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Toll like Receptor 4 is involved in antiphospholipid- mediated thrombosis: In vivo studies
  1. Silvia S. Pierangeli (sspieran{at}
  1. University of Texas Medical Branch, United States
    1. Mariano E Vega-Ostertag (marvegos{at}
    1. Morehouse School of Medicine, United States
      1. Elena Raschi (e.raschi{at}
      1. Istituto Auxiologico Italiano, Italy
        1. Xiaowei Liu (xliu{at}
        1. Morehouse School of Medicine, United States
          1. Zurina Romay-Penabad (zuromayp{at}
          1. University of Texas Medical Branch, United States
            1. Valeria De Micheli
            1. Ambulatorio Patologie Trombotiche e Emorragiche Ospedale San Leopoldo Mandic, Italy
              1. MOnica Galli
              1. Ospedali Riuniti, Italy
                1. Marco Moia
                1. ISCCS Maggiore Hospital, Italy
                  1. Angela Tincani
                  1. Spedali Civili, Italy
                    1. Maria Orietta BOrghi (maria.borghi{at}
                    1. Istituto Auxologico Italiano, Italy
                      1. Tracy Nguyen-Oghalai
                      1. University of Texas Medical Branch, United States
                        1. Pier Luigi Meroni (pierluigi.meroni{at}
                        1. Istituto Auxologico Italiano, Italy


                          Objective: The aim of the study is to investigate the in vivo pathogenic role of toll like receptor-4 (TLR- 4) in the anti-phospholipid syndrome (APS) by looking at the thrombogenic aPL activity in LPS non-responsive (LPS- /-) mice and at the association between tlr4 gene polymorphisms and APS in patients.

                          Methods: IgGs from two APS patients, one aPL- negative Systemic Lupus Erythematosus (SLE) patient and one normal human serum (NHS) were evaluated for thrombosis, Tissue Factor (TF) activity and endothelial cell activation in LPS-/- mice displaying a tlr4 spontaneous mutation vs LPS-responsive (LPS+/+) mice. Human tlr4 Asp299Gly and Thr399Ile polymorphisms were evaluated by allele-specific polymerase chain reaction in 110 APS patients with arterial/venous thrombosis and in 220 controls of the same ethnic origin.

                          Results: IgG-APS produced significantly larger thrombi and number of adhering leukocytes (WBC) to endothelial cells in the cremaster muscle microcirculation of LPS +/+ mice when compared to IgG- NHS or aPL-negative SLE-IgG. These effects were abrogated after absorption of the anti-?2glycoprotein I activity by an affinity column. The two IgG-APS induced significantly smaller thrombus size and lower number of endothelial WBC adhering in LPS -/- compared to LPS +/+ mice. IgG-APS induced higher TF activity in carotid artery homogenates of LPS +/+ compared to LPS -/- mice. Asp299Gly and Thr399Ile tlr4 polymorphism prevalence was significantly lower than in controls.

                          Conclusions: The findings in LPS -/- mice and the reduction in the “protective” polymorphism in APS patients with thrombosis suggest that TLR-4 is involved in in vivo aPL interaction with endothelial cells.

                          • antiphospholipid antibodies
                          • antiphospholipid syndrome
                          • endothelial cells
                          • thrombosis
                          • tissue factor

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