Antiphospholipid Syndrome - APS

  • Diagnosis
  • Algorithms
  • Screening
  • Background
  • Lab Tests
  • References
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Indications for Testing

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
      • Anti-beta-2 glycoprotein 1 (anti-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 "non-criteria" tests for patients with repeatedly negative “criteria” aPL test results with high suspicion for APS
    • Phosphatidylserine/prothrombin antibodies, IgG and IgM
    • Phosphatidylserine antibodies, IgG and IgM
    • Prothrombin antibody, IgG
    • Anti-β2GP1 antibody, IgA
    • ​Anticardiolipin antibody, IgA

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 systemic lupus erythematosus (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.


  • 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 beta-2 glycoprotein 1 (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-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


Refer to individual components


Positive results – confirm at least 12 weeks apart

Lupus Anticoagulant Reflexive Panel 0030181
Method: Electromagnetic Mechanical Clot Detection


No single testing system will identify 100% of LA activity

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 and IgM 0099344
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay


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 and IgM 0050321
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay


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) (aPs, aPt, aPs/aPt) Antibodies Panel 2012729
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Phosphatidylserine Antibodies, IgG and IgM 2006495
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Prothrombin Antibody, IgG 0051302
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Phosphatidylserine and Prothrombin Antibody, IgG 2009447
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Phosphatidylserine and Prothrombin Antibodies, IgG and IgM 2009451
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay


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, 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, 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, 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. 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®

Amengual O, Forastiero R, Sugiura-Ogasawara M, Otomo K, Oku K, Favas C, Alves D, Žigon P, Ambrožič A, Tomšič M, Ruiz-Arruza I, Ruiz-Irastorza G, Bertolaccini ML, Norman GL, Shums Z, Arai J, Murashima A, Tebo AE, Gerosa M, Meroni PL, Rodriguez-Pintó I, Cervera R, Swadzba J, Musial J, Atsumi T. Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study. Lupus. 2017; 26(3): 266-276. PubMed

Bertolaccini ML, 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

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

Peterson LK, Willis R, Harris N, Branch WD, Tebo AE. Antibodies to Phosphatidylserine/Prothrombin Complex in Antiphospholipid Syndrome: Analytical and Clinical Perspectives. Adv Clin Chem. 2016; 73: 1-28. 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, Willis R, Jaskowski TD, Guerra M, Pierangeli SS, Salmon J, Petri M, Branch W. Clinical significance and correlations between anti-β2 glycoprotein I IgA assays in antiphospholipid syndrome and/or systemic lupus erythematosus. Clin Chim Acta. 2016; 460: 107-13. PubMed

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

Willis R, Pierangeli SS, Jaskowski TD, Malmberg E, Guerra M, Salmon JE, Petri M, Branch W, Tebo AE. Performance Characteristics of Commercial Immunoassays for the Detection of IgG and IgM Antibodies to β2 Glycoprotein I and an Initial Assessment of Newly Developed Reference Materials for Assay Calibration. Am J Clin Pathol. 2016; 145(6): 796-805. 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: April 2017