The document discusses alpha thalassemia and provides details on its classifications, causes, clinical syndromes, and diagnostic workup. It describes the four types of alpha thalassemia (silent carrier state, trait, hemoglobin H disease, and Bart's Hydrops Fetalis) based on the number of defective alpha globin genes. The diagnostic workup involves examination of blood counts, peripheral smear, bilirubin, iron studies, and globin chain or DNA testing to identify the genetic defect. Management depends on severity but may include folic acid, transfusions, splenectomy, or stem cell transplantation.

2. KANDAHAR MEDICAL FACULTY

3. 3
Presenters:
1. Shir Ahmad
10mins
2. Abd. Samad
6mins
3. Waliullah
6mins
4. M. Qasim Khan
(Achak)6mins
5. K. Almaas
6mins

4. ALPHA THALASSEMIA

5. • Has wide range clinical expressions. 1
• Is difficult to classify alpha thalassemias due to wide variety of
possible genetic combinations, though there are some
classifications made according to the number of defective or
absent genes:2
9
Alpha Talassemia
1,2: Harrison principles of int. Medicine,17th, Longo et al

6. • Due to complete loss of one or more of the four copies of the
Alpha-globulin chain gene any of four types of alpha-
thalassemia can ensue. The loss of one copy of the gene is
silent (the patient is a carrier), and the loss of two
copies is asymptomatic (called alpha-Thal. Trait/minor). The
loss of three copies of the gene (called HbH disease) and of
four copies (called Hydrops Fetalis) produces symptoms.1
• Absence of alpha chains will result in increase of gamma
chains during fetal life and excess beta chains later in
life; Causes molecules like Bart's Hemoglobin (γ4) or
Hemoglobin H (β4), which are stable molecules but
physiologically useless. 2
10
Alpha Talassemia
1,2: Harrison principles of int. Medicine,17th, Longo et al

7. • Predominant cause of alpha Thalassemias is large number of
gene deletions in the alpha-globin gene. 1
• There are four clinical syndromes present in alpha
thalassemia: 2
1. Alpha Thalassemia Trait (Alpha Thalassemia Minor)
2. Hemoglobin H Disease
3. Bart's Hydrops Fetalis Syndrome
4. Silent Carrier State
11
Alpha Thalassemia
1: Harrison principles of int. Medicine,2: Cecil Medicine

8. • Deletion of one alpha gene, leaving three functional alpha
genes.
• Alpha/Beta chain ratio nearly normal.
• No hematologic abnormalities present.
• No reliable way to diagnose silent carriers by hematologic
methods; Must be done by genetic mapping.
• May see borderline low MCV .
12
Silent Carrier State
1: Cecil Medicine;23rd ed. Goldman et al

9. • Caused by two missing alpha genes. May be homozygous
(-a/-a) or heterozygous (--/aa).
• Exhibits mild microcytic, hypochromic anemia.
• MCV is very low.
• May be confused with iron deficiency anemia.
• Although some Bart's hemoglobin (γ4) present at birth, no
Bart's hemoglobin present in adults.
13
Alpha Thalassemia Trait
1: Cecil Medicine;23rd ed. Goldman et al

10. • Second most severe form alpha thalassemia.
• Usually caused by presence of only one gene producing alpha
chains (--/-a).
• Results in accumulation of excess unpaired gamma or beta
chains. Born with 10-40% Bart's hemoglobin (γ4). Gradually
replaced with Hemoglobin H (β4). In adult, have about 30-
50% Hb H.
• γ4  β4
14
Hemoglobin H disease
1: Cecil Medicine;23rd ed. Goldman et al

11. • Live normal life; however, infections, pregnancy, exposure to
oxidative drugs may trigger hemolytic crisis.
• RBCs are microcytic, hypochromic with marked
poikilocytosis. Numerous target cells.
• Cells been described has having "golf ball" appearance,
especially when stained with brilliant crystal blue.
15
Hemoglobin H disease
1: Cecil Medicine;23rd ed. Goldman et al

12. • Most severe form. Incompatible with life. Have no
functioning alpha chain genes (--/--).
• Baby born with hydrops fetalis, which is edema and ascites
caused by accumulation serous fluid in fetal tissues as result of
severe anemia. Also seen hepato-splenomegaly and
cardiomegaly.
16
Bart’s Hydrops Fetalis
1: Cecil Medicine;23rd ed. Goldman et al

13. • Predominant hemoglobin is Hemoglobin Bart, along with
Hemoglobin Portland and traces of Hemoglobin H.
• Hemoglobin Bart's has high oxygen affinity so cannot carry
oxygen to tissues. Fetus dies in utero or shortly after birth. At
birth, see severe hypochromic, and microcytic anemia.
• Pregnancies dangerous to mother. Increased risk of toxemia
and severe postpartum hemorrhage.
17
Bart’s Hydrops Fetalis
1: Cecil Medicine;23rd ed. Goldman et al

14. 18
Comparison
Genotype Hb A Hb Bart Hb H
Normal 97-98% 0 0
Silent Carrier 96-98% 0-2% 0
Alpha Thalassemia
Trait
85-95% 5-10% 0
Hemoglobin H Disease Dec 25-40% 2-40%
Hydrops Fetalis 0 80% (with 20%
Hgb Portland)
0-20%
1: Cecil Medicine;23rd ed. Goldman et al

15. • Need to start with patient's individual history and family
history. Ethnic background important.
Perform physical examination:
• Pallor indicating anemia.
• Jaundice indicating hemolysis.
• Splenomegaly due to pooling of abnormal cells.
• Skeletal deformity, especially in beta thalassemia major.
19
Lab Dx
1: Harrison Principles of Int. Medicine, 17th ed, Longo et al

16. • See decrease in hemoglobin, hematocrit, mean corpuscular
volume (MCV), and mean corpuscular hemoglobin
(MCH). See normal to slightly decreased Mean Corpuscular
Hemoglobin Concentration (MCHC). Will see microcytic,
hypochromic pattern.
20
Lab Dx
1: Harrison Principles of Int. Medicine, 17th ed, Longo et al

17. • Elevated RBC count with markedly decreased MCV
differentiates thalassemia from iron deficiency anemia.
• On differential, see microcytic, hypochromic RBCs (except in
carrier states). See mild to moderate poikilocytosis. In more
severe cases, see marked number of target cells and
elliptocytes. Will see polychromasia, basophilic stippling.
21
Lab Dx
1: Harrison Principles of Int. Medicine, 17th ed, Longo et al

18. • Usually elevated. Degree of elevation depends upon severity of
thalassemia.
22
Lab Dx
The big picture pathology, Walter l. Kemp

19. • Indirect bilirubin elevated in thalassemia major and
intermedia.
• Assessment of iron status, total iron binding capacity, and
ferritin level important in differentiating thalassemia from iron
deficiency anemia.
23
Lab Dx
The big picture pathology, Walter l. Kemp

20. • Globin Chain Testing - determines ratio of globin chains being
produced.
• DNA Analysis - Determine specific defect at molecular DNA
level.
24
Lab Dx
The big picture pathology, Walter l. Kemp

21. MANAGEMENT

22. • Patients with mild thalassemia (α-thalassemia trait or β-thalassemia
minor) require no treatment and should be identified so that they will
not be subjected to repeated evaluations and treatment for iron
deficiency. Patients with hemoglobin H disease should take folic acid
supplementation (1 mg/d orally) and avoid oxidative drugs such as
sulfonamides. Patients with severe thalassemia are maintained on a
regular transfusion schedule and receive folic acid supplementation.
26
Management
1: Harrison Principles of Int. Medicine, 17th ed, Longo et al

23. • Splenectomy is performed if hypersplenism causes a marked increase
in the transfusion requirement
• Allogeneic stem cell transplantation is the treatment of choice for β-
thalassemia major and the only available cure.
• Children who have not yet experienced iron overload and chronic
organ toxicity do well, with long-term survival in more than 80% of
cases.
27
Management
1: Harrison Principles of Int. Medicine, 17th ed, Longo et al

25. BETA THALASSEMIA

26. • Absent or non-functional beta-globin genes, caused by various
types of mutations suchas nonsense, splicing, insertions, and even
deletions which give rise to significantchanges inthe level of gene
transcription that lead to absent (β0) or markedly diminished (β+)
amounts of β-globin gene mRNA.
• In addition, long deletions lead to more complex forms of β-
thalassemiasyndromes, such as β-thalassemiaor hereditary
persistence of fetal hemoglobin. These large deletions in the β-
globin cluster occur less commonly than in the α-globin cluster.
30
Lab Dx

27. • The condition is ubiquitous but is especially common in
Mediterranean, Asian, and African populations (and their
American descendants), in whom the high gene frequency has
been thought to reflect geographic areas with a high prevalence of
malaria. Within a given ethnic group, relatively few genotypes
account for most cases, each of which now has been defined by
DNA analysis.
31
Lab Dx

28. • The clinical spectrum of disease severity in the β-thalassemia
syndromes is related directly to the quantitative effect of individual
mutations on β-globin synthesis. Although β-thalassemia trait is
asymptomatic, disease occurs in homozygotes or compound
heterozygotes such as patients with β-thalassemia/HbE. In these latter
instances, reduced or absent β-globin synthesis results in the
accumulation of free α-globin chains that precipitate during early
erythroblast development because of their relative insolubility. These
inclusions lead to ineffective erythropoiesis in the bone marrow and
enhanced peripheral destruction of the erythrocytes that emerge from
thebonemarrow.
32
Lab Dx

29. • The associated pathophysiologic changes resulting from the
subsequent anemia include splenomegaly, which may lead to
hypersplenism; osteoporosis and other skeletal and soft tissue
changes associated with an expanded bone marrow; and iron
overload resulting from a combination of enhanced
gastrointestinal iron absorption and red blood cell transfusions.
The liver, heart, pancreas, pituitary, and other endocrine organs
are the major sites of excessive iron deposition, which ultimately
leads to damage andfailure of these organs.
33
Lab Dx

30. • Historically, the diagnosis of β-thalassemia and α-thalassemia has
relied heavily on clinical and hematologic features ( Fig. 166-5 ).
Often, patients were referred for evaluation of anemia or
microcytosis or both, or in the context of neonatal or population
screening. The discovery of low mean corpuscular volume and
hemoglobin on automated complete blood counts has increased
the number of these referrals. In the presence of normal iron
status, increased levels of HbA2 (as high as 4 to 6%) and/or HbF (5
to 20%) on quantitative hemoglobin analysis support the
diagnosis.
34
Lab Dx

31. • In the contemporary era of DNA technology, reference
laboratories can swiftly clone and directly sequence the α-globin
or β-globin genes or perform other techniques of DNA analysis for
patients with suspected thalassemia syndromes. This approach,
which has revolutionized prenatal diagnosis of the severe
thalassemia syndromes, can be performed at 14 weeks' gestation
on amniotic fluid cells and at 10 weeks if chorionic villus sampling
is performed. These procedures carry a risk of miscarriage of 1%
and5%, respectively.
35
Lab Dx

32. • Despite an almost comprehensive understanding of the molecular
and cellular pathogenesis of the β-thalassemia syndromes, a
widely available curative form of treatment for homozygotes
remains elusive. Nonetheless, dramatic improvement in life
expectancy and morbidity has been observed since the 1980s,
primarily because of aggressive transfusion support and the
institution of effective iron chelation therapy in these regularly
transfused patients. Except for curative allogeneic bone marrow
transplantation, therapy is considered symptomatic and
supportive.
36
Lab Dx