For a patient being evaluated for non‑infective (Libman‑Sacks or marantic) endocarditis, should we test IgG, IgM, or both antiphospholipid antibodies (anticardiolipin and β2‑glycoprotein I) together with a lupus‑anticoagulant assay?

Testing for Antiphospholipid Antibodies in Non-Infective Endocarditis

Test both IgG and IgM isotypes for anticardiolipin (aCL) and anti-β2-glycoprotein I (aβ2GPI) antibodies, along with lupus anticoagulant (LA), as this complete panel is mandatory for diagnosing antiphospholipid syndrome (APS) associated with non-infective endocarditis. 1

Core Testing Algorithm

When evaluating a patient with suspected Libman-Sacks or marantic endocarditis, the complete antiphospholipid antibody workup must include:

• Lupus anticoagulant (LA) using both dRVVT and APTT screening tests in parallel 1, 2
• Anticardiolipin antibodies (aCL) - both IgG and IgM isotypes by ELISA or validated solid-phase assay 1
• Anti-β2-glycoprotein I antibodies (aβ2GPI) - both IgG and IgM isotypes by ELISA or validated solid-phase assay 1

All three tests must be performed together, as omitting any component risks missing the diagnosis in a substantial proportion of patients. 1, 2

Why Both IgG and IgM Matter

IgG vs IgM Clinical Relevance

• IgG isotypes carry greater clinical significance than IgM for both aCL and aβ2GPI antibodies 1, 3
• However, IgM cannot be omitted from initial testing because isolated IgM positivity, while less common in thrombotic presentations, can still be clinically relevant 3
• Double positivity (both aCL and aβ2GPI of the same isotype, whether IgG or IgM) significantly increases diagnostic confidence for APS 1

Risk Stratification Based on Antibody Profile

The antibody profile directly impacts risk assessment:

• Triple positivity (LA + aCL + aβ2GPI) confers the highest thrombotic risk 1, 3, 2
• Double positivity with concordant isotype (e.g., both aCL IgG and aβ2GPI IgG) represents high risk 1
• Isolated IgM positivity is considered lower risk but still requires clinical correlation 1, 3
• Medium to high titers (>99th percentile) are of utmost importance for diagnosis, regardless of isotype 1

Confirmation Testing Requirements

• Two consecutive positive tests at least 12 weeks apart are required to confirm persistent positivity and rule out transient antibodies 1, 3
• The same antibodies must remain positive on repeat testing 1
• This confirmation step is critical because transient positivity is insufficient for APS diagnosis 1

Critical Pitfalls to Avoid

Anticoagulation Interference

• Never perform LA testing during anticoagulation therapy - this is the most common source of false results 2, 4
• If the patient is already anticoagulated for suspected endocarditis, LA testing becomes unreliable 1, 2
• Solid-phase assays (aCL and aβ2GPI) are not affected by anticoagulants and can be performed regardless of anticoagulation status 5

Interpretation Errors

• Do not rely on isolated IgM positivity alone - single IgM positivity without other antibodies requires careful clinical correlation and is considered less clinically relevant 1, 3
• Low-positive results near threshold values should be interpreted cautiously due to 10% assay imprecision 2
• Results must be interpreted in clinical context with knowledge of the patient's anticoagulation status 1, 2

Clinical Context for Non-Infective Endocarditis

In patients with Libman-Sacks endocarditis (associated with SLE) or marantic endocarditis:

• The complete antiphospholipid profile helps distinguish between primary cardiac pathology and APS-related valvular disease 1, 6
• Medium-high titers of aCL and aβ2GPI of the same isotype (most often IgG) identify patients at highest risk for thrombosis 1, 4
• The antibody profile informs both prognosis and long-term anticoagulation decisions 2