The paradox of hemoglobin SC disease
Introduction
Hemoglobin (Hb) C (β6Glu6Lys), is one of the three most prevalent abnormal Hbs of man. The unique pathology of HbC is due to the capacity of HbC to induce erythrocyte dehydration and intracellular crystal formation. The homozygous state of the HbC gene (HbC disease) results only in mild hemolytic anemia. In HbSC disease, where equal concentrations of HbS and HbC coexist, HbC enhances the pathogenic properties of HbS, resulting in a clinically significant disorder. Nevertheless, in most individuals, HbSC disease is clinically milder that sickle cell anemia.
The apparent paradox is that HbSC disease is a compound heterozygous condition, equivalent to a mixture of sickle trait and HbC trait (HbAC), neither of which has significant pathology. Hence, why does the combination of these two Hbs result in a serious disease? To facilitate the understanding of SC disease we need first to review the properties of HbC.
Section snippets
The origin and selection of the HbC gene
Most likely, the βC mutation first occurred among ethnic groups living in Burkina Faso (previously known as Upper Volta).1 HbC reaches its highest frequency in Central West Africa and its gene frequency decreases concentrically from this epicenter. HbC in Africa is found almost exclusively west of the Niger River and in areas where HbS is also present.
The HbC gene exists at polymorphic frequencies (that is, over 1% gene frequency) in several human populations suggesting that its presence has a
HbSC disease
As we have seen, in HbC a negatively charged β6-glutamic acid causes a very different pathophysiology than does the hydrophobic β6-valine present in HbS. The tendency to crystallization, which, along with cell dehydration caused by the HbC induced loss of K+ and water, is the basis of the pathophysiology of HbC disease, particularly, the hemolytic process. Similar mechanisms contribute to the pathology of HbSC disease with the addition that here, the presence of intra-erythrocytic HbC increases
Clinical features of HbSC disease
HbSC disease has an incidence of about 1:833 live births in African-Americans.39 In some West African regions such as Northern Ghana, Burkina Faso, and Western Nigeria about a quarter of the population may have HbSC disease.40 All complications that are found in patients with sickle cell anemia have occurred in individuals with HbSC disease. Yet, most—but not all—of these complications are seen less often and appear at a later time in HbSC disease compared with sickle cell anemia. Hemolysis is
Conclusions
The paradoxical pathophysiology of HbSC disease offers a unique avenue for its treatment and possible clinical “cure”. HbSC disease has a fundamental pathophysiological difference from sickle cell anemia stemming not from the abundance of polymerizing HbS but from the indispensable role of red cell dehydration that brings a 50% HbS to a concentration capable of pathology.. The correction of the dehydration of HbSC red cells will correct the polymerization tendency of HbS to the level of sickle
References (99)
- et al.
Synchronized cultures of P falciparum in abnormal red cells: the mechanism of the inhibition of growth in HbCC
Blood
(1986) - et al.
The inhibition of hemoglobin C crystallization by hemoglobin F
J. Biol. Chem.
(1988) - et al.
Compound heterozygosity for hemoglobin C and Korle-Bu: moderate microcytic hemolytic anemia and acceleration of crystal formation
Corrected Blood
(1993) - et al.
Solution-active structural alterations in liganded hemoglobins C (∃6Glu6Lys) and S (∃6Glu6Val
J. Biol. Chem.
(1999) - et al.
Intermolecular interactions, nucleation, and thermodynamics of crystallization of hemoglobin C
Biophys. J.
(2002) - et al.
Ligand state of intraerythrocytic circulating HbC crystals in homozygous CC patients
Blood
(1985) - et al.
Homozygous hemoglobin C disease: report of a case with studies on the pathophysiology and neonatal formation of hemoglobin C
Am. J. Med.
(1955) - et al.
Red cell life span in hemoglobin C disorders (with special reference to hemoglobin C trait
Blood
(1970) - et al.
Volume-dependent and NEM-stimulated K+Cl− transport is elevated in oxygenated SS, SC and CC human cells
FEBS Let.
(1986) - et al.
The unique red cell heterogeneity of SC disease: crystal formation, dense reticulocytes, and unusual morphology
Blood
(1991)
Intraerythrocytic crystals in a white patient with hemoglobin C in the absence of other types of hemoglobin
Blood
Acceleration of hemoglobin C crystallization by hemoglobin S
Blood
Dense cells in sickle cell anemia: the effects of gene interaction
Blood
An objective sign in painful crisis in sickle cell anemia: the concomitant reduction of high density red cells
Blood
Red blood cell changes during the evolution of the sickle cell painful crisis
Blood
Mortality in children and adolescents with sickle cell disease
Pediatrics
Molecular interactions between Hb alpha-G Philadelphia, HbC, and HbS. phenotypic implications for SC alpha-G Philadelphia disease
Blood
Ocular findings in hemoglobin SC disease in Jamaica
Am. J. Ophthalmol.
Coop Study of Sickle Cell Disease: The acute chest syndrome in sickle cell disease: Incidence and risk factors
Blood
Acute chest syndrome in sickle cell disease: Clinical presentation and course
Blood
Acute splenic complications in children with sickle cell hemoglobin C disease
J. Pediatr.
Recurrent acute splenic sequestration crisis due to interacting genetic defects: hemoglobin SC disease and hereditary spherocytosis
Blood
Fatal pneumococcal septicemia in hemoglobin SC disease
J. Pediatr.
Bacteremia in children with sickle hemoglobin C disease and sickle beta (+)-thalassemia: is prophylactic penicillin necessary
J. Pediatr.
The relation between age and renal concentrating capacity in sickle cell disease and hemoglobin C disease
Clin. Chim. Acta.
Cooperative Study Sickle Cell Disease: Cerebrovascular accidents in sickle cell disease: Rates and risk factors
Blood
A collaborative double-blind randomized study of cetiadil citrate in sickle cell crisis
Blood
Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter Study of Hydroxyurea
Blood
Hemoglobins S and C in Upper Volta
Hum. Genet.
Haemoglobin C protects against clinical Plasmodium falciparum malaria
Nature
Pathophysiological effects of some abnormal hemoglobins
Medicine
The solubility of sickle and non-sickle hemoglobins in concentrated phosphate buffer
J. Biol. Chem.
HbC compound heterozygotes [HbC/Hb Riyadh and HbC/Hb N- Baltimore] with opposing effects upon HbC crystallization
Br. J. Haematol.
A potential determinant of enhanced crystallization of Hbc: spectroscopic and functional evidence of an alteration in the central cavity of oxyHbC
Br. J. Haematol.
Differential pathways in oxy and deoxy HbC aggregation/crystallization
Proteins
Microvascular sites and characteristics of sickle cell adhesion to vascular endothelium in shear flow conditions: pathophysiological implications
Proc. Natl. Acad. Sci. USA
Clinical and necropsy findings in hemoglobin C disease
Blood
Regulation of cation content and cell volume in hemoglobin erythrocytes from patients with homozygous hemoglobin C disease
J. Clin. Invest.
Electrolyte composition and equilibrium in hemoglobin CC red blood cells
Transactions of the Association of American Physicians
Hemoglobin CC erythrocytes:decreased intracellular pH and decrease 02 affinity anemia
Seminars In Hematology
SC cells have an abnormally high intracellular hemoglobin concentration: Pathophysiological consequences
J. Clin. Invest.
Interaction of sickle cell hemoglobin with erythrocyte membranes
Proc. Natl. Acad. Sci. USA
Association of hemoglobin C with erythrocytes ghosts
J. Clin. Invest.
Binding of beta S, beta C and beta O Arab globins to the erythrocyte membrane
Hemoglobin
The interaction of hemoglobin O Arab with Hb S and beta+ thalassemia among Israeli Arabs
Hum. Genet.
The erythrocyte effects of haemoglobin O (ARAB
Br. J. Haematol.
Pitted red cell counts in sickle cell disease. Relationship to age, hemoglobingenotype, and splenic size
Am. J. Pediatr Hematol. Oncol.
Molecular and cellular pathogenesis of hemoglobin SC disease
Proc. Natl. Acad. Sci. USA
Cited by (184)
Acute macular infarctions in pediatric patients with hemoglobin SS disease
2023, American Journal of Ophthalmology Case ReportsMost adults with severe HbSC disease are not treated with hydroxyurea
2023, Blood Advances