Anti-Cardiolipin IgA

Anticardiolipin IgA antibodies are autoantibodies that target cardiolipin, a negatively charged phospholipid found primarily in the inner mitochondrial membrane and human plasma lipoproteins. 

These antibodies also bind to other negatively charged phospholipids like phosphatidylserine and phosphatidylinositol. 

The presence of anticardiolipin IgA antibodies is associated with various clinical complications, including arterial and venous thrombosis, recurrent pregnancy loss, and thrombocytopenia. 

Although IgG is often the most clinically relevant isotype, IgA antibodies are significant in diagnosing antiphospholipid syndrome (APS). 

New ELISA tests using beta2-glycoprotein 1 as an antigen have improved the specificity of detecting these antibodies, aiding in the more reliable diagnosis of APS.

What is Cardiolipin?

Cardiolipin and Its Function in Cell Membranes [13.]

Cardiolipin is a phospholipid component found primarily in the inner mitochondrial membrane of cells, where it is important in maintaining mitochondrial function and energy production. 

It interacts with respiratory chain complexes and substrate carrier proteins, contributing to the formation of respiratory supercomplexes.

Cardiolipin (CL) is a unique phospholipid found exclusively in mitochondrial membranes of mammalian cells, so it is particularly abundant in tissue that is rich in mitochondria including the heart, skeletal muscle, and liver tissues [8., 10.].  

Cardiolipin is a negatively charged phospholipid, which helps it maintain the structure of the inner mitochondrial membrane and the charge which is essential for proper functioning of the electron transport chain. 

Cardiolipin is also found in normal human plasma lipoproteins including very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). The majority of CL (67%) is in LDL [4.].

Essential Functions of Cardiolipin [13.].

Energy Production in Cells

• Crucial for the proper function of the energy-making process in mitochondria

• Works with parts of the electron transport chain (ETC) and ATP production system, and helps keep these parts stable and working well

• Needed for forming larger structures that make energy production more efficient

Maintaining Mitochondrial Structure

• Keeps the inner structure of mitochondria intact

• Supports the formation of supercomplexes that are important for mitochondrial efficiency

Role in Cell Death

• Plays a part in the process of programmed cell death (apoptosis)

• Interacts with a protein called cytochrome c (Cyt c) to trigger cell death

• Helps Cyt c to function in a way that leads to the release of signals that cause the cell to die

Protein Interaction

• Binds with various proteins in the mitochondria

• Works with proteins involved in energy production and transportation

• Ensures these proteins remain stable and function correctly

What are Anti-Cardiolipin IgA Antibodies? [6.]

Anti-cardiolipin (anti-CL) antibodies are autoantibodies targeting cardiolipin, a negatively charged phospholipid. 

These antibodies also bind to other negatively charged phospholipids such as phosphatidylserine and phosphatidylinositol but not to phospholipids that contain a positive charge like phosphatidylcholine. 

This suggests anti-CL antibodies are specific to negatively charged phospholipids in general.

Anti-cardiolipin IgA antibodies are antibodies of the IgA subclass that target cardiolipin and other negatively charged phospholipids. 

Clinical Significance of Anti-Cardiolipin IgA Antibodies

Anti-cardiolipin antibodies are primarily associated with the immune system's attack on negatively charged phospholipids, potentially leading to various clinical complications. 

Changes in cardiolipin content, acyl chain composition, or peroxidation are linked to mitochondrial dysfunction across various diseases including ischemia, hypothyroidism, neurodegenerative diseases, aging, and heart failure [3.].

As a manifestation of Anti-Phospholipid Thrombosis Syndrome, anti-cardiolipin antibodies are also clinically correlated with  thrombosis, recurrent fetal loss, and thrombocytopenia [6.].

The presence of these antibodies, particularly IgG, is prevalent in patients with conditions like thrombosis, fetal loss, and thrombocytopenia, although no single isotype was directly linked to specific clinical outcomes [6.].

While IgG antibodies seem to be the most clinically relevant anti-cardiolipin antibodies, the presence of anti-cardiolipin IgA antibodies may also signal Anti-Phospholipid Thrombosis Syndrome [6.].

What Is Anti-Phospholipid Thrombosis Syndrome?

Antiphospholipid Thrombosis Syndromes (APS) [2.]

APS includes several subgroups of antiphospholipid antibodies, such as lupus anticoagulant (LA) and anti-cardiolipin antibodies, as well as antibodies against β2-glycoprotein I (β2-GP-I), phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylcholine, and anti-annexin-V. 

APS is the most common acquired blood protein defect associated with venous and arterial thrombosis. 

APS can occur independently, it is frequently associated with SLE [15.].

Clinical manifestations include:

• Venous thrombosis (deep vein thrombosis, pulmonary embolism, hepatic vein thrombosis)

• Arterial thrombosis (coronary artery disease, cerebrovascular disease, retinal vascular thrombosis)

• Recurrent miscarriage

• Thrombocytopenia

• Manifestations associated with SLE as well as APS: including arthralgias and hemolytic anemia, as well as increased risk of thrombosis and pregnancy complications [14.].

Subgroups of Antiphospholipid Antibodies

The antiphospholipid syndrome consists of closely related but distinct clinical syndromes:

• Lupus Anticoagulant Thrombosis Syndrome: Primarily associated with venous thrombosis.

• Anti-Cardiolipin Antibody Thrombosis Syndrome: More commonly associated with both arterial and venous thrombosis.

• Thrombosis Associated with Subgroups of Antiphospholipid Antibodies: Includes antibodies against β2-GP-I and other phospholipids.

Laboratory Testing for Anti-Cardiolipin IgA

Anti-Cardiolipin IgA Test Information [7.]

Antiphospholipid antibodies are diverse, with a subset linked to arterial and venous thrombosis and recurrent pregnancy loss 

These antibodies are best diagnosed using the lupus anticoagulant test and solid-phase anticardiolipin tests, which employ enzyme-linked immunosorbent assays (ELISA) using cardiolipin or other negatively charged phospholipids as antigens. 

Patients with anti-cardiolipin antibodies often have a persistent, high-level IgG isotype.

However, the anti-cardiolipin ELISA test, which uses cardiolipin on plastic plates, is very sensitive but not very specific because it can give positive results for other infections like syphilis and HIV, or autoimmune diseases besides anti-phospholipid syndrome. 

To improve specificity, new ELISA tests using different antigens, such as beta2-glycoprotein 1 on oxidized plates or a mix of phospholipids, have been developed. 

Sample Collection and Preparation

Testing for the presence of anti-cardiolipin antibodies requires a blood draw.  While special preparation is often not required, it is important to consult with the ordering provider to confirm this.

Interpretation of Anti-Cardiolipin IgA Test Results

Optimal Levels of Anti-Cardiolipin Antibodies

The presence of anti-cardiolipin antibodies signals an autoimmune process, where the body mistakenly attacks its own cells or structures, which can have massive clinical consequences.  

Optimal levels of anti-cardiolipin antibodies are considered undetectable, or very low. 

Clinical Significance of Elevated Anti-Cardiolipin Antibodies

Anticardiolipin antibodies, particularly moderate to high titer IgG, are strongly linked to arterial and venous thrombosis as well as recurrent pregnancy loss. IgM and IgA isotypes are also associated with venous thrombosis [1.].

The distribution of anticardiolipin antibody subtypes in patients with thrombosis has been shown to be: [2.]

• IgG: 36%

• IgM: 17%

• IgA: 14%

• Multiple: 33%

Elevated anti-cardiolipin antibodies have also been associated with ischemia, hypothyroidism, neurodegenerative diseases, aging, and heart failure [3.].

Related Biomarkers to Test

In addition to Anti-Cardiolipin IgA, several other biomarkers are often tested to provide a comprehensive assessment of antiphospholipid syndrome (APS) and related autoimmune disorders. 

Anti-β2-Glycoprotein I Antibodies

Anti-β2-Glycoprotein I (aβ2GPI) antibodies are crucial in the diagnosis of APS. These antibodies target β2-glycoprotein I, a plasma protein that binds to negatively charged phospholipids [16.].

While the anticardiolipin and lupus anticoagulant tests are commonly used to detect these antibodies, the anticardiolipin ELISA lacks specificity because it can show positive results for other infections and autoimmune diseases [7.].

To improve accuracy, new ELISA tests using beta2-glycoprotein 1 as an antigen have been developed. These tests are more specific for anti-phospholipid antibodies and are more reliable for diagnosing APS [7.].

Lupus Anticoagulant

Lupus anticoagulant (LA) is a key biomarker in diagnosing antiphospholipid syndrome (APS) alongside anti-cardiolipin and anti-β2GPI antibodies [9., 12.].

Despite its name, LA is associated with thrombosis risk rather than bleeding [11.].

Dilute Russell's viper venom time (dRVVT) and activated partial thromboplastin time (aPTT) are also widely recommended as confirmatory tests [9., 12.].

However, LA testing faces challenges such as poor standardization, result interpretation difficulties, and interference from anticoagulant drugs, particularly direct oral anticoagulants (DOACs) and vitamin K antagonists [5., 11.].

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