Page 690 - Hematology_ Basic Principles and Practice ( PDFDrive )

582 Part V Red Blood Cells

be a substantial problem in sickle cell anemia of transient elevations evident in countries where greater survival and stability derives from
of pulmonary pressure unrelated to histopathologic pulmonary accessible medical care, lower infant mortality, and lesser childhood
hypertension, as discussed later under “Mortality and Sudden Death”. infection burden. The innumerable questions regarding phenotypic
diversity are of great importance. In sickle cell anemia, why do some
children, but not others, develop stroke? Why do only a small fraction
Kidney Disease of adults develop pulmonary hypertension, even though all have
ongoing hemolysis? Why does pain severity vary so widely irrespective
In sickle cell anemia renal hyposthenuria is a nearly universal problem of globin genotype? And so on.
arising from medullary hypoperfusion resulting from the harsh renal
medullary environment; its hypoxia, acidosis, and hyperosmolarity
all would promote HbS polymerization and adverse changes in blood Level of Hemoglobin F
viscosity. Indeed, this even occurs in sickle trait as well. The renal
cortex, on the other hand, exhibits hyperperfusion, believed to HbF level varies amongst individuals as a quantitative trait and is
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underlie glomerular dysfunction with albuminuria. Patients can also determined approximately 80% by genetics. After its decline over
develop acute renal injury, papillary necrosis and chronic renal the first 6 months of life, most of the antisickling protection from its
disease, the latter being a significant contributor to mortality. Hema- high level at birth is lost, but its level still varies among sickle adults
turia from papillary damage is very common. over a 20-fold range. HbF level reflects the number of F cells, the
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amount of HbF per F cell, and the preferential survival of F cells.
Known determinants account for perhaps one-half of its variance: a
Mortality and Sudden Death polymorphic XmnI site (11p) upstream of the Gγ gene; the HBSIL-
MYB intergenic region (6q23); SNPs in TOX (8q12.1); and poly-
Mortality rate is increased in sickle cell anemia patients having higher morphisms of BCL11A (2p16), a transcriptional silencer of the HBG
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rates of acute painful episodes, with notable risk indicators includ- gene. HbF is somewhat higher levels in females, hinting at a con-
ing low HbF, high WBC count, chronic renal failure, and elevated tributing locus on the X chromosome. Polymorphisms in trans-acting
tricuspid regurgitant jet velocity. Among apparent causes of death at enhancers of BCL11A account for some, but not all, of the regional
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autopsy, cardiopulmonary disease is most prominent. In 1994, a variations in HbF level. Among the African autochthonous haplo-
large study from the United States identified a median survival of 42 types, the Benin haplotype is associated with higher HbF level;
years for men and 48 years for women with sickle cell anemia; the however, it is twice again as high among those with the Arab-India
comparable ages were 60 years and 68 years, respectively, for HbSC haplotype.
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disease. This reflected large past improvement after introduction of
prophylactic penicillin for children, revealing the earlier dominance
of pneumococcal sepsis in disease natural history. Further improve- α-Thalassemia
ment has derived from chronic use of hydroxyurea, an agent that
boosts HbF level, lowers WBC count, improves RBC hydration and The normal genotype is αα/αα, but about 30% of African Americans
survival, and blunts inflammatory biology and RBC adhesivity. have a single α deletion (–α/α), so concordance with sickle cell
Unfortunately, survival is much worse in parts of the world with less disease is common; and homozygosity for the allele is seen (–α/–α).
access to medical care and greater abundance of comorbidities (e.g., Its prevalence elsewhere varies regionally. An α-gene deletion has
malaria, diarrheal disease). minimal effect on the HbF level but results in improved RBC hydra-
Sickle cell anemia entails risk for sudden death, tending to occur tion (see Fig. 41.6), a lower ISC count, improved RBC survival, and
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during painful episodes or other acute events. Although unexplained, less severe anemia. Perhaps loss of one α gene nudges α/β chain
S
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this suggests acute cardiac catastrophe. A candidate mechanism may balance toward normal, given the mild instability of β globin. Yet
be occurrence of transient, explosively abrupt elevations of pulmonary there is no amelioration of pain severity, and some complications
artery pressure, even in absence of histopathologic pulmonary hyper- (osteonecrosis, retinopathy) increase, possibly because of the increased
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tension. This derives from an important principle: the underlying, blood viscosity.
preexisting endothelial dysfunction of sickle disease enables and
predicts exaggerated vasoconstrictive responses to unrelated potential
vasoconstrictors such as hypoxia, augmented NO consumption and β-Globin Alleles
inflammatory signaling. Each can fluctuate in short time scale, e.g.,
during acute painful episodes, and thereby might create risk for Compound heterozygosity for the sickle gene and another β allele
sudden death from rapidly elevated right heart pressure. can affect clinical phenotype, with amelioration to, e.g., in the direc-
A
S
tion of amelioration by admixing β or γ chains with β . However,
HbSC disease presents a unique case caused by the lesser electronega-
Sickle Trait tivity of HbC compared with HbS. Rather than simulating sickle
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trait (see Fig. 41.5A), presence of HbC stimulates of KCl cotransport,
Sickle trait typically is associated with renal hyposthenuria. More causing RBC dehydration and increasing concentration of HbS.
seriously, it comprises risk for exertional sudden death, probably Combined with a concurrent augmentation of HbS proportion
precipitated by effects of dehydration on RBC and blood viscosity. (~50% versus ~40% in HbAS), this creates a sickling disorder only
At an epidemiologic level, trait also involves heightened risk for somewhat less severe than sickle cell anemia. Although pain and
venous thromboembolism, chronic renal disease, and thromboembo- anemia are lessened a bit, there is an increased propensity for retino-
lism complicating pregnancy. It may predispose toward ischemic pathy and osteonecrosis. It has been assumed that this derives from
stroke. the somewhat higher blood viscosity when anemia is less severe.
Other less common β gene alleles can likewise interact with HbS and
affect clinical phenotype via impact on polymerization.
BASIS OF PHENOTYPIC DIVERSITY
Factors aside from the beta globin contribute to the remarkable Unexplained Phenotypic Diversity
interindividual diversity of clinical phenotype and severity in sickle
cell anemia. Both can be significantly influenced by environment, Beyond these well-defined influences, there is still enormous unex-
nutrition, socioeconomic status, endemic infectious agents, and avail- plained variability in the clinical phenotype of sickle cell anemia. The
ability of medical care. Therefore, phenotypic variability is most disparate biologic processes that participate in vasoocclusion,