The Effect Of Short-Term Hydroxychloroquine Use On Criteria And Selected Non-Criteria Antiphospholipid Antibody Tests

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Background/Purpose:  One proposed mechanism of antiphospholipid antibody (aPL)-mediated thrombosis is disruption of the Annexin A5 (AnxA5) anticoagulant shield, allowing initiation of coagulation reactions on phospholipid surfaces.  The AnxA5 resistance assay (AnxA5-RA) measures resistance to AnxA5 anticoagulant activity in the plasmas of aPL-positive patients. Based on in vitro studies, hydroxychloroquine (HCQ) interferes with aPL binding to cell surfaces and helps repair disrupted AnxA5 shields; however, no in vivo human studies exist. Other non- criteria aPL tests, including anti-domain-I B2-glycoprotein-I IgG (aDI-B2GPI) and activated protein C (APC) resistance may be associated with thrombosis in patients with antiphospholipid syndrome (APS). The purpose of this prospective study is to determine the effect of HCQ on the AnxA5-RA, as well as criteria and other non- criteria aPL tests, in persons with aPL. Methods:  We recruited persons with aPL (lupus anticoagulant [LAC], anticardiolipin antibody [aCL] ? 40 GPL/MPL, and/or anti-B2-glycoprotein-I [aB2GPI] antibody ? 40 SGU/SMU at two time points at least 12 weeks apart) starting HCQ to give blood at baseline, 6 weeks, and 12 weeks (primary outcome measure: AnxA5-RA; secondary outcome measures: LAC, aCL, aB2GPI, aDI-B2GPI, APC resistance, and D-dimer). As a control group, we also recruited aPL (LAC, aCL, and aB2GPI)-negative systemic lupus erythematosus (SLE) patients starting HCQ . We compared the baseline characteristics of patients with aPL to aPL-negative SLE patients (Mann-Whitney test) as well as a change in results from baseline to week 12 (Wilcoxon signed-rank test). Results: We compared baseline data from 21 aPL-positive patients (mean age 44.7 +/- 11.0 years [range 27-61], 15 [71%] female, 17 [81%] Caucasian; 13 had APS and 8 had asymptomatic aPL) to 12 aPL-negative SLE patients (mean age 45.4 +/- 15.0 years [range 22-64], 12 [100%] female, 7 [58%] Caucasian). Mean baseline values for AnxA5-RA were lower (more abnormal) for aPL-positive subjects compared to aPL- negative subjects (134.1 +/- 15.6 vs. 168.3 +/- 21.9; p<0.0001); no patients in the aPL- negative group exhibited resistance to AnxA5 anticoagulant activity. Mean baseline values of aDI-B2GPI were higher for aPL-positive subjects as compared to aPL- negative subjects (4.40 +/- 4.38 vs. 0.76 +/- 0.44; p=0.0002); no patients in the aPL- negative group had aDI-B2GPI. There was no significant change between mean baseline and week 12 values for LAC, aCL, aB2GPI, AnxA5-RA, aDI-B2GPI, APC resistance, or D-dimer in aPL-positive subjects receiving HCQ (Table). Conclusion: Patients with aPL have positive AnxA5-RA and aDI-B2GPI; our findings support the use of these non-criteria tests to detect aPL. HCQ use was not associated with a change in AnxA5 anticoagulant activity or other criteria or non-criteria aPL tests; duration of HCQ treatment, HCQ dosing, sample size, and lack of efficacy in vivo are possible explanations for these findings. Our findings suggest that HCQ may not act through an AnxA5 resistance mechanism.

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2016
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annexin A5; antiphospholipid; hydroxychloroquine; lupus
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Clinical & Translational Investigation
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Master of Science
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Government Document
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Attribution-NonCommercial-NoDerivatives 4.0 International
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dissertation or thesis
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