Thrombosis and Secondary Hemochromatosis Play Major Roles in the Pathogenesis of Jaundiced and Spherocytic Mice, Murine Models for Hereditary Spherocytosis

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Abstract
Jaundiced mice, ja/ja, suffer from a severe hemolytic anemia caused by a complete deficiency of erythroid β-spectrin. We used these mice as a model to investigate the pathophysiological consequences of the deficiency, including the effects in the nonerythroid tissues where this protein is expressed. Because the ja/ja mice rarely survive beyond the 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 pathophysiology. Blood parameters and histopathology of the jaundiced mouse were compared with that from spherocytic mice, which have a hemolytic anemia caused by deficiency of erythroid α-spectrin, yet can survive the postnatal period transfusion free. The adult jaundiced and spherocytic mice present with greatly decreased hematocrit and red blood cell counts, reticulocytosis, and bilirubinemia, leading secondarily to hepatosplenomegaly and cardiomegaly. Jaundiced and spherocytic mice were analyzed histopathologically between 1.0 and 9.5 months of age. Interestingly, the complete absence of erythroid β-spectrin in jaundiced mice leads to no detectable structural defects in brain, cardiac, or skeletal muscles. However, fibrotic lesions and lymphocytic infiltration were observed in cardiac tissue from 4 of 13 jaundiced mice and 15 of 15 spherocytic mice, and thrombi were detected at either the atrioventricular valves or within the atria of 2 of 13 jaundiced mice and 15 of 15 spherocytic mice. In addition, all affected mice had a progressive renal hemosiderosis concurrent with hydronephrosis and glomerulonephritis. The severity of the renal disease and its presence in all moribund mice suggests kidney failure rather than the fibrotic heart lesions as the major cause of death in these mice.