HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Correlation between antiphospholipid antibodies that recognize domain I of 2-glycoprotein I and a reduction in the anticoagulant activity of annexin A5

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– 2-glycoprotein I ( 2GPI) 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 2GPI-dependent LAC that recognize domain I (n 11), with 2GPI-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 2GPIdependent LAC (group A, all with thrombosis) had significantly lower AnxA5anticoagulant ratios than those with 2GPI-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 2GPI-dependent LAC that recognize domain I displayed significantly increased AnxA5 resistance, suggesting that specifically anti2GPI 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. (Blood. 2007;109:1490-1494)