Chapter 099. Disorders of Hemoglobin (Part 14) docx

Chapter 099. Disorders of
Hemoglobin
(Part 14)

Deferasirox is a promising oral iron-chelating agent. Single daily doses of
20 or 30 mg deferasirox produced reductions in liver iron concentration
comparable to desferoxamine in chronically transfused adult and pediatric
patients. Deferasirox produces some elevations in liver enzymes and slight but
persistent increases in serum creatinine, without apparent clinical consequence.
Other toxicities are similar to those of desferoxamine. Its toxicity profile is
acceptable, although long-term effects are still being evaluated.
Bone Marrow Transplantation, Gene Therapy, and Manipulation of
HbF
Bone marrow transplantation provides stem cells able to express normal
hemoglobin; it has been used in a large number of patients with β-thalassemia and
a smaller number of patients with sickle cell anemia. Early in the course of
disease, before end-organ damage occurs, transplantation is curative in 80–90% of
patients. In highly experienced centers, the treatment-related mortality is <10%.
Since survival into adult life is possible with conventional therapy, the decision to
transplant is best made in consultation with specialized centers.
Gene therapy of thalassemia and sickle cell disease has proved to be an
elusive goal. Uptake of gene vectors into the nondividing hematopoietic stem cells
has been inefficient. Lentiviral-type vectors that can transduce nondividing cells
may solve this problem.
Reestablishing high levels of fetal hemoglobin synthesis should ameliorate
the symptoms of β-thalassemia. Cytotoxic agents such as hydroxyurea and
cytarabine promote high levels of HbF synthesis, probably by stimulating
proliferation of the primitive HbF-producing progenitor cell population (i.e., F cell
progenitors). Unfortunately, no regimen has yet been identified that ameliorates
the clinical manifestations of β-thalassemia. Butyrates stimulate HbF production,
but only transiently. Pulsed or intermittent administration has been found to

sustain HbF induction in the majority of patients with sickle cell disease. It is
unclear whether butyrates will have similar activity in patients with β-thalassemia.
Aplastic and Hypoplastic Crisis in Patients with Hemoglobinopathies
Patients with hemolytic anemias sometimes exhibit an alarming decline in
hematocrit during and immediately after acute illnesses. Bone marrow suppression
occurs in almost everyone during acute inflammatory illnesses. In patients with
short RBC life spans, suppression can affect RBC counts more dramatically.
These hypoplastic crises are usually transient and self-correcting before
intervention is required.
Aplastic crisis refers to a profound cessation of erythroid activity in patients
with chronic hemolytic anemias. It is associated with a rapidly falling hematocrit.
Episodes are usually self-limited. Aplastic crises are caused by infection with a
particular strain of parvovirus, B19A. Children infected with this virus usually
develop permanent immunity. Aplastic crises do not often recur and are rarely
seen in adults. Management requires close monitoring of the hematocrit and
reticulocyte count. If anemia becomes symptomatic, transfusion support is
indicated. Most crises resolve spontaneously within 1–2 weeks.
Further Readings
Ataga KI, Orringa EP: Hypercoagulability in sickle
cell disease: A curious
paradox. Am J Med 115:721, 2003 [PMID: 14693325]
DeSimone J et al: Maintenance of elevated fetal hemoglobin levels by
decitabine during dose interval treatment of sickle cell anemia. Blood 99:3905,
2002 [PMID: 12010787]
Neufeld
EJ: Oral chelators deferasirox and deferiprone for transfusional
iron overload in thalassemia major: New data, new questions. Blood 107:3436,
2006 [PMID: 16627763]
Quek L, Thein SL: Molecular therapies in beta-
thalassaemia. Br J Haematol

136:353, 2007 [PMID: 17129232]
Steinberg MH: Pathophysiologically based drug treatment of sickle cell
disease. Trends Pharmacol Sci 27:204, 2006 [PMID: 16530854]
Switzer JA et al: Pathophysiology and treatment of stroke in sickle-
cell
disease: Present and future. Lancet Neurol 5:501, 2006 [PMID: 16713922]
Ware RE et al: Predictors of fetal hemoglobin response in children with
sickle cell anemia receiving hydroxyurea therapy. Blood 99:10, 2002 [PMID:
11756146]
Bibliography
Benz EJ: Hemoglobin variants associated with hemolytic anemia, altered
oxygen affinity, and methemoglobinemias, in
Hematology: Basic Principles and
Practice
, 3d ed, R Hoffman et al (eds). New York, Churchill Livingstone, 2000,
pp 554–561
Clasta S, Vichin
sky EP: Managing sickle cell disease. BMJ 327:1151,
2003
Embury SH, Vichinsky EP: Sickle cell disease, in
Hematology: Basic
Principles and Practice
, 3d ed, R Hoffman et al (eds). New York, Churchill
Livingstone, 2000, pp 510–554
Forget BG: Thalassemia syndromes, in
Hematology: Basic Principles and
Practice
, 3d ed, R Hoffman et al (eds). New York, Churchill Livingstone, 2000,
pp 485–510
Steinberg MH, Benz EJ Jr: Pathobiology of the human erythrocyte and its

hemoglobins, in Hematology: Basic Principles and Practice
, 3d ed, R Hoffman et
al (eds). New York, Churchill Livingstone, 2000, pp 356–367