What is the clinical significance of a positive anti-cardiolipin antibody (Anti-Cardiolipin Ab), Immunoglobulin M (IgM)?

From the Guidelines

A positive anti-cardiolipin Ab, IgM is clinically significant and warrants consideration for prophylactic treatment with aspirin (75–100 mg daily) to reduce the risk of stroke, especially in patients with a high-risk antiphospholipid profile or those with systemic lupus erythematosus (SLE) and no history of thrombosis or pregnancy complications. The presence of anti-cardiolipin antibodies, including IgM, is a key component of antiphospholipid syndrome (APS) diagnosis when accompanied by clinical manifestations such as thrombosis or pregnancy morbidity 1. According to the 2024 guideline for the primary prevention of stroke by the American Heart Association/American Stroke Association, patients without a history of stroke but with a high-risk aPL profile, which includes triple-positive antiphospholipid testing or double-positive results, should be considered for prophylactic aspirin treatment to reduce stroke risk 1. Key points to consider include:

• The level of antibody titer, with medium to high titers being more clinically significant
• The presence of other antiphospholipid antibodies such as lupus anticoagulant or anti–β2-glycoprotein 1
• Clinical symptoms or history of thrombosis, pregnancy complications, or SLE
• The need for repeat testing to confirm persistent positivity, as transient positivity can occur due to various factors In clinical practice, the management of patients with a positive anti-cardiolipin Ab, IgM should be individualized, taking into account their overall risk profile, including the presence of other cardiovascular risk factors and the potential benefits and risks of anticoagulant therapy 1.

From the Research

Significance of Positive Anti-Cardiolipin Ab, IgM

• The clinical value of IgM antibodies in thrombotic antiphospholipid syndrome (APS) is debated, with more significant correlations with thrombosis found for the IgG compared to IgM isotype 2
• In a minority of studies, significant associations with thrombosis were found for IgM but not IgG antibodies, highlighting the complexity of the relationship between antibody isotypes and thrombotic risk 2
• The unavailability of paired results of IgG and IgM for each separate patient hampers evaluation of the added value of isolated IgM positivity, emphasizing the need for comprehensive testing 2

Association with Thrombosis

• Triple-positivity (i.e., positivity for lupus anticoagulant, anti-cardiolipin, and anti-β2-glycoprotein I antibodies) is associated with a high risk for a first thrombotic event and recurrence, but identification is assay dependent 3
• In triple-positivity, IgM only adds value in thrombotic risk stratification together with IgG, suggesting that IgM antibodies may play a role in certain contexts 3
• The clinical spectrum of APS encompasses additional (extracriteria) clinical manifestations, including cardiac diseases, which may be related to direct (autoimmune-mediated) or indirect (thrombosis) mechanisms 4

Diagnostic and Therapeutic Implications

• Diagnosis of APS is based on the presence of at least one clinical criterion (thrombotic events or pregnancy morbidity) and at least one of the laboratory criteria, including persistently medium/high titer immunoglobulin G (IgG)/immunoglobulin M (IgM) anticardiolipin antibodies 4, 5
• Treatment strategies for APS center on anticoagulation, but individualized approaches are necessary, and the use of direct oral anticoagulants (DOACs) versus warfarin is still being evaluated 5, 6
• A meta-analysis of randomized controlled trials found that DOACs were associated with higher rates of arterial thrombosis than warfarin in patients with APS, especially in the triple-positive group 6