Diagnosis of antiphospholipid syndrome
- Doruk Erkan, MD, MPH
Doruk Erkan, MD, MPH
- Associate Attending Rheumatologist, Hospital for Special Surgery
- Associate Professor of Medicine, Weill Cornell Medicine
- Thomas L Ortel, MD, PhD
Thomas L Ortel, MD, PhD
- Professor of Medicine & Pathology
- Hemostasis & Thrombosis Center, Duke University
- Section Editor
- David S Pisetsky, MD, PhD
David S Pisetsky, MD, PhD
- Section Editor — Lupus
- Professor of Medicine and Immunology
- Duke University Medical Center
Antiphospholipid syndrome (APS) is characterized by venous or arterial thrombosis and/or an adverse pregnancy outcome in the presence of persistent laboratory evidence of antiphospholipid antibodies (aPL). APS occurs either as a primary condition or in the setting of an underlying disease, usually systemic lupus erythematosus (SLE).
The diagnosis of APS will be reviewed here. The clinical manifestations and treatment of this disorder are presented separately. (See "Pathogenesis of antiphospholipid syndrome" and "Clinical manifestations of antiphospholipid syndrome" and "Treatment of antiphospholipid syndrome".)
The effect of aPL on coagulation tests is also discussed separately. (See "Clinical use of coagulation tests".)
●Antiphospholipid syndrome – Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by venous or arterial thrombosis and/or pregnancy morbidity in the presence of persistent laboratory evidence of antiphospholipid antibodies (aPL) . APS occurs as a primary condition, or it can occur in the presence of systemic lupus erythematosus (SLE) or another systemic autoimmune disease.
●Antiphospholipid antibodies – aPL are a heterogeneous group of antibodies directed against phospholipid-binding proteins . The aPL detection tests included in APS classification criteria are anticardiolipin (aCL) antibody (immunoglobulin G [IgG] or IgM) enzyme-linked immunosorbent assay (ELISA), anti-beta2-glycoprotein (GP) I antibody (IgG or IgM) ELISA, and lupus anticoagulant (LA) assay. Although cardiolipin is a phospholipid, most of the clinically relevant antibodies detected in this assay are actually binding to phospholipid-binding protein(s), frequently beta2-GP I, that bind to the cardiolipin in the assay. There are other aPL that are not included in APS classification criteria (eg, antibodies directed against prothrombin, phosphatidylserine, or phosphatidylinositol) which are not routinely obtained because of lack of standardized testing and uncertainty about their clinical significance. (See 'Antiphospholipid antibody testing' below.)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Lim W. Antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program 2013; 2013:675.
- Khamashta MA, Amigo MC. Antiphospholipid syndorme: overview of pathogenesis, diagnosis, and management. In: Rheumatology, 6, Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH (Eds), Elsevier, Philadelphia 2015. Vol 2, p.1144.
- Pengo V, Tripodi A, Reber G, et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2009; 7:1737.
- Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA. Antiphospholipid syndrome. Lancet 2010; 376:1498.
- Giannakopoulos B, Passam F, Ioannou Y, Krilis SA. How we diagnose the antiphospholipid syndrome. Blood 2009; 113:985.
- Sebastiani GD, Galeazzi M, Tincani A, et al. Anticardiolipin and anti-beta2GPI antibodies in a large series of European patients with systemic lupus erythematosus. Prevalence and clinical associations. European Concerted Action on the Immunogenetics of SLE. Scand J Rheumatol 1999; 28:344.
- Bertolaccini ML, Amengual O, Andreoli L, et al. 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun Rev 2014; 13:917.
- Bertolaccini ML, Amengual O, Artim-Eser B, et al. Clinical and prognostic significance of non-criteria antiphospholipid antibody tests. In: Antiphospholipid Syndrome: Current Research Highlights and Clinical Insights, Erkan D, Lockshin MD (Eds), Springer International Publishing, 2017. p.171.
- Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012; 64:2677.
- Vila P, Hernández MC, López-Fernández MF, Batlle J. Prevalence, follow-up and clinical significance of the anticardiolipin antibodies in normal subjects. Thromb Haemost 1994; 72:209.
- Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46:1019.
- Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4:295.
- Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999; 42:1309.
- Kaul M, Erkan D, Sammaritano L, Lockshin MD. Assessment of the 2006 revised antiphospholipid syndrome classification criteria. Ann Rheum Dis 2007; 66:927.
- Bobba RS, Johnson SR, Davis AM. A review of the sapporo and revised Sapporo criteria for the classification of antiphospholipid syndrome. Where do the revised sapporo criteria add value? J Rheumatol 2007; 34:1522.
- Reber G, Tincani A, Sanmarco M, et al. Proposals for the measurement of anti-beta2-glycoprotein I antibodies. Standardization group of the European Forum on Antiphospholipid Antibodies. J Thromb Haemost 2004; 2:1860.
- Clinical and Laboratory Standards Institute (CLSI). Laboratory Testing for the Lupus Anticoagulant; Approved Guideline. CLSI document H60-A. Wayne, PA. Clinical and Laboratory Standards Institute, 2014.
- http://shop.clsi.org/c.1253739/site/Sample_pdf/H60A_sample.pdf (Accessed on February 17, 2016).
- Groot N, de Graeff N, Avcin T, et al. European evidence-based recommendations for diagnosis and treatment of paediatric antiphospholipid syndrome: the SHARE initiative. Ann Rheum Dis 2017; 76:1637.
- Abreu MM, Danowski A, Wahl DG, et al. The relevance of "non-criteria" clinical manifestations of antiphospholipid syndrome: 14th International Congress on Antiphospholipid Antibodies Technical Task Force Report on Antiphospholipid Syndrome Clinical Features. Autoimmun Rev 2015; 14:401.
- Taraborelli M, Leuenberger L, Lazzaroni MG, et al. The contribution of antiphospholipid antibodies to organ damage in systemic lupus erythematosus. Lupus 2016; 25:1365.
- Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med 1990; 112:682.
- Abu-Shakra M, Gladman DD, Urowitz MB, Farewell V. Anticardiolipin antibodies in systemic lupus erythematosus: clinical and laboratory correlations. Am J Med 1995; 99:624.
- McNeil HP, Chesterman CN, Krilis SA. Immunology and clinical importance of antiphospholipid antibodies. Adv Immunol 1991; 49:193.
- Cervera R, Asherson RA. Clinical and epidemiological aspects in the antiphospholipid syndrome. Immunobiology 2003; 207:5.
- Triplett DA. Many faces of lupus anticoagulants. Lupus 1998; 7 Suppl 2:S18.
- McNally T, Purdy G, Mackie IJ, et al. The use of an anti-beta 2-glycoprotein-I assay for discrimination between anticardiolipin antibodies associated with infection and increased risk of thrombosis. Br J Haematol 1995; 91:471.
- Santiago M, Martinelli R, Ko A, et al. Anti-beta2 glycoprotein I and anticardiolipin antibodies in leptospirosis, syphilis and Kala-azar. Clin Exp Rheumatol 2001; 19:425.
- García Moncó JC, Wheeler CM, Benach JL, et al. Reactivity of neuroborreliosis patients (Lyme disease) to cardiolipin and gangliosides. J Neurol Sci 1993; 117:206.
- Prieto J, Yuste JR, Beloqui O, et al. Anticardiolipin antibodies in chronic hepatitis C: implication of hepatitis C virus as the cause of the antiphospholipid syndrome. Hepatology 1996; 23:199.
- Matsuda J, Saitoh N, Gotoh M, et al. High prevalence of anti-phospholipid antibodies and anti-thyroglobulin antibody in patients with hepatitis C virus infection treated with interferon-alpha. Am J Gastroenterol 1995; 90:1138.
- Leroy V, Arvieux J, Jacob MC, et al. Prevalence and significance of anticardiolipin, anti-beta2 glycoprotein I and anti-prothrombin antibodies in chronic hepatitis C. Br J Haematol 1998; 101:468.
- Muñoz-Rodríguez FJ, Tàssies D, Font J, et al. Prevalence of hepatitis C virus infection in patients with antiphospholipid syndrome. J Hepatol 1999; 30:770.
- Uthman IW, Gharavi AE. Viral infections and antiphospholipid antibodies. Semin Arthritis Rheum 2002; 31:256.
- Von Landenberg P, Lehmann HW, Knöll A, et al. Antiphospholipid antibodies in pediatric and adult patients with rheumatic disease are associated with parvovirus B19 infection. Arthritis Rheum 2003; 48:1939.
- Merrill JT, Shen C, Gugnani M, et al. High prevalence of antiphospholipid antibodies in patients taking procainamide. J Rheumatol 1997; 24:1083.
- Dlott JS, Roubey RA. Drug-induced lupus anticoagulants and antiphospholipid antibodies. Curr Rheumatol Rep 2012; 14:71.
- Vassalo J, Spector N, de Meis E, et al. Antiphospholipid antibodies in critically ill patients with cancer: a prospective cohort study. J Crit Care 2014; 29:533.
- WHEN TO SUSPECT THE DIAGNOSIS
- DIAGNOSTIC EVALUATION
- Physical examination
- Antiphospholipid antibody testing
- - Timing of testing
- - Patients on an anticoagulant
- - Interpretation of positive results
- Evaluation for other conditions
- CLASSIFICATION CRITERIA
- Patients who meet classification criteria
- Patients who do not meet classification criteria
- DIFFERENTIAL DIAGNOSIS
- Other causes of thrombosis
- Other causes of recurrent pregnancy loss
- Asymptomatic individuals with aPL
- - Transient aPL
- - Persistent medium or high titer aPL
- Other conditions associated with aPL
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS