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774 Part VI: The Erythrocyte Chapter 49: Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities 775

Polymorphisms in the TGF-β–BMP pathway, a ubiquitous signal- TABLE 49–3. Antiswitching Therapies
ing pathway that is involved in many cellular processes and pathways,
have emerged as recurrent findings in many of these studies. Some of Drug Mechanism
the associations have functional consequences; the association of biliru- Hydroxyurea Myelosuppression
bin levels in polymorphisms in the UGT1A1 gene promoter is such an Antiinflammatory
example. The 7TA repeat in the promoter leads to a decreased activity
of this enzyme and hence a decrease in glucuronidation of bilirubin. Nitric oxide donor
Thus, the association of this polymorphism with higher bilirubin levels Increased cyclic guanosine
can be understood. On the other hand, the mechanisms by which poly- monophosphate
morphisms in the ubiquitous TGF-β–BMP pathway are associated with Decitabine DNA methyltransferase 1 inhibi-
various complications of SCD are unknown, and thus a causal relation- tion, i.e., hypomethylation
ship cannot yet be established. Functional studies of these variants and
genomewide association studies are expected to provide a better insight 5′-Azacitidine DNA methyltransferase 1 inhibi-
into genetic modulation of the phenotype of SCD. tion, i.e., hypomethylation
Butyrate derivatives Histone deacetylase inhibition
GENERAL MANAGEMENT OF SICKLE CELL Histone deacetylase inhibitors Histone deacetylase inhibition
DISEASE Immunomodulatory drugs P38 mitogen-activated protein
kinase pathway
Pharmacotherapeutics to Increase Fetal Hemoglobin Levels
The observation that HbF results in ameliorating the phenotype of SCD
led to research focused on HbF modulation as a therapy for SCD. The
γ-chains of HbF are excluded from the deoxy HbS polymer; thus the in the cell cycle. The mechanism by which hydroxyurea increases HbF
presence of HbF in sickle red cells exerts a potent antisickling effect. synthesis is not fully understood; it has been postulated that the myelo-
This effect has also been supported by clinical observations; the man- suppressive effect leads to the recruitment of early erythroid progenitors
ifestations of SCD do not become apparent in the first few months of that have retained their fetal (γ) globin synthesis capability, giving rise
life until the switch from γ-chain production to β-chain production is to the production of red cells with a higher HbF content. Some studies
almost complete in the postnatal period. Additionally, the phenotypes show that hydroxyurea acts as a NO donor and increases HbF synthe-
of some compound heterozygous states with HbS and other inherited sis via the cyclic guanosine monophosphate (cGMP) pathway. Others
345
globin disorders that lead to increased expression of HbF in the adult suggest it works by reducing the neutrophil count, thereby reducing the
life (δβ-thalassemias, hereditary persistence of HbF) are very mild contributions of neutrophils to the abnormal vascular adhesion of sickle
(Chap. 47). In fact, compound heterozygotes for HbS and deletional red cells. It has several other actions that explain its efficacy in SCD
hereditary persistence of HbF, in which there is continued high levels other than increasing HbF. These include decrease in platelets and retic-
of HbF expression (30 to 35 percent) uniformly distributed in all red ulocytes, improvement in red cell hydration, and a decrease in red cell
cells (pancellular), are clinically asymptomatic and hematologically adhesiveness to the vascular endothelium (Fig. 49–10). 346–348
normal. In the late 1970s, further evidence in support of the amelio- In the landmark Multicenter Study of Hydroxyurea, hydroxyurea
rating effect of high HbF came from the observation of Saudi Arabian was shown to decrease frequency of painful crises, ACS, hospitaliza-
sickle cell anemia patients who had few, if any, symptoms of SCD, had tions, and blood transfusions. Followup showed a 40 percent decrease
344
mild anemia, and were not diagnosed until adult age. These individ- in mortality in patients randomized to the drug. 160,349 Hydroxyurea is
uals had HbF levels in the 20 to 25 percent range as opposed to the recommended in patients with three or more VOEs or history of ACS.
African patients or American patients of African descent, the majority It can be started at a dose of 15 mg/kg given as a single daily dose and
of whom had HbF levels of approximately 5 percent. Similar patients escalated by 5 mg/kg per day every 8 weeks until toxicity or a maximum
were reported from India, and this genetic propensity for high HbF dose of 35 mg/kg is reached. Maximum tolerated dose is defined as the
production in SCD patients was linked to a unique β-globin gene clus- dose that targets an absolute neutrophil count of 2 to 4 × 10 /L and
9
ter haplotype (Saudi Arabian–Indian) that is distinct from those found absolute reticulocyte count 100 to 200 × 10 /L. 350,351 Periodic monitoring
9
in Africa. These observations paved the way for intense investigations of blood cell counts and serum chemistries, especially in the first year
on the cellular and molecular mechanisms of the fetal to adult (γ to β) of treatment is important. Maximal effect on HbF may not be seen until
switch during the perinatal period and the search for “antiswitching” 6 to 12 months of therapy is completed. The dose should be decreased
agents, agents that would facilitate retaining elevated HbF levels. The in renal failure. Although not proven to have teratogenic or leukemo-
observation that there is a transient increase in HbF production dur- genic potential in SCD patients, it is recommended that it not be used in
ing recovery from marrow aplasia or suppression provided the ratio- pregnant or breastfeeding patients. Concerns about detrimental effect
nale for the use of myelosuppressive agents as antiswitching therapy on spermatogenesis have also been raised based on studies in mice. 352–355
(Table 49–3). Antiswitching indicates a mechanism to prevent the Patients receiving hydroxyurea who die while on treatment are
switch from γ-globin chains to β-globin chains. likely to be older when therapy is initiated, more anemic, likely to have
Hydroxyurea Although many myelosuppressive agents have Bantu or Cameron β-globin gene haplotypes, and have impaired renal
been studied in primates and some have been used in a small number of function. 324
patients, only one of these, hydroxyurea, has been used, starting in the Several studies have now been published on the use of hydroxyurea
early 1980s, in large-scale clinical trials. This is largely attributable to its in infants and children. Therapy can begin between 6 and 9 months of
excellent oral bioavailability, relatively short half-life (important from age, is safe and well tolerated with improved growth rates, preserves
the standpoint of rapid reversibility of toxicity), no evidence that its use organ function, and the additional benefits as seen in adults. 161,351,356,357
leads to an increase in cancer prevalence, and few side effects. Other Fetal Hemoglobin-Inducing Agents Although significant
Hydroxyurea is the only FDA-approved agent for the treatment of advances have been made in understanding the basic mechanism(s) of
SCD. It is a ribonucleotide reductase inhibitor and is S-phase specific the perinatal switch from γ- to β-globin synthesis, this knowledge is

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