Intracellular Hemoglobin S Polymerization and the Clinical Severity of Sickle Cell Anemia

Abstract

Recent work has enabled us to quantitate the four variables (2,3-DPG concentration, pHi, non-S hemoglobin composition, and O2 saturation) that modulate the equilibrium solubility (csat) of Hb S inside sickle erythrocytes (SS RBCs). Using measured values of mean corpuscular hemoglobin concentration (MCHC), 2,3-DPG concentration, and %Hb (F+A2), along with estimates of pHiand the Δcsat due to partial oxygenation of SS RBCs in the microcirculation, we calculated the mean polymer fraction (fp) in erythrocytes from 46 SS homozygotes. Values of fp derived from the conservation of mass equation ranged from 0.30 to 0.59. MCHC and %Hb F were major determinants of the magnitude of fp; 2,3-DPG concentration and pHialso contributed, but to a lesser extent. A clinical severity score (CSS) was assigned to each patient based on mean hospitalization rate. There was a weak, but statistically significant, negative correlation between fp and steady state hematocrit (P = .017), but none between fp and whole blood hemoglobin concentration (P = .218). Although there was no correlation between fp and mean number of hospitalization days per year, patients with the greatest number of admissions and hospitalization days were found only among those who had an fp > 0.45. All five patients who died during the follow-up period (median, 7 years; range, 3 to 10 years) had fp values ≥0.48. However, patients with few admissions, low hospitalization days, and long survivals occurred at all fp levels. These results suggest that the clinical course of homozygous SS disease cannot be predicted by mean fpcalculations, which assume a homogeneous distribution of the five variables that modulate intraerythrocytic polymerization. A heterogeneous distribution is more likely; so the amount of polymerized Hb S could vary considerably among cell populations. Factors such as membrane abnormalities and endothelial cell interactions may also contribute to clinical severity.

Controlling the Oxygenation Level of Hemoglobin by Using a Synthetic Receptor for 2,3‐Bisphosphoglycerate

“…Increased levels of 2,3‐BPG are present in patients suffering from hypoxemia and anemia, because this facilitates the oxygen release of oxyhemoglobin into tissue 6. In contrast, high 2,3‐BPG levels in individuals with sickle cell anemia are harmful, because 2,3‐BPG favors sickling by facilitating the polymerization of sickle hemoglobin 7–9. Controlling the physiological concentration of 2,3‐BPG could yield a treatment for these diseases.…”

Socio-environmental exposures and health outcomes among persons with sickle cell disease

“…The primary cause of the clinical symptomatology of sickle cell disease is the intracellular polymerization of sickle hemoglobin (HbS) that occurs when sickle erythrocytes are partially deoxygenated under the hypoxic conditions of the microcirculation [3]. The clinical manifestations of the disease include repeated painful vaso-occlusive, haemolytic, aplastic episodes, and sequestration crises.…”

Sickle cell disease: the Lebanese experience

“…Sickle cell anemia (SCA), is the consequence of a single amino-acid substitution in the beta globin chain that produces a hemoglobin (Hb) tetramer that is poorly soluble when deoxygenated (Ingram, 1957). This molecular disorder is responsible for a wide range of clinical manifestations (Bookchin et al, 1977;Poillon, Kim & Castro, 1998). Prospective studies such as the Cooperative Study of Sickle Cell Disease (CSSCD), the Jamaican cohort study and the newborn Dallas cohort studies enabled researchers to study the clinical course of SCD (Leikin et al, 1989;Thomas, Pattison & Serjeant, 1982;CT Quinn, Rogers & Buchanan, 2004).…”