7B.1 Pathogenesis of the antiphospholipid syndrome (APS)

Abstract

The APS is a thrombophilic condition that is identified by phenomenologic surrogate tests that were derived from the biologic false positive (BFP) syphilis test and the paradoxical “lupus anticoagulant” (LAC) phenomenon, described about 50 years ago [1]. Current diagnosis of the syndrome requires that the patients have clinical manifestations such as thrombosis and/or spontaneous pregnancy losses and at least 1 positive test that is confirmed at least 12 weeks later [2]. The major antigenic target for “antiphospholipid” antibodies is b2-glycoprotein I (b2GPI), a phospholipid-binding protein that is a member of the short-chain consensus repeat (SCR) superfamily. The protein has a “J” shape and is composed of an extended chain of 5 SCR domains. The structure of SCR domain V deviates from the standard fold of the 4 other domains and contains the putative phospholipid-binding site [3]. It has recently been reported that IgG antibodies recognizing an epitope in domain I of b2GPI consisting of Gly40 Arg43 have LAC activity and are strongly associated with thrombosis [4]. Several mechanisms have been proposed to explain how antiphospholipid antibodies might cause susceptibilities to pregnancy losses and to thrombosis [1]. Among these are mechanisms that affect platelet function, prostaglandin synthesis, endothelial cell signaling, apoptosis, effects on protein C and S activities, the endothelial protein C receptor, protein Z function and antiphospholipid antibody-mediated activation of complement with subsequent release of TNF-alpha, and the antiphospholipid antibodymediated disruption of annexin A5 (AnxA5) discussed below. AnxA5 is a potent anticoagulant protein whose anticoagulant properties are a consequence of its high affinity for anionic phospholipid [5,6]. The protein forms 2-D crystals on phospholipid surfaces [7 9] that shield the phospholipid from availability for the critical phospholipid-dependent coagulation reactions. AnxA5 forms noncovalent polymers by forming trimers [7 9], and then trimers of the trimers over phospholipid bilayers. Figure 1 shows a colorized lower power AFM image of the crystal array, demonstrating the highly ordered screen-like structure; panel B shows a higher power detail of this array, with the central space filled with an individual trimer; panel C shows 6 trimers (the thin black circle delineates 1 trimer) that are arrayed in a hexagonal configuration. These 2-D arrays shield phospholipids from availability for the phospholipiddependent coagulation reactions. Fig. 1.