Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes

Abstract

Hemolysis, long discounted as a critical measure of sickle cell disease severity when compared with sickle vaso-occlusion, may be the proximate cause of some disease complications. New mechanistic information about hemolysis and its effects on nitric oxide (NO) biology and further examination of the subphenotypes of disease requires a reappraisal and deconstruction of the clinical features of sickle cell disease. The biology underlying clinical phenotypes linked to hemolysis may increase our understanding of the pathogenesis of other chronic hemolytic diseases while providing new insights into treating sickle cell disease. The pathophysiological roles of dysregulated NO homeostasis and sickle reticulocyte adherence have linked hemolysis and hemolytic rate to sickle vasculopathy. Nitric oxide binds soluble guanylate cyclase which converts GTP to cGMP, relaxing vascular smooth muscle and causing vasodilatation. When plasma hemoglobin liberated from intravascularly hemolyzed sickle erythrocytes consumes NO, the normal balance of vasoconstriction:vasodilation is skewed toward vasoconstriction. Pulmonary hypertension, priapism, leg ulceration and stroke, all subphenotypes of sickle cell disease, can be linked to the intensity of hemolysis. Hemolysis plays less of a role in the vaso-occlusive-viscosity complications of disease like the acute painful episode, osteonecrosis of bone and the acute chest syndrome. Agents that decrease hemolysis or restore NO bioavailability or responsiveness may have potential to reduce the incidence and severity of the hemolytic subphenotypes of sickle cell disease. Some of these drugs are now being studied in clinical trials.

Figures

Figure 1

Intravascular hemolysis reduces nitric oxide bioactivity. Nitric oxide is produced by isoforms of nitric oxide (NO) synthase, using the substrate L-arginine. Intravascular hemolysis simultaneously releases hemoglobin, arginase, and lactate dehydrogenase (LDH) from red cells into blood plasma. Cell-free plasma hemoglobin stochiometrically inactivates NO, generating methemoglobin and inert nitrate (A). Plasma arginase consumes plasma L-arginine to ornithine, depleting its availability for NO production (B). LDH also released from the red cell into blood serum serves as a surrogate marker for the magnitude of hemoglobin and arginase release. NO is also consumed by reactions with reactive oxygen species (O2−) produced by the high levels of xanthine oxidase activity and NADPH oxidase activity seen in sickle cell disease, producing oxygen radicals like peroxynitrite (ONOO-)(C). The resulting decreased NO bioactivity in sickle cell disease is associated with pulmonary hypertension, priapism, leg ulceration, and possibly with non-hemorrhagic stroke. A similar pathobiology is seen in other chronic intravascular hemolytic anemias.

Figure 2

Model of overlapping subphenotypes of sickle cell disease. Published data suggest that patients with sickle cell disease with higher hemoglobin levels have a higher frequency of viscosity-vaso-occlusive complications closely related to polymerization of sickle hemoglobin, resulting in erythrocyte sickling and adhesion. Such complications include vaso-occlusive pain crisis, acute chest syndrome, and osteonecrosis. In contrast, a distinct set of hemolysis-endothelial dysfunction complications involving a proliferative vasculopathy and dysregulated vasomotor function, including leg ulcers, priapism, pulmonary hypertension, and possibly non-hemorrhagic stroke, is associated with low hemoglobin levels, and high levels of hemolytic markers such as reticulocyte counts, serum lactate dehydrogenase, plasma hemoglobin and arginase, producing a state of impaired nitric oxide bioavailability. The spectrum of prevalence and severity of each of these subphenotypes overlap with each other. Patients with α-thalassemia trait tend to have less hemolysis and higher hemoglobin levels, tending to decrease the prevalence of hemolysis-endothelial dysfunction, and tending to increase the prevalence of viscosity-vaso-occlusion. The effect of fetal hemoglobin expression or chronic red cell transfusion is more complex, simultaneously increasing hemoglobin level, but reducing sickling and hemolysis.