Chemistry, toxicology & urinalysis
Serology
Anticardiolipin antibodies
Author: Qian Sun, Ph.D.
Board of reviewers: Jieli (Shirley) Li, M.D., Ph.D.
Editorial Board Member: Melissa R. George, D.O.
Last author update: 8 October 2024
Last staff update: 8 October 2024
Copyright: 2002-2024, PathologyOutlines.com, Inc.
PubMed Search: Anticardiolipin antibodies
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Diagrams / tables | Pathophysiology | Clinical features | Test indications | Laboratory | Common commercial platforms and methodologies | Comparison studies of platforms or methodologies | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Sun Q. Anticardiolipin antibodies. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/chemistryanticardiolipinantibodies.html. Accessed December 24th, 2024.
Definition / general
- One of the key antiphospholipid antibody tests for the diagnosis of antiphospholipid syndrome (APS); other antiphospholipid antibody tests include lupus anticoagulant (LA) and anti-β2 glycoprotein I antibodies
- Anticardiolipin antibodies (aCL) include immunoglobulins IgA, IgG and IgM
Essential features
- Patients who tested positive for anticardiolipin antibodies can present with venous thrombosis, arterial thrombosis, microvascular disease, adverse pregnancy outcomes and nonthrombotic manifestations, such as thickening of heart valve
- Anticardiolipin antibodies are positive in 20 - 30% of patients with systemic lupus erythematosus (Khamashta: Hughes Syndrome - Antiphospholipid Syndrome, 2nd Edition, 2005)
- Transient increase in anticardiolipin antibodies can be observed in infectious diseases and other inflammatory conditions; therefore, it is important to repeat the test ≥ 12 weeks after the first positive test result (J Clin Med 2022;11:2164)
Terminology
- Anticardiolipin antibodies (aCL)
- Antiphospholipid syndrome (APS)
- Systemic lupus erythematosus (SLE)
ICD coding
Pathophysiology
- APS is an autoimmune disorder characterized by 1 or more clinical manifestations (including venous and arterial thrombosis, pregnancy morbidity, thrombocytopenia) and persistently elevated antiphospholipid antibodies (aCL, LA, anti-β2 glycoprotein I antibodies)
- Phospholipids, including cardiolipin, are molecules present in cell membranes, including cells that line blood vessels
- In patients with APS, their immune system mistakenly creates antiphospholipid antibodies that target tissues in the body, increasing the risk of developing recurrent inappropriate blood clots (thrombi) in both arteries and veins
- Not all people with antiphospholipid antibodies, including anticardiolipin antibodies, develop clots or other complications
- In addition to patients with APS, infection and medications have been associated with antiphospholipid antibodies; however, the increase of anticardiolipin antibodies in these cases should be transient and often of the IgM isotype (Semin Arthritis Rheum 2002;31:256, Curr Rheumatol Rep 2012;14:71)
- Studies suggest that β2 glycoprotein I serves as a serum cofactor required for the binding of cardiolipin and anticardiolipin antibodies (Lancet 1991;337:671, J Immunol 1992;148:3885)
Clinical features
- APS is more common in women than in men (F:M = ~3.5:1); most patients are women of reproductive age (Front Immunol 2022;13:932181)
- Clinical criteria of APS include
- Venous thromboembolism, such as pulmonary embolism, deep vein thrombosis, cerebral venous thrombosis
- Arterial thrombosis, such as myocardial infarction, stroke, other organ infarcts (kidney, liver or spleen) in the absence of visualized thrombus
- Microvascular involvement, such as diffuse alveolar hemorrhage or antiphospholipid nephropathy, without moderate to large vessel thrombosis
- Obstetric APS, such as multiple embryonic losses, fetal death after 10 weeks gestation, premature birth due to severe preeclampsia
- Cardiac valve thickening or vegetation that is otherwise unexplained
- Thrombocytopenia that is otherwise unexplained
- Catastrophic APS is a life threatening form characterized by severe thrombotic complications with multiple organ involvement that develop simultaneously or over a short period of time; catastrophic APS affects ~1% of individuals with APS (Ther Adv Musculoskelet Dis 2013;5:305)
Test indications
- Patients with venous thromboembolism (particularly if no family history or associated with autoimmune disease)
- Unexplained stroke (young person or autoimmune disease), cerebral venous thrombosis
- Recurrent or late pregnancy loss
- Test may be considered for arterial thrombosis, particularly in young patients or no documented atherosclerosis
- 2023 American College of Rheumatology (ACR) / European Alliance of Associations for Rheumatology (EULAR) classification criteria may help physicians establish a diagnosis (see Diagrams / tables) (Arthritis Rheumatol 2023;75:1687)
Laboratory
- Medium and high titers of IgG and IgM anticardiolipin antibodies are associated with clinical manifestations of APS; it was recommended that the threshold for positive anticardiolipin antibodies test be > 40 IgG phospholipid (GPL) or IgM phospholipid (MPL) units using solid phase enzyme linked immunosorbent assays (ELISAs) in the 2006 international consensus statement as well as the 2023 American College of Rheumatology / European League Against Rheumatism (ACR / EULAR) APS classification criteria (J Thromb Haemost 2006;4:295, Arthritis Rheumatol 2023;75:1687)
- Traditionally, anticardiolipin antibodies are measured by ELISA; however, alternative detection techniques such as chemiluminescent and multiplex flow immunoassays are now available (J Thromb Haemost 2018;16:809)
- Differences between ELISA and platforms using newer techniques such as chemiluminescence have been observed (J Thromb Haemost 2022;20:508, Thromb Haemost 2019;119:797)
- It is therefore recommended that patient follow up testing should be performed within the same laboratory as platforms cannot be used interchangeably
- Patients with syphilitic infection may have false positive anticardiolipin antibodies test results because cardiolipin is the antigen used for the venereal disease research laboratory (VDRL) test (Clin Exp Immunol 1984;56:193)
- IgG anticardiolipin antibodies are more strongly associated with hypercoagulability compared to IgM anticardiolipin antibodies (J Thromb Haemost 2020;18:169)
- Interpretation (based on ELISAs) of anticardiolipin antibody titers includes
- Negative (lower than assay cutoff)
- Low (between cutoff and 40 GPL/MPL)
- Moderate (between 40 and 80 GPL/MPL)
- High (above 80 GPL/MPL)
- Higher titers of IgG anticardiolipin antibodies are associated with more clinical APS events compared to lower titers (Arthritis Rheumatol 2023;75:1687)
Common commercial platforms and methodologies
| Company | Methodology |
| Bio-Rad Bio-Plex | Multiplex flow immunoassay |
| INOVA QUANTA Lite | ELISA |
| INOVA QUANTA Flash | Chemiluminescent immunoassay |
| Phadia EliA | Fluorescence enzyme immunoassay |
| EUROIMMUN | ELISA |
Comparison studies of platforms or methodologies
- Comparison of different test systems for the detection of antiphospholipid antibodies in a Chinese cohort (Front Immunol 2021;12:648881)
- Comparison between the standard anticardiolipin antibody test and a new phospholipid test in patients with connective tissue diseases (J Rheumatol 1999;26:591)
- Semiquantitative interpretation of anticardiolipin and anti-β2 glycoprotein I antibodies measured with various analytical platforms: communication from the International Society on Thrombosis and Haemostasis (ISTH) Committee and the Scientific Standardization Committee (SSC) on lupus anticoagulant / antiphospholipid antibodies (J Thromb Haemost 2022;20:508)
- Detection of anticardiolipin and anti-β2 glycoprotein I antibodies differs between platforms without influence on association with clinical symptoms (Thromb Haemost 2019;119:797)
Additional references
Board review style question #1
A transient increase in anticardiolipin antibodies (aCL) can be observed in infectious diseases and other inflammatory conditions. For the diagnosis of antiphospholipid syndrome, what should be the timing of testing to ensure anticardiolipin antibodies are persistently elevated?
- aCL testing must be positive on 2 separate occasions at least 8 weeks apart
- aCL testing should be performed at the time of the thrombosis or adverse pregnancy outcome
- Initial positive test should be followed by at least 2 confirmatory tests
- Initial testing is usually done shortly after a clinical event, followed by confirmatory testing at least 12 weeks later
Board review style answer #1
D. Initial testing is usually done shortly after a clinical event, followed by confirmatory testing at least 12 weeks later. In patients with initial positive testing for anticardiolipin antibodies, testing should be repeated ≥ 12 weeks after the first test, confirming the persistence of the antibodies. Transiently elevated levels of IgG or IgM anticardiolipin antibodies can occur with certain infections or drug exposures. Answer A is incorrect because testing should be repeated ≥ 12 weeks after the first test, confirming the persistence of the antibodies. Answer B is incorrect because anticardiolipin antibodies tests should be repeated after the initial positive result. Answer C is incorrect because only 1 confirmatory test is required.
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Board review style question #2
Which of the following statements is true regarding antiphospholipid syndrome (APS)?
- APS is more common in men than in women
- In patients with APS, their immune system mistakenly creates antiphospholipid antibodies that target tissues in the body
- Patients with APS have a transient increase in lupus anticoagulant, anticardiolipin antibodies and anti-β2 glycoprotein I antibodies
- Titers of anticardiolipin antibodies and anti-β2 glycoprotein I antibodies are not associated with clinical APS events
Board review style answer #2
B. In patients with APS, their immune system mistakenly creates antiphospholipid antibodies that target tissues in the body. APS is an autoimmune disorder and patients with APS have persistently elevated antiphospholipid antibodies (anticardiolipin antibodies [aCL], lupus anticoagulant [LA], anti-β2 glycoprotein I antibodies). Answer A is incorrect because APS is more common in women than in men. Answer C is incorrect because patients with APS have persistent increases in lupus anticoagulant, anticardiolipin antibodies and anti-β2 glycoprotein I antibodies. Answer D is incorrect because higher titers of autoantibodies are associated with more clinical events than lower titers.
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