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Blood, 1 April 2004, Vol. 103, No. 7, pp. 2827-2834.
Prepublished online as a Blood First Edition Paper on November 26, 2003; DOI 10.1182/blood-2003-09-3057.
Submitted September 9, 2003
Accepted November 21, 2003
A novel mechanism of complement independent clearance of red cells deficient in glycosyl phosphatidylinositol linked proteins
Marek Jasinski, Panagiotis Pantazopoulos, Russell P Rother, Nico van Rooijen, Wen-Chao Song, Hector Molina, and Monica Bessler*
Division of Hematology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
Alexion Pharmaceuticals Inc., Cheshire, CT, USA
Department of Molecular Cell Biology, Vu Medisch Centrum, Amsterdam, The Netherlands
Center for Experimental Therapeutics, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Division of Rheumatology, Department of Pathology, Washington University School of Medicine, St. Louis, MO, USA
* Corresponding author; email: mbessler{at}im.wustl.edu.
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia characterized by the increased sensitivity of red blood cells (RBCs) to complement leading to intravascular hemolysis and hemoglobinuria. PNH is due to the expansion of a cell clone that has acquired a mutation in the PIGA gene. Mice with targeted Piga gene inactivation genetically mimic the human disease and have PIGA- RBCs with a reduced half-life in circulation. Although PIGA- RBCs are hypersensitive to complement in vitro, their complement sensitivity in vivo is barely detectable. Here we show that the shortened survival of PIGA- RBC is independent of complement either by using inhibitory C5 antibodies or by transfusion into C5-, C4-, C3- or Factor B-deficient mice. Splenectomy or high dose cortisone treatment had no effect on the shorter survival of PIGA- RBC. However, treatment with liposome-encapsulated clodronate, an agent that depletes macrophages in vivo, normalized the half-life of PIGA- RBCs. This indicates that the shortened survival of PIGA- RBCs is due to a novel pathway of PIGA- RBC clearance that is mediated by macrophages, but occurs independently of complement. Future investigations will show whether this novel pathway of PIGA- RBC destruction identified in mice may also operate in patients with PNH.
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