Submitted July 18, 2006
Accepted September 30, 2006
Correlation between antiphospholipid antibodies that recognize domain I of 
2-glycoprotein I and a reduction in the anticoagulant activity of annexin A5
Bas de Laat, Xiao-Xuan Wu, Menno van Lummel, Ronald H.W.M. Derksen, Philip G. de Groot*, and Jacob H. Rand
University Medical Center Utrecht, Netherlands
Montefiore Medical Center, Albert Einstein College of Medicine
* Corresponding author; email: ph.g.degroot{at}umcutrecht.nl.
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 aPL disrupt an anticoagulant annexin A5 (AnxA5) crystal shield. We investigated whether anti-domain 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), 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 2GPI-dependent LAC (Group A, all with thrombosis) had significantly lower AnxA5-anticoagulant ratios than those with 2GPI-independent LAC (Group B, thrombosis n=4)(157.8% vs 235.6%, p<0.001) and those without LAC (Group C, thrombosis n=2) (157.8% vs 232.5%, p<0.001). There was no difference in the ratios between group B and C (P=0.92).
Plasmas with 2GPI-dependent LAC that recognize domain I displayed significantly increased AnxA5 resistance, suggesting that specifically anti-2GPI 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.
