Antiphospholipid Syndrome - APS

  • Diagnosis
  • Algorithms
  • Screening
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Recurrent vascular thromboses, recurrent pregnancy loss, unexplained prolonged PTT in an asymptomatic patient (indication for lupus anticoagulant testing)
  • Additional indications for testing may also include the presence of endocarditis, livedo reticularis, thrombocytopenia, hemolytic anemia, and thrombotic microangiopathy

Criteria for Diagnosis

Laboratory Testing

  • Current recommendations for first-line laboratory testing should include the following
    • Three tests
      • LA activity
        • At least 2 phospholipid-dependent clotting assays, based on different principles, should be performed to identify LA activity
      • aCL IgG and IgM antibodies
      • β2GP1 IgG and IgM antibodies
    • Combination of three tests reduces rate of false-positive results
    • Repeat positive laboratory tests after 12 weeks to confirm persistent positivity
    • Repeat testing if a strong clinical suspicion exists for APS but criteria laboratory tests are negative (seronegative APS)
    • Testing for IgA antibodies is not recommended
  • Consider the following noncriteria tests for patients with repeatedly negative results from criteria tests and high suspicion for APS
    • aCL antibody, IgA
    • β2GP1 antibody, IgA
    • Phosphatidylserine antibodies, IgG, IgM, & IgA
    • Prothrombin antibodies, IgG and IgM

Differential Diagnosis

  • Not recommended for patients with single deep vein thrombosis unless a risk factor is present
  • Test for antibodies in the following situations
    • Thrombosis
      • Arterial thrombosis <50 years
      • Unprovoked venous thrombosis <50 years
      • Recurrent thrombosis
      • Thrombosis at unusual site
      • Patients with both arterial and venous thrombotic events
      • Patients admitted with thrombotic microangiopathy of unknown etiology
    • Obstetric manifestations
      • ≥1 unexplained fetal loss after 10th week of gestation
      • Unexplained severe intrauterine growth restriction
      • Early or severe preeclampsia
      • ≥3 spontaneous miscarriages before 10th week of gestation
    • Patients with SLE
      • Perform baseline test
      • Repeat testing
        • Before pregnancy, surgery, transplantation, and use of estrogen-containing treatments
        • New neurologic, vascular or obstetric event present

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.

Epidemiology

  • Prevalence
    • Present in a small percentage of young healthy subjects (1-5%) and in up to 10% of patients with venous thrombosis
      • Estimates of prevalence are hampered by the variety of testing systems available for diagnosis
    • Higher prevalence in patients with connective tissue disease, but most patients with aPL antibodies do not have an underlying autoimmune disease

Risk Factors

  • Connective tissue disease
  • Infections – no increase in thrombotic risk
  • Malignancy
  • Liver disease
  • Vascular disease
  • Medications – increased thrombotic risk

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 protein function
  • LAs are autoantibodies that target complexes of phospholipids with either β2GP1 or another plasma protein 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
  • aPL antibodies are often classified as either lupus anticoagulant (LA), or anticardiolipin (aCL) antibodies, or anti-beta-2 glycoprotein 1 (β2GP1) antibodies
    • Thrombosis appears to be more common in patients with LA activity
    • Positivity for all 3 (LA activity, aCL and β2GP1 antibodies) is a strong independent risk factor for thrombosis
  • Transient aPL antibodies may occur in association with infections and with 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, neurologic, dermatologic, or cardiopulmonary abnormalities
  • Catastrophic APS is a multi-organ illness caused by diffuse small vessel thrombosis and tissue ischemia
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.

Antiphospholipid Syndrome Reflexive Panel 2003222
Method: Electromagnetic Mechanical Clot Detection/Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Limitations 

Refer to individual components

Follow-up 

Positive results – confirm at least 12 weeks apart

Lupus Anticoagulant Reflexive Panel 0030181
Method: Electromagnetic Mechanical Clot Detection

Limitations 

No single testing system will identify 100% of LA activity

Anticoagulant therapy may interfere with test results

Follow-up 

Negative results – consider repeat testing if clinical suspicion is high

Positive results – confirm at least 12 weeks apart

Cardiolipin Antibodies, IgG and IgM 0099344
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Limitations 

False-positive results may occur with infectious and autoimmune diseases 

Follow-up 

Inconclusive results – consider repeat testing

Positive results – confirm at least 12 weeks apart

Beta-2 Glycoprotein 1 Antibodies, IgG and IgM 0050321
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Follow-up 

Inconclusive results – consider repeat testing

Positive results – confirm at least 12 weeks apart

High-Specificity Antiphospholipid Antibodies, IgG and IgM 2005457
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Non-Criteria Antiphospholipid Syndrome (APS) (aPa, aPc, aPe, aPg, aPi) Antibodies Extended Panel 2012730
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Non-Criteria Antiphospholipid Syndrome (APS) (aPs, aPt, aPs/aPt) Antibodies Panel 2012729
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Guidelines

Antiphospholipid syndrome. American College of Obstetricians and Gynecologists - Medical Specialty Society. 2005 Nov (Revised 2011 Jan). NGC: 008207

Bertolaccini ML, Amengual O, Atsumi T, Binder WL, de Laat B, Forastiero R, Kutteh WH, Lambert M, Matsubayashi H, Murthy V, Petri M, Rand JH, Sanmarco M, Tebo AE, Pierangeli SS. 'Non-criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, TX, USA, April 2010. Lupus. 2011; 20(2): 191-205. PubMed

Keeling D, Mackie I, Moore GW, Greer IA, Greaves M, British Committee for Standards in Haematology. Guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol. 2012; 157(1): 47-58. PubMed

Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH W M, 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. PubMed

Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, DE Groot PG, Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. 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(10): 1737-40. PubMed

Wong RC W, Favaloro EJ. A consensus approach to the formulation of guidelines for laboratory testing and reporting of antiphospholipid antibody assays. Semin Thromb Hemost. 2008; 34(4): 361-72. PubMed

General References

Aguiar CL, Soybilgic A, Avcin T, Myones BL. Pediatric antiphospholipid syndrome. Curr Rheumatol Rep. 2015; 17(4): 27. PubMed

Cohen D, Berger SP, Steup-Beekman GM, Bloemenkamp KW M, Bajema IM. Diagnosis and management of the antiphospholipid syndrome. BMJ. 2010; 340: c2541. PubMed

Devreese K, Hoylaerts MF. Challenges in the diagnosis of the antiphospholipid syndrome. Clin Chem. 2010; 56(6): 930-40. PubMed

Favaloro EJ, Wong RC W. Laboratory testing for the antiphospholipid syndrome: making sense of antiphospholipid antibody assays. Clin Chem Lab Med. 2011; 49(3): 447-61. PubMed

Giannakopoulos B, Passam F, Ioannou Y, Krilis SA. How we diagnose the antiphospholipid syndrome. Blood. 2009; 113(5): 985-94. PubMed

Hoppensteadt DA, Fabbrini N, Bick RL, Messmore HL, Adiguzel C, Fareed J. Laboratory evaluation of the antiphospholipid syndrome. Hematol Oncol Clin North Am. 2008; 22(1): 19-32, v. PubMed

Myones BL. Update on antiphospholipid syndrome in children. Curr Rheumatol Rep. 2011; 13(1): 86-9. PubMed

Ortel TL. Antiphospholipid syndrome: laboratory testing and diagnostic strategies. Am J Hematol. 2012; 87 Suppl 1: S75-81. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Bertolaccini MLaura, Amengual O, Andreoli L, Atsumi T, Chighizola CB, Forastiero R, de Groot P, Lakos G, Lambert M, Meroni P, Ortel TL, Petri M, Rahman A, Roubey R, Sciascia S, Snyder M, Tebo AE, Tincani A, Willis R. 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun Rev. 2014; 13(9): 917-30. PubMed

Chen ZWill, Perkins SL, Weiss RL, Bahler DW, Hussong JW, Salama ME. A limited plasma cell flow cytometry panel with reflex CD138 immunohistochemistry is an optimal workflow process for evaluating plasma cell neoplasms in bone marrow specimens Am J Clin Pathol. 2015; 143(1): 78-83. PubMed

Heikal NM, Jaskowski TD, Malmberg E, Lakos G, Branch DW, Tebo AE. Laboratory evaluation of anti-phospholipid syndrome: a preliminary prospective study of phosphatidylserine/prothrombin antibodies in an at-risk patient cohort Clin Exp Immunol. 2015; 180(2): 218-26. PubMed

Jaskowski TD, Wilson AR, Hill HR, Branch WD, Tebo AE. Autoantibodies against phosphatidylserine, prothrombin and phosphatidylserine-prothrombin complex: identical or distinct diagnostic tools for antiphospholipid syndrome? Clin Chim Acta. 2009; 410(1-2): 19-24. PubMed

Li D, Miles R, Tripp SR, Glenn MJ, Perkins SL, Salama M. Clinicopathologic evaluation of MYC expression in primary mediastinal (thymic) large B-cell lymphoma Am J Clin Pathol. 2015; 143(4): 598-604. PubMed

Shiramizu B, Goldman S, Smith L, Agsalda-Garcia M, Galardy P, Perkins SL, Frazer K, Sanger W, Anderson JR, Gross TG, Weinstein H, Harrison L, Barth MJ, Mussolin L, Cairo MS. Impact of persistent minimal residual disease post-consolidation therapy in children and adolescents with advanced Burkitt leukaemia: a Children's Oncology Group Pilot Study Report. Br J Haematol. 2015; 170(3): 367-71. PubMed

Smock KJ, Rodgers GM. Laboratory identification of lupus anticoagulants. Am J Hematol. 2009; 84(7): 440-2. PubMed

Suh-Lailam BB, Cromar A, Davis W, Tebo AE. APhL antibody ELISA as an alternative to anticardiolipin test for the diagnosis of antiphospholipid syndrome. Int J Clin Exp Pathol. 2012; 5(3): 210-5. PubMed

Tebo AE, Jaskowski TD, Hill HR, Branch DW. Clinical relevance of multiple antibody specificity testing in anti-phospholipid syndrome and recurrent pregnancy loss. Clin Exp Immunol. 2008; 154(3): 332-8. PubMed

Tebo AE, Jaskowski TD, Phansalkar AR, Litwin CM, Branch W, Hill HR. Diagnostic performance of phospholipid-specific assays for the evaluation of antiphospholipid syndrome. Am J Clin Pathol. 2008; 129(6): 870-5. PubMed

Tebo AE. Antiphospholipid syndrome and the relevance of antibodies to negatively charged phospholipids in diagnostic evaluation. Lupus. 2014; 23(12): 1313-6. PubMed

Win K, Rodgers GM. New oral anticoagulants may not be effective to prevent venous thromboembolism in patients with antiphospholipid syndrome. Am J Hematol. 2014; 89(10): 1017. PubMed

Medical Reviewers

Last Update: August 2016