Gregory J. Kato

Disorders of Hemoglobin: Mechanisms and Clinical Complications of Hemolysis in Sickle Cell Disease and Thalassemia

OVERVIEW OF HEMOLYSIS IN SICKLE CELL DISEASE AND THAL ASSEMIA Anemia is the most basic clinical characteristic of sickle cell disease and thalassemia. In sickle cell disease, the polymerization of sickle hemoglobin (HbS) causes profound changes in the integrity and viability of the erythrocyte, leading to both extravascular and intravascular hemolysis. The lifespan of the erythrocyte in sickle cell disease is often shortened to less than one-tenth of normal. In β-thalassemia intermedia and major, but not in sickle cell disease, a substantial portion of the hemolysis occurs in the intramedullary space before the developing erythrocytes can even exit the bone marrow, referred to as ineffective erythropoiesis. In either case, erythropoiesis is markedly increased, but insufficient to compensate completely for the accelerated hemolysis, resulting in chronic anemia. This chapter examines the mechanisms that give rise to the accelerated hemolysis characteristic of these hemoglobinopathies and considers emerging data suggesting that chronic intravascular hemolysis produces endothelial dysfunction and a progressive vasculopathy. The latter mechanism of disease contributes to a clinical subphenotype of complications shared by many of the hemolytic anemias, including pulmonary arterial hypertension, cutaneous leg ulceration, priapism, and perhaps stroke. The mechanisms and consequences of hemolysis differ by two main anatomical compartments: extravascular hemolysis, which primarily involves phagocytosis by macrophages in the reticuloendothelial system, and intravascular hemolysis, which occurs within the blood vessel lumen. Approximately two-thirds of hemolysis in sickle cell disease is extravascular and one-third intravascular.