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Researchers assessed the role of complement activation in antiphospholipid syndrome (APS)-associated thrombosis. Results were presented at the 61st American Society of Hematology (ASH) Annual Meeting in Orlando, Florida.
Complement activation was evaluated in 59 patients with thrombotic APS, 10 patients with catastrophic APS (CAPS), and 74 patients with systemic lupus erythematosus (SLE), using the modified Ham (mHam) test and cell death as measures. Targeted sequencing was conducted on a panel of 15 complement genes for all patients with APS and SLE as well as for 33 patients with atypical hemolytic uremic syndrome (aHUS) and 43 healthy individuals. In addition, the resarchers added patient-derived antiphospholipid antibodies to normal serum from 4 patients in order to assess how complement activation was affected.
Of patients with CAPS, 85.7% had a positive mHam assay, compared with 35.6% of patients with thrombotic APS and 6.8% of patients with SLE (P <.001). Positive mHam assay was associated with triple positivity for lupus anticoagulant, anti-beta-2-glycoprotein-1 antibody (anti-B2-GP-1 Ab), and anticardiolipin anitbody, which in turn conferred a higher risk for thrombosis compared with single or double positivity (P =.002). More patients with mHam positivity had a history of thrombosis compared with patients with mHam negativity (79.3% vs 38.4%), and 66.7% of patients who experienced recurrent thrombosis demonstrated mHam positivity. Patients were more likely to exhibit mHam positivity closer to experiencing a thrombotic event, suggesting a temporal correlation between mHan positivity and thrombosis.
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Complement activation was induced by both serum from patients with APS and patient-derived anti-B2-GP-1 Ab, suggesting not only that complement activation is linked to APS-associated thrombosis but also that “it is the anti-B2-GP-1 Ab itself that activates complement,” stated Shruti Chaturvedi, MBBS, MS, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, in her presentation.
The researchers found that patients with CAPS were more likely to have rare germline mutations in complement genes (60%) compared with patients with thrombotic APS (21.8%), SLE (28.6%), and atypical hemolytic uremic syndrome (51.5%), as well as healthy individuals (23.3%). Patients with CAPS also experienced higher mutation rates compared with the thrombotic APS (P =.019), SLE (P =.051), and control cohorts, and a similar mutation rate compared with the aHUS cohort (P =.36).
Taken together, these results suggest a “multi-hit model for APS and CAPS, in which antiphospholipid antibodies activate complement and can lead to thrombosis, frequently in the presence of a trigger such as infection or surgery,” Dr Chaturvedi said. She added that patients with CAPS may be predisposed to excessive activation and, therefore, disseminated thrombosis due to inherited mutations in complement regulatory genes.
Dr Chaturvedi concluded by recommending further analysis of complement inhibition as a potential treatment strategy for thrombotic APS and CAPS.
Disclosures: Some authors have declared affiliations with the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Reference
1. Chaturvedi S, Braunstein E, Yuan X, et al. Rare germline mutations in complement regulatory genes make the antiphospholipid syndrome catastrophic. Oral presentation at: 61st ASH Annual Meeting and Exposition; December 7-10; Orlando, FL. Abstract 4.
