The role of thrombospondin-1 in the pathogenesis of antiphospholipid syndrome

Objective: Antiphospholipid syndrome (APS) is an acquired thrombophilia characterized by recurrent throm-bosis and/or pregnancy morbidity, in the presence of antibodies to beta 2 glycoprotein-I (beta 2GPI), prothrombin or Lupus anticoagulant (LA). Anti-beta 2GPI antibodies recognize complexes of beta 2GPI dimers with CXCL4 chemokine and activate platelets. Thrombospondin 1 (TSP-1) is secreted by platelets and exhibits prothrombotic and proinflammatory properties. Therefore, we investigated its implication in APS. Methods: Plasma from APS patients (n = 100), Systemic Lupus Erythematosus (SLE) (n = 27) and healthy donors (HD) (n = 50) was analyzed for TSP-1, IL-10, IL-17A and free active TGF-beta 1 by ELISA. Human Umbilical Vein Endothelial Cells (HUVECs) and HD monocytes were treated with total HD-IgG or anti-beta 2GPI, beta 2GPI and CXCL4 and CD4(+) T-cells were stimulated by monocyte supernatants. TSP-1, IL-10, IL-17A TGF-beta 1 levels were quantified by ELISA and Real-Time PCR. Results: Higher plasma levels of TSP-1 and TGF-beta 1, which positively correlated each other, were observed in APS but not HDs or SLE patients. Patients with arterial thrombotic events or those undergoing a clinical event had the highest TSP-1 levels. These patients also had detectable IL-1 beta, IL-17A in their plasma. HD-derived monocytes and HUVECs stimulated with anti-beta 2GPI-IgG-beta 2GPI-CXCL4 secreted the highest TSP-1 and IL-10 levels. Supernatants from anti-beta 2GPI-beta 2GPI-CXCL4 treated monocytes induced IL-17A expression from CD4(+) T-cells. Transcript levels followed a similar pattern. Conclusions: TSP-1 is probably implicated in the pathogenesis of APS. In vitro cell treatments along with high TSP-1 levels in plasma of APS patients suggest that high TSP-1 levels could mark a prothrombotic state and an underlying inflammatory process.