematosus)
Drugs
Stroke
Endocarditis

Algorithm(s)

PDF algorithm(s) available at www.arupconsult.com.

Antiphospholipid Syndrome Testing Algorithm

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: Lupus Anticoagulant Reflexive Panel

ARUP #: 0030181

Methodology: Clotting

Use:

Diagnose APS or assess risk for thrombosis or unexplained, recurrent fetal loss

Order along with
- Cardiolipin Antibodies, IgG & IgM
- Beta-2 Glycoprotein 1 Antibodies, IgG & IgM

ARUP Panel includes PTT and dilute Russell Viper Venom (dRVVT) for screening; followed, if appropriate, by platelet neutralization for confirmation

This is a first line test in the evaluation of acquired thrombophilia

Limitations:

Anti-coagulant therapy will interfere with test results

Follow-up:

Although patients on warfarin or patients with deficiencies of factor II, V and X may show prolonged times, the final ratio will be normal unless LA are present

For inconclusive results, consider repeat testing. All positive results must be confirmed at least 12 weeks apart

Test name: Cardiolipin Antibodies, IgG & IgM

ARUP #: 0099344

Methodology: Enzyme-Linked Immunosorbent Assay

Use:

Diagnose APS or assess risk for thrombosis or unexplained, recurrent fetal loss

Order along with
- Lupus Anticoagulant Panel with Reflex to 1:1 Mixes & Confirmations (0030181)
- Beta-2 Glycoprotein 1 Antibodies, IgG & IgM (0050321)

Limitations:

False-positive results may occur with infectious diseases

Follow-up:

For inconclusive results, consider repeat testing. All positive results must be confirmed at least 12 weeks apart

Test name: Beta-2 Glycoprotein 1 Antibodies, IgG & IgM

ARUP #: 0050321

Methodology: Enzyme-Linked Immunosorbent Assay

Use:

Use for APS diagnosis and confirmation

Limitations:

Diagnosis should NOT be made solely on the basis of a single specimen

Follow-up:

For inconclusive results, consider repeat testing. All positive results must be confirmed at least 12 weeks apart

Additional Tests Available

Test name: Beta-2 Glycoprotein 1 Antibody, IgA

ARUP #: 0050324

Methodology: Enzyme-Linked Immunosorbent Assay

Comments: Not recommended

Test name: Cardiolipin Antibodies, IgG, IgM, & IgA

ARUP #: 0051162

Methodology: Enzyme-Linked Immunoassay

Comments: IgG and IgM panel test preferred

Test name: Cardiolipin Antibody, IgG

ARUP #: 0050901

Methodology: Enzyme-Linked Immunosorbent Assay

Comments: Panel test preferred

Test name: Cardiolipin Antibody, IgM

ARUP #: 0050902

Methodology: Enzyme-Linked Immunosorbent Assay

Comments: Panel test preferred

Test name: Cardiolipin Antibody, IgA

ARUP #: 0098358

Methodology: Enzyme-Linked Immunosorbent Assay

Comments: Not recommended

Test name: Phosphatidylcholine Antibodies, IgG, IgM & IgA

ARUP #: 0051590

Methodology: Enzyme Immunoassay

Comments: Not recommended

Test name: Phosphatidylethanolamine Antibodies, IgG, IgM & IgA

ARUP #: 0051622

Methodology: Enzyme Immunoassay

Comments: Not recommended

Test name: Phospholipid Antibodies, IgG, IgM, & IgA

ARUP #: 0051600

Methodology: Enzyme Immunoassay

Comments: Not recommended

Test name: Phosphatidylinositol Antibodies, IgG, IgM & IgA

ARUP #: 0051624

Methodology: Enzyme Immunoassay

Comments: Not recommended

Test name: Phosphatidylglycerol Antibodies, IgG, IgM & IgA

ARUP #: 0051623

Methodology: Enzyme Immunoassay

Comments: Not recommended

Test name: Phosphatidylserine Antibodies, IgG, IgM, & IgA

ARUP #: 0050905

Methodology: Enzyme Immunoassay

Comments: Not recommended

Test name: Prothrombin Antibody, IgG

ARUP #: 0051302

Methodology: Enzyme-Linked Immunosorbent Assay

Comments: Not recommended

Test name: Prothrombin Antibody, IgM

ARUP #: 0051303

Methodology: Enzyme-Linked Immunosorbent Assay

Comments: Not recommended

Test name: Dilute Russell Viper Venom Time (dRVVT) with Reflex to dRVVT 1:1 Mix & Confirmation

ARUP #: 0030461

Methodology: Clotting

Comments:

Additional Information

All tests must be repeated at least 12 weeks apart to demonstrate antibody persistence.
Assay results by themselves are not diagnostic; they must be interpreted with other laboratory tests and clinical presentation of the patient.
Syphilis and other infectious diseases may cause false-positives for anticardiolipin and antiphospholipid antibody testing.

References

Guidelines

Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295-306.

Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, Brey R, Derksen R, Harris EN, Hughes GR, Triplett DA, Khamashta MA. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999;42(7):1309-1311.

General References

Abo SM, DeBari VA. Laboratory evaluation of the antiphospholipid syndrome. Ann Clin Lab Sci. 2007;37(1):3-14.

Asherson RA. The catastrophic antiphospholipid (Asherson's) syndrome. Autoimmun Rev. 2006;6(2):64-67.

Bertolaccini ML, Hughes GR. Antiphospholipid antibody testing: which are most useful for diagnosis?. Rheum Dis Clin North Am. 2006;32(3):455-463.

Bertolaccini ML, Khamashta MA, Hughes GR. Diagnosis of antiphospholipid syndrome. Nat Clin Pract Rheumatol. 2005;1(1):40-46.

Black A. Antiphospholipid syndrome: an overview. Clin Lab Sci. 2006;19(3):144-147.

Blume JE, Miller CC. Antiphospholipid syndrome: a review and update for the dermatologist. Cutis. 2006;78(6):409-415.

D'Cruz DP, Khamashta MA, Hughes GR. Systemic lupus erythematosus. Lancet. 2007;369(9561):587-596.

Espinosa G, Bucciarelli S, Cervera R, Gomez-Puerta JA, Font J. Laboratory studies on pathophysiology of the catastrophic antiphospholipid syndrome. Autoimmun Rev. 2006;6(2):68-71.

Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med. 2002;346(10):752-763.

Lockshin MD. Update on antiphospholipid syndrome. Bull NYU Hosp Jt Dis. 2006;64(1-2):57-59.

Miesbach W, Asherson RA, Cervera R, Shoenfeld Y, Gomez Puerta J, Bucciarelli S, Espinoza G, Font J. The catastrophic antiphospholipid (Asherson's) syndrome and malignancies. Autoimmun Rev. 2006;6(2):94-97.

Pengo V, Ruffatti A, Iliceto S. The diagnosis of the antiphospholipid syndrome. Pathophysiol Haemost Thromb. 2006;35(1-2):175-180.

Pierangeli SS, Chen PP, Gonzalez EB. Antiphospholipid antibodies and the antiphospholipid syndrome: an update on treatment and pathogenic mechanisms. Curr Opin Hematol. 2006;13(5):366-375.

Wisloff F, Jacobsen EM, Liestol S. Laboratory diagnosis of the antiphospholipid syndrome. Thromb Res. 2002;108(5-6):263-271.

References from the ARUP Institute for Clinical and Experimental Pathology Research®

Tebo AE, Jaskowski TD, Phansalkar AR, Litwin CM, Branch DW, Hill HR. Diagnostic performance of phospholipid-specific assays for the evaluation of antiphospholipid syndrome. Am J Clin Pathol. 2008;129(6):870-875.

Medical Reviewers

Hill, Harry R., M.D. Group Medical Director, Laboratory of Immunology, ARUP Laboratories, and Executive Director of the ARUP Institute for Clinical and Experimental Pathology; Professor and Division Head, Clinical Pathology, University of Utah

Litwin, Christine, M.D. Medical Director, Immunology at ARUP Laboratories; Professor, Clinical Pathology, University of Utah

Rodgers, George M. III, M.D., Ph.D. Medical Director, Hemostasis/Thrombosis at ARUP Laboratories; Professor, Medicine, Adjunct Professor, Pathology, University of Utah

Tebo, Anne E., Ph.D. Assistant Medical Director, Immunology at ARUP Laboratories; Clinical Assistant Professor, Clinical Pathology, University of Utah

Comprehensive Review: January 2008
Last Update: September 2008