Hemoglobin S polymerization: primary determinant of the hemolytic and clinical severity of the sickling syndromes

Abstract

We examined the extent to which the intracellular polymerization of sickle hemoglobin (HbS) can account for the severity of anemia and of vaso-occlusive manifestations in the various sickling syndromes. Polymer formation in sickle cell disease depends principally on the intraerythrocytic hemoglobin composition and concentration. In our studies, the polymer fraction in sickle red cells was determined from reported mean values for hemoglobin composition and mean corpuscular hemoglobin concentration (MCHC) in 12 groups of patients with sickle hemoglobinopathies (homozygotes for HbS, with and without coexistent alpha-thalassemia or various forms of the hereditary persistence of fetal hemoglobin [HPFH], beta+-, beta 0-, and delta beta-thalassemia, and heterozygotes for HbS with HbA). The calculated HbS polymer fractions at full deoxygenation and at physiologic oxygen saturation values were closely correlated with mean blood hemoglobin concentrations. In addition, polymer fraction correlated with the ranking of the sickling syndromes by vaso-occlusive severity. We find that polymer fraction accounts for about 80% of the variability in hemolytic and clinical severity. The method of analysis presented here provides a quantitative and systematic means of assessing the role of polymer formation in the pathophysiologic manifestations of the sickling syndromes. Our results support the hypothesis that the intracellular polymerization of HbS is the primary determinant of the severity of both anemia and clinical symptomatology in the sickle hemoglobinopathies.

Sickle cell rheology is determined by polymer fraction–not cell morphology

“…We recently used such cells to show that impaired filtration in a nickel mesh gravity-driven filtration system is linearly related to Hb S polymer fraction, when the effects of membrane abnormalities are removed from consideration, and that polymer causes much greater rheological impairment than the high CHC or abnormal membranes per se [25]. Hb S polymer fraction appears to account for about 80% of the variability in anemia among the different sickle syndromes (and much of overall clinical severity) [26], although correlations within individuals within each syndrome have been weaker. In this study, we investigated potential interrelationships among the effects of cell morphology and the amount of polymer on erythrocyte filterability.…”

Hemoglobin S polymerization and sickle cell disease: A retrospective on the occasion of the 70th anniversary of Pauling's Science paper

“…Consequently, it is the delay time, which allows the majority of cells to escape the narrowest vessels of the tissues before fibers form, a conclusion also reached in recent calculations by is determined by polymerization. 63…”

Haematological Diseases in the Tropics

“…This phenomenon occurs where there is deoxygenation and is due to the binding between β1 and β2 chains of two haemoglobin molecules, a property unique to haemoglobin variants that have the Glu-6-Val substitution. 74 The polymerized haemoglobin fills the erythrocyte and deforms its architecture and flexibility to form a sickle shape. This alteration in the structure promotes cellular dehydration, 70,75,76 Upon reoxygenation, the polymers dissolve thus reversing the sickling process.…”

“…The two main approaches to transfusion 74 in SCD are simple top-up transfusion and exchange transfusion. Target haemoglobin level in SCD therapy is 100 g/L or a haematocrit of 30%; higher target levels are associated with hyperviscosity and of multi-organ failure.…”