Anemia

Elias s. (MD+)
August 2015
DBU
 Outline
• Introduction

• Classification

• Iron deficiency anemia

• Anemia of chronic illness

• Megaloblastic anemia

• Hemolytic anemia
 Introduction
• Anemia is defined as a reduced absolute number of circulating RBCs

• Can be measured by the following parameters

– Hemoglobin concentration
• <13 g/dL for men
• <12 g/dL for women

– hematocrit
• <40% for men
• <36% for women

– RBC count

• Results in manifestations due to reduced oxygen delivery to tissues

 Classification
• Designed for systematic approach of different causes of
anemia

• There are two approaches of classification

I. Kinetic approach
– Based on the mechanisms responsible for the anemia

II. Morphologic approach

– Based on the size of RBCs and the reticulocyte response
 Kinetic approach
A. Anemia due to decreased RBC production
– Also known as ineffective erythropoesis
– Causes include
• Lack of nutrients- iron, folate, or B12
• Bone marrow disorders- aplastic anemia, MDS, tumor infiltration
• Bone marrow suppression- drugs, irradiation
• Anemia of chronic disease/inflammation

B. Anemia due to increased RBC destruction

– Hemolytic anemias

C. Anemia due to blood loss

– Obvious or occult bleeding
 Morphologic approach
• The normal RBC has a volume of 80-100 femtoliters (fL),
equal to that of the nucleus of a small lymphocyte

• RBCs larger than the nucleus of a small lymphocyte on a

peripheral smear are considered macrocytic, while those
that appear smaller are considered microcytic

• Normochromic
– MCH- 27-33 or central pallor of RBCS <1/3rd of the size of RBC

• Hypochromic
– MCH <27 or central pallor >1/3rd of the size of RBC
 Macrocytic normochromic
anemia
• MCV >100fL

• Causes include
– Folate deficiency
– Cobalamin deficiency
– Any condition causing marked reticulocytosis
– Alcohol abuse, hypothyroidism
– Drugs- zidovudine, methotrexate, and hydroxyurea

• Megaloblastic anemia
– Due to folate and cobalamin deficiency
– Characterized by hypersegmented neutrophils
• Microcytic hypochromic anemia
– Iron deficiency
– Lead poisoning
– Sideroblastic anemia
– Thalassemia
– Anemia of chronic illness (30% of the cases)

• Normocytic normochromic anemia

– Anemia of chronic illness (70% of the cases)
– CKD
– Early iron deficiency anemia
– Acute blood loss
ANEMIAS OF DIMINISHED
ERYTHROPIESIS
• Result from deficiency of some vital nutrients necessary for
RBC formation
 Anemia of Vit B12 and folate deficiency-Megaloblastic anemia

 Iron deficiency anemia

 Anemia of chronic illness

 Anemia of renal failure

 Aplastic anemia

 Pure red cell aplasia

 Megaloblastic anemia

• Two principal types

1. Cobalamin deficiency anemia
2. Folate deficiency anemia

• It results in defect in DNA synthesis which lead to

 Enlargement of erythroid precursors (megaloblast)
 Large cells in peripheral blood (macrocytes)
 Hypersegmented neutrophils

• The precise basis for the changes is not fully

understood
• Vit B12 and Folate are coenzymes required for synthesis of
thymidine

• Deficiency or impairment in their metabolism results in defective

nuclear maturation

• Delay or block cell division

• The synthesis of RNA and protein is relatively unaffected

• Cytoplasmic maturation proceeds in advance of nuclear

maturation-
Nuclear/Cytoplasmic asynchrony
 Morphology
Certain morphologic features are common to all
 Pancytopenia

 Marked variation in size and shape of red cells(Anisopoikliocytosis)

 RBC-macrocytic & oval(Macro-ovalocytes)

 MCV > 100fl

 Reticulocyte count is low

 Nucleated red cells occasionally

• Neutrophils
 Larger –Macropolymorphonuclear
 Hypersegmented-Five or six nuclear lobules

• Marrow is hypercellular

• Megaloblastic change is detected in all stages of red

cell development

• The nucleus fails to undergo the chromatin clumping

• Granulocytes precursors also display
nuclear/cytoplasm asynchrony

• Megakaryocytes-Abnormally large and have

bizarre, multilobed nuclei

• The anemia is further exacerbated by increased

hemolytic destruction

• Mild to moderate Fe overload

Anemia due to Vitamin B12
Deficiency
 Normal Vit B12 Metabolism
• Human are totally dependent on diet

• Daily requirement-1-3µg.

• Absorption require intrinsic factor

• Vit B12 freed from binding protein by pepsin

• Free Vit B12 binds to cobalophilins(R-binder)

• This complexes are broken down by pancreatic protease

• Vit B12 then associates with intrinsic factor

• Endocytosis

• Binding with transcobalamin II

 Etiology
• Inadequate diet- stricts vegans

• Impaired absorption
 Intrinsic factor deficiency
 Gasterectomy
 Ileal resection
 Tape worm infestation
 Diffuse intestinal disease
 Chronic pancreatitis

• Increased requirement
 Pregnancy, cancer, chronic infection, hyperthyroidism
 Pernicious anemia
• A specific form of megaloblastic anemia caused by
 Atrophic gastritis and

 An attendant failure of intrinsic factors production

• Leads to vitamin B12 deficiency

• Commonly associated with other autoimmune diseases like

Grave’s disease, Addison’s disease, vitiligo, and
hypoparathyroidism

• Peak age of onset is 60 years

 Biochemical function
• Two reactions in human are known to require
vit B12

1. Thymidylate synthesis DNA

2. Isomerization of methylmalonyl coenzyme A

to succinyl coenzyme A
 Incidence
• Occur in all racial group

• More prevalent in Scandinavian and ‘English

speaking’ population

• Disease of older age

• Genetic predisposition is strongly suspected

 Pathogenesis
• Pernicious anemia believed to result from
immunologically mediated destruction of gastric
mucosa.

• The resultant chronic atrophic gastritis is marked by

 Loss of parietal cells
 Prominent infiltrate of lymphocyte and plasma cells,
 Megaloblastic changes in mucosal cells

• Three type of antibodies are present

• Type I antibody-block binding of Vit B12 to IF

• Type II-Prevent binding of IF-VitB12 complex to ileal

receptor

• Type III-non specific

• Autoreactive T-cell response initiate gastric mucosal injury

• When the mass of IF-secreting cells falls below threshold

and reserve depleted- anemia develops
 Morphology
Bone marrow
• The change in bone marrow and blood are similar to
megaloblastic anemia

Alimentary system
• The tongue-shiny, glazed and ‘beefy’-atrophic glossitis

• Stomach-
 Diffuse chronic gastritis
 Atrophy of fundic glands
 Intestinalization
 Megaloblastic change
CNS manifestations
• Found in 3/4th patients

• The spinal cord

 Degeneration of myelin in the dorsal and lateral tract
 Sometimes followed by loss of axon

• Degenerative change in the ganglia of posterior roots and

peripheral nerves

• Psychiatric features are also seen in some patients with

cobalamin or folate deficiencies
 Diagnostic features
• Megaloblastic anemia
• Leukopenia with hypersegmented granulcytes
• Thrombocytopenia
• Mild jaundice
• Neurologic changes
• Achlorhydria
• Inability to absorb an oral dose of cobalamin
• Low serum level Vit B12
• Elevated levels of homocystiene and MMA
• Striking reticulocytosis and improvement in Hct about 5
days after parenteral Vit B12
 Folate deficiency
• A deficiency of folic acid result in megaloblastic anemia

• Have the same characteristic as vit B12 but no neurologic

changes

• FH4 is biological ‘middleman’ in one carbon metabolic process

 Purine synthesis

 dTMP synthesis

• Depressed synthesis of DNA is the immediate cause

Etiology
• Diagnosis can be made only by demonstration of
decreased folate levels in the serum or red cells

• Elevated homocystein with normal MMA level

• Hematologic symptoms of vit B12 deficiency

anemia respond to Folate therapy

• But doesn’t prevent the progression of

neurologic deficits ( May even exacerbate)
 Treatment of megaloblastic
anemia
• Cobalamin deficiency
– Lifelong regular cobalamin injections
– Hydroxycobalamin or cyanocobalamin can be used
– Hydroxycobalamin 1000µg IM weekly for 6 wks followed by 1000µg IM every 3
months lifelong

• Folate deficiency
– Folic acid 5-15 mg po/day
– Rule out cobalamin deficiency before initiating folic acid
– Duration of treatment depends on the underlying cause

• Prophylactic folic acid is indicated during

– Pregnancy
– Premature infants
– Chronic dialysis patients
– Patients on total parentral nutrition
 Iron deficiency anemia
 The most common nutritional disorder world wide

 Globally, 50% of anemia is attributable to iron deficiency

 Prevalence higher in developing countries

 Africa and Asia bear 71% of the global mortality burden

due to iron deficiency anemia

 Common also in US-toddlers, adolescent girls

 Iron metabolism

 The normal diet of western diet contains-10-20mg per day

 The total body iron content is normally about 2gm in

women & 6 gm in men

 It is divided into functional & storage comportment

 About 80% of functional found in Hb, myoglobin and

enzymes

 The storage pool is represented by ferritin & hemosiderin-

15-20% of total body Fe
• Free Fe is highly toxic, and storage iron is tightly bound to either
ferritin or hemosiderin

• Very small amount of ferritin normally circulate in the plasma

• Level correlate with body Fe store

• Fe is transported in plasma by Fe-binding glycoprotein-

transferrin

• 33% of transferrin saturated with Fe yielding serum Fe level-

120µg/dL in men and 100µg/dL in women
• So total iron binding capacity of serum is 300-
350µg/dL

• Most Fe is absorbed in duodenum through two

distinct pathways

• Since body loss of Fe is limited, Fe balance is

maintained by regulating absorptive intake

• Mechanisms are still incompletely understood

 Etiology
 Decreased intake
 Rare in industrialized countries(Can occur in infants, children,
elderly)

 Increased demand
 Growing infants, children and adolescents
 during pregnancy

 Impaired absorption
 Celiac disease,Tropical sprue
 Gasterectomy

 Chronic blood loss

 Commonest cause in western
 Morphology

In peripheral smear RBCs are

 Small (microcytic) &

 Pale (hypochromic)

 Poikilocytosis in the form of small elongated red cells (pencil

cells) are characteristic

In bone marrow,
 Erythroid hyperplasia

 The disappearance of stainable iron from monocyte phagocytic

cells is a diagnostic finding-Prussian blue stain
 Prussian Blue Stain
of Bone Marrow

Iron Present No Iron Present

 Clinical features
• Non specific Sx and Sn of anemia

• In addition to the anemia other changes can

occur with severe deficiency – koilonychia,
alopecia, atrophic changes in tongue & gastric
mucosa and intestinal malabsorption

• The dominating Sn and Sx relate to the

underlying cause
Koilonychias
 Diagnosis
Laboratory findings
 Decreased Hct & Hb level

 Hypochromia, microcytosis with poikilocytosis

 Low serum iron & ferritin level

 Total iron binding capacity ( reflecting transferrin

saturation) is high
 Treatment of iron deficiency
anemia
• Red cell transfusion- indications
– Cardiovascular instability
– HCT <15%
– Continued and excessive blood loss
– Patients requiring immediate intervention

• Oral iron therapy

– 300mg of elemental iron per day
– Ideally, should be taken on empty stomach
– Should continue for a period of 6-12 months after correction of the
anemia
– Response- the reticulocyte count begin to increase after 4-7days of
therapy and peak at 10 days
– S/E include abdominal pain, nausea, vomiting, and constipation
• Parentral iron therapy- indicated for patients
– Who are unable to tolerate oral iron
– Whose needs are relatively acute
– Who need iron on an ongoing basis, usually due to persistent GI blood
loss
– Taking EPO

• Preparations include
– Iron dextran
– Ferric gluconate

• Feared complication- anaphylaxis, especially with iron dextran

infusion
– Anaphylaxis is much rarer with the newer preparations
 Anemia of chronic disease

 Impaired red cell production associated with chronic disease

 Most common cause of anemia in hospitalized patients

 It is associated with reduced erythroid proliferation & impaired iron

utilization

 Mimic Iron deficiency anemia

 The clinical conditions associated with this anemia can be grouped

into three.
 Chronic microbial infection
 Chronic immune disorders
 Neoplasms
• Common features
 Low serum iron
 Reduced TIBC in association with abundant stored Fe

• Impairment of iron transfer from the storage pool to the

erythroid precursors

• Inadequate proliferation of erythroid progenitors

because erythropoitin levels are inappropriately low for
the degree of anemia

• Reduction caused by the action of IL-1, TNF , IFN-γ

• The anemia is usually mild

• The red blood cells could be normocytic

normochromic or microcytic hypochromic

• How to differentiate from Fe deficieny anemia?

Increased storage Fe
High serum ferritin
Reduced TIBC
 Fe TIBC Ferritin

Fe Deficiency low High(>300) low

Anemia of low low Normal to high

Chronic Dx

Aplastic anemia High Extremely high Normal to high

 Aplastic anemia

• Aplastic anemia is pancytopenia with bone

marrow hypocellularity

• It is a syndrome of marrow failure

characterized by suppression of multipotent
myeloid stem cells, associated with anemia,
thrombocytopenia & neutropenia
(pancytopenia)
 Etiology
• Usually idiopathic(65%)

• Drugs & chemicals

• Whole body irradiation

• Infection

• Fanconi anemia
Pathogenesis
• Not fully understood

• Two major etiologies have been invoked;

Immunologically mediated suppression
Intrinsic abnormality of stem cells

• Most commonly result from suppression of stem

cell function by activated T cells
Morphology
 Markedly hypocellular marrow largely devoid of
hematopoitic cells,

 Often only fat cell, fibrous stroma & scattered lymphocytes

& plasma cells remain

 Marrow aspiration is usually dry

 The diagnosis rests on examination of bone marrow biopsy

 Granulocytopenia and thrombocytopenia

Clinical course
 Aplastic anemia can occur at any age

 The onset is usually insidious

 Anemia, petechiae & ecchymoses and infections occur

 Splenomegally is characteristically absent

 The red cells are typically normocytic normochromic

 Reticulocytopenia is the rule

Diagnosis
• Bone marrow biopsy and peripheral blood

• Marrow is hypocellular

• It’s important to distinguish it from other

causes of pancytopenia
PROGNOSIS
• Unpredictable