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 Blood, 20 August 2009, Vol. 114, No. 8, pp. 1675-1683.
Prepublished online as a Blood First Edition Paper on June 17, 2009; DOI 10.1182/blood-2009-01-199117.

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THROMBOSIS AND HEMOSTASIS

Role of tissue factor in a mouse model of thrombotic microangiopathy induced by antiphospholipid antibodies

Surya V. Seshan1, Claus-Werner Franzke2, Patricia Redecha2, Marc Monestier3, Nigel Mackman4, and Guillermina Girardi2

1 Department of Pathology and 2 Hospital for Special Surgery, Department of Medicine, Weill Cornell Medical College, New York, NY; 3 Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA; and 4 Department of Medicine, University of North Carolina, Chapel Hill

Using different mouse monoclonal and human antiphospholipid (aPL) antibodies, we developed a new animal model of renal injury that shares many features with thrombotic microangiopathy (TMA). We found that more than 1 mechanism/signaling pathway is involved in glomerular injury induced by aPL antibodies in this model. Both complement-dependent and complement-independent pathways were identified that lead to glomerular endothelial cell damage and renal function impairment. We also found that C5a-C5aR interaction is a crucial step for the activation of the coagulation cascade and glomerular injury induced by complement-activating antibodies. In addition, our studies demonstrated complement-independent mechanisms in which reactivity with β2 glycoprotein I (β2GPI) plays an important role in aPL-induced glomerular damage and renal failure. Independently of the mechanism responsible for aPL-induced TMA, mice that express low levels of tissue factor (TF) were protected from glomerular injury. That genetic reduction of TF prevents renal injury induced by different aPL antibodies indicates that TF is a common mediator of glomerular damage and a possible target for selective pharmacologic intervention. Treatment with pravastatin, which down-regulates glomerular TF synthesis, prevents aPL-induced TMA in this mouse model, thus emphasizing that targeting TF might be a good therapeutic intervention in patients with TMA.


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