Mechanisms of Disease: antiphospholipid antibodies—from clinical association to pathologic mechanism


The discovery that antiphospholipid antibodies recognize plasma proteins that bind to phospholipids rather than recognizing phospholipids themselves has been a major advance in research into antiphospholipid syndrome (APS). It is now established that β2-glycoprotein I (β2 GPI) is the most important antigen for antiphospholipid antibodies. However, the possible pathologic mechanism is still much debated. This is mainly because not all patients with anti-β2 GPI antibodies show clinical symptoms that are related to APS. Several reports indicate that anti-β2 GPI antibodies with lupus anticoagulant (LA) activity are clinically of much importance. Most patients with LA caused by anti-β2 GPI antibodies suffer from thrombosis as a result of recognition of the first domain of β2 GPI by these antibodies. In the search for a pathologic mechanism that might explain the high occurrence of thrombosis in patients with anti-domain I antibodies (LA-causing anti-β2 GPI antibodies), it was found that these antibodies show increased resistance to the anticoagulant activity of annexin A5. We have shown that the same population of antibodies also displays increased resistance to activated protein C. Owing to the diversity of clinical symptoms related to APS, it is likely that other pathologic mechanisms also contribute to the occurrence of APS-related symptoms.

Key Points

  • Current assays to detect antiphospholipid antibodies are not specific enough to predict thrombosis and pregnancy morbidity

  • Lupus anticoagulant activity correlates best with clinical symptoms in antiphospholipid syndrome

  • The main cofactor in antiphospholipid syndrome is β2-glycoprotein I (β2 GPI)

  • Only anti-β2 GPI antibodies directed against domain I of β2 GPI (anti-domain I antibodies) are clinically relevant

  • Anti-domain I antibodies have multiple actions on hemostasis; further research is required to characterize these actions

  • More research is needed to find other populations of antiphospholipid antibodies that are also clinically relevant

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Figure 1: Chronology of significant events in research into antiphospholipid syndrome.
Figure 2: Correlation between antibody specificity and thrombosis.
Figure 3: Possible pathogenetic mechanisms of anti-domain I antibodies.


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Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Correspondence to Bas de Laat.

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de Laat, B., Mertens, K. & de Groot, P. Mechanisms of Disease: antiphospholipid antibodies—from clinical association to pathologic mechanism. Nat Rev Rheumatol 4, 192–199 (2008).

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