Hemoglobinopathies are inherited abnormalities of hemoglobin synthesis characterized by structurally abnormal hemoglobin variants. Sickle cell anemia is the prototype hemoglobinopathy caused by a single point mutation that results in production of abnormal hemoglobin S. This leads to polymerization of hemoglobin S molecules under conditions of low oxygen, causing distortion of red blood cells into a sickle shape and various complications. Other hemoglobinopathies include Hemoglobin C, E, and D disease, which typically have milder phenotypes.

1. HEMOGLOBINOPATHIES
Dr. M. N. Astagimath, M.D.

2. DEFINITION:
Inherited abnormalities of hemoglobin synthesis
characterised by structurally abnormal
hemoglobin variants.

3. SICKLE CELL ANEMIA
• Prototype of hereditary
hemoglobinopathies. It occurs due to
production of a physiochemically abnormal
hemoglobin. It offers a protection against
malaria for unknown reasons.
• Nearly 20 million people affected in India.
• It is inherited as an autosomal recessive
trait.
• Presents as sickle cell trait (heterozygous)
and sickle cell disease(homozygous).

4. • Normal hemoglobin
2 alpha and 2 beta chains
form a 4 chain tetramer
• HbS:
Valine substituted for
glutamic acid in both beta
chains (HbSS).
This occurs due to single
point mutation at sixth
position of beta globin chain
which has thymine instead
of adenine.

5. •Due to the change in the amino acid
sequence,there is an alteration in
charge at the site.
•This allows for aggregation &
polymerisation of HbS
molecules.(formation of tactoids)
•Acidosis,Hb concentration,presence
of other types of Hb affect
polymerisation.
•It is a relatively reversible
phenomenon but with repeated cycles
it becomes irreversible.
PATHOGENESIS

6. PATHOGENESIS
Arterial pO2
oxyHbS(soluble)
Stiff,viscous sickle cell
Venous pO2 deoxyHbS
polymerised)
Membrane changes
Ca2+ influx,K+leakage
Capillary venule occlusion
Shortened red cell survival
Microinfarction
Ischemic tissue pain
Ischemic organic malfn. Anemia, jaundice

7. CLINICAL COURSE
• Disease is not evident in newborns.
• 2-4 months : Symptoms of Hemolytic Anemia start
developing like anemia, jaundice. This
is parallel to replacement of HbF by
HbS.
• 5-6 months : Symptoms arising due to infarction
and ischemia start developing.
• By the age of 5 yrs almost 95% are functionally
asplenic.

8. INFARCTION
• Slow, tortuous circulation leads to repeated
infarctions.
• Effects of the HbS polymerisation, infarction and
ischemia are seen in most of the body organs :
• Bones
• Spleen
• Kidney
• Lungs
• Liver
• Brain

9. DACTYLITIS
(HAND-FOOT SYNDROME)
• First overt manifestation
• Painful, usually symmetric
swelling with erythema of
dorsa of hands & feet.
• Sudden in onset and lasts
for 1-2 weeks.
• Needs medical attention.
• Radiographic changes
appear 2-3 weeks after
appearance of symptoms.

10. •Marked congestion of
the red pulp due to
trapping of sickled red
cells in splenic cords.
•The spleen is palpable
in most of the children
by the age of 9 months.
(increased almost up to
500gms.)
SPLENIC INVOLVEMENT

11. • Continued scarring causes
progressive shrinkage of the
spleen. Finally leading to
autosplenectomy
• Hence they are more prone
to infection
• Penicillin prophylaxis is begun
at 3 months.

12. ACUTE CHEST SYNDROME
•Presents with
tacypnea,fever,cough,chest
pain,arterial O2
desaturation.
•Can mimic
pneumonia,pulmonary
embolism.
•Thought to reflect in situ
sickling within the lung
causing temporary and
permanent dysfunction.

13. PNEUMONIA
Frequently seen in children with SCA, has high severity
because of the relative immunodeficiency. The
commonest organism is pneumococcus.

14. GALL STONES
Frequent complication of hemolytic anemias

15. OTHER FEATURES
•Abdominal crises: severe abdominal pain & signs of peritoneal
irritation.
•Aplastic crises: infection in adult sicklers with parvovirus B19
results in severe red cell aplasia.
•Liver cells may undergo sequestration with severe pain due to
capsular stretching.
•Aseptic necrosis of head of femur,humerus.
•Chronic osteomyelitis: Salmonella sp. most frequently seen
organism.

16. •Chronic leg ulcers: seen in adult sicklers. Non healing
ulcers usually present on the medial aspect of leg.
•Eyes: retinal infarcts, preretinal hemorrhage.
•Kidney:limited capacity of H+
excretion,hematuria,hypoastheniuria.
•CNS:strokes, focal deficits may occur.
•Priapism: due to pooling of blood in corpora cavernosa.

17. DIAGNOSIS
• Evidence of red cell destruction:
• peripheral blood smear
• plasma haptoglobin,hemopexin
• Evidence of red cell generation:
• reticulocytosis, extramedullary
hematopoeisis
• Laboratory diagnosis
• Blood picture

18. Hair on end
appearance
Marrow expansion

19. LAB DIAGNOSIS
• SICKLE TEST:Red cells with HbS take a sickle
shape when mixed with a freshly prepared solution
of the reducing agent sodium metabisulphite.(2%)
Giving an appearance of turbidity.
• SOLUBILITY TEST:Hb added to solution of
sodium dithionite(reducing agent) in phosphate
buffer.Turbidity shows presence of HbS.
• Hb ELECTROPHORESIS

20. Hb ELECTROPHORESIS

21. BLOOD PICTURE
• Hb : 6-9gm%, may be lower
• Anemia: normocytic,normochromic
• MCV,MCH: Normal
• Stained film:Moderate
anisopoikilocytosis,sickle cells,oval cells,occ
target cells,Howell-Jolly bodies
• Reticulocytosis (10-20%)

23. MANAGEMENT
•Vaso-occlusive crises managed by aggressive
rehydration, oxygen therapy, adequate analgesia and
antibiotics.
•Prophylactic antibiotics: Penicillin prophylaxis to
protect against infections which are lethal in presence
of asplenia.
•Vaccination against pneumococcus, hepatitis B and
haemophilus.

24. • Transfusion to suppress HbS production and
maintain HbS levels below 30%.
• Fetal Hb induction with hydroxyurea
(hydroxycarbamide) replaces some HbSS with
HbF. As high level of HbF inhibits polymerization
• Bone marrow or stem cell transplant appears to be
potentially curative.
• PROPHYLAXIS Factors that promote sickling
should be avoided that is hypoxia, dehydration,
acidosis etc.

25. OTHER
HEMOGLOBINOPATHIES
•Hemoglobin H. Hemoglobin H is a tetramer composed of
four beta globin chains. Hemoglobin H occurs only with
extreme limitation of alpha chain availability. Hemoglobin H
forms in people with three-gene alpha thalassemia
•Hemoglobin Barts. Hemoglobin Barts develops in fetuses
with four-gene deletion alpha thalassemia. Due to this
deletion no alpha chain is produced. The gamma chains
produced during fetal development combine to form gamma
chain tetramers. These molecules transport oxygen poorly.
Most individuals with four-gene deletion thalassemia and
consequent hemoglobin Barts die in utero (hydrops fetalis).

26. •Hemoglobin C. Hemoglobin C results from a
mutation in the beta globin gene and is the
predominant hemoglobin found in people with
hemoglobin C disease. (a2bC
2).It has Lysine for
glutamic acid at 6th position in beta chain.
Hemoglobin C disease is relatively benign, producing a
mild hemolytic anemia and splenomegaly. Hemoglobin
C trait is benign.
•Hemoglobin E. This variant results from a mutation
in the hemoglobin beta chain. People with hemoglobin
E disease have a mild hemolytic anemia and mild
splenomegaly. Hemoglobin E trait is benign.

27. •Hemoglobin D: It has the glutamic acid at
the 121st position on the beta chain instead of
glutamine. It is relatively benign, producing a
mild hemolytic anemia and splenomegaly.
•Other examples: Hb-Koln, Hb-Zurich, Hb-
Sydney, HbO-Arab etc.

28. What is thalassemia?
• Genetic blood disorder resulting in a mutation or
deletion of the genes that control globin production.
• Normal hemoglobin is composed of 2 alpha and 2 beta
globins
• Mutations in a given globin gene can cause a decrease
in production of that globin, resulting in deficiency
• aggregates become oxidized  damage the cell
membrane, leading either to hemolysis, ineffective
erythropoiesis, or both.
• 2 types of thalassemia: alpha and beta.

29. Demographics
• The thalassemia gene may be maintained in the
human population, in part because of the greater
immunity of heterozygous individuals against
malaria and is found in parts of the world where
malaria is common
• These include Southeast Asia, China, India,
Africa, and parts of the Mediterranean.

30. Alpha Thalassemia
• mutation of 1 or more of the 4 alpha globin
genes on chromosome 16
• severity of disease depends on number of genes
affected
• results in an excess of beta globins

31. Silent Carriers (heterozygotes +/-)
• 3 functional alpha globin genes
• No symptoms, but thalassemia could potentially
appear in offspring

32. Alpha Thalassemia Trait
• 2 functional globin genes
• results in smaller blood cells that are lighter in
colour
• no serious symptoms, except slight anemia

33. Hemoglobin H Disease
• 1 functional globin gene
• results in very lightly coloured red blood cells
and possible severe anemia
• hemoglobin H is susceptible to oxidation,
therefore oxidant drugs and foods are avoided
• treated with folate to aid blood cell production

34. Alpha Thalassemia Major
• no functional globin genes
• death before birth (embryonic lethality)

35. Beta Thalassemia
• mutations on chromosome 11
• hundreds of mutations possible in the beta
globin gene, therefore beta thalassemia is more
diverse
• results in excess of alpha globins

36. Beta Thalassemia Trait
• slight lack of beta globin
• smaller red blood cells that are lighter in colour
due to lack of hemoglobin
• no major symptoms except slight anemia

37. Beta Thalassemia Intermedia
• lack of beta globin is more significant
• bony deformities due to bone marrow trying to make
more blood cells to replace defective ones
• causes late development, exercise intolerance, and
high levels of iron in blood due to reabsorption in the GI
tract
• if unable to maintain hemoglobin levels between 6 gm/dl
– 7 gm/dl, transfusion or splenectomy is recommended

38. Beta Thalassemia Major
• complete absence of beta globin
• enlarged spleen, lightly coloured blood cells
• severe anemia
• chronic transfusions required, in conjunction with
chelation therapy to reduce iron (desferoxamine)

39. More Permanent Options
 Bone Marrow Transplants
 Replacing patient’s marrow with donor marrow
 First performed on thalassemia patient in 1981
 Difficult, because donor must be exact match for
recipient
 Even a sibling would only have a 1 in 4 chance of
being a donor
 Cord Blood Transplants
 Rich in stem cells
 Also needs to be an exact match

40. THANK YOU