The mechanisms by which unstable hemoglobin mutations produce hemoglobin precipitation remain incompletely understood; however, the major outlines of the process have been described (Fig.1). The fundamental step in pathogenesis appears to be derangement of the normal linkages between heme and globin. Loss of appropriate glo bin chain folding and interaction ultimately destabilizes the heme globin linkage and likely leads to partial proteolysis of the chain, thereby releasing heme from that linkage. Once freed from its cleft, heme probably binds nonspecifically to other regions of the globin molecule, forming precipitated hemichromes, these lead to further denaturation and aggregation of the globin subunits. These form a precipitate containing α- and β-globin chains, globin fragments, and heme, called the Heinz body.

Fig1. PRESUMED MECHANISMS BY WHICH DENATURATION OF HEMOGLOBIN LEADS TO ERYTHROCYTE DESTRUCTION. The rate of travel through the various pathways probably differs for the different hemoglobin variants and for a variety of stresses to which the protein is subjected. RBC, Red blood cell. (From Wynngaarden JB, Smith LH Jr, Bennett JC, eds. Cecil Textbook of Medicine. Philadelphia: WB Saunders; 1992.)

Heinz bodies interact with delicate red blood cell membrane components, thereby reducing red blood cell deformability. These rigid cells tend to be detained in the splenic microcirculation and “pitted,” reflecting attempts by the splenic macrophages to remove the Heinz bodies. Red blood cell damage can be aggravated by the release of free heme into the red blood cell. Several biochemical perturbations correlate with the presence of free heme, such as generation of reactive oxidants (i.e., hydrogen peroxide, super oxide, and hydroxyl radicals). The end result of this process is premature destruction of the red blood cell, producing hemolytic anemia.

Individual unstable hemoglobins vary in their propensity to generate Heinz bodies and hemolysis. For example, Hb Zurich exhibits relatively mild insolubility. Hemolysis is minimal in nonstressed patients with this variant and becomes clinically apparent only in the presence of additional oxidant stresses, such as infection, fever, or the ingestion of oxidant agents. Because of the propensity of unstable hemoglobins to be hypersensitive to oxidation, some patients with unstable hemoglobins can exhibit episodic appearance or aggravation hemolysis in response to many of the same oxidative stressors as those exacerbating the clinical phenotype of glucose-6-phosphate dehydrogenase (G6PD)-deficient patients.

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