GENERAL APPROACH TO DIAGNOSIS OF HEMOLYTIC ANEMIA

Dr jp,asst prof,ich,mch,kottayam

LEARNING OBJECTIVES

To identify hemolytic anemia

To list 3 common causes of hemolytic anemia

Name 4 specific tests for diagnosis of hemolytic anemia

How to identify and treat thalassemia,hereditary spherocytosis and sickle cell

anemia?

What is hemolytic anemia?

An essential feature of hemolytic anemia is a reduction in the normal red cell

survival of 120 days. Premature destruction of red cells may result from

orpuscular abnormalities (within the red cell corpuscle), that is,

abnormalities of membrane,enzymes, or hemoglobin; or from

extracorpuscular abnormalities, that is, immune or nonimmune mechanisms.

Case scenarios

2wks old child has unconjugated hyperbilirubinemia. He has no blood loss.

His and mother’s blood group is o+. his father had jaundice in childhood .

he had splenectomy later

Wha t is your comment ?

6 month old child has anemia. She had swelling fingers two times so far. His

anemia has not responded with hematinics.what are the possibilities?

3 yr old child needs monthly transfusion to treat anemia. He has hemolytic

facies hsm,pigmentation He is on defersirox .what is the dx?

What is the approach to hemolytic anemia?

The approach to the diagnosis of hemolytic anemia should include:

• Consideration of the clinical features suggesting hemolytic disease

• Laboratory demonstration of the presence of a hemolytic process

• Determination of the precise cause of the hemolytic anemia by special

hematologic

investigations.

History- key points

Jaundice in newborn period/later

Recurrent transfusion

Ftt

Abnormal facies

Drug induced hemolysis

What are the Clinical Features?

The following clinical features suggest a hemolytic process:

• Ethnic factors: Incidence of sickle gene carrier in the African-American

population (8%), high incidence of thalassemia trait in people of Mediterranean

ancestry and high incidence of glucose-6-phosphate dehydrogenase (G6PD)

deficiency among Sephardic Jews.chetti tribe in wayanad has sickle cell anemia

running through families

• Age factors: Anemia and jaundice in an Rh-positive infant born to a mother who

is Rh negative or a group A or group B infant born to a group O mother (setting for

a hemolytic anemia)

• History of anemia, jaundice, or gallstones in family

• Persistent or recurrent anemia associated with reticulocytosis

• Anemia unresponsive to hematinics

• Intermittent bouts or persistent indirect hyperbilirubinemia/jaundice

• Splenomegaly.

• Hemoglobinuria

• Presence of multiple gallstones

• Chronic leg ulcers

• Development of anemia or hemoglobinuria after exposure to certain drugs

• Cyanosis without cardiorespiratory distress

• Polycythemia (2,3 Diphosphoglycerate mutase deficiency)

• Dark urine due to dipyrroluria (unstable hemoglobins, thalassemia and ineffective

erythropoiesis).

What are the Laboratory Findings?

Laboratory findings of hemolytic anemia consist of:

• Evidence of accelerated hemoglobin catabolism due to reduced red cell survival

• Evidence of increased erythropoiesis.

Accelerated Hemoglobin Catabolism

Accelerated hemoglobin catabolism varies with the type of hemolysis as follows:

• Extravascular hemoglobin catabolism ()

• Intravascular hemoglobin catabolism ().

The two may not be easily distinguished if the cause for hemolysis is not obvious,

hence the long lists of markers of testing indicated below. The presence of

hemoglobinuria and hemosidenuria and the absence of haptoglobin are the major

markers of intravascular hemolysis in practice.

What are the Markers of Extravascular Hemolysis?

1. Increased unconjugated bilirubin.

2. Increased lactic acid dehydrogenase in serum.

3. Decreased plasma haptoglobin (normal level, 128625 mg/dl).

4. Increased fecal and urinary urobilinogen.

5. Increased rate of carbon monoxide production.

This is a personAL TEACHING FILE WHICH IS NOT INTENDED TO BE

PRINTED SOLD,OR PHOTOCOPIED.

What are the Markers of Intravascular Hemolysis?

1.Increased unconjugated bilirubin.

2. Increased lactic acid dehydrogenase in serum.

3. Hemoglobinuria).

4. Low or absent plasma haptoglobin.

5. Hemosiderinuria (due to sloughing of iron-laden tubular cells into urine).

6. Raised plasma hemoglobin level (normal value ,1 mg hemoglobin/dl plasma,

visibly red plasma contains .50 mg hemoglobin/dl plasma).

7. Raised plasma methemalbumin (albumin bound to heme; unlike haptoglobin,

albumin does not bind intact hemoglobin).

8. Raised plasma methemoglobin (oxidized free plasma hemoglobin) and raised

levels of hemopexin–heme complex in plasma.

Thalassemia major. Unless they have had transfusions, patients with this disease

usually have severe anemia. This peripheral blood film demonstrates many

nucleated red blood cells, microcytosis, and hypochromasia with multiple

morphologic changes: target cells, teardrop cells, fragments, basophilic stippling,

and Pappenheimer bodies. The nucleated red blood cells may be dysplastic or show

abnormal hemoglobinization. Neutrophilia and thrombocytosis may occur. This

patient has undergone splenectomy for hypersplenism and increased transfusion

requirements. Howell-Jolly bodies are present.

Hereditary spherocytosis. Peripheral blood film of spherocytic hemolysis.

Spherocytes are round, are slightly smaller than normal red blood cells, and lack

central pallor. Note the nucleated red blood cells and polychromatophilic cells. It is

important to look in the area of the slide where red blood cells are nearly touching

each other to properly identify spherocytes. Red blood cells normally have a

spherical appearance at the tail (thin) end of the blood smear

Sickle cell anemia. Top panel:

Peripheral blood film of hemoglobin

SS (HbS disease). The numerous

elongated erythrocytes with sharp

points are classic sickle cells. Sickle

cells that appear folded over are called

envelope cells. Target cells are

present, in this case because of

hyposplenism from the splenic

infarction that occurs in HbSS

patients. Howell-Jolly bodies may be

seen as well

What is the evidence of Increased Erythropoiesis?

Erythropoiesis increases in response to a reduction in hemoglobin and is

manifested by:

• Reticulocytosis: Frequently up to 10–20%; rarely, as high as 80%

• Increased mean corpuscular volume (MCV) due to the presence of reticulocytosis

and increased red cell distribution width (RDW) as the hemoglobin level falls

Supravital stain of reticulocytes with brilliant cresyl blue. The blue-stained

reticular inclusions in the red blood cells represent ribosomes that are precipitated

when exposed to brilliant cresyl blue

Increased normoblasts in peripheral blood

• Specific morphologic abnormalities: Sickle cells, target cells, basophilic

stippling,irregularly contracted cells or fragments (schistocytes), eliptocytes,

acanthocytes and spherocytes

• Erythroid hyperplasia of the bone marrow: Erythroid:myeloid ratio in the marrow

increasing from 1:5 to 1:1

• Expansion of marrow space in chronic hemolysis resulting in:

• Prominence of frontal bones

• Broad cheekbones

• Widened intratrabecular spaces, hair-on-end appearance of skull radiographs

• Biconcave vertebrae with fish-mouth intervertebral spaces.

• Decreased red cell survival demonstrated by 51Cr red cell labeling

• Red cell creatine levels increased.

What are Thalassemia Syndromes ?

Thalassemia refers to genetic disorders in globin chain production. In

individuals with beta thalassemia, there is either a complete absence of β

globin production (β-thalassemia major) or a partial reduction in β globin

production (β thalassemia minor). In alpha thalassemia, there is an absence

of or partial reduction in α globin production. The primary pathology in

thalassemia stems from the quantity of globin production, whereas the

primary pathology in sickle cell disease is related to the quality of globin

produced.

What is the Pathophysiology ?

Two related features contribute to the sequelae of β-thalassemia: inadequate

β-globin gene production leading to decreased levels of normal hemoglobin

(Hb A) and unbalanced α- and β-globin chain production.. In the bone

marrow, thalassemia mutations disrupt the maturation of erythrocytes,

resulting in ineffective erythropoiesis; the marrow is hyperactive, but there

are relatively few reticulocytes and severe anemia exists.

In β-thalassemia, there is an excess of α-globin chains relative to β- and γ-

globin chains, and α-globin tetramers (α4) are formed. These inclusions

interact with the red cell membrane and shorten red cell survival, leading to

anemia and increased erythroid production. The γ-globin chains are

produced in increased amounts, leading to an elevated Hb F (α2γ2). The δ-

globin chains are also produced in increased amounts, leading to an elevated

Hb A2 (α2δ2) in β-thalassemia.

THE THALASSEMIAS

THALASSE

MIA

GLOBIN

GENOTY

PE

FEATURES EXPRESSION

HEMOGLO

BIN

ANALYSIS

α-THALASSEMIA

1 gene

deletion -,α/α,α Normal Normal

Newborn:

Bart's 1-2%

2 gene

deletion trait

-,α/-,α -, -

/α,α

Microcytosis, mild

hypochromasia

Normal, mild

anemia

Newborn:

Bart's: 5-10%

3 gene -,-/-,α Microcytosis, Mild anemia, Newborn:

THALASSE

MIA

GLOBIN

GENOTY

PE

FEATURES EXPRESSION

HEMOGLO

BIN

ANALYSIS

deletion

hemoglobin H

hypochromic transfusions not

required

Bart's: 20-

30%

2 gene

deletion +

Constant

Spring

-,-

/α,αConstant

Spring

Microcytosis,

hypochromic

Moderate to

severe anemia,

transfusion,

splenectomy.

2-3%

Constant

Spring, 10-

15%

hemoglobin H

4 gene

deletion -,-/-,-

Anisocytosis,

poikilocytosis Hydrops fetalis

Newborn: 89-

90% Bart's

with Gower 1

and 2 and

Portland

Nondeletional α,α/α,αvariant

Microcytosis, mild

anemia Normal

1-2% variant

hemoglobin

β-THALASSEMIA

β0 or β

+

heterozygote:

trait

β0/A,β

+/A

Variable

microcytosis Normal

Elevated A2,

variable

elevation of F

β0-

Thalassemia

β0/β

0, β

+/β

0,

E/β0

Microcytosis,

nucleated RCB

Transfusion

dependent

F 98% and A2

2%

E 30-40%

β+-

Thalassemia

severe

β+/β

+

Microcytosis

nucleated RBC

Transfusion

dependent/thalass

emia intermedia

F 70-95%, A2

2%, trace A

Silent β+/A Microcytosis

Normal with only

microcytosis A2 3.3-3.5%

β+/β

+

Hypochro

mic,

microcytos

is

Mild to moderate

anemia

A2 2-5%, F 10-

30%

Dominant

(rare) B

0/A

Microcytosis,

abnormal RBCs

Moderately

severe anemia,

splenomegaly

Elevated F

and A2

THALASSE

MIA

GLOBIN

GENOTY

PE

FEATURES EXPRESSION

HEMOGLO

BIN

ANALYSIS

δ-Thalassemia A/A Normal Normal A2 absent

(δβ)0-

Thalassemia (δβ)

0/A Hypochromic Mild anemia F 5-20%

(δβ)+-

Thalassemia

Lepore

βLepore

/A Microcytosis Mild anemia Lepore 8-20%

Lepore β

Lepore/β

Lepor

e

Microcytic,

hypochromic

Thalassemia

intermedia

F 80%,

Lepore 20%

γδβ-

Thalassemia (γ

Aδβ)

0/A

Microcytosis,micro

cytic, hypochromic

Moderate anemia,

Splenomegaly,

Homozygote:

thalassemia

intermedia

Decreased F

and A2

compared

with δβ-

thalassemia

γ-Thalassemia (γAγ

G)

0/A Microcytosis

Insignificant

unless

homozygote

Decreased F

HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN

Deletional A/A Microcytic Mild anemia F 100%

homozygotes

Nondeletional A/A Normal Normal F 20-40%

In α-thalassemia there are relatively fewer α-globin chains and an excess of

β- and γ-globin chains. These excess chains form Bart's hemoglobin (γ4) in

fetal life and Hb H (β4) after birth. These abnormal tetramers are not lethal

but lead to extravascular hemolysis. Prenatally a fetus with α-thalassemia

can become symptomatic because Hb F requires sufficient of α-globin gene

production, whereas postnatally infants with β-thalassemia become

symptomatic because Hb A requires sufficient production of β-globin genes.

Homozygous β-Thalassemia (Thalassemia Major, Cooley Anemia)

Clinical Manifestations

If not treated, children with β-thalassemia usually become symptomatic from

progressive hemolytic anemia, with profound weakness and cardiac

decompensation during the 2nd 6 mo of life. Depending on the mutation and

degree of fetal hemoglobin production, transfusions in β-thalassemia major

are necessary beginning in the 2nd mo to 2nd yr of life, but rarely later. The

decision to transfuse depends on the child's ability to compensate for the

degree of anemia.

Most infants and children have cardiac decompensation at hemoglobins of

4 g/dL or less. Generally, fatigue, poor appetite, and lethargy are late

findings of severe anemia in an infant or child and were more common

before transfusions were standard therapy.

The classic presentation of children with severe disease includes

thalassemic facies (maxilla hyperplasia, flat nasal bridge, frontal bossing),

pathologic bone fractures, marked hepatosplenomegaly, and cachexia and

is now primarily seen in developing countries. The spleen can become so

enlarged that it causes mechanical discomfort and secondary

hypersplenism. The features of ineffective erythropoiesis include expanded

medullary spaces (with massive expansion of the marrow of the face and

skull producing the characteristic thalassemic facies), extramedullary

hematopoiesis, and higher metabolic needs. The hepatosplenomegaly can

interfere with nutritional support. Pallor, hemosiderosis, and jaundice can

combine to produce a greenish brown complexion.

Figure 456-7 Ineffective erythropoiesis in a 3 yr old patient who has

thalassemia major and has not received a transfusion. A, Massive widening

of the diploic spaces of the skull as seen on MRI. B, Radiographic

appearance of the trabeculae as seen on plain radiograph. C, Obliteration of

the maxillary sinuses with hematopoietic tissue as seen on CT scan.

The chronic anemia produces an increase in iron absorption from the

gastrointestinal tract, with toxicity leading to further complications. Many of

these features become less severe and infrequent with transfusion therapy,

but excessive iron stores associated with transfusional iron overload is a

major concern in patients with β-thalassemia. Many of the complications of

thalassemia seen in developed countries today are the result of increased iron

deposition. Most of these complications can be avoided by the consistent use

of an iron chelator. However, chelation therapy also has associated

complications, including hearing loss, peripheral neuropathy, and poor

growth.

Endocrine and cardiac pathology are often associated with excessive iron

stores in patients with β-thalassemia major who are chronically transfused.

Endocrine dysfunction can include hypothyroidism, hypogonadotrophic

gonadism, growth hormone deficiency, hypoparathyroidism, and diabetes

mellitus. Congestive heart failure and cardiac arrhythmias are potentially

lethal complications of excessive iron stores in children with thalassemia.

What are the Laboratory Findings ?

The infant is born only with Hb F or, in some cases, Hb F and Hb E

(heterozygosity for β-thalassemia zero). Eventually, there is severe anemia,

reticulocytopenia, numerous nucleated erythrocytes, and microcytosis with

almost no normal-appearing erythrocytes on the peripheral smear (). The

hemoglobin level falls progressively to <5 g/dL unless transfusions are

given. The reticulocyte count is commonly <8% and is inappropriately low

when compared to the degree of anemia due to ineffective erythropoiesis.

The unconjugated serum bilirubin level is usually elevated, but other

chemistries may be normal at an early stage. Even if the child does not

receive transfusions, eventually there is iron accumulation with elevated

serum ferritin and transferrin saturation. Bone marrow hyperplasia can be

seen on radiographs ().

What is the Treatment ?

Before initiating chronic transfusions, the diagnosis of β-thalassemia major

should be confirmed and the parents counseled concerning this life-long

therapy. Beginning transfusion and chelation therapy are difficult challenges

for parents to face early in their child's life. Before beginning transfusion

therapy, a red-cell phenotype is obtained; blood products that are

leukoreduced and phenotypically matched for the Rh and Kell antigens are

required for transfusion. If a bone marrow transplant is a possibility, the

blood for transfusion should be negative for cytomegalovirus unless the

child has had a previous cytomegalovirus infection. Transfusion therapy

promotes general health and well-being and avoids the consequences of

ineffective erythropoiesis.

A transfusion program generally requires monthly transfusions, with the

pretransfusion hemoglobin level between 9.5 and 10.5 g/dL. In patients

with cardiac disease, higher pretransfusion hemoglobin levels may be

beneficial. Some blood centers have donor programs, pairing donors and

recipients, which decreases the exposure to multiple red cell antigens.

Excessive iron stores from transfusion cause many of the complications of

β-thalassemia major. Accurate assessment of excessive iron stores is

essential to optimal therapy. The serum ferritin is useful in assessing iron

balance trends but does not accurately predict quantitative iron stores.

Undertreatment or overtreatment of presumed excessive iron stores can

occur in managing a patient based on serum ferritin alone.

Quantitative iron by liver biopsy is the standard method for accurately

determining iron store for patients. T2* MRI software is now being used to

estimate iron stores in the liver and heart among patients with β-thalassemia

major. One reason for the preference of T2* MRI over liver biopsy is that

liver iron stores might not accurately reflect cumulative changes in cardiac

iron. Patients can have cardiac iron overload at the time of a safe liver iron

measurement. Many thalassemia centers now monitor cardiac iron with T2*

MRI imaging.

Excessive iron stores can be prevented by the use of deferoxamine

(Desferal) or deferasirox (Exjade). Deferoxamine chelates iron and some

other divalent cations, allowing their excretion in the urine and the stool.

Deferoxamine is given subcutaneously over 10-12 hr, 5-6 days a week. The

side effects include ototoxicity with high-frequency hearing loss, retinal

changes, and bone dysplasia with truncal shortening. The number of hours

that deferoxamine is used daily is more important than the daily dosage.

High dose, short-term infusions increase toxicity with little efficacy.

Plasma non–transferrin bound iron (NTBI) is most likely responsible for

serious iron injury. When deferoxamine is infusing, it binds NTBI. When

deferoxamine is stopped, there are rebound increases in NTBI levels and risk

for injury. In patients with excessive iron stores in the heart resulting in

symptomatic congestive heart failure, 24-hr deferoxamine has been shown to

reverse cardiomyopathy.

The oral iron chelator deferasirox (Exjade) is commercially available For

many patients and families, deferasirox has replaced deferoxamine because

the latter must be given subcutaneously for 10 hr a night, typically 5 of 7

nights a week. Although the optimal dose of deferasirox is well defined,

some patients have a less-than-expected response to the maximum approved

doses (30 mg/kg/day). The optimal dose beyond 30 mg/kg/day is not known,

but it should be evaluated carefully if evidence of a positive iron balance

continues to occur while the patient is adherent to the medication.

Hematopoietic stem cell transplantation has cured >1,000 patients who have

β-thalassemia major. Most success has been in children younger than 15 yr

of age without excessive iron stores and hepatomegaly who undergo sibling

HLA-matched allogeneic transplantation. All children who have an HLA-

matched sibling should be offered the option of bone marrow

transplantation.

Other β-Thalassemia Syndromes

The β-thalassemia syndromes are broken into six groups: β-thalassemia, δβ-

thalassemias, γ-thalassemias, δ-thalassemias, ϵγδβ-thalassemias, and the

HPFH syndrome. Most of these thalassemias are relatively rare, some being

found only in family groups. The β-thalassemias can also be classified

clinically as thalassemia trait, minima, minor, intermedia, and major,

reflecting the degree of anemia. The genetic classification does not

necessarily define the phenotype, and the degree of anemia does not always

predict the genetic classification.

Thalassemia intermedia can be any combination of β-thalassemia mutations

(β0/β

+, β

0/β

variant, E/β

0), which will lead to a phenotype of microcytic anemia

with hemoglobin of about 7 g/dL. There is controversy about whether these

children should receive transfusions. They will certainly develop a degree of

medullary hyperplasia, nutritional hemosiderosis perhaps requiring

chelation, splenomegaly, and other complications of β-thalassemia

associated with excessive iron stores. Extramedullary hematopoiesis can

occur in the vertebral canal, compressing the spinal cord and causing

neurologic symptoms; the latter is a medical emergency requiring immediate

local radiation therapy to halt erythropoiesis. Transfusion alleviates the

thalassemic manifestations; the decision to transfuse must be balanced

against the future need for chelation therapy.

Splenectomy may be indicated for patients with thalassemia intermedia who

have a falling steady-state hemoglobin and for transfused patients with rising

transfusion requirements. However, splenectomy can have serious

consequences, including infection, pulmonary hypertension, and thrombosis.

All patients should be fully immunized against encapsulated bacteria before

splenectomy and subsequently should be on long-term penicillin prophylaxis

with appropriate instructions regarding fever management.

The thalassemias classified as minima and minor are usually heterozygotes

(β0/β, β

+/β

+), having a phenotype more severe than trait but not as severe as

intermedia. These children should be investigated for their genotype and

monitored for iron accumulation. The β-thalassemias are influenced by the

presence of α-thalassemia: α-thalassemia trait leading to less severe anemia

and duplicated α genes (ααα/αα) leading to a more severe thalassemia.

Often, patients who are in these groups require transfusions in adolescence

or adulthood; some may be candidates for chemotherapy such as

hydroxyurea.

Thalassemia trait is often misdiagnosed as iron deficiency in children

because the 2 produce similar hematologic abnormalities on CBC, and iron

deficiency is much more prevalent. A short course of iron and re-evaluation

is all that is required to identify children who will need further evaluation.

Children who have β-thalassemia trait have a persistently normal red cell

distribution width and low mean corpuscular volume (MCV). On

hemoglobin analysis, they have an elevated Hb F and diagnostically elevated

Hb A2. There are “silent” forms of β-thalassemia trait, and if the family

history is suggestive, further studies may be indicated.

α-Thalassemia

The same evolutionary pressures that produced β-thalassemia and sickle cell

disease produced α-thalassemia. Infants are identified in the newborn period

by the increased production of Bart's hemoglobin (γ4) during fetal life and its

presence at birth. The α-thalassemias occur most commonly in Southeast

Asia. Deletion mutations are common in α-thalassemia. In addition to

deletional mutations, there are nondeletional α-globin gene mutations, the

most common being Constant Spring (αCS

α); these mutations cause a more

severe anemia and clinical course than the deletional mutations. There are

four α-globin genes and four deletional α-thalassemia phenotypes.

The deletion of one α-globin gene (silent trait) is not identifiable

hematologically. Specifically, no alterations are noted in the mean

corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH).

Persons with this deletion are usually diagnosed after the birth of a child

with a 2-gene deletion or Hb H (β4). During the newborn period, <3% Hb

Bart's is observed. The deletion of one α-globin gene is common in African-

Americans.

The deletion of 2 α-globin genes results in α-thalassemia trait. The α-globin

genes can be lost in a trans-(−α/−α) or cis- (α,α/-SEA

) configuration. The

trans or cis mutations can combine with other mutations and lead to Hb H or

α-thalassemia major. In persons from Africa or of African descent the most

common α-globin gene deletion is in the trans configuration, whereas in

persons from Asia or the Mediterranean region the cis deletion is most

common.

The α-thalassemia traits manifest as a microcytic anemia that can be

mistaken for iron-deficiency anemia). The hemoglobin analysis is normal,

except during the newborn period, when Hb Bart's is commonly <8% but

>3%. Children with a deletion of 2 α-globin genes are commonly thought to

have iron deficiency, given the presence of both low MCV and MCH. The

simplest approach to distinguish between iron deficiency and α-thalassemia

trait is with a good dietary history. Children with iron-deficiency anemia

often have a diet that is low in iron. Alternatively, a brief course of iron

supplementation along with monitoring of erythrocyte parameters might

confirm the diagnosis of iron deficiency, or α-globin gene deletion analysis

may be necessary.

The deletion of three α-globin genes leads to the diagnosis of Hb H disease.

In California, where a large population of Asians resides, ~1 : 15,000

newborns have Hb H disease. The simplest manner of diagnosing Hb H

disease is during the newborn period, when excess in γ-tetramers are present

and Hb Bart's is commonly >25%. Obtaining supporting evidence from the

parents is also necessary. Later in childhood, there is an excess in β-globin

chain tetramers that results in Hb H. A definitive diagnosis of Hb H disease

requires DNA analysis with supporting evidence. Brilliant cresyl blue can

stain Hb H, but it is rarely used for diagnosis. Patients with Hb H disease

have a marked microcytosis, anemia, mild splenomegaly, and, occasionally,

scleral icterus or cholelithiasis. Transfusion is not commonly used for

therapy because the range of hemoglobin is 7-11 g/dL, with MCV 51-73 fl.

The deletion of all four α-globin genes causes profound anemia during fetal

life, resulting in hydrops fetalis; the ζ-globin gene must be present for fetal

survival. There are no normal hemoglobins present at birth (primarily Hb

Bart's, with Hb Gower 1, Gower 2, and Portland). If the fetus survives,

immediate exchange transfusion is indicated. These infants with α-

thalassemia major are transfusion dependent, and hematopoietic stem cell

transplant is the only cure.

The presence of a nondeletional α-globin mutation with a 2-gene deletion

results in a more severe anemia, increased hepatosplenomegaly, increased

jaundice, and a much more severe clinical course than Hb H disease. Hb H

Constant Spring is the most common form (−α/α,αCS

).

Treatment of the α-thalassemia deletion syndromes consists of folate

supplementation, possible splenectomy (with the attendant risks),

intermittent transfusion during severe anemia for the nondeletional Hb

H diseases, and chronic transfusion therapy or bone marrow transplant for

survivors of hydrops fetalis. These children also should not be exposed to

oxidative medications

Hemoglobin H disease. This blood film demonstrates microcytosis,

hypochromasia, and numerous morphologic abnormalities, including target cells,

microspherocytes, and fragments. Basophilic stippling may occur. Polychromasia

is present.