Decreased Erythrocyte Survival in Hemoglobin H Disease As a Result of the Abnormal Properties of Hemoglobin H: The Benefit of Splenectomy

Abstract

Abstract Two of three siblings with hemoglobin H disease were splenectomized. Both were benefited as judged by improved feeling of well-being, exercise tolerance and improvement in hemoglobin level and in erythrocyte mean lifespan. However, they were still susceptible to hemolytic crises, and their erythrocyte mean lifespan was below the normal range. Erythrocyte survival studies by the Cr51 method indicated a finite lifespan of 40-45 days before splenectomy, which increased to normal following splenectomy. In addition, there was random destruction of the erythrocytes, which was slightly reduced following splenectomy. The erythrocyte survival of a member of this family who had the hereditary leptocytosis trait, but no hemoglobin H, was normal. Evidence is presented indicating that hemoglobin H denatures and precipitates irreversibly at a cell age of 40-45 days, forming intraerythrocytic inclusions which lead to shortening of the erythrocyte finite lifespan due to rapid removal of such erythrocytes by the spleen. In addition, hemoglobin H has a lower solubility in the deoxygenated state and precipitates reversibly, regardless of cell age, in the capillary bed, causing random erythrocyte destruction. Splenectomy is beneficial because of survival of erythrocytes with inclusions whose hemoglobin A presumably retains its function in oxygen transport. Methemoglobin-forming chemicals such as amyl nitrite and drugs such as sulfisoxazole were found to denature hemoglobin H and produce in vitro inclusions in every erythrocyte of these patients but not of normal subjects. It is suggested that the shortening of the erythrocyte survival and the degree of postsplenectomy improvement is greater the higher the amount of hemoglobin H present in the erythrocytes. The apparent aging of the hemoglobin H molecule which leads to shortened erythroctye finite lifespan is discussed, and a concept of aging proteins determining the lifespan and/or the function of cells is advanced.