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C H A P T E R 43

HEMOGLOBIN VARIANTS ASSOCIATED WITH HEMOLYTIC

ANEMIA, ALTERED OXYGEN AFFINITY, AND

METHEMOGLOBINEMIAS

Edward J. Benz, Jr. and Benjamin L. Ebert

Hemoglobinopathies are inherited diseases caused primarily by muta- clinical manifestations. Both α- and β-globin variants can cause this
tions affecting the globin genes. Nearly 1000 mutations are known condition. Approximately 75% of the mutations described, however,
to alter the structure, expression, or developmental regulation of are β-globin variants. This probably reflects the potential for α-globin
individual globin genes and the hemoglobins that they encode. Of variants to exert pathologic effects in utero. Clinical symptoms of
these, only a few produce clinical disease. Many are highly instructive unstable hemoglobins also depend, in part, on the quantitative pro-
for students, of gene structure, function, and regulation, but further portion of the abnormal hemoglobin. Because the α-globin genes are
consideration of most is not warranted in a clinically oriented text- duplicated, mutations in an individual locus generally produce only
book. The gene mutations that cause sickle cell anemia and the 25% to 35% abnormal globin. By contrast, a simple heterozygote at
thalassemia syndromes are by far the most important mutations that the single β-globin locus usually produces approximately 50% of the
cause clinical morbidity, in terms of both the complexity of the clini- abnormal variant.
cal syndromes they cause and the number of patients affected. These The mutations that impair hemoglobin solubility usually disrupt
conditions are considered in detail in other chapters (see Chapters hydrogen bonding or the hydrophobic interactions that either retain
40, 41 and 42). This chapter reviews other abnormalities of the the heme moiety within the heme-binding pockets or hold the tet-
hemoglobin molecule that produce clinical syndromes. Even though ramer together (Fig. 43.1). Some alter the helical segments (e.g.,
each variant is uncommon, these hemoglobinopathies represent, in hemoglobin [Hb] Geneva [β 28Leu→Pro ]), others weaken contact points
the aggregate, important problems for hematologists, because they between the α and β subunits (e.g., Hb Philadelphia [β 35Tyr→Phe ]), and
must be considered as possible causes for conditions about which still others derange interactions of the hydrophobic pockets of the
hematologists are often consulted: hemolytic anemia, cyanosis, globin subunits with heme (e.g., Hb Köln [β 98Val→Met ]). The common
polycythemia, jaundice, rubor, splenomegaly, and reticulocytosis. In pathway to reduced solubility invariably involves weakening of the
some patients, secondary hematologic complications such as hyper- binding of heme to globin. Actual loss of heme groups can occur, for
coagulable states are also encountered. example, in Hb Gun Hill, in which five amino acids, including the
The major inherited hemoglobinopathies producing clinical F8 histidine, are deleted. In other cases, mutations that introduce
symptoms (other than sickle cell anemia and thalassemias) can be prolines into helical segments disrupt the helices and interfere with
classified as those hemoglobins exhibiting altered solubility (unstable normal folding of the polypeptide around the heme group. Another
hemoglobins), hemoglobins with increased oxygen affinity, hemoglo- feature of these mutations is disruption of the integrity of the tetra-
bins with decreased oxygen affinity, and methemoglobins (Table meric structure of globin chains. Only the intact hemoglobin tetramer
43.1). A few acquired conditions in which toxic modifications of the can remain dissolved at the high concentrations that must be achieved
hemoglobin molecule are important (e.g., carbon monoxide poison- within the circulating red blood cell (see Chapters 30 and 40).
ing) also merit consideration.
The sections that follow emphasize hemoglobinopathies that
produce the most severe or dramatic alterations in clinical phenotype Pathophysiology of Unstable Hemoglobin Disorders
and those in which a single clinical abnormality (e.g., hemoglobin
precipitation) predominates. It is important to emphasize at the The mechanisms by which unstable hemoglobin mutations produce
outset, however, that although more than 100 mutations affect solu- hemoglobin precipitation remain incompletely understood; however,
bility or affinity, only a few are clinically important. The abnormal the major outlines of the process have been described (Fig. 43.2). The
functional properties of most mutant hemoglobins can be readily fundamental step in pathogenesis appears to be derangement of the
detected in sophisticated research laboratories, but only a few mutant normal linkages between heme and globin. Loss of appropriate globin
hemoglobins produce laboratory or clinical abnormalities relevant to chain folding and interaction may ultimately destabilize the heme-
clinical practice. Moreover, many mutations are pleiotropic, affecting globin linkage or lead to partial proteolysis of the chain, thereby
several functional properties of the hemoglobin molecule. Thus a releasing heme from that linkage. Once freed from its cleft, heme
single mutation can increase oxygen affinity and reduce solubility, or probably binds nonspecifically to other regions of the globin molecule,
produce methemoglobinemia and reduce solubility. forming precipitated hemichromes, which leads to further denatur-
Table 43.2 summarizes the major forms of structurally abnormal ation and aggregation of the globin subunits. These form a precipitate
hemoglobin, with examples. This table serves as a point of reference containing α- and β-globin chains, globin fragments, and heme,
for the remaining sections of the chapter. called the Heinz body.
Heinz bodies interact with delicate red blood cell membrane
components (see Chapters 43 and 45), thereby reducing red blood
UNSTABLE HEMOGLOBINS cell deformability. These rigid cells tend to be detained in the splenic
microcirculation and “pitted,” reflecting attempts by the splenic
Unstable hemoglobins are hemoglobins exhibiting reduced solubility macrophages to remove the Heinz bodies. Red blood cell damage can
or higher susceptibility to oxidation of amino acid residues within be aggravated by the release of free heme into the red blood cell.
the individual globin chains. More than 100 unique unstable hemo- Several biochemical perturbations correlate with the presence of free
globin mutants have been documented. Most exhibit only mild heme, such as generation of reactive oxidants (i.e., hydrogen peroxide,
instability in in vitro laboratory tests and are associated with minimal superoxide, and hydroxyl radicals). The end result of this process is

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