Hemoglobin S gelation and sickle cell disease.

By William A. Eaton and James Hofrichter T HE FUNDAMENTAL cause ofsickle cell disease is the decreased deformability of the sickled red cell produced by gelation of hemoglobin S. Partial inhibition of gelation should therefore reduce clinical severity, while complete inhibition should result in a “cure.” These basic ideas have stimulated an enormous effort to understand the gelation process in detail and to relate the results of these studies to the pathophysiology of sickle cell disease. Discoveries concerning gelation have also led to new lines of research on a specific therapy. The early finding that fetal hemoglobin inhibits gelation.”2 has ultimately led to the development of methods to increase the production of F cells in the bone marrow of sickle cell patients,35 while the discovery of the enormous sensitivity of the rate of gelation to hemoglobin concentration6 has stimulated studies on the reduction of intracellular hemoglobin concentration as a means of therapy.6 ’2 Studies on the structure of the hemoglobin S polymer,’3’8 moreover, have guided the development of agents designed to inhibit gelation by interfering with the formation of intermolecular contacts in the polymer.”2’ The purpose of this article is to review recent developments in the relation between hemoglobin S gelation and sickle cell disease. We first present our current understanding of the major features of the gelation process. Since gelation is a physical rather than a chemical process, its description necessarily requires more physical detail than that of most biological processes. From these studies we are able to develop a more rigorous and comprehensive description of the relation between gelation and the pathophysiology than has been possible up to now. By combining the gelation studies with work on the rheology of sickle cells and blood flow in the microvasculature, a clearer picture emerges of the outstanding issues in understanding the mechanism of vasoocclusion in patients and the resulting cardiovascular response. Finally we discuss the variation in clinical severity and analyze the problem of inhibiting gelation in patients. Throughout this discussion we shall see that the kinetics of gelation is a dominant factor in understanding gelation both in vitro and in vivo, and it will become clear that discussions of the pathophysiobogy that do not include a kinetic analysis22’23 are inadequate. A broader treatment of sickle cell disease, including genetic and clinical aspects, has recently appeared in two excellent books.24’25 Also the structure, physical chemistry, and rheology of hemoglobin S gelation in solution and in red cells is discussed much more extensively in an article that is being published elsewhere.26