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Laboratory Testing in the Identification of Antiphospholipid Syndrome

Laboratory Testing in the Identification of Antiphospholipid Syndrome

Test Guide

Laboratory Testing in the Identification of
Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by one or both of the following: 1) vascular thrombosis that may be arterial, venous, or both; and 2) pregnancy morbidity.1 Other features include cardiac valve disease, cerebral ischemia, stroke, renal nephropathy, livedo reticularis, and thrombocytopenic purpura.1 Although the prevalence of APS in the general population is unknown, the disease affects 5% to 15% of patients who have recurrent arterial and venous thrombosis.2,3 APS may be more prevalent in women than in men, with onset typically occurring in the fourth or fifth decades of life.4 APS criteria have also been associated with stroke in young adults, who often lack other stroke risk factors.3

Laboratory Identification of APS

According to the 2006 international consensus statement on APS classification criteria, identification of APS requires the presence of vascular thrombosis and/or pregnancy morbidity, along with at least 1 of the following antiphospholipid antibodies: lupus anticoagulant (LA) antibodies, cardiolipin IgG and IgM antibodies, and β2-glycoprotein I (β2-GPI) IgG and IgM antibodies.1 Assays for the 3 antibody types are often performed in parallel. Detection of more than 1 antibody type is associated with more severe APS than the detection of a single antibody.2 If none of the 3 antiphospholipid antibodies are detected, APS is unlikely.1

Lupus anticoagulant and β2-GPI antibodies appear to be more specific and less sensitive than cardiolipin antibodies for identification of APS.1,3,4 Cardiolipin and β2-GPI IgM and IgA antibodies are less strongly associated with APS than are IgG antibodies.1,5-7 Cardiolipin and β2-GPI IgA antibodies may only be associated with thrombosis in specific patient subgroups and are excluded from the international consensus APS laboratory criteria.1 The algorithm in the Figure shows first-line serologic testing for classification of APS, based on the 2006 international consensus classification criteria.1

Figure. Antiphospholipid Syndrome (APS) Diagnostic Algorithm1,11-13

Additional, non–first-line, serologic markers that have been associated with APS symptoms in limited studies include cardiolipin IgA, β2-GPI IgA, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, prothrombin, and annexin V antibodies. These antibodies are excluded from the classification criteria to preserve diagnostic specificity.1 However, they may be used to identify patients who are at risk of developing APS clinical symptoms but who test negative for LA, cardiolipin, and β2-GPI antibodies.2 For example, phosphatidylserine antibodies are associated with stroke and both phosphatidylserine and phosphatidylinositol antibodies are associated with pregnancy morbidity.8,9 Annexin V antibodies have also been linked to recurrent pregnancy loss.10 Some cases of APS are seronegative—they lack detectable antiphospholipid antibodies and cannot be identified by laboratory testing.6

First-line and non–first-line antibody tests used for APS classification are presented in the Table.

Table. Laboratory Tests Used in Screening and Identification of Antiphospholipid Syndrome (APS)
Test Code Test Name Primary Clinical Use and
Differentiating Factors
Antiphospholipid Antibody Panels
19872(X) Antiphospholipid Syndrome Diagnostic Panel

Includes cardiolipin IgG, IgM, IgA; β2-GPI IgG, IgM,
 IgA; lupus anticoagulant.

Diagnose APS in patients with vascular thrombosis and/or pregnancy morbidity (one positive antibody test required). This panel is consistent with the APS classification criteria.1
14890(X) Antiphospholipid Antibody Panel

Includes cardiolipin IgG, IgM, IgA; β2-GPI IgG, IgM,
 IgA; phosphatidylserine IgG, IgM, IgA.

Identify APS and risk of stroke and other neurologic complications.
1776a Antiphospholipid Evaluation

Includes cardiolipin IgG, IgM, IgA; phosphatidylethanolamine IgG, IgM, IgA; phosphatidic acid IgG, IgM, IgA; phosphatidylserine IgG, IgM, IgA; phosphatidylglycerol IgG, IgM, IgA; phosphatidylinositol IgG, IgM, IgA; phosphatidylcholine IgG, IgM, IgA.

Identify APS; identify patients at risk of developing APS clinical symptoms who are negative for first-line antibodies (LA, cardiolipin, and β2-GPI antibodies).



Lupus Anticoagulant and Antiphospholipid Confirmatory Panel (on Coumadin)

Includes prothrombin time with INR; thrombin clotting time; cardiolipin IgG, IgM; β2-GPI IgG, IgM; hexagonal phase neutralization; and dRVVT screen with reflex to phospholipid neutralization.

Identify APS in patients receiving warfarin therapy.

Lupus Anticoagulant Assays


Lupus Anticoagulant Evaluation with Reflexb

Includes PTT-LA with reflex to hexagonal phase confirm and dRVVT with reflex to dRVVT confirm
and dRVVT mixing study.

Identify APS and risk of thrombosis, nonbacterial thrombotic endocarditis, pregnancy morbidity, stroke, and livedo reticularis.
17408 PTT-LA with Reflex to Hexagonal Phase Confirmationb Screen for clotting abnormalities, especially those associated with lupus anticoagulants (PTT-LA), and confirm presence of lupus anticoagulant (hexagonal phase confirmation).
763 Activated Partial Thromboplastin Time (aPTT) Screen for clotting abnormalities, including those associated with lupus anticoagulant (dRVVT), and confirm presence of lupus anticoagulant (dRVVT confirm and dRVVT 1:1 mixing study).
15780(X) dRVVT Screen with Reflex to dRVVT Confirm and dRVVT 1:1 Mixb
8847 Prothrombin Time (PT) with INR
8922(X) Mixing Study Determine presence of clotting inhibitor.
36573 Hexagonal Phase Neutralization
(Hexagonal Phase Confirmation)
Confirm presence of lupus anticoagulant.

Cardiolipin Antibody Assays

7352 Cardiolipin Antibodies (IgG, IgA, IgM) Identify APS and risk of thrombosis, pregnancy morbidity, thrombocytopenia, and stroke.
36333 Cardiolipin Antibodies (IgG, IgM)
4662 Cardiolipin Antibody (IgG)
4661 Cardiolipin Antibody (IgA) Identify risk of thrombosis, pregnancy morbidity, thrombocytopenia, and stroke.
4663 Cardiolipin Antibody (IgM) Identify APS, with lower specificity than IgG; identify risk of thrombosis, pregnancy morbidity, thrombocytopenia, and stroke.

Beta2-Glycoprotein I (β2-GPI) Antibody Assays

30340(X) β2-Glycoprotein I Antibodies (IgG, IgA, IgM) Identify APS and risk of thrombosis and pregnancy morbidity.
36554 β2-Glycoprotein I Antibody (IgG) Identify APS and risk of thrombosis and pregnancy morbidity.
36552 β2-Glycoprotein I Antibody (IgA) Identify risk of thrombosis and pregnancy morbidity.
36553 β2-Glycoprotein I Antibody (IgM) Identify APS, with lower specificity than IgG; identify risk of thrombosis and pregnancy morbidity.

Non–First-Line Antiphospholipid Antibody Assays

10062 Phosphatidylserine Antibodies (IgG, IgA, IgM) Identify patients at risk of developing APS clinical symptoms who are negative for first-line antibodies (LA, cardiolipin, and β2-GPI antibodies).
36595 Phosphatidylserine Antibodies (IgG, IgM)
10163(X) Phosphatidylserine Antibody (IgA)
10480(X) Phosphatidylinositol Antibodies (IgG, IgA, IgM)
16684(X) Phosphatidylinositol Antibody (IgG)
16686(X) Phosphatidylinositol Antibody (IgA)
16685(X) Phosphatidylinositol Antibody (IgM)
30037(Z) Phosphatidylcholine Antibodies (IgG, IgA, IgM)
16677(X) Phosphatidylcholine Antibody (IgG)
16679(X) Phosphatidylcholine Antibody (IgA)
16678(X) Phosphatidylcholine Antibody (IgM)
16619(X) Phosphatidylethanolamine Antibodies (IgG,
IgA, IgM)
16680(X) Phosphatidylethanolamine Antibody (IgG)
16682(X) Phosphatidylethanolamine Antibody (IgA)
16681(X) Phosphatidylethanolamine Antibody (IgM)
1775a Phosphatidylglycerol Antibodies (IgG, IgA, IgM)
1771a Phosphatidic Acid Antibodies (IgG, IgA, IgM)
11265 Prothrombin Antibodies (IgG, IgM)

LA, lupus anticoagulant; β2-GPI, beta2-glycoprotein I; PTT-LA, activated partial thromboplastin time assay that is sensitive for lupus anticoagulant; dRVVT, dilute Russell’s viper venom time assay.

a Test codes 1771, 1775, and 1776 are specific to the performing laboratory. When ordering through your regional business unit, please indicate that the test code is specific for Quest Diagnostics Nichols Institute, Valencia, CA.

b Reflex tests are performed at additional charge and are associated with an additional CPT code(s).


  1. 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;4:295-306.

  2. Hoppensteadt DA, Fabbrini N, Bick RL, et al. Laboratory evaluation of the antiphospholipid syndrome. Hematol Oncol Clin N Am. 2008;22:19-32.

  3. Piette J-C, Cacoub P. Antiphospholipid syndrome in the elderly: caution. Circulation. 1998;97:2195-2196.

  4. Ruffatti A, Pengo V. Antiphospholipid syndrome classification criteria: comments on the letter of Swadzba and Musial. J Thromb Haemost. 2009;7:503-504.

  5. Galli M, Luciani D, Bertolini G, et al. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood. 2003;101:1827-1832.

  6. Favaloro EJ, Wong RCW. Laboratory testing and identification of antiphospholipid antibodies and the antiphospholipid syndrome: a potpourri of problems, a compilation of possible solutions. Sem Thromb Haemost. 2008;34:389-410.

  7. Swadzba J, Musial J. More on: the debate on antiphospholipid syndrome classification criteria. J Thromb Haemost. 2009;7:501-502.

  8. Kahles T, Humpich M, Steinmetz H, et al. Phosphatidylserine IgG and beta-2-glycoprotein I IgA antibodies may be a risk factor of ischaemic stroke. Rheumatology. 2005;44:1161-1165.

  9. Ulcova-Gallova Z, Krauz V, Novakova P, et al. Anti-phospholipid antibodies against phosphatidylinositol, and phosphatidylserine are more significant in reproductive failure than antibodies against cardiolipin only. Am J Reprod Immunol. 2005;54:112-117.

  10. Bizzaro N, Tonutti E, Villalta D, et al. Prevalence and clinical correlation of anti-phospholipid-binding protein antibodies in anticardiolipin-negative patients with systemic lupus erythematosus and women with unexplained recurrent miscarriages. Arch Pathol Lab Med. 2005;129:61-68.

  11. Brandt JT, Triplett DA, Alving B, et al. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the subcommittee on lupus anticoagulant/antiphospholipid antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost. 1995;74:1185-1190.

  12. Pengo V, Tripodi A, Reber G, et al. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost. 2009;7:1737-1740.

  13. Triplett DA, Barna LK, Unger GA. A hexagonal (II) phase phospholipid neutralization assay for lupus anticoagulant identification. Thromb Haemost. 1993;70:787-793.

Content reviewed 02/2013
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