What is the clinical significance of a patient with elevated Phosphatidylserine/Prothrombin (Phos_serine/PT) Immunoglobulin M (IgM) antibodies and normal Immunoglobulin G (IgG) levels, and what treatment options should be considered?

Elevated Phosphatidylserine/Prothrombin IgM with Normal IgG

Isolated IgM anti-phosphatidylserine/prothrombin (aPS/PT) antibodies without IgG positivity represent a lower-risk antiphospholipid antibody profile that does not meet current diagnostic criteria for antiphospholipid syndrome (APS) and requires confirmation testing at 12 weeks along with complete antibody panel assessment before any treatment decisions are made. 1, 2

Diagnostic Approach and Risk Stratification

Immediate Next Steps

• Complete the full antiphospholipid antibody panel including lupus anticoagulant (LA), anticardiolipin antibodies (aCL) IgG/IgM, and anti-β2 glycoprotein I (aβ2GPI) IgG/IgM to establish the complete antibody profile, as aPS/PT is not part of the standard diagnostic criteria. 1, 2

• Repeat all testing in 12 weeks to confirm persistence and distinguish transient from persistent antibody positivity, as transient elevations can occur with infections or medications and do not warrant long-term anticoagulation. 2, 3

• Assess clinical context for thrombotic events (arterial or venous), pregnancy complications, or other APS-related manifestations, as laboratory findings must be interpreted in clinical context. 1, 2

Clinical Significance of Isolated IgM aPS/PT

The 2025 ISTH guidance provides critical context for interpreting your result:

• IgM aPS/PT shows weaker association with thrombosis compared to IgG, with meta-analyses showing contradictory results about IgM as an independent risk factor for thrombotic events. 1

• Isolated IgM positivity is relatively uncommon in thrombotic APS patients, with prevalence of aPS/PT IgM in non-APS thrombotic patients being only 5%, comparable to healthy populations. 1

• Specificity concerns exist as aPS/PT positivity (particularly IgM) has higher prevalence in autoimmune diseases without APS manifestations (12.4-25.5%), raising questions about potential overdiagnosis if used in first-line workup. 1

Risk Profile Classification

Based on the complete antibody panel results:

High-Risk Profile (requires aggressive management):

• Triple positivity (LA + aCL + aβ2GPI of same isotype) with or without aPS/PT positivity 2, 4
• Double positivity with concordant isotype (e.g., LA + IgG aCL) 2, 4
• aPS/PT IgG positivity in addition to standard criteria antibodies 5

Low-Risk Profile (conservative management):

• Isolated IgM aPS/PT alone (your current scenario) 1, 2
• Single positive standard antibody at low-medium titers 2, 3

Management Recommendations

If Standard Antibody Panel is Negative (Isolated IgM aPS/PT Only)

No anticoagulation is indicated for isolated IgM aPS/PT without meeting full APS diagnostic criteria or having thrombotic events. 1, 2

Primary prevention considerations:

• Consider low-dose aspirin (75-100 mg daily) only if additional cardiovascular risk factors are present. 2, 3
• Avoid estrogen-containing contraceptives due to increased thrombosis risk with any antiphospholipid antibody positivity. 2
• Repeat complete antibody panel in 12 weeks to confirm persistence. 2, 3

If Standard Antibody Panel Shows Additional Positivity

For patients with thrombotic events meeting full APS criteria:

• Indefinite anticoagulation with warfarin targeting INR 2.0-3.0 is the standard treatment. 2
• Avoid direct oral anticoagulants (DOACs), particularly rivaroxaban, which shows excess thrombotic events compared to warfarin in triple-positive patients. 2

For obstetric APS:

• IgM antibodies (including aPS/PT IgM) show comparable odds ratios to IgG for pregnancy complications in some studies. 1
• Combination therapy with low molecular weight heparin plus low-dose aspirin throughout pregnancy is recommended if full APS criteria are met. 2

Special Considerations for aPS/PT Testing

The 2025 ISTH guidance clarifies the role of aPS/PT:

• aPS/PT is not included in diagnostic criteria but may be useful in second-line testing to consolidate APS diagnosis in high-risk patients. 1

• aPS/PT shows strong correlation with LA positivity (85% prevalence in LA-positive patients), but the overlap is incomplete and LA cannot be replaced by aPS/PT testing. 1

• When aPS/PT IgG is positive (not your case), it identifies a subgroup of more severe APS patients with increased renal impairment, thrombocytopenia, and thrombotic recurrences. 5

• Tetra-positivity (LA + aCL + aβ2GPI + aPS/PT) is associated with more severe APS including catastrophic antiphospholipid syndrome. 5

Common Pitfalls to Avoid

• Do not diagnose APS based on isolated IgM aPS/PT alone without confirming persistence at 12 weeks and completing the standard antibody panel. 1, 2

• Do not initiate anticoagulation for isolated antibody positivity without clinical manifestations (thrombosis or pregnancy morbidity). 2

• Do not assume isolated IgM carries the same risk as IgG or triple positivity, as IgG antibodies show stronger association with clinical events. 1, 4

• Do not overlook autoimmune disease screening, particularly systemic lupus erythematosus, as aPS/PT positivity is more common in secondary APS. 1

• Do not use aPS/PT as a surrogate for LA testing when anticoagulation interferes with LA assays, as the overlap is incomplete. 1

Ongoing Monitoring

• Repeat complete antiphospholipid antibody panel (LA, aCL IgG/IgM, aβ2GPI IgG/IgM, and aPS/PT IgG/IgM) at 12 weeks. 2, 3
• Screen for development of additional positive markers over time. 2, 3
• Monitor for thrombotic events, pregnancy complications, thrombocytopenia, and renal impairment. 5
• Assess for systemic lupus erythematosus and other autoimmune diseases. 1, 3