ReviewDeconstructing sickle cell disease: Reappraisal of the role of hemolysis in the development of clinical subphenotypes
Introduction
Sickle cell disease, a systemic disorder whose proximate cause is a mutation in the β-globin chain of hemoglobin, has as its major clinical features acute episodes of pain, stroke, priapism and acute chest syndrome and chronic organ damage, like osteonecrosis, renal failure and chronic hemolytic anemia.1 Dysregulated NO homeostasis, a consequence of hemolytic anemia, may be responsible for some of the complications of sickle cell disease and other chronic forms of hemolytic anemia. This article will review the evidence for a pathophysiological model of sickle cell disease that relates certain clinical complications primarily to blood viscosity and vaso-occlusion, and other complications mainly to hemolysis-linked endothelial dysfunction.
Section snippets
Nitric oxide and the hemolysis phenotype
Hemolytic anemia varies in intensity among the genotypes of sickle cell disease. It is most severe in patients with sickle cell anemia who are homozygous for the sickle hemoglobin gene mutation (HBB; glu6val), less severe in individuals with sickle cell anemia and concurrent α thalassemia (homozygous or heterozygous for a single α-globin gene (HbA1, HBA2) deletion, a genotype found in a third of individuals with sickle cell anemia, and least severe in patients with HbSC disease (compound
Pulmonary hypertension and hemolysis
Pulmonary hypertension affects about 30% of patients with sickle cell anemia and is a major risk factor for near-term death.21, 22, 23, 24 Other varieties of hemolytic anemia have also been linked to pulmonary hypertension, particularly in splenectomized patients, including beta-thalassemia intermedia and major, pyruvate kinase deficiency, and hereditary spherocytosis.11, 12, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 Pulmonary thrombosis, a common complication of pulmonary hypertension, is
Hemolysis and the priapism paradox
Priapism has a distinctive relationship to hemolysis and pulmonary hypertension. It is one of the only complications of sickle cell disease found to be associated with pulmonary hypertension in sickle cell disease.22, 43 Priapism is associated with reduced hemoglobin level and the hemolytic markers, reticulocyte count, bilirubin, LDH and aspartate aminotransferase (AST).43, 47 Patients with a history of priapism have a fivefold greater risk of developing pulmonary hypertension.22 Consistent
Leg ulcers and hemolysis
Patients with leg ulcers had lower hemoglobin levels and higher levels of lactate dehydrogenase, bilirubin, aspartate aminotransferase and reticulocytes than did age and sex matched control patients with sickle cell anemia but without leg ulcers.59 Age-adjusted comparisons showed that sickle cell anemia-α thalassemia and HbSC disease were more frequent among controls than leg ulcer cases. These results strongly suggested that the likelihood of having leg ulcers was related to the intensity of
Stroke and hemolysis
The evidence linking stroke to hemolysis is more circumstantial and less definitive. In several studies of stroke in sickle cell disease, stroke was associated with lower hemoglobin concentration.71 Coexistent α thalassemia protects patients with sickle cell anemia from stroke.72 Likewise, the prevalence of α thalassemia was significantly higher in children with normal transcranial Doppler (TCD) flow rates than in patients with high flow velocity, a risk factor for stroke.73 Whether this is due
Fetal hemoglobin (HbF), α thalassemia and the viscosity-vaso-occlusive phenotype
High HbF levels reduce the incidence of some subphenotypes of sickle cell disease, like osteonecrosis,78 acute chest syndrome79, 80 and acute painful episodes (Table 1).80, 81 HbF level has not been associated with protection from pulmonary hypertension, stroke or priapism.22, 47, 71 This is paradoxical, since HbF expression in patients with sickle cell disease is well known to be associated with decreased overall hemolysis. The solution to the paradox may lie in the remarkably high rate of
Hemolysis and the sickle reticulocyte, initiators of vaso-occlusion
Hemolysis promotes adhesive properties of circulating cells and the vessel wall. Sickle reticulocytes, increased in number in response to hemolysis, display receptors and ligands responsible for their adherence to endothelium and leukocytes. Under flow conditions, reticulocytes were the most adherent of the heterogeneous population of sickle erythrocytes.95 Reticulocyte adherence provides an additional link between hemolytic anemia and sickle vaso-occlusion. Sickle erythrocytes adhere to
Hemolysis in geographic subgroups
The prevalence of priapism and leg ulcers is reported to be much higher in patients with sickle cell disease in Jamaica, who manifest severe hemolysis, than those in India or Greece, in whom less severe hemolysis is seen.106, 107, 108 However, the rates of vaso-occlusive crisis and acute chest syndrome are comparable between these geographic subgroups. Although one might suspect the geographic difference in priapism and leg ulcer rates to be due to differences in fetal hemoglobin levels, in the
Hemolysis and desaturation
Several groups have found an association of low transcutaneous oxygen saturation of hemoglobin with elevated serum lactate dehydrogenase, severity of anemia and reticulocytosis, suggesting a link between hemolysis and hypoxemia.43, 109, 110, 111, 112 Speculatively, this link might involve hemolysis-associated pulmonary hypertension and consequent ventilation-perfusion mismatch, although other factors may also play a role.113 Further investigation is required to understand this observation.
Hemolysis and animal models
More definitive scientific evidence has been obtained in animals showing that hemolysis causes vasomotor instability, supporting the extensive epidemiological evidence in humans. Experimentally induced hemolysis in dogs provokes systemic and pulmonary hypertension, renal dysfunction, and diminished vascular response to NO donors.114 These findings are directly associated with biochemical evidence of stoichiometric oxidation of nitric oxide by cell-free plasma hemoglobin. Furthermore, they are
Augmenting the NO pathway in sickle cell disease
Therapies directed at restoring NO homeostasis have shown promise in preliminary studies in patients with sickle cell disease. In children with sickle cell disease presenting to the emergency department with vaso-occlusive pain crisis, inhaled nitric oxide therapy was associated with trends toward lower pain scores, decreased analgesic requirements, and shorter hospital stay.115 A larger scale study is currently under way. Oral administration of the NO synthase substrate L-arginine has been
Conclusions: A new perspective on sickle subphenotypes and goals for treatment
Hemolytic and viscosity-vaso-occlusive phenotypes must have substantial areas of overlap. Nevertheless, this dichotomization helps place subphenotypes of sickle cell disease into a new context (Fig. 2).121 Hemolytic anemia and increased NO scavenging play a major role in the propensity to acquire the subphenotypes of pulmonary hypertension, stroke, leg ulcer and priapism. At least the latter three are ameliorated by α thalassemia that reduces hemolysis and improves anemia. HbF, while it should
Practice points
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Adults with sickle cell disease and thalassemia intermedia or major should be screened by echocardiogram for a tricuspid regurgitant jet velocity (TRV) ⩾2.5 m/sec, suggestive of pulmonary hypertension. Patients with elevated TRV should be referred to a pulmonologist or cardiologist knowledgeable in hemoglobinopathy-associated pulmonary hypertension.
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Clinicians should be alert to a syndrome of hemolysis-endothelial dysfunction, including high serum lactate dehydrogenase levels, pulmonary
Research Agenda
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Role of oxidant stress in reducing nitric oxide bioactivity in sickle cell disease.
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Efficacy of the endothelin receptor antagonist bosentan or phosphodiesterase-5 inhibitors in hemolysis-associated pulmonary hypertension.
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Efficacy of novel nitric oxide donors in acute and chronic sickle cell ischemic tissue injury.
Acknowledgement
Supported in part by NHLBI grants HL R01 68970, HL R01 70735 and 1U54 HL 0708819 (M.H.S.) and by intramural funding from the NHLBI and NIH Clinical Center (G.J.K. and M.T.G.). Vikki Nolan, Diego Wyszynski, John Farrell, Alice Bisbee, Lindsay Farrer and Paola Sebastiani participated in the collection and analysis of data reported from Dr. Steinberg’s laboratory.
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