Molecular and cellular pathogenesis of hemoglobin SC disease.

Abstract

Solution and cell studies were performed to ascertain why individuals with hemoglobin (Hb) SC have disease whereas those with Hb AS do not. The polymerization of deoxygenated mixtures containing sickle cell Hb (Hb S; a2P26GIu-VaI) and Hb C (a2f326GIu Lys) was investigated by measurements of delay times and solubilities. In mixtures containing more than 40% Hb S. polymerization takes place by the same mechanism as in solutions of Hb S alone, with no evidence for independent crystallization of Hb C. A detailed comparison of Hb S/Hb C and Hb S/Hb A mixtures with identical concentrations and proportions of Hb S show that there is no significant difference in the tendency of Hb C and Hb A to copolymerize with Hb S. In 50:50 Hb S/ Hb C mixtures, polymerization is about 15 times more rapid than in 40:60 Hb S/Hb A mixtures at the same total Hb concentration. Measurements on density-fractionated erythrocytes show that SC cells contain a higher total Hb concentration and a more uniform distribution, of reticulocytes compared to normal (AA) or sickle trait (AS) cells. The concentration distribution for C trait (AC) cells is much closer to that of SC cells than to AS or AA cells. It appears, therefore, that the presence of Hb C results in the SC cell beginning its life-with an abnormally high Hb concentration. From these findings we conclude that both the larger proportion of Hb S and the higher intracellular Hb concentration contribute to the pathogenesis of Hb SC disease.Hemoglobin (Hb) SC disease is one of the most prevalent ofthe sickling disorders. Patients with Hb SC disease are double (or compound) heterozygotes. They inherit a s35-globin gene from one parent and a I3C-globin gene from the other. The erythrocytes from these individuals usually contain about 50% sickle cell Hb (Hb S) (a2p26 Glu-Val), 50% Hb C (a2026 Glu-*Lys) and no Hb A (a2 326 Glu). In contrast, the most frequently observed composition in the more common heterozygous state, sickle trait (AS), is 40% Hb S and 60% Hb A. Another important difference is that the mean intracellular Hb concentration (MCHC) is higher for SC erythrocytes compared to either AS cells or cells from patients homozygous for the PS gene (1).SC patients have a life-long hemolytic anemia of moderate severity and develop vaso-occlusive episodes and organ damage similar to that encountered in homozygous (SS) sickle cell anemia (1, 2). Why do SC individuals have significant clinical abnormalities, while sickle trait is essentially benign? It is generally assumed that the clinical manifestations of SC disease reflect more extensive formation of intracellular polymer compared to AS erythrocytes subjected to a comparable degree of deoxygenation (2). This is based on early in vitro measurements ofcell morphology and blood viscosity (3, 4). More recent work, including kinetic (5-7) and NMR studies (8-10), is consistent with these findings.Three factors could contribute to the increased polymerization in SC cells in vitro-the higher proportion of Hb S, the higher total intracellula...

Hemoglobin sickle cell disease complications: a clinical study of 179 cases

“…Hyperfiltration was associated to albuminuria in only one patient compared with the SCA population in whom eGFR values were higher (< 300 mL/min/1.73m 2 ) and albuminuria was observed in 51% of patients with hyperfiltration. 4 In our series, renal failure was due to HIV-associated nephropathy in one case, thrombotic thrombocytopenic purpura in one case and undetermined vascular nephropathy in 2 cases.…”

“…Among the 69% of foreign born patients, the mean duration of residence in France was 13.8 years and the mean duration of follow up at the center was 5.1 years. Fifty-eight percent of female patients had been pregnant with a mean of 1.9 children per woman and 32 spontaneous abortions were reported in 12 females (5 multiple abortions, range [2][3][4][5][6][7][8][9][10][11]. High body mass index (≥25kg/m 2 ) and blood hypertension (> 130/80 mmHg) were reported in 33% and 14% of HbSC patients, respectively.…”

“…The main reason is that HbC enhances the formation of intracellular polymer of HbS by dehydrating red cells. 2,3 The major acute features of SCA are recurrent painful vasoocclusive crisis (VOC) and acute chest syndrome (ACS), priapism and anemia. Chronic organ dysfunctions are of increasing concern in adult patients leading to lifethreatening end-stage organ failures.…”

Elevated hypercoagulability markers in hemoglobin SC disease

“…1,2 Erythrocytes containing HbC have high K-Cl cotransport activity with high K + and water efflux, leading to cellular dehydration; this results in erythrocytes that are denser than normal red blood cells, microcytic, hyperchromic and have a markedly increased mean corpuscular hemoglobin concentration. [1][2][3][4] While HbC in homozygosity produces only a mild hemolytic anemia, the coexistence of HbC and HbS results in a significantly more serious disorder, as the dehydration induced by HbC enhances the pathogenic properties of HbS. 1,2 Hemoglobin SC disease is considered to be a milder hemoglobinopathy than sickle cell anemia (SCA), the homozygous state of HbS (HbSS).…”

“…[1][2][3][4] While HbC in homozygosity produces only a mild hemolytic anemia, the coexistence of HbC and HbS results in a significantly more serious disorder, as the dehydration induced by HbC enhances the pathogenic properties of HbS. 1,2 Hemoglobin SC disease is considered to be a milder hemoglobinopathy than sickle cell anemia (SCA), the homozygous state of HbS (HbSS). All of the clinical complications seen in SCA are also present in HbSC disease, but in the latter they generally occur less frequently and are less severe.…”