it is important to medical student

1. THALASEMIA
Dr Saif Rahman, MD, PGY2 Internal Medicine

2. ANEMIA
• Anemia:
• Hb <13.6 g/dL in males
• Hb <12 g/dL in females
• Or
• Hematocrit below 41% in males
• Hematocrit below 36% in females
• Hematocrit levels are less useful than hemoglobin levels in
assessing anemia because they are calculated rather than
measured directly

3. RPI<2.5%
RPI<2.5% RPI > 2.5%
RPI < 2.5%
RPI: Reticulocyte
production index
1. Blood loss
2. Intravascular
hemolysis

4. HEMOGLOBIN
• Heme + Globin
• Alpha globin
• 4 genes
• 2 on each chromosome 16
• Same in utero and adult HB
• Beta Globin
• 2 gene on chromosome 16
• Beta like Globins:
• Globin delta
• Globin gamma

5. • Hb F: in utero; alpha 2,Gamma2;
• Prod. begins at 6–8 weeks’ gestation, peaks during mid-gestation, then
falls to <1% of total hemoglobin during the first 6 months of extrauterine
life.
• HbA: 2 alpha 2 beta, 98% adult Hb
• HbA2: 2 alpha 2 delta, 1-3% Normal adult Hb
• The hemoglobin composition of normal adults is >95% HbA, ~1% HbF, and
2–3% HbA 2 (α2δ2)

7. • Definiation
• Epidemiology and Etiology
• Pathophysiology
• Clinical features
• Diagnosis and Lab Exam
• Differential Diagnosis
• Treatment

8. DEFINIATION
• thalassemias are hereditary disorders characterized by reduction in the
synthesis of globin chains (alpha or beta)
• Reduced globin chain synthesis causes reduced hemoglobin synthesis and a
hypochromic microcytic anemia
• Hallmark: are small (low MCV) and pale (low mean corpuscular hemoglobin
[MCH]) RBCs, anemia
• and a normal to elevated RBC count (ie, a large number of the small and pale
RBCs are being produced)
• RBC dest. > RBC production

9. THALASEMIA FORMS
•thalassemia trait when there are laboratory features
without significant clinical impact
•thalassemia intermedia when there is an occasional RBC
transfusion requirement or other moderate clinical impact
•thalassemia major when the disorder is life-threatening
and the patient is transfusion dependent.
• Most patients with thalassemia major die of the consequences
of iron overload from RBC transfusions.

10. B THALASSEMIA

11. BETA THALASEMIA
• Usually point mutations of beta globins genes
• Mutations result in premature chain termination or in problems with
transcription of RNA and ultimately cause reduced or absent beta-globin
chain synthesis.
• Beta 0: Defects that result in absent beta-globin chain expression
• Beta +: causing reduced but not absent synthesis are termed beta+.
• In beta+ thalassemia, the degree of reduction of beta-globin synthesis is
consistent within families but is quite variable between families

12. BETA THALASEMIA

13. PATHOPHYSIOLOGY
• reduced beta-globin chain synthesis in beta thalassemia results in
a relative increase in the proportions of hemoglobins A2 and F
compared to hemoglobin A on
hemoglobin electrophoresis, as the beta-like globins (delta and
gamma) substitute for the missing beta chains.
• In the presence of reduced beta chains, the excess alpha chains
are unstable and precipitate, causing damage to RBC membranes.
This leads to both intramedullary (bone marrow) and peripheral
blood hemolysis.

14. PATHOPHYSIOLOGY
• The bone marrow demonstrates erythroid hyperplasia under the
stimuli of anemia and ineffective erythropoiesis (intramedullary
destruction of the developing erythroid cells).
• In cases of severe thalassemia, the marked expansion of the
erythroid compartment in the bone marrow may cause severe
bony deformities, osteopenia, and pathologic bone fractures

15. SIGNS AND SYMPTOMS
• primarily affects persons of Mediterranean origin (Italian, Greek)
and to a lesser extent Asians and Blacks
• Patients heterozygous for beta-thalassemia (beta/beta0 or
beta/beta+) have beta-thalassemia minor and a clinically
insignificant microcytic anemia

16. SIGNS AND SYMPTOMS
• beta-thalassemia intermedia:
• homozygous for a milder form of beta thalassemia (beta+/beta+, higher
amount of beta globin production)
• chronic hemolytic anemia but
• do not require transfusions except under periods of stress or during
aplastic crises.
• may develop iron overload because of periodic transfusion.
• Survive into adult life but with hepatosplenomegaly and bony deformities

17. SIGNS AND SYMPTOMS
• Patients homozygous for betathalassemia (beta0/beta0 or some
with beta+/beta+) have beta-thalassemia major (Cooley anemia).
• Affected children are normal at birth, but after 6 months, when
hemoglobin synthesis switches from hemoglobin F to hemoglobin
A, severe anemia develops that requires transfusion
• stunted growth,
• bony deformities (abnormal facial structure, pathologic bone
fractures)

18. SIGNS AND SYMPTOMS
• Hepatosplenomegaly
• jaundice (due to gallstones, hepatitis-related cirrhosis, or both),
and
• thrombophilia
• Before iron chelation and stem cell transplantation death occur
due to Hemochromatosis beteween 20-30 year old

19. SIGNS AND SYMPTOMS
• clinical course is modified significantly by transfusion therapy:
• clinical picture similar to hemochromatosis
• heart failure
• cardiac arrhythmias
• Cirrhosis
• endocrinopathies,
• pseudoxanthoma elasticum (calcification and fragmentation of the elastic
fibers of the skin, retina, and cardiovascular system)
• usually after more than 100 units of RBCs have been transfused

20. LAB EXAM AND DIAGNOSIS
• Beta thalassemia trait:
• Hb: modest anemia, 10-14, RBC count increased
• HCT: 28% and 40%
• MCV: 55-75
• Reticulocytes: normal or slightly increased
• Peripheral Smear: mildly abnormal, with hypochromia, microcytosis, and
target cells
• Hb Fractions:
• HbA: 94%
• HbA2: 4-8%
• HbF: 1-5%

21. LAB DX
• Beta thalassemia intermedia: Non transfusion dependent
• Hb: moderate anemia, 7-12, RBC count normal or increased
• HCT: 17% and 33%
• MCV: 55-75
• Reticulocytes: elevated
• Peripheral Smear: abnormal with hypochromia, microcytosis, basophilic
stippling, and target cells
Hb Fractions:
• HbA: 60%
• HbA2: 4-6%
• HbF: 10-40%

22. LAB
• Beta thalassemia major: transfusion dependent
• Hb: severe anemia, 2-4
• HCT: without transfusion can low upto 10%
• MCV: 50-75
• Peripheral Smear: is bizarre, showing severe poikilocytosis, hypochromia,
microcytosis, target cells, basophilic stippling, and nucleated RBCs
Hb Fractions:
• HbA: Little or no, 0-5%
• HbA2: 2-5%
• HbF: predominant, 90-100%

23. COMPLICATIONS
• Many due to chronic hemolytic anemia, chronic transfusion, and iron loading
• Develop because of either inadequate blood transfusion and/or poor iron
chelation and iron loading.
• Even when chelation is optimized, some complications attributable to iron
toxicity will develop.
• Many complications have complex and multifactorial etiologies.
• Iron stores are estimated by serum ferritin levels; MRI is the most widespread
means of noninvasively measuring iron accumulation in liver and heart

26. TREATMENT
• Patients with mild thalassemia (alpha-thalassemia trait or beta-thalassemia
minor) require no treatment and should be identified so that they will not be
subjected to repeated evaluations and treatment for iron deficiency
• Severe Thalassemia:
• Regular scheduled Transfusion and Iron chelating therapy
• Spleenectomy
• Improving Ineffective Erythropoiesis: luspatercept
• Allogeneic stem cell transplantation
• Gene therapy
• Screening

27. REGULAR TRANSFUSION AND
CHELATION THERAPY
• Transfusion every 2–4 weeks with a goal pretransfusion
hemoglobin concentration of 9–10.5 g/dL, coupled with oral iron
chelation to prevent the accumulation of excess toxic iron that
accompanies transfusion, has prevented the development of
cardiomyopathy and endocrinopathies while extending life to at
least 50 years
• When to begin transfusions, whether partial exchange transfusion
is preferable to simple transfusion, and the choice of blood
product require consultation with experts

28. TRANSFUSION AND CHELATION
• To be effective, transfusions and iron chelation must be started
early, be uninterrupted, and continue lifelong.
• Older patients who did not have the advantage of effective
chelation are more likely to develop multiple disease-related
morbidities such as osteoporosis, endocrinopathies, liver disease,
and renal failure.
• Two orally effective chelating agents, deferasirox and deferiprone,
and one intravenous chelator, deferoxamine, are available

29. LUSPATERCEPT
• approved for treatment of transfusion-dependent thalassemia
• By binding transforming growth factor β superfamily ligands and
reducing Smad2/3 signaling, luspatercept enhances late-stage
erythropoiesis.
• Given subcutaneously, 1 mg/kg every 3 weeks, it was associated
with a 33% reduction in transfusion requirements

30. STEM CELL TRANSPLANTATION
• patients with available donors should be offered transplantation
because of the difficulty of lifelong transfusion and chelation and its
imperfect efficacy
• Allogeneic stem cell transplantation is the treatment of choice for beta-thalassemia major
and the only available cure.
• Children who have not yet experienced organ damage from iron overload do well, with
long-term survival in more than 80% of cases
• The best results are in the youngest patients who have been effectively
chelated and received fewer transfusions
• Graft failure, graft rejection, graft-versus-host disease, and a mortality of 5–20% depending
on risk factors are the major drawbacks of this procedure

31. GENE THERAPY
• Lentiviral mediated gene therapy using autologous CD34+ hematopoietic stem cells has
been approved in Europe for some patients with transfusion-dependent thalassemia who
lack a matched donor.
• In a clinical trial with a median follow-up of 26 months, where patients received autologous
CD34+ cells transduced with a lentiviral vector containing a modified HbA, transfusions were
reduced or eliminated and hemoglobin levels stabilized between 8.2 and 13.7 g/dL.
• However, the results were dependent on the β thalassemia mutation, and although
transfusion independence was achieved, some features of disease such as ineffective
erythropoiesis were not eliminated. The initial results of CRISPR/Cas editing to downregulate
BCL11A in β thalassemia have eliminated the need for transfusion and normalized
hemoglobin levels

32. SCREENING AND COUNSELING
• Heterozygote screening and counseling couples at risk for
affected fetuses, with antenatal diagnosis, if needed, is an
effective preventive approach
• Splenectomy is performed if hypersplenism causes a marked
increase in the transfusion requirement or refractory symptoms.

33. ALPHA THALASSEMIA

34. ALPHA THALASEMIA
• gene deletions causing reduced alpha-globin chain synthesis
• Each alpha-globin gene produces one-quarter of the total alpha-
globin quantity, so there is a predictable proportionate decrease
in alpha-globin output with each lost alpha-globin gene.
• Since all adult hemoglobins are alpha containing, alpha-
thalassemia produces no change in the proportions of
hemoglobins A, A2, and F on hemoglobin electrophoresis.

35. ALPHA THALASEMIA
• In severe forms of alpha-thalassemia, excess beta chains
may form a beta-4 tetramer called hemoglobin H. In the
presence of reduced alpha chains, the excess beta chains
are unstable and precipitate, leading to damage of red
blood cell membranes. This leads to both intramedullary
(bone marrow) and peripheral blood hemolysis

36. SYMPTOMS AND SIGNS
• seen primarily in persons from southeast Asia and China and, less commonly,
in Blacks and persons of Mediterranean origin
• Normally, adults have four copies of the alphaglobin chain.
• When three alpha-globin genes are present, the patient is hematologically
normal (silent carrier).
• When two alpha-globin genes are present, the patient is said to have alpha-
thalassemia trait, a form of thalassemia minor.
• In alpha-thalassemia-1 trait, the alpha gene deletion is heterozygous (alpha –
/alpha –) and affects mainly those of Asian descent

37. SYMPTOMS AND SIGNS
• In alpha-thalassemia-2 trait, the alpha gene deletion is
homozygous (alpha alpha/– –) and affects mainly Blacks.
• These patients are clinically normal and have a normal life
expectancy and performance status, with a mild
microcytic anemia.

38. • hemoglobin H disease (alpha-thalassemia-3): one alpha globin
chain is present (alpha –/– –)
• This is a chronic hemolytic anemia of variable severity
(thalassemia minor or intermedia).
• Physical examination might reveal pallor and splenomegaly
• Affected individuals usually do not need transfusions; however,
they may be required during transient periods of hemolytic
exacerbation caused by infection or other stressors or during
periods of erythro-poietic shutdown caused by certain viruses
(“aplastic crisis”)

39. SIGNS AND SYMPTOMS
• When all four alpha-globin genes are deleted, no normal
hemoglobin is produced and the affected fetus is stillborn
(hydrops fetalis).
• In hydrops fetalis, the only hemoglobin species made is
gamma and is called hemoglobin Bart’s (gamma4)

41. LAB EXAM AND DIAGNOSIS
• alpha thalassemia trait:
• Hb: mild or no anemia, 10-14, RBC count increased
• HCT: 28% and 40%
• MCV: 60-75
• Reticulocytes: normal or slightly increased
• Peripheral Smear: microcytes, hypochromia, occasional target
cells, and acanthocytes (cells with irregularly spaced spiked
projections)
Hb Electrophoresis are Normal
• Usually diagnosed by exclusion

42. LAB DX
• Hemoglobin H Diseases
• Hb: more marked anemia, 5-12, RBC count normal or increased
• HCT: 22% and 32%
• MCV: 60-70
• Reticulocytes: normal or elevated
• Peripheral Smear: markedly abnormal, with hypochromia, microcytosis,
target cells, and poikilocytosis
• can be stained with supravital dyes to demonstrate the presence of
hemoglobin H
• Hb Electrophoresis: fast-migrating hemoglobin (hemoglobin H), which
comprises 10–40% of the hemoglobin

43. LAB
• Hemoglobin bart’s Hydrops Fetalis
• No alpha gene
• Fatal in birth or in utero with rare survivors, Hydropes can
also result from combination of gene deletion and non-
gene deletion alpha thalasemia

44. COMPLICATIONS
• Hepatosplenomegaly, jaundice, thalassemic bone changes in the face, and
growth impairment are seen 20–50% of cases, depending on the underlying
genotype.
• Iron loading occurs but is not the severe problem it is in β thalassemia.
• Pregnancy in these patients should be considered high risk and managed
accordingly.
• Mothers of infants with Hb Bart’s hydrops fetalis have a history of stillbirth
and develop preeclampsia, polyhydramnios, and antepartum hemorrhage
and have difficult labor and delivery. Intrauterine transfusion of the fetus is
possible

45. DIFFERENTIAL DIAGNOSIS
• Causes of Microcytic anemia:
• Iron deficiency anemia
• Anemia of chronic disease
• Thalasemia alpha and beta
• Sideroblastic Anemia (Lead poisoning and enzyme deficiencies)
• First step in evaluation is iron panel

46. DIFFERENTIAL DIAGNOSIS
• Iron deficiency anemia
• patients with thalassemia have:
• a lower MCV
• a normal or elevated red blood cell count (rather than low)
• a more abnormal peripheral blood smear at modest levels of anemia
• usually a reticulocytosis
• Iron studies are normal or the transferrin saturation or ferritin (or both)
are elevated

47. DDX AND DX
• Severe forms of thalassemia be confused with other
hemoglobinopathies
• diagnosis of beta-thalassemia is made by the above findings and:
• hemoglobin electrophoresis showing elevated levels of
hemoglobins A2 and F (provided the patient is replete in iron)
• beta-gene sequencing

48. DDX AND DX
• diagnosis of alpha-thalassemia is made by exclusion since
there is no change in the proportion of the normal adult
hemoglobin species or confirmed by alpha gene deletion
studies.
• The only other microcytic anemia with a normal or
elevated red blood cell count is iron deficiency in a
patient with polycythemia vera

49. DDX

50. TREATMENT
• Mild thalassemia 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/day orally) and avoid medicinal iron and oxidative drugs such as
sulfonamides
• Iron should be avoided in noniron-deficient individuals with α thalassemia
trait and microcytosis.
• Transfusions are not usually needed in HbH disease
• transfusions might be necessary especially when anemia becomes more
severe, for example, with acute anemic episodes or pregnancy

51. TREATMENT
• Iron stores should be checked periodically by measuring serum ferritin or
MRI;
• chelation does not appear to be needed.
• Hb Bart’s hydrops fetalis is best prevented by screening couples at risk and
antenatal diagnosis.
• Intrauterine therapy and perinatal intensive care have permitted survival of
some infants with Hb Bart’s hydrops fetalis.
• As growth retardation affects ~40% and neurodevelopmental delay is
present in 20% of survivors, prevention is the best approach

52. TREATMENT AND COUNSELLING
• When planning families, couples from regions where α
thalassemia is common who have red cell indices that
suggest the possibility of carrying an α thalassemia gene
should have genetic counseling based on DNA analysis of
their globin genes

53. WHEN TO REFER
• All patients with thalassemia intermedia or major should be
referred to a hematologist.
• Any patient with an unexplained microcytic anemia should be
referred to help establish a diagnosis.
• Patients with thalassemia minor or intermedia should be offered
genetic counseling because offspring of thalassemic couples are
at risk for inheriting thalassemia major

54. Thanks