THROMBOSIS AND SECONDARY HEMOCHROMATOSIS PLAY MAJOR ROLES IN THE PATHOGENESIS OF JAUNDICED AND SPHEROCYTIC MICE, MURINE MODELS FOR HEREDITARY SPHEROCYTOSIS

Jaundiced mice, ja/ja, suffer from a severe hemolytic anemia caused by a complete deficiency of erythroid beta-spectrin. We used these mice as a model to investigate the pathophysiological consequences of the d eficiency, including the effects in the nonerythroid tissues where thi s protein is expressed. Because the ja/ja mice rarely survive beyond t he fourth postnatal day, methods were assessed for extending lifespan into adulthood. Neonatal transfusion increased lifespan to a mean of 3 .7 months, allowing a more complete characterization of the pathophysi ology, Blood parameters and histopathology of the jaundiced mouse were compared with that from spherocytic mice, which have a hemolytic anem ia caused by deficiency of erythroid alpha-spectrin, yet can survive t he postnatal period transfusion free. The adult jaundiced and spherocy tic mice present with greatly decreased hematocrit and red blood cell counts, reticulocytosis, and bilirubinemia, leading secondarily to hep atosplenomegaly and cardiomegaly. Jaundiced and spherocytic mice were analyzed histopathologically between 1.0 and 9.5 months of age. Intere stingly, the complete absence of erythroid beta-spectrin in jaundiced mice leads to no detectable structural defects in brain, cardiac, or s keletal muscles. However, fibrotic lesions and lymphocytic infiltratio n were observed in cardiac tissue from 4 of 13 jaundiced mice and 15 o f 15 spherocytic mice, and thrombi were detected at either the atriove ntricular valves or within the atria of 2 of 13 jaundiced mice and 15 of 15 spherocytic mice. In addition, all effected mice had a progressi ve renal hemosiderosis concurrent with hydronephrosis and glomerulonep hritis. The severity of the renal disease and its presence in all mori bund mice suggests kidney failure rather than the fibrotic heart lesio ns as the major cause of death in these mice. (C) 1997 by The American Society of Hematology.