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Blood, 1 March 2005, Vol. 105, No. 5, pp. 1845-1846.
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HEMOSTASIS
Comment on Zhang and McCrae, page 1964
Annexin A2: better left alone
Alisa S. Wolberg, and
Robert A. S. Roubey
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL
Zhang and McCrae demonstrate that APLA/b2GPI-mediated endothelial cell activation occurs via dimerization of annexin A2 molecules on the cell surface.
The association of antiphospholipid antibodies (APLAs) with thrombosis is well established, and there is growing evidence that APLAs themselves contribute to hypercoagulability. The mechanisms of APLA-associated hypercoagulability are less clear, however. A confusing variety of antibody effects has been proposed. One important line of research involves the activation of endothelial cells by certain APLAs, specifically those directed against  2-glycoprotein I(2GPI). In their current study, Zhang and McCrae make an important next step in this endeavor.
Previously, APLAs, in a 2GPI-dependent manner, were shown to stimulate endothelial cells to a procoagulant phenotype by increasing monocyte adhesion and the expression of E-selectin, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1.1,2 These events presumably require the transduction of a signal into the cell and, therefore, the involvement of a cell surface receptor. Since the effects of APLA/2GPI do not appear to be mediated by Fc receptors,1 investigators posited the existence of a cell surface receptor for 2GPI. In previous work, McCrae and colleagues identified annexin A2 as a high-affinity receptor for 2GPI on endothelial cells (Ma et al3). The current paper ties this finding to the earlier functional studies, demonstrating that cross-linking of annexin A2 by APLA/ 2GPI activates endothelial cells (see figure).
The key observation by Zhang and McCrae is that cross-linking of annexin A2 on the endothelial cell surface induces the expression of cell adhesion molecules. Cross-linking was achieved using bivalent anti–annexin A2 antibodies or APLA/2GPI. The critical role of bivalent cross-linking was demonstrated using monovalent antibody fragments that (a) did not activate cells, and (b) blocked the effects of bivalent antibodies.
These findings establish at least 2 important points. First, a cell surface receptor (ie, annexin A2) is critical in mediating the in vitro effects of APLAs on endothelial cells. Second, the data highlight the role of immunoglobulin G (IgG) bivalency. Antibody bivalency has been shown to explain how antibodies to 2GPI, a relatively weak phospholipid-binding plasma protein, lead to high avidity binding of IgG-2GPI complexes to phospholipid membranes. Now, bivalency has been shown to play a critical role in cross-linking annexin A2 and transducing an activation signal to cells.
As noted by the authors, important questions remain. How does annexin A2, which does not have a transmembrane domain, transduce a signal? Recently, Raschi et al4 have demonstrated that APLA activation of endothelial cells occurs via the MyD88 pathway that is commonly associated with toll-like receptor (TLR) signaling. Does annexin A2 signal through the MyD88 pathway? Is annexin A2 physically associated with a TLR? In addition to transducing a signal, what is the effect of APLA/2GPI on annexin A2's role as a coreceptor for plasminogen and tissue plasminogen activator? Does binding of APLA/ 2GPI to annexin A2 inhibit plasmin generation? Once annexin A2 is cross-linked by APLA/2GPI, what is the fate of this complex? If it is internalized or shed, the amount of annexin A2 available to support plasmin generation may be decreased. Finally, and perhaps most importantly, might the APLA/2GPI/annexin A2 complex provide a molecular target for antithrombotic therapies in the antiphospholipid syndrome? 
References
- Simantov R, LaSala JM, Lo SK, et al. Activation of cultured vascular endothelial cells by antiphospholipid antibodies. J Clin Invest. 1995;96: 2211-2219.[Medline]
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- Del Papa N, Guidali L, Sala A, et al. Endothelial cells as target for antiphospholipid antibodies: human polyclonal and monoclonal anti-2-glycoprotein I antibodies react in vitro with endothelial cells through adherent 2-glycoprotein I and induce endothelial activation. Arthritis Rheum. 1997;40: 551-561.[Medline]
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- Ma K, Simantov R, Zhang J-C, et al. High affinity binding of b2-glycoprotein I to human endothelial cells is mediated by annexin II. J Biol Chem. 2000;275: 15541-15548.[Abstract/Free Full Text]
- Raschi E, Testoni C, Bosisio D, et al. Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies. Blood. 2003;101: 3495-3500.[Abstract/Free Full Text]
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Related Article in Blood Online:
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Annexin A2 mediates endothelial cell activation by antiphospholipid/anti-2 glycoprotein I antibodies
- Jianwei Zhang and Keith R. McCrae
Blood 2005 105: 1964-1969.
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