Discussion of each type of anemia based on etiological classification, investigation and management options for each type.

1. Anemia
MURAD A3MAR

2. What is anemia?
 any condition in which the number of red cells, the amount of hemoglobin
or the volume of packed red blood cells per unit volume is less than
normal.
 a pathophysiological condition in which the body cannot meet its
demands for oxygen

3. Blood reference values:
 WBC 4,800-10,800/mm3
 RBC M: 4.7-6.1 mil/mm3 F: 4.2-5.4 mil/mm3 ( or x 106/mL)
 Plt 130,000-400,000/mm3
 Hgb M: 14.0-18.0 g/dL F: 12.0-16.0 g/dL
 Hct M: 42-52% F: 37-47%
 MCV [= Hct(%) / RBC count(x106/mL)/10] 80-100m3(or fL)
 MCH [= Hgb(g/dL) / RBC count(x106/mL)/10] 27-33 pg
 MCHC [= Hgb(g/dL) / Hct(%)/100] 32-36 g/dL
 RDW 8.5-11.5 %

4. Erythrocyte Indices:
 Hemoglobin (Hgb)
 Hematocrit (Hct)
 Mean Corpuscular Volume (MCV)
 Mean Corpuscular Hemoglobin (MCH)
 Mean Corpuscular Hemoglobin Concentration (MCHC)
 Red Cell Distribution Width (RDW)
 [Packed Cell Volume (PCV)]

5. RBC “rule of 3’s”:
For normal erythrocytes:
hemoglobin (g/dL)  3 x RBC count (millions)
hematocrit (%)  3 x hemoblogin (g/dL)  3%
Failure to obey this “rule of 3’s” suggests an
abnormality in erythrocytes (sickle cells, etc)

6. classification of anemia by color:
1. hypochromic (decreased color)
• increased central pallor
2. normochromic (normal color)
• central pallor ~1/3 of the RBC diameter
3. hyperchromic (increased color)
(~spherocytosis)
• loss of central pallor

7. Morphologic classification :
microcytic
normocytic
macrocytic
MCV <80 MCV 80-100 MCV >100

8. When to say anemia?
M: Hb <13.5 Hct <41
F: Hb <12 Hct <36

9. classification by volume:
I. microcytic anemia (MCV <80)
1. iron deficiency anemia
2. thalassemia syndromes
3. anemia of chronic disease
4. sideroblastic anemia
II. normocytic anemia (MCV 80-100)
1. anemia of blood loss
2. hemolytic anemia
III. macrocytic anemia (MCV >100)
1. megaloblastic anemia

10. 1-Iron Deficiency Anemia
Iron: absorbed in duodenum
When iron loss exceeds its intake for a long time, iron storage decreases and
insufficient amount of iron is available for hemoglobin production
Iron deficiency anemia develops in sequence of stages:
1. Iron Depletion
2. Iron Deficient Erythropoiesis
3. Iron Deficiency Anemia

11. Iron Deficiency Anemia cont.
 This occurs when
1- iron losses or
2- iron malabsorption
3- physiological requirements exceed absorption.
 Daily requirement is 10 mg.

12. Iron Deficiency Anemia cont.
 Blood loss
 The most common explanation in men and postmenopausal women is
gastrointestinal blood loss, (malignancy, gastritis, peptic ulceration,
inflammatory bowel disease).
 In women of child-bearing age, menstrual blood loss, pregnancy and
breastfeeding contribute to iron deficiency.

13. Iron Deficiency Anemia cont.
 Malabsorption
 Gastric acid is required to release iron from food and helps to keep iron in the soluble
ferrous state.
 Causes:
1. Achlorhydria in the elderly.
2. Drugs such as proton pump inhibitors.
3. Previous gastric surgery.
4. Coeliac disease.
 Physiological demands
 Iron requirement increased in infancy, puberty and pregnancy.

15. Clinically:
Clinical:
- general fatigue
- SOB
- spoon nails (koilonychia)
- smooth, sore tongue
- epithelial atrophy
- cheilosis; scaling and fissures at the corners of the mouth
- pica (eating unusual things [e.g., dirt])

16. Koilonychia:

17. Smooth tounge:

18. Pallor:

19. Cheilosis:

20. Pica:

21. Lab findings:
Blood: - normochromic-normocytic
 microcytosis, anisocytosis, poikilocytosis,
hypochromia
- decreased reticulocytes
- low MCV
- relatively low Hgb, Hct

22. Microcytosis:

23. Anisocytosis:

24. Poikilocytosis:

25. Iron labs:
Serum iron (nl = 50-160 mg/dL) : low
Serum iron-binding capacity (nl = 250-400 mg/L) : increased
% saturation of TIBC (nl = 20-55%) : <15%
Serum ferritin (nl = 12-300 mg/L) : low

26. Treatment:
 Transfusion is not necessary and oral iron replacement is appropriate.
 Ferrous sulphate 200 mg 3 times daily is adequate.
 It should be continued for 3–6 months to replete iron stores.
 Many patients suffer gastrointestinal side-effects with ferrous sulphate,
including dyspepsia and altered bowel habit.

27. Treatment cont.:
 When this occurs, reduction in dose to 200 mg twice daily or a switch to
ferrous gluconate 300 mg twice daily
 The haemoglobin should rise by around 10 g/L every 7–10 days and a
reticulocyte response will be evident within a week.
 Patients with malabsorption or chronic gut disease may need parenteral
iron therapy.

28. 2-Thalassemia Syndromes:
~heterogeneous hemolytic disorders characterized by
quantitative abnormalities of hemoglobin synthesis
• genetic defect in globin production
• selective depression or absence of a- or b- chain of hemoglobin
• broad spectrum of presentation
• predominantly seen in persons of Mediterranean, African and
Asian ancestry

29. Thalasemia types:
α-thalassemia : α-chain deficiency due to gene deletion
β-thalassemia : β-chain deficiency due to point mutation
(Cooley’s anemia)

30. Thalasemia cont.:
Two (2) pathological mechanisms to contribute to develop
anemia
1. inadequate Hgb formation  low MCHC,
hypochromasia
2. relative excess of unaffected Hgb chain
 aggregation and precipitation of excess chain
 damage to the cell membrane
 loss of K+ and impaired DNA synthesis
 apoptosis of RBCs in BM
(“ineffective erythropoiesis”)

31. Thalasemia cont.:
ineffective erythropoiesis
+  severe erythroid hyperplasia
hemolysis excess absorption of iron

severe iron overload

32. B-thalassemia :
 Beta thalassemia syndromes are a group of hereditary
disorders characterized by a genetic deficiency in the
synthesis of beta-globin chains. In the homozygous
state, beta thalassemia (ie, thalassemia major) causes
severe, transfusion-dependent anemia. In the
heterozygous state, the beta thalassemia trait (ie,
thalassemia minor) causes mild to moderate microcytic
anemia

33. B-thalassemia cont.:
 Mutations in globin genes cause thalassemias.
 Beta thalassemia affects 1 or both of the beta-globin
genes.
 These mutations, by causing impaired synthesis of the
beta-globin protein component of Hb, result in anemia.
β+ → some β chain production
β0 → no β chain production

34. B-thalassemia cont.:
 The most common type of thalassaemia.
 Most prevalent in the (Mediterranean area).
 Heterozygotes have thalassaemia minor, a condition in which there
is usually mild anaemia and little or no clinical disability.
 Homozygotes have thalassaemia major, either are unable to
synthesise haemoglobin b or, at best, produce very little; after the
first 4–6 months of life, they develop profound hypochromic
anaemia.

35. Thalasemia major:
• homozygous β+/β+ or β0/β0
• severe anemia at 6 to 9 months of age requiring
blood transfusion
• death at early age, if not transfused
• severe erythrophagocytosis and extramedullary
hematopoiesis
 hepatosplenomegaly

36. Thalasemia major cont.:
• marked red marrow expansion  “Crew-Cut” sign
• hemosiderosis
• heart disease 2º to hemochromatosis is the major
cause of death in older patients

37. Crew-cut sign:

38. Haemosidrosis:

39. Haemochromatosis:

40. Thalasemia minor:
• much more common than Thalassemia major
• heterozygous b+/b or b0/b
• peripheral smear: hypochromia, microcytosis,
basophilic stippling, target cells
 usually asymptomatic or mild anemia (microcytic
anemia)

41. A-thalassemia:
 The alpha thalassemia (α-thalassemia) syndromes are a
group of hereditary anemias of varying clinical severity.
 They are characterized by reduced or absent
production of 1 or more of the globin chains of which
human hemoglobin is composed

42. A-thalassemia cont.:
 There are two alpha gene loci on chromosome 16 and therefore each
individual carries four alpha gene alleles.
 If one is deleted, there is no clinical effect.
 If two are deleted, there may be a mild hypochromic anaemia.
 If three are deleted, the patient has haemoglobin H disease.
 If all four are deleted, the baby is stillborn (hydrops fetalis).

43. Work up:
 Check for iron deficiency anemia: serum iron/ TIBC/ serum ferritin.
 Blood film: may show target cells, microcytosis, hypochromia, and
anisopoikilocytosis
 hemoglobin electrophoresis.
 Ultrasonography of the liver, gallbladder, and spleen
 Polymerase chain reaction (PCR) and restriction endonuclease
 gene mapping and anti-L globin monoclonal antibodies.

44. Management of thelasemia:
 Allogeneic haematopoietic stem cell transplantation (HSCT) from HLA-
compatible sibling.
 Transfusion to maintain Hb > 10 g/dL.
 Folic acid 5 mg daily.
 Splenectomy; if there is splenomegaly causing mechanical problems or
there is excessive transfusion needs.

45. 3-anemia ofchronic disease:
 A common type of anaemia, particularly in hospital populations.
 It occurs in the setting of chronic infection, chronic inflammation or
neoplasia.
 The anaemia is not related to bleeding, haemolysis or marrow infiltration.
 It is mild, with haemoglobin in the range of 8,5–11,5 g/dL, and is usually
associated with a normal MCV (normocytic, normochromic).
 The serum iron is low but iron stores are normal.

46. Anemia of chronic disease cont.:
 Pathogenesis
 Hepcidin production is induced by proinflammatory cytokines, especially
IL-6.
 Hepcidin binds to ferroportin on the membrane of iron-exporting cells,
such as small intestinal enterocytes and macrophages, internalising the
ferroportin and thereby inhibiting the export of iron from these cells into the
blood.
 The iron remains trapped inside the cells in the form of ferritin, levels of
which are therefore normal or high in the face of significant anaemia.

47. Anemia of chronic disease cont.:
 Diagnosis
 It is often difficult to distinguish ACD associated with a low MCV from iron
deficiency.
 Examination of the marrow may ultimately be required to assess iron stores
directly

48. Anemia of chronic disease cont.:

49. Anemia of chronic disease cont.:
 Treatment: The preferred initial form of therapy for
anemia of chronic illness is treatment of the underlying
disease
 Use of erythropoiesis-stimulating agents (ESAs)
and blood transfusion are reserved for severe and
symptomatic cases.

50. 4-sideroblastic anemia:
a heterogeneous group of disorders associated with
various defects in the porphyrin biosynthetic
pathway:
-porphyrn biosynthesis defects
-diminished heme synthesis
-increased cellular iron uptake

51. sideroblastic anemia cont.:
 characterized by the association of anemia with
presence of ringed sideroblast (a normoblast containing
excessive deposits of iron within mitochondria) in bone
marrow

52. sideroblastic anemia cont.:
 characterized by the association of anemia with
presence of ringed sideroblast (a normoblast containing
excessive deposits of iron within mitochondria) in bone
marrow

53. Ringed sideroblast:

54. sideroblastic anemia cont.:
Sub-types:
1-Hereditary Sideroblastic Anemias:
-hereditary sex-linked
-inheritance undetermined

55. sideroblastic anemia cont.:
2-Acquired Sideroblastic Anemias
1-primary (idiopathic) sideroblastic anemia
2-secondary (drug- or toxin-induced) sideroblastic anemia
-anti TB drugs (isoniazid, cycloserine, pyrazinamide)
-lead poisoning
-chloramphenicol
-ethanol

56. sideroblastic anemia cont.:
 clinical: characterized by hypochromic, often microcytic, red
cells in the blood usually mixed with normochromic cells
hypochromic anemia
hyperferremia
increased transferrin saturation

57. sideroblastic anemia cont.:
Lab: serum iron: increased
TIBC: decreased
% saturation: greatly elevated
bone marrow: - markedly increased iron storage
- erythroid hyperplasia
- increased sideroblasts

58. sideroblastic anemia cont.:
 Treatment:Treatment of sideroblastic anemia may include
 1- removal of toxic agents;
 2- administration of pyridoxine, thiamine, or folic acid;
 3-transfusion (along with antidotes if iron overload develops from
transfusion);
 4- other medical measures; or bone marrow or liver transplantation.

59. 5-hemolytic anemia:
Inherited
causes
Red cell membrane
abnormality (hereditary
spherocytosis, elliptocytosis)
Red cell enzyme deficiency
(G6PD)
Haemoglobin deficiency
(thalassaemias) Haemoglbin
abnormality (sickle cell
disease)
Acquired
causes
Immunological causes
Non-immunological
causes

60. Hereditary spherocytosis:
-intrinsic defect in the membrane cytoskeleton
-genetic:autosomal dominant
-pathoetiology: spectrin deficiency → decreased RBC
surface memb.→ loss of biconcavity
-anemia: moderate anemia
normocytic
hyperchromic
reticulocytosis
-entrapment of spherocytes in the spleen
(splenomegaly) (extravascular
hemolysis)
-increased erythrocyte osmotic fragility

61. Hereditary spherocytosis:

62. Hereditary spherocytosis:
What will be seen?
1. mild to moderate hemolytic anemia
2. splenomegaly
3. marked compensatory erythroid hyperplasia in BM
4. jaundice, pigment cholelithiasis ← ( ↑ bilirubin )
5. increased risk for acute red-cell aplasia due to parvovirus B19
infection

63. Hereditary spherocytosis:
 Lab:
 Complete blood cell count
 Reticulocyte count: >
 Mean corpuscular hemoglobin concentration (MCHC)>
 Peripheral blood smear
 Lactate dehydrogenase (LDH) level
 Fractionated bilirubin>
 Osmotic fragility test>

64. Hereditary spherocytosis:
 Treatment:
 1- Aplastic crises occasionally can cause the hemoglobin level to fall
because of ongoing destruction of spherocytes that is not balanced by
new red blood cell (RBC) production. RBC transfusions often are necessary
in these cases
 2- Patients with HS are instructed to take supplementary folic acid for life in
order to prevent a megaloblastic crisis.
 3-Splenectomy is the definitive treatment for HS

65. Ellipticosis:
-intrinsic defect in the membrane cytoskeleton
-genetic: autosomal dominant
-pathoetiology: impaired aggregation of spectrin
-anemia:90% of pt. are non-anemic
non-hypochromic elliptocytes >25%
(nl=<15%)
Sx: splenomegaly

66. ellipticosis

67. G6DP
-Pathophysiology: decreased half life of G6PD
increased vulnerability to oxidative denaturation due to
limited generation of NADPH (older RBCs are preferentially
destroyed)
-Genetics:
high genetic heterogeneity
x-linked recessive ( full expression in male hemizygote)

68. G6DP
hemolysis after exposure to oxidant stress
- drugs: primaquine, chloroquine, sulfonamides, nitrofurantoins
- infections: viral hepatitis, pneumonia, typhoid fever
“favism” : hemolysis after ingestion of fava beans (Mediterranean
type)

69. G6DP
 LABS:
 Complete blood cell count (CBC) and reticulocyte count
 Lactate dehydrogenase (LDH) level
 Indirect and direct bilirubin level
 Serum haptoglobin level
 Urinalysis for hematuria
 Urinary hemosiderin
Peripheral blood smear poikilocytes, some spherocytes
- Heinz bodies : precipitates of denatured hemoglobin material
- “bite cells”

70. G6PD
Heinz bodies
bite cell

71. G6PD
 TREATMENT:
 Most individuals with glucose-6-phosphate dehydrogenase (G6PD)
deficiency do not need treatment. However, they should be taught to
avoid drugs and chemical exposures that can cause oxidant stress

72. Sickle cell disease
prototype of hereditary hemoglobinopathies
structurally abnormal hemoglobin from a point
mutation

73. Sickle cell disease

74. Sickle cell disease
severe anemia  generalized growth and developmental
impairment
- vaso-occlusive complications
- painful crisis: bones, lungs, liver, brain, spleen, penis
- acute chest syndrome
- aplastic crisis
- sequestration crisis (splenic hyperplasia  pooling of blood)
- chronic hyperbilirubinemia
- increased susceptibility to infection  septicemia, meningitis
(encapsulated bacteria)

75. Sickle cell disease
 Typical baseline abnormalities in the patient with SCD are as follows:
 Hemoglobin level is 5-9 g/dL
 Hematocrit is decreased to 17-29%
 Total leukocyte count is elevated to 12,000-20,000 cells/mm 3 (12-20 X
109/L), with a predominance of neutrophils
 Platelet count is increased
 Erythrocyte sedimentation rate is low
 Peripheral blood smears demonstrate target cells, elongated cells, and
characteristic sickle erythrocytes
 Presence of RBCs containing nuclear remnants (Howell-Jolly bodies)
indicates that the patient is asplenic

76. Sickle cell disease

77. Sickle cell disease

78. Sickle cell disease
 Traetment:The drugs used in treatment of sickle cell disease (SCD) include
antimetabolites, analgesics, antibiotics, and vaccines.
 Management of vaso-occlusive crisis
 Management of chronic pain syndromes
 Management of chronic hemolytic anemia
 Prevention and treatment of infections
 Management of the complications and the various organ damage
syndromes associated with the disease
 Prevention of stroke
 Detection and treatment of pulmonary hypertension

79. Megaloblastic anemia
 This results from a deficiency of vitamin B12 or folic acid, or from
disturbances in folic acid metabolism.
 Folate is an important substrate of, and vitamin B12 a co-factor for, the
generation of the essential amino acid methionine from homocysteine.
 Deficiency of either vitamin B12 or folate will therefore produce high
plasma levels of homocysteine and impaired DNA synthesis.
 The end result is cells with arrested nuclear maturation but normal
cytoplasmic development: so-called nucleocytoplasmic asynchrony.

80. Megaloblastic anemia
 Vitamin B12 deficiency, is associated with neurological disease in up to
40% of cases, although advanced neurological disease due to B12
deficiency is now uncommon in the developed world.
 The main pathological finding is focal demyelination affecting the (spinal
cord, peripheral nerves, optic nerves and cerebrum).
 The most common manifestations are sensory, with peripheral
paraesthesiae and ataxia of gait

81. Megaloblastic anemia

82. Megaloblastic anemia

83. Megaloblastic anemia
 Vitamin B12
 1 μg daily requirement.
 The liver stores enough vitamin B12 for 3 years, so B12 deficiency takes years to
become manifest.
 Measurements:
 Normal > 210 ng/L
 Intermediate 180–200 ng/L
 Low < 180 ng/L

84. Megaloblastic anemia
 Causes of deficiency:
1. Dietary deficiency.
2. Gastric pathology.
3. Pernicious anemia.
4. Small bowl pathology.

85. Megaloblastic anemia
 Treatment of B12 deficiency:
 Treat with hydroxycobalamin 1000 μg IM for 6 doses 2 or 3 days apart, followed
by maintenance therapy of 1000 μg every 3 months for life.
 The reticulocyte count will peak by the 5th–10th day after starting replacement
therapy.
 The haemoglobin will rise by 10 g/L every week until normalised.
 A sensory neuropathy may take 6–12 months to correct.
 Long-standing neurological damage may not improve

86. Megaloblastic anemia
 Folic acid
 The minimum daily intake of 50 μg.
 Excess cooking destroys folates.
 Total body stores of folate are small and deficiency can occur in a matter
of weeks.

87. Megaloblastic anemia
 Causes of deficiency:
1. diet.
2. Malabsorption.
3. Increased demands.
4. Drugs; (phenytoin, methotrexate and contraceptive pills)

88. Megaloblastic anemia
 Pregnancy-induced folate deficiency is the most common cause of
megaloblastosis worldwide and is more likely in the context of twin
pregnancies, multiparity and hyperemesis gravidarum.

89. Megaloblastic
 Treatment of folic acid deficiency:
 Oral folic acid 5 mg daily for 3 weeks will treat (acute deficiency).
 5 mg once weekly is adequate (maintenance therapy).
 Prophylactic folic acid in pregnancy prevents megaloblastosis in women
at risk, and reduces the risk of fetal neural tube defects.
 The use of folic acid alone in the presence of vitamin B12 deficiency may
result in worsening of neurological deficits.