anemia full review of the causes, etiology, diagnosis and treatments

1. By Ali S. Mayali
Anemia

2. DEFINITION
• any condition in which the number of red cells or the
amount of hemoglobin in the blood is less than
normal.
• pathophysiological condition in which the body
cannot meet its demands for oxygen.

3. BLOOD REFERENCE VALUES
• Hemoglobin (M: 13.0 – 17.0 g/dl and F: 12.0 – 15.0 g/dl)
• RBC count RBC count Males range 5.5 x 1012/L, Females 4.5 x 1012/L.
• Mean cell volume MCV (80 – 100 fl)
• Mean cell hemoglobin (27 – 32 pg)? the average mass of hemoglobin per red
blood cell in a sample of blood. MCH value is diminished in hypochromic
anemias.
• Mean cell hemoglobin concentration MCHC (30-35 g/dl).

4. CLASSIFICATION OF ANEMIA
• By color
• Hypochromic
• Normochromic
• Hyperchromic
• By volume
• Microcytic
• Normocytic
• Macrocytic
• Pathophysiologic classification
• RBC loss
• Decreased RBC production

5. CLASSIFICATION BY VOLUME
I. microcytic anemia (MCV <80 fl)
1. iron deficiency anemia
2. thalassemia syndromes
3. anemia of chronic disease
4. sideroblastic anemia
II. normocytic anemia (MCV 80-100 fl)
1. anemia of blood loss
2. hemolytic anemia
III. macrocytic anemia (MCV >100 fl)
1. megaloblastic anemia

6. PATHOPHYSIOLOGIC
CLASSIFICATION
I RBC loss
• Blood loss
• Increased RBC destruction
a. intrinsic abnormality
b. extrinsic abnormality
II Decreased RBC production
• Stem cell abnormality
• erythroblast abnormality
• Unknown/multiple mechanism

7. PATHOPHYSIOLOGIC
CLASSIFICATION
I RBC loss
• Blood loss
• acute : trauma, massive hemorrhage
• chronic : GI lesion, GYN lesion
• Increased RBC destruction
a. intrinsic abnormality
b. extrinsic abnormality

8. PATHOPHYSIOLOGIC
CLASSIFICATION
I RBC loss
• Blood loss
• Increased RBC destruction
a. intrinsic abnormality
i. membrane disorder (e.g. hereditary spherocytosis)
ii. enzyme disorder (e.g. G6PD deficiency & PKD)
iii. Hgb synthesis disorder (e.g. Thalassemia & sickle cell disease)
iv. acquired membrane defect
a. extrinsic abnormality

9. PATHOPHYSIOLOGIC
CLASSIFICATION
I RBC loss
• Blood loss
• Increased RBC destruction
a. intrinsic abnormality
b. extrinsic abnormality
a. mechanical trauma (e.g. TTP/HUS, DIC)
b. chemical injury (e.g. lead poisoning)
c. Infection (e.g. malaria)
d. immunologic injury (e.g. autoimmune hemolytic anemia)

10. PATHOPHYSIOLOGIC
CLASSIFICATION
I RBC loss
• Blood loss
• Increased RBC destruction
a. intrinsic abnormality
b. extrinsic abnormality
II Decreased RBC production
• Stem cell abnormality
• erythroblast abnormality
• Unknown/multiple mechanism

11. PATHOPHYSIOLOGIC
CLASSIFICATION
I RBC loss
• Blood loss
• Increased RBC destruction
a. intrinsic abnormality
b. extrinsic abnormality
II Decreased RBC production
• Stem cell abnormality (aplastic anemia)
• erythroblast abnormality (megaloblastic anemia & IDA)
• Unknown/multiple mechanism (sideroblastic anemia)

12. PATHOPHYSIOLOGIC
CLASSIFICATION
I RBC loss
• Blood loss
• Increased RBC destruction
a. intrinsic abnormality
i. membrane disorder (hereditary spherocytosis & elliptocytosis)
ii. enzyme disorder (e.g. G6PD deficiency & PKD)
iii. Hgb synthesis disorder (Thalassemia & sickle cell disease)
iv. acquired membrane defect (PNH)
a. extrinsic abnormality

13. HEREDITARY SPHEROCYTOSIS
• Deficiency of Beta Spectrin or Ankyrin  Loss of membrane surface
area becomes more spherical Destruction in Spleen
• Clinical findings:
2. splenomegaly
3. marked compensatory erythroid hyperplasia in BM
4. jaundice, pigment cholelithiasis (↑ bilirubin)
• Laboratory findings : normal MCV with increased MCHC
• Treatment: splenectomy

14. HEREDITARY ELLIPTOCYTOSIS
• Abnormally large number of patient’s erythrocytes are
elliptical rather than typical biconcave shape.
• Inherited disease (autosomal dominant)
• Impaired aggregation of spectrin.
• majority require no treatment.

15. PATHOPHYSIOLOGIC
CLASSIFICATION
I RBC loss
• Blood loss
• Increased RBC destruction
a. intrinsic abnormality
i. membrane disorder (hereditary spherocytosis & elliptocytosis)
ii. enzyme disorder (e.g. G6PD deficiency & PKD)
iii. Hgb synthesis disorder (Thalassemia & sickle cell disease)
iv. acquired membrane defect (PNH)
a. extrinsic abnormality

16. G6PD DEFICIENCY
• G6PD deficiency is an X-linked inherited condition in which the body
doesn't have enough of the enzyme glucose-6-phosphate
dehydrogenase
• Function? Pivotal enzyme in HMP Shunt & produces NADPH to
protect RBC against oxidative stress
• Most common enzymopathy -10% world’s population
• Neonatal jaundice
• Hemolysis after exposure to oxidant stress
• Drugs
• Fava beans

17. G6PD DEFICIENCY

18. G6PD DEFICIENCY
• Lab findings:
• Heinz bodies : precipitates of denatured hemoglobin material
• “bite cells”? When a macrophage in the spleen identifies a RBC with
a Heinz body, it removes the precipitate and a small piece of the
membrane, leading to characteristic "bite cells“
• Treatment:
• Stop the precipitating drug or treat the infection
• Acute transfusions if required

19. G6PD DEFICIENCY

20. PYRUVATE KINASE DEFICIENCY
• also called erythrocyte pyruvate kinase deficiency, is an inherited metabolic
disorder of the enzyme pyruvate kinase which affects the survival of red blood cells
due to inability to maintain normal ATP levels.
• Splenomegaly
• Diagnosis: 1. fluorescent spot test 2. enzyme assay
• patients tolerate anemia rather well ( result in: high levels of 2,3-DPG)
phosphoenol pyruvate pyruvate lactat
e
P
K
ADP ATP *NADH NAD

21. PATHOPHYSIOLOGIC
CLASSIFICATION
I RBC loss
• Blood loss
• Increased RBC destruction
a. intrinsic abnormality
i. membrane disorder (hereditary spherocytosis & elliptocytosis)
ii. enzyme disorder (G6PD deficiency & PKD)
iii. Hgb synthesis disorder (Thalassemia & sickle cell disease)
iv. acquired membrane defect (PNH)
a. extrinsic abnormality

22. THALASSEMIA SYNDROMES
• heterogeneous hemolytic disorders characterized by
quantitative abnormalities of hemoglobin synthesis.
• genetic defect in globin production > inadequate Hgb
formation > hypochromic anemia (low hemoglobin in
RBC)
• Types:
• α-thalassemia : α-chain deficiency
• β-thalassemia : β-chain deficiency

23. THALASSEMIA SYNDROMES
• There are many forms of thalassemia. Each type has
many different subtypes. Both alpha and beta
thalassemia include the following two forms:
• Thalassemia major (gene defect from both parents)
• Thalassemia minor (faulty gene from only one parent)
• α thalassemia major causes stillbirth
• Children born with β thalassemia major (Cooley's
anemia) are normal at birth, but develop severe
anemia after 6 months where HbF must be replaced
with HbA .

24. α-Thalassemia
• There are a total of 4 alpha globin genes, alpha
thalassemia result from the deletions of some or all
of the genes.Disease Defect Hb A % HbH % MCV,fl
Silent carrier (asymptomatic) One deletion 97 0 90
Thalassemia traits Two deletions 90-95 rare 70-80
HbH (B4) Three deletions 70-95 5-30 60-70
Hb Bart (hydrops fetalis) Four deletions
Death in utero
0 5-10

25. β Thalassemia Major
• Severe, homozygous
• Childhood, growth delay, chipmunk face.
• Severe anemia , hepatosplenomegaly
• Treatment:
• Require transfusion once to twice a month
• Treat iron overload (due to chronic transfusion, give deferasirox or
deferoxamine)
• splenectomy reduce hemolysis
• Bone marrow tranplantation might be used.
• Diagnosis:
• P. Smear- severe microcytosis, target cells
• Hb electrophoresis: HbF - 90-96 % HbA2- 3.5 %- 5.5% HbA - 0 %

26. β Thalassemia Intermedia
• Similar stigmata like major
• Survive without transfusion
• Less severe than major
• Moderate anemia, microcytosis, hypochromia
• Diagnosis:
• P. Smear- severe microcytosis, target cells
• Hb electrophoresis: HbF - 20% - 100% HbA2 3.5 % -
5.5% HbA 0% - 30%

27. β Thalassemia Minor
• Most of the time, they do not have symptoms.

28. SICKLE CELL DISEASE
• Severe hereditary form of anemia (recessive) in which
an abnormal hemoglobin (hemoglobin S) leads to
chronic hemolytic anemia, pain and organ failure.
• Structurally abnormal hemoglobin (hemoglobin S)
result from a point mutation in the β chain of
hemoglobin molecule (glutamic acid  valine).
• If only one parent has sickle cell; their child would have
sickle cell trait. People with sickle cell trait do not have
the symptoms of sickle cell anemia.
• Symptoms appears after 8 to 10 weeks of age, when
the HbF has been replaced by HbS.

29. SICKLE CELL DISEASE
• There are two major consequences of RBC sickling
• Chronic hemolytic anemia.
• Blood vessels occlusion.
• Premature destruction of RBC in the spleen causes
hemolysis and anemia.
• Vessels occlusion disrupt blood flow causing tissue
ischemia and pain crisis.
• Other symptoms: Fatigue, paleness, rapid heart rate and
shortness of breath
• Splenic infraction may lead to splenic dysfunction which
predispose the patient to infections.

30. SICKLE CELL DISEASE
• Neonatal diagnosis of sickle cell disease is made on
the basis of clinical findings and hemoglobin
electrophoresis.
• The goal of treatment is to manage and control
symptoms, and to limit the number of crises.

31. PATHOPHYSIOLOGIC
CLASSIFICATION
I RBC loss
• Blood loss
• Increased RBC destruction
a. intrinsic abnormality
i. membrane disorder (e.g. hereditary spherocytosis)
ii. enzyme disorder (G6PD deficiency & PKD)
iii. Hgb synthesis disorder (Thalassemia & sickle cell disease)
iv. Acquired membrane defect (PNH)
a. extrinsic abnormality

32. PAROXYSMAL NOCTURNAL
HEMOGLOBINURIA
• Is a rare disease in which red blood cells break down
earlier than normal.
• Persons with this disease have blood cells that are
missing a gene called PIG-A. This gene allows a substance
called glycosyl-phosphatidylinositol (GPI) to help certain
proteins stick to cells.
• Without PIG-A, important proteins cannot connect to the
cell surface and protect the cell from substances in the
blood called complement. As a result, red blood cells
break down too early. The red cells leak hemoglobin into
the blood, which can pass into the urine. This can happen
at any time, but is more likely to occur during the night or
early morning.
• Risk Factors: Unknown!

33. PATHOPHYSIOLOGIC
CLASSIFICATION
I RBC loss
• Blood loss
• Increased RBC destruction
a. intrinsic abnormality
b. extrinsic abnormality
a. mechanical trauma (e.g. TTP/HUS, DIC)
b. chemical injury (e.g. lead poisoning)
c. Infection (e.g. malaria)
d. immunologic injury (e.g. autoimmune hemolytic anemia)

34. MECHANICAL TRAUMA
• Mechanical heart valves, Arterial grafts: cause
shear stress damage
• March hemoglobinuria: Red cell damage in
capillaries of feet
• Thermal injury: burns
• Microangiopathic hemolytic anemia (MAHA):
by passage of RBC through fibrin strands
deposited in small vessels  disruption of RBC

35. PATHOPHYSIOLOGIC
CLASSIFICATION
I RBC loss
• Blood loss
• Increased RBC destruction
a. intrinsic abnormality
b. extrinsic abnormality
a. mechanical trauma (e.g. TTP/HUS, DIC)
b. chemical injury (e.g. lead poisoning)
c. Infection (e.g. malaria)
d. immunologic injury (e.g. autoimmune hemolytic anemia)

36. LEAD POISONING
• inhibition of 5’-nucleotidase and
sodium-potassium pump  decreased
RBC survival.
• Other chemical injury by drugs: oxidant
denaturation of hemoglobin e.g:
Dapsone, sulphasalazine, Arsenic gas,
Cu, Nitrates & Nitrobenzene.

37. PATHOPHYSIOLOGIC
CLASSIFICATION
I RBC loss
• Blood loss
• Increased RBC destruction
a. intrinsic abnormality
b. extrinsic abnormality
a. mechanical trauma (e.g. TTP/HUS, DIC)
b. chemical injury (e.g. lead poisoning)
c. Infection (e.g. malaria)
d. immunologic injury (e.g. autoimmune hemolytic anemia)

38. MALARIA
• intracellular protozoan parasite
(Plasmodium)
• intravascular hemolysis: severe called
‘Blackwater fever’
• worldwide infection affecting 100 million
people 1 to 1.5 million deaths each year.

39. PATHOPHYSIOLOGIC
CLASSIFICATION
I RBC loss
• Blood loss
• Increased RBC destruction
a. intrinsic abnormality
b. extrinsic abnormality
a. mechanical trauma (e.g. TTP/HUS, DIC)
b. chemical injury (e.g. lead poisoning)
c. Infection (e.g. malaria)
d. immunologic injury (e.g. autoimmune hemolytic anemia)

40. AUTOIMMUNE HEMOLYTIC
ANEMIA
• Result from RBC destruction due to RBC
autoantibodies: Ig G, M, E, A
• Most commonly-idiopathic
• Classification
• Warm AI hemolysis: Ab binds at 37degree
Celsius
• Cold AI Hemolysis: Ab binds at 4 degree
Celsius

41. Warm Al Hemolysis
• Can occurs at all age groups
• F > M
• Causes:
• 50% Idiopathic
• Rest - secondary causes: Lymphoid neoplasm, Solid
Tumors, Autoimmune and drugs like Alpha methyl
DOPA.
• Investigations:
• Normocytic, Increased LDH, Reticulocytosis, decreased
haptoglobin
• Increased indirect Bilirubin.
• Direct Coomb’s Test / Antiglobulin test
Direct antiglobulin test
demonstrating the presence of
autoantibodies (shown here) or
complement on the surface of
the red blood cell.
complement

42. Warm Al Hemolysis
•Treatment:
• Correct the underlying cause
• Prednisolone 1mg/kg orally until Hb reaches 10mg/dl then
taper slowly and stop
• Transfusion: for life threatening problems
• If no response to steroids > Splenectomy or
immunosuppressive: Azathioprine, Cyclophosphamide

43. Cold AI Hemolysis
• Usually IgM
• Acute or Chronic form
• Chronic:
• C/F:
• Elderly patients
• Cold , painful & often blue fingers, toes, ears, or nose ( Acrocyanosis)
• Investigations:
• e/o hemolysis
• P Smear: Microspherocytosis
• Ig M with specificity to I or I Ag

44. Cold AI Hemolysis
• Treatment:
• Treatment of the underlying
cause
• Keep extremities warm
• Steroids treatment
• Blood transfusion