title: Correlation between antiphospholipid antibodies that recognize domain I of beta2-glycoprotein I and a reduction in the anticoagulant activity of annexin A5.
abstract: The paradoxical correlation between thrombosis and the lupus anticoagulant (LAC) effect is an enigmatic feature of the antiphospholipid (aPL) syndrome. The Dutch authors previously reported that thrombosis-related anti-beta2-glycoprotein I (beta2GPI) antibodies recognize domain I and cause LAC. The American authors reported that aPLs disrupt an anticoagulant annexin A5 (AnxA5) crystal shield. We investigated whether antidomain I antibodies correlate with disruption of AnxA5-anticoagulant activity. We studied a well-characterized group of 33 patients including subgroups with beta2GPI-dependent LAC that recognize domain I (n=11), with beta2GPI-independent LAC (n=12), and lacking LAC (n=10). The effects on AnxA5-anticoagulant activity were determined with an AnxA5 resistance assay that measures coagulation times with and without AnxA5. Patients with beta2GPI-dependent LAC (group A, all with thrombosis) had significantly lower AnxA5-anticoagulant ratios than those with beta2GPI-independent LAC (group B, thrombosis n=4; 157.8% versus 235.6%, P<.001) and those without LAC (group C, thrombosis n=2; 157.8% versus 232.5%, P<.001). There was no difference in the ratios between groups B and C (P=.92). Plasmas with beta2GPI-dependent LAC that recognize domain I displayed significantly increased AnxA5 resistance, suggesting that specifically anti-beta2GPI antibodies compete with AnxA5 for anionic phospholipids. These results are consistent with a model in which aPL antibodies may promote thrombosis by interfering with the anticoagulant activity of AnxA5.
authors.affiliation: Department of Haematology, University Medical Center Utrecht, The Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: de Laat
authors.forename: Xiao-Xuan
authors.initials: XX
authors.lastname: Wu
authors.forename: Menno
authors.initials: M
authors.lastname: van Lummel
authors.forename: Ronald H W M
authors.initials: RH
authors.lastname: Derksen
authors.forename: Philip G
authors.initials: PG
authors.lastname: de Groot
authors.forename: Jacob H
authors.initials: JH
authors.lastname: Rand
mesh_terms: D000328:Adult; D017304:Annexin A5 / Q000502:physiology*; D017152:Antibodies, Antiphospholipid / Q000276:immunology*; D001665:Binding Sites / Q000276:immunology; D001777:Blood Coagulation; D016022:Case-Control Studies; D000939:Epitopes; D005260:Female; D006801:Humans; D016682:Lupus Coagulation Inhibitor / Q000097:blood; D008297:Male; D019851:Thrombophilia / Q000209:etiology*; D013927:Thrombosis / Q000209:etiology; D053482:beta 2-Glycoprotein I / Q000276:immunology*
chemical_list: D017304:Annexin A5; D017152:Antibodies, Antiphospholipid; D000939:Epitopes; D016682:Lupus Coagulation Inhibitor; D053482:beta 2-Glycoprotein I