ROLE OF MICROPARTICLES IN THE ANTI-PHOSPHOLIPID SYNDROME

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Antiphospholipid antibodies (APLA) are associated with arterial and venous thrombosis, as well as recurrent fetal loss, and are the most common cause of acquired thrombophilia. In vitro studies have suggested several mechanisms that might account for the pathogenic effects of these antibodies. APLA comprise a heterogeneous family of antibodies, and rather than binding anionic phospholipid as originally proposed, react preferentially with phospholipid binding proteins such as beta2 glycoprotein I (beta2GPI), prothrombin, or oxidized phospholipids; of these, beta2GPI is the most common. Several groups, including our own, have reported that APLA bind to endothelial cells, and we have recently demonstrated that "APLA"/anti-beta2GPI antibodies induce endothelial cell activation by cross-linking annexin II through binding of annexin ll-bound beta2GPI and initiation of an activation pathway involving TLR-4 and NF-KB. Despite these mechanistic observations, however, there are no specific markers of the prothrombotic state in patients with APLA. Two reports have suggested that increased levels of procoagulant microparticles circulate in the plasma of these patients; however, the origin of these microparticles, their association with "APLA" of defined specificity (i.e. anti-beta2GPI, anti-oxidized LDL), or their correlation with thrombotic events have not been well delineated. In Specific Aim 1 of this application, we propose to compare the levels of circulating microparticles in 200 patients with APLA with those in 50 normal individuals. We will also determine the cellular origin of the circulating microparticles, and whether the number of microparticles or their cell of origin correlates with the serologic specificity of the "APLA". In Specific Aim 2, we will assess the correlation between the level of circulating microparticles and a clinical history of thrombosis, compare the procoagulant activity of microparticles from patients and controls, determine whether therapy of patients with "APLA" with aspirin and heparin reduces the level of microparticles, and evaluate the relationship between circulating microparticles and the ability of APLA to activate cells in vitro. In Specific Aim 3, we will assess the thrombogenicity of "APLA" in a mice, and determine the role of annexin II in thrombus formation. These clinical/translational studies should provide new information concerning the role of circulating microparticles in APLA-associated thrombosis, as well as the in vivo mechanisms of APLA in patients.