What is the clinical significance of borderline positive anti-cardiolipin (Anticardiolipin Antibody) Immunoglobulin M (IgM) and anti-beta 2 glycoprotein 1 (Anti-β2 Glycoprotein 1) IgM in relation to thrombosis (clot) versus pregnancy loss?

From the Guidelines

Borderline positivity of anticardiolipin IgM and anti-beta-2 glycoprotein 1 IgM antibodies is not sufficient for diagnosis of antiphospholipid syndrome (APS) and requires careful interpretation in the context of clotting events or pregnancy loss, with current evidence suggesting that persistent positivity (at least 12 weeks apart) and medium-to-high titers are more clinically significant than isolated borderline results 1.

Key Considerations

• A single borderline positive result is generally not sufficient for diagnosis of APS, and repeat testing in 12 weeks is recommended for patients with borderline positivity and a history of thrombosis or pregnancy complications 1.
• If persistently positive, especially with clinical symptoms, anticoagulation therapy may be considered - typically starting with low-dose aspirin (81-100mg daily) for pregnancy loss prevention, or therapeutic anticoagulation with heparin/low molecular weight heparin for those with thrombotic events 1.
• For pregnant women with recurrent losses and persistent positivity, combination therapy with low-dose aspirin plus prophylactic heparin (such as enoxaparin 40mg daily) is often recommended 1.
• The pathophysiology involves these antibodies interfering with coagulation pathways and placental function, and borderline IgM positivity alone, particularly without IgG antibodies, carries less clinical significance and may sometimes represent transient responses to infections or medications rather than true APS 1.

Clinical Implications

• Retesting of an equivocal result should be performed to confirm positivity or negativity, and low positive results around the cutoff value of aCL and aβ2GPI should be interpreted with care 1.
• Imprecision of the solid phase method should be considered with a maximal acceptable imprecision of 10%, and retesting of LA if a potentially unreliable result was obtained during VKA treatment to check the similarity of results, or in double-positive patients (aCL and aβ2GPI positive) or when tested in the acute phase might overcome false positive or false negative results 1.
• Ideally, LA is assessed 1 to 2 weeks after discontinuation of VKA (whether or not with bridging to LMWH), but this may not be feasible or preferred by the clinician and should be assessed case by case 1.

Management

• For patients with borderline positivity and a history of thrombosis or pregnancy complications, a comprehensive approach including repeat testing, clinical evaluation, and consideration of anticoagulation therapy is recommended 1.
• The management of APS in pregnancy should be individualized, taking into account the patient's clinical history, antibody profile, and risk factors for thrombosis and pregnancy complications 1.
• A multidisciplinary approach, involving obstetricians, rheumatologists, and hematologists, is essential for optimal management of APS in pregnancy 1.

From the Research

Borderline Positivity of Anti-Cardiolipin IgM and Anti-Beta 2 Glycoprotein 1 IgM

• The role of anti-cardiolipin and anti-beta 2 glycoprotein 1 IgM antibodies in antiphospholipid syndrome (APS) is debated 2
• Studies have shown that isolated IgM positivity is rare in thrombotic APS, but more frequent in obstetric APS, ranging from 3.5% to 12.3% depending on the solid phase assay 2
• Detection of IgM antibodies may be useful as a second-line test to improve thrombotic risk stratification, particularly in women suspected of obstetric APS 2

Clot vs Pregnancy Loss

• Double-positivity for anti-cardiolipin and anti-beta 2 glycoprotein 1 antibodies may be a risk factor for pregnancy loss 3
• Anti-beta 2 glycoprotein 1 antibody may be a better prognostic marker than anti-cardiolipin antibody for pregnancy outcome 3
• Thrombosis is a major manifestation in patients with antiphospholipid antibodies, but the spectrum of symptoms and signs associated with these antibodies has broadened considerably 4
• Pregnancy morbidity, including recurrent pregnancy losses, is a common clinical manifestation of APS 5, 6

Diagnostic and Clinical Value of IgM Antiphospholipid Antibodies

• Positivity for anti-cardiolipin and/or anti-beta 2 glycoprotein 1 antibodies is significantly correlated with thrombosis and pregnancy morbidity, independent of the isotype and solid phase assay 2
• Higher odds ratios are obtained for IgG compared to IgM positivity 2
• Combined positivity for lupus anticoagulant, IgG, and IgM is highly associated with thrombosis and pregnancy morbidity 2