Hemoglobinopathies

HEMOGLOBINOPATHIESHEMOGLOBINOPATHIES
Presenter: Dr.Jeetendra K. SinghPresenter: Dr.Jeetendra K. Singh
Guide: Dr. Santosh SinghGuide: Dr. Santosh Singh

IntroductionIntroduction
Hemoglobinopathies are disordersHemoglobinopathies are disorders
affecting the structure, function, oraffecting the structure, function, or
production of hemoglobin.production of hemoglobin.
22

HemoglobinHemoglobin
 Normal hemoglobins are tetramers ofNormal hemoglobins are tetramers of
twotwo αα-like and two-like and two ββ-like globin-like globin
polypeptide chains.polypeptide chains.
 αα-like: 141 amino acids-like: 141 amino acids
 ββ-like: 146 amino acids-like: 146 amino acids
33

 αα-like genes are located near the-like genes are located near the
telomere of the short arm oftelomere of the short arm of
chromosome 16 (16p13.3).chromosome 16 (16p13.3).
 ββ-like genes are located on-like genes are located on
chromosome 11 (11p15.5).chromosome 11 (11p15.5).
 Their control is complex, including anTheir control is complex, including an
upstream locus control region onupstream locus control region on
each respective chromosome and aneach respective chromosome and an
X-linked control site.X-linked control site.
44

 On chromosome 16, there are 3On chromosome 16, there are 3
genes within the α gene cluster,genes within the α gene cluster,
namely zeta (ζ), alpha 1 (α1), andnamely zeta (ζ), alpha 1 (α1), and
alpha 2 (α2).alpha 2 (α2).
 On chromosome 11, there are 5On chromosome 11, there are 5
genes within the beta gene cluster,genes within the beta gene cluster,
namely epsilon (namely epsilon (ε), 2ε), 2 gamma genesgamma genes
((γ),γ), aa delta gene (δ), and a betadelta gene (δ), and a beta
gene (β).gene (β).
66

 DuplicatedDuplicated αα1 and1 and αα2 genes encode2 genes encode
identical polypeptides.identical polypeptides.
 FetalFetal γγ genes are duplicated (Ggenes are duplicated (Gγγ,A,Aγγ))
but encode globins differing only atbut encode globins differing only at
AA 136.AA 136.
77

 Pseudogenes: Although resemble thePseudogenes: Although resemble the
functional genes, sequencefunctional genes, sequence
difference in coding or criticaldifference in coding or critical
regulatory regions render theseregulatory regions render these
genes inactive.genes inactive.
88

 After 8 wk of fetal life the embryonicAfter 8 wk of fetal life the embryonic
hemoglobins, Gower-1 (hemoglobins, Gower-1 (ζ2ε2),ζ2ε2), Gower-2Gower-2
((α2ε2),α2ε2), and Portland (ζ2γ2), are formed.and Portland (ζ2γ2), are formed.
 At 9 wk of fetal life, the major hemoglobinAt 9 wk of fetal life, the major hemoglobin
is Hb F (α2γ2).is Hb F (α2γ2).
 Hb A (α2β2) appears at ~1 mo of fetal lifeHb A (α2β2) appears at ~1 mo of fetal life
but does not become the dominantbut does not become the dominant
hemoglobin until after birth, when Hb Fhemoglobin until after birth, when Hb F
levels start to decline.levels start to decline.
99

 Predominant(major ) adult Hb: HbA(Predominant(major ) adult Hb: HbA(αα22ββ2)2)
(≥95%)(≥95%)
 Minor adult Hb: HbA2 (Minor adult Hb: HbA2 (αα22δδ2)2)
(≤3.5%)(≤3.5%)
 HbF (HbF (αα22γγ2) predominates during most of2) predominates during most of
the gestation. HbF constitutes a smallthe gestation. HbF constitutes a small
fraction of the total Hb in adult red cellsfraction of the total Hb in adult red cells
(0.3-1.2%) in which it is largely restricted(0.3-1.2%) in which it is largely restricted
to a small subset of circulating RBCs (0.2-to a small subset of circulating RBCs (0.2-
7%) referred to as F cells.7%) referred to as F cells.
1010

Sites of erythropoiesis and pattern of globinSites of erythropoiesis and pattern of globin
biosynthesis during developmentbiosynthesis during development
1111

 Each globin chain enfolds a singleEach globin chain enfolds a single
heme moiety, consisting of aheme moiety, consisting of a
protoporphyrin IX ring complexedprotoporphyrin IX ring complexed
with a single iron atom in the ferrouswith a single iron atom in the ferrous
state (Festate (Fe2+2+
).).
 Each heme moiety can bind a singleEach heme moiety can bind a single
oxygen molecule; a molecule ofoxygen molecule; a molecule of
hemoglobin can transport up to fourhemoglobin can transport up to four
oxygen molecules.oxygen molecules.
1313

 Iron is coordinated to four pyrrole nitrogens ofIron is coordinated to four pyrrole nitrogens of
protoporphyrin IX, and to an imidazole nitrogenprotoporphyrin IX, and to an imidazole nitrogen
of a histidine residue from the globin side of theof a histidine residue from the globin side of the
porphyrin. The sixth coordination position isporphyrin. The sixth coordination position is
available for binding withavailable for binding with oxygenoxygen and otherand other
small molecules.small molecules.
1414

 The amino acid sequences of theThe amino acid sequences of the
various globins are highlyvarious globins are highly
homologous to one another.homologous to one another.
 Each has a highly helicalEach has a highly helical secondarysecondary
structurestructure..
 The D helix ofThe D helix of ββ subunit is requiredsubunit is required
for retention of heme.for retention of heme.
 ΑΑ subunit lacks D helix because ofsubunit lacks D helix because of
deletion of five consecutive residues.deletion of five consecutive residues.
1515

 Their globularTheir globular tertiary structurestertiary structures
cause the exterior surfaces to be richcause the exterior surfaces to be rich
in polar (hydrophilic) amino acidsin polar (hydrophilic) amino acids
that enhance solubility, and thethat enhance solubility, and the
interior to be lined with nonpolarinterior to be lined with nonpolar
groups, forming a hydrophobicgroups, forming a hydrophobic
pocket into which heme is inserted.pocket into which heme is inserted.
1616

 The tetramericThe tetrameric quaternary structurequaternary structure
of HbA contains two dimers.of HbA contains two dimers.
 Numerous tight interactions (i.e.,Numerous tight interactions (i.e., αα11ββ11
contacts) hold the and chainscontacts) hold the and chains
together. The complete tetramer istogether. The complete tetramer is
held together by interfaces (i.e.,held together by interfaces (i.e., αα11ββ22
contacts) between the -like chain ofcontacts) between the -like chain of
one dimer and the non- chain of theone dimer and the non- chain of the
other dimer.other dimer.
1717

α1 β1
β2 α2
Packing
contact
Sliding contact
1818

 The hemoglobin tetramer is highlyThe hemoglobin tetramer is highly
soluble but individual globin chainssoluble but individual globin chains
are insoluble.are insoluble.
 Unpaired globin precipitates, formingUnpaired globin precipitates, forming
inclusions that damage the cell.inclusions that damage the cell.
 Normal globin chain synthesis isNormal globin chain synthesis is
balanced so that each newlybalanced so that each newly
synthesized or non-globin chain willsynthesized or non-globin chain will
have an available partner with whichhave an available partner with which
to pair.to pair. 1919

Classification of HbPathiesClassification of HbPathies
I. Structural hemoglobinopathies—hemoglobins withI. Structural hemoglobinopathies—hemoglobins with
altered amino acid sequences that result in derangedaltered amino acid sequences that result in deranged
function or altered physical or chemical propertiesfunction or altered physical or chemical properties
A. Abnormal hemoglobin polymerization—HbS,A. Abnormal hemoglobin polymerization—HbS,
hemoglobin sicklinghemoglobin sickling
B. Altered O2 affinityB. Altered O2 affinity
1. High affinity—polycythemia1. High affinity—polycythemia
2. Low affinity—cyanosis, pseudoanemia2. Low affinity—cyanosis, pseudoanemia
C. Hemoglobins that oxidize readilyC. Hemoglobins that oxidize readily
1. Unstable hemoglobins—hemolytic anemia,1. Unstable hemoglobins—hemolytic anemia,
jaundicejaundice
2. M hemoglobins—methemoglobinemia, cyanosis2. M hemoglobins—methemoglobinemia, cyanosis
2020

II. Thalassemias—defectiveII. Thalassemias—defective
biosynthesis of globin chainsbiosynthesis of globin chains
A.A. αα ThalassemiasThalassemias
B.B. ββ ThalassemiasThalassemias
C.C. δβδβ,, γδβγδβ,, αβαβ ThalassemiasThalassemias
2121

III. Thalassemic hemoglobin variants—III. Thalassemic hemoglobin variants—
structurally abnormal Hb associatedstructurally abnormal Hb associated
with co-inherited thalassemicwith co-inherited thalassemic
phenotypephenotype
A. HbEA. HbE
B. Hb Constant SpringB. Hb Constant Spring
C. Hb LeporeC. Hb Lepore
IV. Hereditary persistence of fetalIV. Hereditary persistence of fetal
hemoglobin—persistence of highhemoglobin—persistence of high
levels of HbF into adult lifelevels of HbF into adult life
2222

V. Acquired hemoglobinopathiesV. Acquired hemoglobinopathies
A. Methemoglobin due to toxicA. Methemoglobin due to toxic
exposuresexposures
B. Sulfhemoglobin due to toxicB. Sulfhemoglobin due to toxic
exposuresexposures
C. CarboxyhemoglobinC. Carboxyhemoglobin
D. HbH in erythroleukemiaD. HbH in erythroleukemia
E. Elevated HbF in states ofE. Elevated HbF in states of
erythroid stress and bone marrowerythroid stress and bone marrow
dysplasiadysplasia
2323

CC
2424
SI KLE CELL DISEASESI KLE CELL DISEASE

 HbSHbS ((αα22ββ22
6 Glu Va16 Glu Va1
)) is the result of ais the result of a
single base-pair change, thymine forsingle base-pair change, thymine for
adenine, at the sixth codon of theadenine, at the sixth codon of the ββ
globin gene.globin gene.
 This change encodes valine insteadThis change encodes valine instead
of glutamic acid in the sixth positionof glutamic acid in the sixth position
in the β globin molecule.in the β globin molecule.
2525

 Sickle cell anemia, homozygous HbSickle cell anemia, homozygous Hb
S, occurs when both β globin genesS, occurs when both β globin genes
have the sickle cell mutation.have the sickle cell mutation.
2626

 Sickle cell disease refers to not only patientsSickle cell disease refers to not only patients
with sickle cell anemia but also to compoundwith sickle cell anemia but also to compound
heterozygotes where one β globin geneheterozygotes where one β globin gene
mutation includes the sickle cell mutationmutation includes the sickle cell mutation
and the second β globin allele includes aand the second β globin allele includes a
gene mutation other than the sickle cellgene mutation other than the sickle cell
mutation, such as mutations associated withmutation, such as mutations associated with
Hb C, Hb SHb C, Hb S β-thalassemia, Hb D, and Hb Oβ-thalassemia, Hb D, and Hb O
Arab.Arab.
2727

 In sickle cell anemia, HbIn sickle cell anemia, HbS isS is
commonly as high as 90% of thecommonly as high as 90% of the
total hemoglobin.total hemoglobin.
 In sickle cell disease, Hb S is >50%In sickle cell disease, Hb S is >50%
of all hemoglobin.of all hemoglobin.
2828

Sickle HemoglobinopathiesSickle Hemoglobinopathies
Condition Hemoglobin Level
g/L (g/dL)
MCV, fL Hemoglobin
Electrophoresis
Sickle cell trait Normal Normal Hb S/A:40/60
Sickle cell anemia 70–100 (7–10) 80–100 Hb S/A:100/0
Hb F:2–25%
S/β° thalassemia 70–100 (7–10) 60–80 Hb S/A:100/0
Hb F:1–10%
S/β+ thalassemia 100–140 (10–14) 70–80 Hb S/A:60/40
Hemoglobin SC 100–140 (10–14) 80–100 Hb S/A:50/0
Hb C:50%
2929

PathophysiologyPathophysiology
of Sickle Cell Anemiaof Sickle Cell Anemia
 SS cells may look normal when fully oxygenated;SS cells may look normal when fully oxygenated;
Sickling occurs when OSickling occurs when O22 decreased.decreased.
 Other causes of sickling include decrease in pHOther causes of sickling include decrease in pH
and dehydration of patient.and dehydration of patient.
 Cells become rigid, impeding blood flow toCells become rigid, impeding blood flow to
tissues. Tissue death, organ infarction, and paintissues. Tissue death, organ infarction, and pain
result.result.
 Sickling is reversible up to a point.Sickling is reversible up to a point.
 Have both extravascular hemolysis andHave both extravascular hemolysis and
intravascular hemolysis.intravascular hemolysis.

Pathophysiology of Sickle Cell AnemiaPathophysiology of Sickle Cell Anemia
 Have three types ofHave three types of
crises:crises:
– Aplastic crisisAplastic crisis: associated: associated
with infections which causeswith infections which causes
temporary suppression oftemporary suppression of
erythropoiesis.erythropoiesis.
– Hemolytic crisisHemolytic crisis: Results in: Results in
exaggerated anemia.exaggerated anemia.
– Vaso-occlusive crisisVaso-occlusive crisis::
Associated with severe pain.Associated with severe pain.
Hallmark symptom of sickle cellHallmark symptom of sickle cell
anemia.anemia.

Clinical ManifestationsClinical Manifestations
 Infants with sickle cell anemia haveInfants with sickle cell anemia have
abnormal immune function and, asabnormal immune function and, as
early as 6 mo of age, may haveearly as 6 mo of age, may have
functional asplenia.functional asplenia.
 Bacterial sepsis is one of the greatestBacterial sepsis is one of the greatest
causes for morbidity and mortality incauses for morbidity and mortality in
this patient population.this patient population.
 By 5 yr of age, most children withBy 5 yr of age, most children with
sickle cell anemia havesickle cell anemia have functionalfunctional
aspleniaasplenia.. 3333

 Regardless of age, all patients withRegardless of age, all patients with
sickle cell anemia are at increasedsickle cell anemia are at increased
risk of infection and death fromrisk of infection and death from
bacterial infection, particularlybacterial infection, particularly
encapsulated organisms such asencapsulated organisms such as
Streptococcus pneumoniaeStreptococcus pneumoniae andand
Haemophilus influenzae type b.Haemophilus influenzae type b.
3434

 Children with sickle cell anemia shouldChildren with sickle cell anemia should
receivereceive prophylactic oral penicillin VKprophylactic oral penicillin VK
until at least 5 yr of age (125 mg twice auntil at least 5 yr of age (125 mg twice a
day up to age 3 yr, and then 250 mg twiceday up to age 3 yr, and then 250 mg twice
a day).a day).
 Continuation of penicillin prophylaxisContinuation of penicillin prophylaxis
should be considered for children beyond 5should be considered for children beyond 5
yr of age with previous diagnosis ofyr of age with previous diagnosis of
pneumococcal infection, due to thepneumococcal infection, due to the
increased risk of a recurrent infection.increased risk of a recurrent infection.
3535

 An alternative for children who areAn alternative for children who are
allergic to penicillin isallergic to penicillin is erythromycinerythromycin
ethyl succinateethyl succinate 10 mg/kg twice a10 mg/kg twice a
day.day.
 In addition to penicillin prophylaxis,In addition to penicillin prophylaxis,
routine childhood immunizations asroutine childhood immunizations as
well as the annual administration ofwell as the annual administration of
influenza vaccine are highlyinfluenza vaccine are highly
recommended.recommended.
3636

 Human parvovirus B19:Human parvovirus B19: Any childAny child
withwith reticulocytopeniareticulocytopenia should beshould be
considered to have parvovirus B19considered to have parvovirus B19
until proved otherwise.until proved otherwise.
 Acute infection with parvovirus B19Acute infection with parvovirus B19
is associated with red cell aplasiais associated with red cell aplasia
(aplastic crisis), fever, pain, splenic(aplastic crisis), fever, pain, splenic
sequestration, acute chest syndromesequestration, acute chest syndrome
(ACS), glomerulonephritis, and(ACS), glomerulonephritis, and
strokes.strokes. 3737

Fever:Fever:
 Medical emergency.Medical emergency.
 Admission(risk factors) vs OPDAdmission(risk factors) vs OPD
treatment with 3treatment with 3rdrd
generationgeneration
cephalosprin.cephalosprin.
 Positive blood culture <20 hr.Positive blood culture <20 hr.
 Admit for 24 hr if no communication/Admit for 24 hr if no communication/
inadequate follow-up.inadequate follow-up.
3838

CLINICAL FACTORS ASSOCIATED WITH INCREASED RISK
OF BACTEREMIA REQUIRING ADMISSION IN FEBRILE
CHILDREN WITH SICKLE CELL DISEASE
Seriously ill appearance
Hypotension: systolic BP <70 mm Hg at 1 year of age or <70
mm Hg + 2 × the age in yr for older children
Poor perfusion: capillary-refill time >4 sec
Temperature >40.0°C
A corrected white-cell count >30,000/mm3 or <500/mm3
Platelet count <100,000/mm3
History of pneumococcal sepsis
Severe pain
Dehydration: poor skin turgor, dry mucous membranes, history
of poor fluid
intake, or decreased output of urine
Infiltration of a segment or a larger portion of the lung
Hb <5.0 g/dL 3939

Dactylitis (Hand-foot syndrome):Dactylitis (Hand-foot syndrome):
 First manifestation of pain in childrenFirst manifestation of pain in children
with sickle cell anemia.with sickle cell anemia.
 Occurs in 50% of children by 2Occurs in 50% of children by 2ndnd
year.year.
 Symmetric or unilateral swelling ofSymmetric or unilateral swelling of
the hands and/or feet.the hands and/or feet.
 Palliation with pain medications, suchPalliation with pain medications, such
as acetaminophen with codeine.as acetaminophen with codeine.
4040

4141
Roentgenograms of an infant with sickle cell anemia and acute dactylitis.
A, The bones appear normal at the onset of the episode.
B, Destructive changes and periosteal reaction are evident 2 wk later.

Splenic Sequestration:Splenic Sequestration:
 Acute splenic sequestration is a life-Acute splenic sequestration is a life-
threatening complication occurringthreatening complication occurring
primarily in infants and can occur asprimarily in infants and can occur as
early as 5 wk of age.early as 5 wk of age.
 Approximately 30% of children withApproximately 30% of children with
sickle cell anemia have a severesickle cell anemia have a severe
splenic sequestration episode, and asplenic sequestration episode, and a
significant percentage of thesesignificant percentage of these
episodes are fatal.episodes are fatal. 4242

 Engorgement of the spleen,Engorgement of the spleen,
subsequent increase in spleen size,subsequent increase in spleen size,
 Evidence of hypovolemia, and declineEvidence of hypovolemia, and decline
in hemoglobin of ≥2 g/dL from thein hemoglobin of ≥2 g/dL from the
patient’s baseline hemoglobin;patient’s baseline hemoglobin;
 Reticulocytosis and a decrease in theReticulocytosis and a decrease in the
platelet count may be present.platelet count may be present.
 Accompanied by URI, bacteremia, orAccompanied by URI, bacteremia, or
viral infection.viral infection.
4343

 Treatment:Treatment: maintenance of hemodynamicmaintenance of hemodynamic
stability using isotonic fluid or bloodstability using isotonic fluid or blood
transfusions.transfusions.
 If blood is required, typically 5 mL/ kg ofIf blood is required, typically 5 mL/ kg of
PRBCs is given.PRBCs is given.
 Recurrence in ~50% of patients, mostlyRecurrence in ~50% of patients, mostly
within 6 mo of the previous episode.within 6 mo of the previous episode.
 Prophylactic splenectomy after resolutionProphylactic splenectomy after resolution
of an acute episode is the only effectiveof an acute episode is the only effective
strategy for preventing future life-strategy for preventing future life-
threatening episodes.threatening episodes. 4444

Pain:Pain:
 Cardinal clinical featureCardinal clinical feature
 Unremitting discomfort that canUnremitting discomfort that can
occur in any part of body, most oftenoccur in any part of body, most often
in chest, abdomen, or extremities.in chest, abdomen, or extremities.
 Abrupt, cause disruption of daily lifeAbrupt, cause disruption of daily life
activities.activities.
 The only measure for pain is theThe only measure for pain is the
patient.patient.
4545

 Pathogenesis is initiated when bloodPathogenesis is initiated when blood
flow is disrupted in theflow is disrupted in the
microvasculature by sickle cells,microvasculature by sickle cells,
resulting in tissue ischemia.resulting in tissue ischemia.
 Precipitating causes of painfulPrecipitating causes of painful
episodes can include physical stress,episodes can include physical stress,
infection, dehydration, hypoxia, localinfection, dehydration, hypoxia, local
or systemic acidosis, exposure toor systemic acidosis, exposure to
cold, and swimming for prolongedcold, and swimming for prolonged
periods.periods. 4646

 The majority of painful episodes inThe majority of painful episodes in
patients with sickle cell anemia arepatients with sickle cell anemia are
managed at home with comfortmanaged at home with comfort
measures, such as heating blanket,measures, such as heating blanket,
relaxation techniques, massage, andrelaxation techniques, massage, and
pain medication.pain medication.
 A patient with sickle cell anemia hasA patient with sickle cell anemia has
~1 painful episode per year that~1 painful episode per year that
requires medical attention.requires medical attention.
4747

 Specific therapy for pain variesSpecific therapy for pain varies
greatly but generally includes thegreatly but generally includes the
use of acetaminophen or ause of acetaminophen or a
nonsteroidal agent early in thenonsteroidal agent early in the
course of pain, followed by escalationcourse of pain, followed by escalation
to acetaminophen with codeine or ato acetaminophen with codeine or a
short- or long-acting oral opioid.short- or long-acting oral opioid.
 Some patients require IV morphine.Some patients require IV morphine.
4848

Myths about pain management in sickle cellMyths about pain management in sickle cell
anemia:anemia:
 Painful episodes in children should bePainful episodes in children should be
managed without opioids.managed without opioids.
 Blood transfusion therapy during anBlood transfusion therapy during an
existing painful episode decreases theexisting painful episode decreases the
intensity or duration of the painfulintensity or duration of the painful
episode.episode.
 IV hydration relieves or prevents pain.IV hydration relieves or prevents pain.
4949

 HydroxyureaHydroxyurea, a myelosuppressive, a myelosuppressive
agent, is the only effective drugagent, is the only effective drug
proved to reduce the frequency ofproved to reduce the frequency of
painful episodes.painful episodes.
 Given the short-term safety profile inGiven the short-term safety profile in
children and the established efficacychildren and the established efficacy
in adults, hydroxyurea is commonlyin adults, hydroxyurea is commonly
used in children with multiple painfulused in children with multiple painful
episodes.episodes.
5050

 The long-term toxicity associatedThe long-term toxicity associated
with hydroxyurea in children has notwith hydroxyurea in children has not
been established, but all evidence tobeen established, but all evidence to
date suggests that the benefits fardate suggests that the benefits far
outweigh the risks.outweigh the risks.
 Well-informed parents and medicalWell-informed parents and medical
care by pediatric hematologists or atcare by pediatric hematologists or at
least comanagement by a physicianleast comanagement by a physician
with expertise in managingwith expertise in managing
chemotherapychemotherapy 5151

 The typical starting dose of hydroxyurea isThe typical starting dose of hydroxyurea is
15-20 mg/kg daily, with an incremental15-20 mg/kg daily, with an incremental
dosage increase every 8 wk of 2.5-5.0dosage increase every 8 wk of 2.5-5.0
mg/kg, if no toxicities occur, up to amg/kg, if no toxicities occur, up to a
maximum of 35 mg/kg per dose.maximum of 35 mg/kg per dose.
 Achievement of the therapeutic effect ofAchievement of the therapeutic effect of
hydroxyurea can require several months.hydroxyurea can require several months.
 Monitor every 2 wk for hematologicMonitor every 2 wk for hematologic
toxicity with dose escalations and thentoxicity with dose escalations and then
monthly after a therapeutic dose has beenmonthly after a therapeutic dose has been
identified.identified.
5252

Priapism:Priapism:
 Involuntary penile erection lastingInvoluntary penile erection lasting
for longer than 30 minutes.for longer than 30 minutes.
 The ventral portion and the glans ofThe ventral portion and the glans of
the penis are typically not involved.the penis are typically not involved.
 Stuttering & Refractory priapismStuttering & Refractory priapism
5353

 Approximately 20% of patients between 5Approximately 20% of patients between 5
and 20 yr of age report having at least 1and 20 yr of age report having at least 1
episode of priapism.episode of priapism.
 Most episodes occur between 3 am and 9Most episodes occur between 3 am and 9
am.am.
 The mean age at first episode is 12 yr,The mean age at first episode is 12 yr,
and the mean number of episodes perand the mean number of episodes per
patient is ~16, with a mean duration of ~2patient is ~16, with a mean duration of ~2
hr.hr.
 The actuarial probability of a patient’sThe actuarial probability of a patient’s
experiencing priapism is ~90% by 20 yr ofexperiencing priapism is ~90% by 20 yr of
age.age. 5454

 Acute treatment- Sitz bath or painAcute treatment- Sitz bath or pain
medication.medication.
 Priapism lasting >4 hr should bePriapism lasting >4 hr should be
treated by aspiration of blood fromtreated by aspiration of blood from
the corpora cavernosa followed bythe corpora cavernosa followed by
irrigation with dilute epinephrine toirrigation with dilute epinephrine to
produce immediate and sustainedproduce immediate and sustained
detumescence.detumescence.
 Preventive therapy- Hydroxyurea,Preventive therapy- Hydroxyurea,
EtilefrineEtilefrine
5555

Neurologic Complications:Neurologic Complications:
 Before the age of 18 yr, 11% childrenBefore the age of 18 yr, 11% children
have overt strokes and 20% children havehave overt strokes and 20% children have
silent strokes.silent strokes.
 Overt stroke is the presence of a focalOvert stroke is the presence of a focal
neurologic deficit that lasts for >24 hrneurologic deficit that lasts for >24 hr
and/or increased signal intensity with aand/or increased signal intensity with a
T2-weighted MRI of the brain indicating aT2-weighted MRI of the brain indicating a
cerebral infarct, corresponding to the focalcerebral infarct, corresponding to the focal
neurologic deficit.neurologic deficit.
5656

 Silent cerebral infarct is the absence of a focalSilent cerebral infarct is the absence of a focal
neurologic deficit lasting >24 hr in the presenceneurologic deficit lasting >24 hr in the presence
of a lesion on T2-weighted MRI indicating aof a lesion on T2-weighted MRI indicating a
cerebral infarct.cerebral infarct.
 Management- O2 to keep SpO2 >96%,Management- O2 to keep SpO2 >96%, bloodblood
transfusion within 1 hr of presentation with a goaltransfusion within 1 hr of presentation with a goal
of increasing the Hb to a maximum of 10of increasing the Hb to a maximum of 10
g/dL.g/dL.
 Subsequently, prompt treatment with anSubsequently, prompt treatment with an
exchange transfusion should be considered,exchange transfusion should be considered,
either manually or with erythrocytapheresis, toeither manually or with erythrocytapheresis, to
reduce the Hb S percentage to at least <50% andreduce the Hb S percentage to at least <50% and
ideally <30%.ideally <30%. 5757

Excessive Iron Stores:Excessive Iron Stores:
 Gold standard- liver biopsyGold standard- liver biopsy
 Serum ferritinSerum ferritin
 MRI- iron content in liver and heart.MRI- iron content in liver and heart.
 3 types of BT therapy-3 types of BT therapy-
– Erythrocytapheresis(minimum net ironErythrocytapheresis(minimum net iron
balance)balance)
– Manual exchange transfusionManual exchange transfusion
– Simple transfusion(highest net positiveSimple transfusion(highest net positive
iron balance)iron balance)
5959

Lung Disease:Lung Disease:
 22ndnd
MC reason for hospitalization.MC reason for hospitalization.
 ACS (Acute Chest Syndrome)-ACS (Acute Chest Syndrome)-
Constellation of findings that includeConstellation of findings that include
a new radiodensity on CXR, fever,a new radiodensity on CXR, fever,
RD, and pain that occurs often in theRD, and pain that occurs often in the
chest, but it can also include thechest, but it can also include the
back and/or abdomen only.back and/or abdomen only.
 All patients with fever shouldAll patients with fever should
receive a CXR.receive a CXR.
6060

 Predominantly left lower lobe or bothPredominantly left lower lobe or both
lower lobe and pleural effusions (UL orlower lobe and pleural effusions (UL or
BL).BL).
 Treatment- O2 supplementation if SpO2Treatment- O2 supplementation if SpO2
<90%.<90%.
 BT- simple or exchange- indications:BT- simple or exchange- indications:
decreasing oxygen saturation, increasedecreasing oxygen saturation, increase
work of breathing, rapid change inwork of breathing, rapid change in
respiratory effort either with or without arespiratory effort either with or without a
worsening chest radiograph, or previousworsening chest radiograph, or previous
history of severe ACS requiring admissionhistory of severe ACS requiring admission
to the intensive care unit.to the intensive care unit.
6161

 Empirical antibiotics (cephalosporin andEmpirical antibiotics (cephalosporin and
macrolide-MC pathogens: Smacrolide-MC pathogens: Streptococcustreptococcus
pneumoniae, Mycoplasma pneumoniae,pneumoniae, Mycoplasma pneumoniae,
and Chlamydia spp.and Chlamydia spp.))
 Continued respiratory therapy (incentiveContinued respiratory therapy (incentive
spirometry and chest physiotherapy asspirometry and chest physiotherapy as
necessary)necessary)
 Bronchodilators and steroids for patientsBronchodilators and steroids for patients
with asthmawith asthma
 Optimum pain control and fluidOptimum pain control and fluid
managementmanagement 6262

 The most common illness preceding ACS isThe most common illness preceding ACS is
a painful episode requiring opioids.a painful episode requiring opioids.
 Risk of ACSRisk of ACS
– morphine>nalbuphine hydrochloride,morphine>nalbuphine hydrochloride,
– oral opiod>IV opioid).oral opiod>IV opioid).
 Under no circumstance should opioidUnder no circumstance should opioid
administration be limited in order toadministration be limited in order to
prevent ACS.prevent ACS.
6363

Kidney Disease:Kidney Disease:
1.1. Gross hematuria,Gross hematuria,
2.2. Papillary necrosis,Papillary necrosis,
3.3. Nephrotic syndrome, renalNephrotic syndrome, renal
4.4. Infarction,Infarction,
5.5. Hyposthenuria,Hyposthenuria,
6.6. Pyelonephritis, andPyelonephritis, and
7.7. Renal medullary carcinomaRenal medullary carcinoma
6464

 Cognitive and psychological problemsCognitive and psychological problems
 Sickle cell retinopathySickle cell retinopathy
 Delayed onset of pubertyDelayed onset of puberty
 Avascular necrosis of femoral andAvascular necrosis of femoral and
humeral headshumeral heads
 Leg ulcersLeg ulcers
6565

SICKLE CELL TRAITSICKLE CELL TRAIT
 HbS <50%, HbA >50%HbS <50%, HbA >50%
 Normal life span with very rareNormal life span with very rare
complications.complications.
 Complications include sudden deathComplications include sudden death
during exercise, splenic infarcts atduring exercise, splenic infarcts at
high altitude, hematuria,high altitude, hematuria,
hyposthenuria, bacteriuria, renalhyposthenuria, bacteriuria, renal
medullary carcinoma.medullary carcinoma.
 No restriction on activities.No restriction on activities.
6666

THALASSEMIA SYNDROMESTHALASSEMIA SYNDROMES
6767

 Syndromes arising form decreasedSyndromes arising form decreased
rate or absence of globin chainrate or absence of globin chain
synthesis.synthesis.
6868

ββ-Thalassemia-Thalassemia
 ββ thalassemias are autosomal inheritedthalassemias are autosomal inherited
disorders ofdisorders of ββ globin synthesis.globin synthesis.
 In most, globin structure is normal but theIn most, globin structure is normal but the
rate of production is reduced because ofrate of production is reduced because of
decrease in transcription of DNA,decrease in transcription of DNA,
abnormal processing of pre-mRNA, orabnormal processing of pre-mRNA, or
decreased translation of mRNA leading todecreased translation of mRNA leading to
decreased Hb-A production (A=Adult).decreased Hb-A production (A=Adult).
6969

PathophysiologyPathophysiology
 In the bone marrow, thalassemia mutationsIn the bone marrow, thalassemia mutations
disrupt the maturation of erythrocytes, resultingdisrupt the maturation of erythrocytes, resulting
in ineffective erythropoiesis; the marrow isin ineffective erythropoiesis; the marrow is
hyperactive, but there are relatively fewhyperactive, but there are relatively few
reticulocytes and severe anemia exists.reticulocytes and severe anemia exists.
 In β-thalassemia, there is an excess of α-globinIn β-thalassemia, there is an excess of α-globin
chains relative to β and γ-globin chains, and α-chains relative to β and γ-globin chains, and α-
globin tetramers (α4) are formed. Theseglobin tetramers (α4) are formed. These
inclusions interact with the red cell membraneinclusions interact with the red cell membrane
and shorten red cell survival, leading to anemiaand shorten red cell survival, leading to anemia
and increased erythroid production.and increased erythroid production.
 The γ-globin chains are produced in increasedThe γ-globin chains are produced in increased
amounts, leading to an elevated Hb F (amounts, leading to an elevated Hb F (α2γ2).α2γ2).
7070

Classical Clinical Syndromes of β
Thalassemia; β thalassemia can be
presented as:
o Silent carrier state – mildest form of β thal.
ο β thalassemia minor - heterozygous disorder
resulting in mild hypochromic, microcytic
hemolytic anemia.
ο β thalassemia intermedia - Severity lies
between the minor and major.
ο β thalassemia major - homozygous disorder
resulting in severe life long transfusion-
dependent hemolytic anemia.

Thalaseemia MajorThalaseemia Major
Clinical manifestations:Clinical manifestations:
 Progressive hemolytic anemia, withProgressive hemolytic anemia, with
profound weakness and cardiacprofound weakness and cardiac
decompensation during the 2nd 6 modecompensation during the 2nd 6 mo
of life.of life.
 Most infants and children haveMost infants and children have
cardiac decompensation atcardiac decompensation at
hemoglobins of 4 g/dL or less.hemoglobins of 4 g/dL or less.
7272

 Generally, fatigue, poor appetite, and lethargyGenerally, fatigue, poor appetite, and lethargy
are late findings of severe anemia in an infant orare late findings of severe anemia in an infant or
Child .Child .
 The classic presentation of children with severeThe classic presentation of children with severe
disease includes thalassemic facies (maxilladisease includes thalassemic facies (maxilla
hyperplasia, flat nasal bridge, frontal bossing),hyperplasia, flat nasal bridge, frontal bossing),
pathologic bone fractures, markedpathologic bone fractures, marked
hepatosplenomegaly, and cachexia.hepatosplenomegaly, and cachexia.
 The spleen can become so enlarged that it causesThe spleen can become so enlarged that it causes
mechanical discomfort and secondarymechanical discomfort and secondary
hypersplenism.hypersplenism.
7373

 The features of ineffective erythropoiesisThe features of ineffective erythropoiesis
include expanded medullary spaces (withinclude expanded medullary spaces (with
massive expansion of the marrow of themassive expansion of the marrow of the
face and skull producing the characteristicface and skull producing the characteristic
thalassemic facies), extramedullarythalassemic facies), extramedullary
hematopoiesis, and higher metabolichematopoiesis, and higher metabolic
needsneeds
 Transfusional iron overload- endocrine andTransfusional iron overload- endocrine and
cardiac complicationscardiac complications
7474

 Laboratory findings:Laboratory findings:
– severe anemia,severe anemia,
– reticulocytopenia,reticulocytopenia,
– numerous nucleated erythrocytes,numerous nucleated erythrocytes,
– microcytosis with almost no normal-microcytosis with almost no normal-
appearing erythrocytes on theappearing erythrocytes on the
peripheral smearperipheral smear
7575

β Thalassemia Major
Target cells, NRBC, microcytosis, poikilocytosis

 The reticulocyte count is commonly <8% and isThe reticulocyte count is commonly <8% and is
inappropriately low when compared to the degreeinappropriately low when compared to the degree
of anemia due to ineffective erythropoiesis.of anemia due to ineffective erythropoiesis.
 The unconjugated serum bilirubin level is usuallyThe unconjugated serum bilirubin level is usually
elevated, but other chemistries may be normal atelevated, but other chemistries may be normal at
an early stage.an early stage.
 Even if the child does not receive transfusions,Even if the child does not receive transfusions,
eventually there is iron accumulation witheventually there is iron accumulation with
elevated serum ferritin and transferrin saturation.elevated serum ferritin and transferrin saturation.
 Bone marrow hyperplasia can be seen onBone marrow hyperplasia can be seen on
radiographsradiographs
7777

Treatment:Treatment:
 Chronic transfusionsChronic transfusions
 Deferoxamine(sc) orDeferoxamine(sc) or
deferasirox(oral) for iron overloaddeferasirox(oral) for iron overload
 Hematopoietic Stem CellHematopoietic Stem Cell
TransplantationTransplantation
7979

ββ-Thalassemia Intermedia-Thalassemia Intermedia
 Patients able to maintain minimum HbPatients able to maintain minimum Hb
(7 g/dL or greater) without transfusion(7 g/dL or greater) without transfusion
dependence.dependence.
 Expression of disorder falls betweenExpression of disorder falls between
thalassemia minor and thalassemiathalassemia minor and thalassemia
major.major.
 We will see increase in both HbAWe will see increase in both HbA22
production and HbF production.production and HbF production.
 Peripheral blood smear picture is similarPeripheral blood smear picture is similar
to thalassemia minor.to thalassemia minor.

 Have varying symptoms of anemia,Have varying symptoms of anemia,
jaundice, splenomegaly and hepatomegaly.jaundice, splenomegaly and hepatomegaly.
 Have significant increase in bilirubin levels.Have significant increase in bilirubin levels.
 May become transfusion dependent.May become transfusion dependent.
 Tend to develop iron overloads as result ofTend to develop iron overloads as result of
increased gastrointestinal absorption.increased gastrointestinal absorption.
 Usually survive into adulthood.Usually survive into adulthood.

β-Thalassemia Minor (Trait(
• Caused by heterozygous (from one parent)
mutations that affect β globin synthesis.
• β Chains production and thus Hb-A production is
more reduced than the silent carrier Hb-A.
• Usually presents as mild, asymptomatic hemolytic
anemia unless patient in under stress such as
infection, or folic acid deficiency.
• Have one normal β gene and one mutated β gene.
• Hemoglobin level in 10-13 g/dL range with normal
or slightly elevated RBC count (RCC).

 Anemia usually hypochromic and microcytic withAnemia usually hypochromic and microcytic with
slight aniso and poik, including target cells andslight aniso and poik, including target cells and
elliptocytes; also may see basophilic stippling.elliptocytes; also may see basophilic stippling.
 Rarely see hepatomegaly or splenomegaly.Rarely see hepatomegaly or splenomegaly.
 Have high HbAHave high HbA22 levels (3.6-8.0%) and normal tolevels (3.6-8.0%) and normal to
slightly elevated HbF levels.slightly elevated HbF levels.
 Normally require no treatment.Normally require no treatment.

 2- 6% HbF (N = < 1% after age2- 6% HbF (N = < 1% after age
1 year)1 year)
 3.6 - 8% HbA3.6 - 8% HbA22 (N = 2.0-3.5%)(N = 2.0-3.5%)
 87 - 95% HbA (N=95-100%)87 - 95% HbA (N=95-100%)

 Thalassemia trait is often misdiagnosed as ironThalassemia trait is often misdiagnosed as iron
deficiency in children because the 2 producedeficiency in children because the 2 produce
similar hematologic abnormalities on CBC, andsimilar hematologic abnormalities on CBC, and
iron deficiency is much more prevalent.iron deficiency is much more prevalent.
 A short course of iron and re-evaluation is all thatA short course of iron and re-evaluation is all that
is required to identify children who will needis required to identify children who will need
further evaluation.further evaluation.
 Children who have β-thalassemia trait have aChildren who have β-thalassemia trait have a
persistently normal red cell distribution width andpersistently normal red cell distribution width and
low mean corpuscular volume (MCV).low mean corpuscular volume (MCV).
 On hemoglobin analysis, they have an elevatedOn hemoglobin analysis, they have an elevated
Hb F and diagnostically elevated Hb A2.Hb F and diagnostically elevated Hb A2.
8686

αα-Thalassemia-Thalassemia
• Predominant cause of alpha thalassemiasPredominant cause of alpha thalassemias
is large number of gene deletions in theis large number of gene deletions in the αα--
globin genes.globin genes.
• There are four clinical syndromes presentThere are four clinical syndromes present
in alpha thalassemia:in alpha thalassemia:
♫ Silent Carrier StateSilent Carrier State
♫ Alpha Thalassemia Trait (Alpha ThalassemiaAlpha Thalassemia Trait (Alpha Thalassemia
Minor)Minor)
♫ Hemoglobin H DiseaseHemoglobin H Disease
♫ Bart's Hydrops Fetalis SyndromeBart's Hydrops Fetalis Syndrome
8787

State Genotype Genes Features
Normal αα/αα 4 normal
Hetero α+
α-thal-2
αα/ – α 3 Essentially normal
Hetero α°
α-thal-1
αα/ – – 2 Micro / Hypo
Mild Anemia
Bart’s 2-8% (at birth)
Hb H <2%
Homo α+
α-thal-1
– α/ – α 2
α+
+ α°
Hb-H
Disease
– α/ – – 1 Moderate Micro/Hypo
anemia: Barts <10%, Hb
H <40%
homo α°
Hydrops
– – / – – 0 Hb A 0%, Bart’s 70-80%
Portland 10-20%

 Treatment of the α-thalassemia deletionTreatment of the α-thalassemia deletion
syndromes consists ofsyndromes consists of
– folate supplementation,folate supplementation,
– possible splenectomy (with the attendantpossible splenectomy (with the attendant
risks),risks),
– intermittent transfusion during severe anemiaintermittent transfusion during severe anemia
for the nondeletional Hb H diseases, andfor the nondeletional Hb H diseases, and
– chronic transfusion therapy or bone marrowchronic transfusion therapy or bone marrow
transplant for survivors of hydrops fetalis.transplant for survivors of hydrops fetalis.
8989

Hemoglobinopathies

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