RED BLOOD CELL DISORDERS

Microcytic Anemias
Chapter 5
 MICROCYTIC, HYPOCROMIC ANEMIAS

• 3.5 million people affected by anemia in the world. 50% is IDA.

• An individual is considered anemic when RBCs are no longer able

to supply oxygen to body tissues.

• Anemias can be classified by their physiology or morphology.

• Morphological class. based on RBCs indices

• Physiological class. based on symptoms and Bone marrow

response.
Normal RBC indices:

1. Mean corpuscular volume (MCV):

is the average red blood cell size in volume units 80 to 100 fl.

2. Mean corpuscular hemoglobin (MCH):

is the amount of hemoglobin per red blood cell in weight units
27 to 31 pg.

3. Mean corpuscular hemoglobin concentration (MCHC):

is the amount of hemoglobin relative to the size of the cell or
hemoglobin concentration per red blood cell in percentage
32 to 36%

4. Red Blood Cell Distribution Width (RDW)

is a parameter that measures the variation in red blood cell size or
red blood cell volume. RDW is elevated in accordance with
variation in red cell size (anisocytosis).
11.5 % to 14.5 %
II. Microcytic, Hypochromic Anemia:

• Hemoglobin synthesis is disrupted

• MCV is less than 80 fL
• MCHC is less than 32%
• RBCs appear as small cells and deficient in hemoglobin.

.
III. Types of Microcytic, Hypochromic Anemias:
1. Iron Deficiency Anemia (IDA)
2. Sideroblastic Anemia (Acquired and Inherited)
3. Thalassemias
4. Some anemias of inflammation or chronic disease which
evolved into IDA
 1. IRON DEFICIENCY ANEMIA (IDA)

A. Iron Intake and Absorption

Iron balance is regulated by various conditions:
• Amount of Iron ingested
• Amount of Iron absorbed
• RBC formation using recycled and new Iron
• Iron storage
• Iron loss through blood loss or other sources
• In an adult RBC production uses 90-95% of stored or
recycled Iron and 10% absorbed iron from ingestion
(small intestine)
Iron Intake and Absorption cont….

• In an infant 1 YR iron needed and absorbed through dietary ingestion

30% and recycled 70%.
• Dietary Iron is available as Heme-Iron through meats and as
nonheme/nonmeat Iron
• Absorbed Iron in the Fe+3 state is Reduced to the Fe +2 state by the stomach
acid and transported through the circulation to the Bone Marrow by the
transport protein Transferrin.

• Transferrin receptors in the Pronormoblast bind iron and ASAP begin

incorporation into the Heme molecule during erythropoiesis.

• Some conditions can compromise Iron absorption:

Gastric bypass, Celiac disease, atrophic gastritis, etc.
B. Stored and Recycled Iron:
• Iron is stored in liver, spleen, bone marrow, and skeletal muscle in
two different forms: Ferritin and Hemosiderin.

• Ferritin can be measured in plasma, whereas hemosiderin is more

often identified in the urine or in stained bone marrow smears.

• Most cases of iron deficiency relate to external blood loss especially

menorrhagia or slow GI bleed.
 IRON DEFICIENCY ANEMIA (IDA)

1. Pathophysiology and Symptoms:

• IDA can be the result of blood loss, inadequate Iron intake or as a

secondary condition caused by a disease process or conditions that
deplete Iron stores; GI bleed or pregnancy.

• IDA manifests as a microcytic, hypochromic process (RBCs small and

hemoglobin deficient).

• Iron starved RBCs divide more rapidly as they search for iron and smaller
because of excess cell divisions.

• Decrease RBC count, hemoglobin, hematocrit, MCV, and MCHC.

• Increased RDW (anisocytosis)

 Iron Deficiency Anemia (IDA) cont ….

2. Pathogenesis or development of IDA is a three-stage process:

Stage 1: Continuous storage iron depletion from bone marrow,

Anemia not apparent (stain BM smear no iron)
Ferritin decreases

Stage 2: Transport iron depleted and Transferrin or TIBC increases

TIBC (Total Iron Binding Capacity)
Iron-deficient erythropoiesis , slight microcytic hypochromic RBCs.

Stage 3 : Iron for HGB decreases, symptoms appears

Frank case of IDA in blood smear, Microcytes and hypochromia
 Peripheral blood smear picture in
Iron Deficiency Anemia

Red Blood Cells

Lack hemoglobin
Iron Deficiency Anemia (IDA) cont….

3. Laboratory Diagnosis:

Screening tests:
• Abnormal CBC results Hb lower, hypochromasia,
• Microcytosis = low MCV
• High RDW = aniso and poikilocytosis

Diagnostic tests:
• Serum iron – iron bound to transferrin – decreased.
• TIBC - available iron binding sites in the plasma – increased.
• Transferrin saturation – decreased.
• Ferritin – reflects iron levels in the cells and decreases as
bone marrow iron decreases.
Iron Deficiency Anemia cont….

4. Epidemiology
• Women more at risk

• Men less at risk

• Parasitism
5. Management of IDA:
• Treat underlying disease

• Ferrous sulfate

Expected response

• Reticulocyte count increases in 5 – 10 days

• Hb begins to increase in 2 – 3 weeks and returns to normal

in around 2 months.
 2. Sideroblastic Anemias
Etiology and patient clinical picture:
• This category of Anemias are related to mitochondrial overload.
• They can be inherited or acquired.
• Iron accumulates and leads to Iron deposits in the RBCs
precursors in the bone marrow, called ringed sideroblasts.

• Increased Ferritin and increased serum Iron.

• The inherited type can be congenital sex-linked
or autosomal recessive and it is the result of
inherited abnormal genes.
• The secondary acquired Iron loading may occur as a result of
alcoholism, lead poisoning, isoniazid, or chloramphenicol treatment.
Sideroblastic Anemias cont….

Patient’s Hematological picture:

Peripheral smear shows :
Microcytes with dimorphism (normal and Microcytes; some
normochromic and some hypochromic cells).
Presence of Pappenheimer bodies (abnormal deposits of iron inside
Red blood cells) that look like grape clusters.

RBC Dimorphism Pappenheimer bodies

 3. Hereditary Hemochromatosis

It is one of the most common major genetic disorders of individuals

of European ancestry. Almost 1 million in the U.S. are affected.
The HH is autosomal recessive disorder in chromosome 6
It can be homo or heterozygous.
Homozygotes and 10 % of heterozygotes are more prone to Iron overload.
These patients star to overload Iron since young age and continue with
every decade.
Diagnosis is made by accident with blood screening for unrelated issues
The Iron absorption overload in these patients is due to an abnormal gene that
regulates the amount of iron absorption from diet.
This faulty mechanism leads to Iron constantly loaded into storage sited and
leads to multi-organ damage and symptoms over decades.
HH cont ….

Patient’s Clinical and laboratory picture:

Symptoms are vague and varied, but common ones include;

• Chronic fatigue and weakness
• Cirrhosis of the liver
• Hyperpigmentation
• Diabetes
• Impotence
• Sterility
• Cardiac arrhythmias
• Tender swollen joints
• Hair loss
• Abdominal symptoms
HH cont ….

Laboratory test showing increased levels indicative of HH

• Serum Iron
• Serum ferritin (> 150 μg/L)
• Transferrin saturation (> 45%)

Laboratory test showing decreased levels:

• TIBC
• Transferrin

Treatment of HH
• Fatal untreated
• Advanced Iron overload leads to liver cancer
• Aggressive therapeutic phlebotomy
• Goal to reduce serum ferritin < 10 μg/ dL and 35% for Hematocrit
HH cont ….

• When ferritin normal, then phlebotomy 3 to 4 times a year

Iron excess depresses the immune system and influences development
of diabetes.

• Deferrioxamine treatment; chelates iron, the chelated iron is excreted in

urine.
 4. Thalassemia Syndromes

A. Etiology of Thalassemia Syndromes

• They have nothing to do with Iron deficiency

• They are globin chain disorders with lack of production of alpha or beta
globin chains.

• They are defects of the α or β hemoglobin chain synthesis in normal

adult Hgb A (α2,β2), Hgb A2 (α2,δ2), and Hgb F (α2,γ2), which affects
negatively the life span of the RBC.

• There are also multi-organ complications, development of microcytic

anemia, and a blood smear with many RBC morphological
abnormalities.
Thalassemias cont….

B. Types of Thalassemias:
Two types of thalassemias: Alpha and Beta thalassemias

C. Alpha (α) Thalassemias

• Results from gene deletions.
• There are four types of alpha thalassemias depending on the
inherited number of gene deletions .
Alpha thalassemias cont ….

1. Incidence od Alpha Thalassemias:

• High incidence in Asian, Saudi Arabian, and Filipino populations.
e.g. Thailand, Vietnam, Cambodia, Indonesia, and Laos.
• The alpha chains are essential to normal adult and fetal Hgbs
and without these globin chains Hgb F does not form.

2. Clinical Conditions of the 4 types of alpha (α) thalassemias:

I. Bart’s Hydrops Fetalis is the most severe with the absence of alpha
chains synthesis.
• No HgbA is form only Hgb Bart’s (γ2), which has a high affinity for
oxygen and fails to deliver it to tissues.
• A severe anemia develops which leads to stillbirth or spontaneous
abortion.
Alpha thalassemias cont ….

II. Hemoglobin H (Hgb H) is the next most severe.

• There is only one functional alpha gene and the other three are deleted
• Small amount of Hgb A is produce.
• Hgb H is produce instead (β4) which is very unstable.
• 40 to 50 % on AHE
• Hgb levels are < 10 g/dL
• Reticulocyte count 5 to 10 %
• Microcytes and Hypochromia with RBC fragments on smear
• Hgb H inclusions in RBCs look like a pitted golf ball
Alpha thalassemias cont ….

• The cells with H inclusions are pitted in the spleen, leaving the cell more
fragile, less elasticity, and a shorten life span.
• Patient with Hgb H disease have lifelong anemia with splenomegaly and
bone changes.
• Diagnosis extremely low MCV (< 60 fL) and RDW extremely elevated

III. Alpha Thalassemia Trait (two gene deletion)

• Less severe
• Patient with the trait type possess only two viable Hgb A genes and
may have mild anemia with microcytic, hypochromic cells
• Some Hgb Bart’s is formed
• Elliptocytes and target cells present
 IV. Alpha Thalassemia Silent Carrier (one gene deletion)
• A silent carrier presents may be unaware of condition
• Hematology normal or slightly microcytic
• Elliptocytes and target cells present

3. Diagnosis and Treatment of α Thalassemias

• Cord blood or amniocentesis fluid examined for the presence of alpha
genes through molecular or electrophoresis techniques.
Thalassemias cont….

D. Beta Thalassemias

1. β Thalassemia Major: Cooley’s Anemia, Mediterranean Anemia

• Inherited blood disorder ( > 2 million in U.S. carriers)

• In β Thalassemia Major (as a result of 2 carrier parents, mendelian

genetics) little or not β chain is synthesized, as a result no or very
little Hgb A is synthesized.

• Serious genetic blood disorder; affecting multiple organs, quality of

life, and longevity.
Beta Thalassemias cont….

• Affected infants do not show symptoms for first 6 months because of

Hgb F. After 6 months, production Hgb F continues. There is
α chain imbalance, cannot combine, are unpaired, and precipitate
inside the RBCs. This causes shortening of life span from
7 to 22 days.

• Children between 2 to 4 years old begin to show S/S (sign/symptom)

• failure to thrive
• irritability
• enlarged spleen (splenomegaly)
• S/S of anemia
• jaundice
β Thalassemias cont….

• Patients Clinical Picture and Prognosis

• Underlying severe anemia
• Hgb about 6 to 9 g/dL
• Peripheral smear shows a severe microcytic, hypochromic with high
numbers of nucleated RBCs, marked polychromasia and
poikilocytosis.
β thalassemias cont ….

• Overexpansion of the capable bone marrow (BM increases output up

to 20 times). Bone quality is thin and fragile.

• Pathological fractures and bony changes in facial structure

(Thalassemic facies) and skull give patients a strange look.

• Protrusion of the skull is prominent with orthodontic misalignment.

• Spleen excessively enlarged due to daily harboring and sequestering

of abnormal RBCs causing severe hemolysis.

• One of the main problems is Iron overload; increased diet Iron

absorption due to increased hematopoiesis and transfusions.
β thalassemias cont ….

Splenomegaly in a child

Removed spleen of a child 10

to 15 times larger than normal
β thalassemias cont ….

Treatment of β thalassemias

• High-transfusion therapy (every 2 to 5 weeks) to keep patient Hgb

close to 10 g/dL.

• Iron overload increases risk of cardiac function and liver and endocrine
complications.

• Bone marrow and Stem cell transplantation

• Iron chelating therapy

β thalassemias cont ….

2. Thalassemia Intermedia or β thalassemia Trait

• Heterozygous condition one abnormal gene inherited.
• Clinically symptoms develop later in life and may not need transfusions.
• Splenomegaly present
• Bone changes may be present, but mild.
• May need chelating therapy
• It mimics IDA due to presence of microcytic, hypochromic indices,
moderately low Hgb and Hct. However, it shows an increased RBC
count.
• Hgb A2 increases to 5 to 10 %.
β thalassemias cont ….
QUESTIONS?