The paradox of hemoglobin SC disease

doi:10.1016/S0268-960X(03)00003-1

Blood Reviews

Volume 17, Issue 3, September 2003, Pages 167-178

https://doi.org/10.1016/S0268-960X(03)00003-1 Get rights and content

Abstract

Homozygous HbC gene results only in mild hemolytic anemia. In HbSC disease red cells contain equal levels of HbS and HbC. It is a paradox that HbSC exhibit a moderately severe phenotype in spite of being a mixture of HbS trait and HbC trait, neither of which has significant pathology. Why does the combination of these two Hbs result in a serious disease? The short answer is that HbC enhances, by dehydrating the SC red cell, the pathogenic properties of HbS, resulting in a clinically significant disorder, but somewhat milder that sickle cell anemia (SCA). Nevertheless, retinnitis proliferans, osteonecrosis, and acute chest syndrome have equal or higher incidence in HbSC disease compared to SCA.

This pathogenic trick is accomplished by HbC inducing, by mechanisms not fully understood, an increase in the activity of K:Cl cotransport that induces the lost of K⁺ and consequently of intracellular water. This event creates a sufficient increase of MCHC, so that the lower levels of HbS found in SC red cells can polymerize rapidly and effectively. This situation offers a unique opportunity: if we could inhibit the effect of HbC on K⁺ transport we can cure the 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 β^C 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

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The paradox of hemoglobin SC disease

Abstract

Introduction

Section snippets

The origin and selection of the HbC gene

HbSC disease

Clinical features of HbSC disease

Conclusions

Blood

J. Biol. Chem.

Corrected Blood

J. Biol. Chem.

Biophys. J.

Blood

Am. J. Med.

Blood

FEBS Let.

Blood

Blood

Blood

Blood

Blood

Blood

Pediatrics

Blood

Am. J. Ophthalmol.

Blood

Blood

J. Pediatr.

Blood

J. Pediatr.

J. Pediatr.

Clin. Chim. Acta.

Blood

Blood

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

Hemoglobin CC erythrocytes:decreased intracellular pH and decrease 0₂ affinity anemia