Classification of Anemia
– Anemia is classified according to:
Red cell volume (MCV)
Hb content (MHC, MCHC)
Microcytic hypochromic anemia
– Low indices
– RBC are small and low Hb
Normocytic normochromic anemia
– Normal indices
– Normal cell and normal Hb but reduced number/ impaired function
Macrocytic anemia
– High MCV
– MCHC is never high (RBCs can’t be overpacked)
Pathophysiology & clinical manifestations of anemia
Pathophysiology
– Reduced blood oxygen-carrying capacity
– Hypoxemia leading to hypoxia which impair functions of al body cells (all organs can be affected)
– Manifestations vary according to severity and the ability of the body to compensate
Classic symptoms
– Fatigue
– Weakness
– Dyspnea
– Pallor
o Key sign of anemia
o *Always check the conjunctiva 
Microcytic-Hypochromic Anemias
Red cells are small and contain less hemoglobin (MCV <80 fL)
General causes:
Iron deficiency
Impaired iron uptake, metabolism, absorption, transport
Impaired porphyrin formation (ring around heme)
Impaired globin synthesis (the structure of the protein that makes hemoglobin; hemoglobinopathies)
Will details 3 examples of microcytic-hypochromic anemias:
– Iron deficiency anemia
– Sideroblastic anemia
– Thalassemia (form of Hemoglobinopathies)
Iron deficiency anemia
The most common type of anemia worldwide
Etiology:
Chronic blood loss. Potential causes include:
– Women with heavy menses or chronic spotting related to menses
– Bleeding gastric or duodenal ulcer
Figure 8: Pallor in the hand (right)
compared to normal coloration
Figure 9: Microscopic comparison of
normal RBCs (left) to Microcytic
hypochromic RBCs (right)
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– Medications:
o E.g. Excessive use of Ibuprofen inducing gastritis or ulcer
Defective iron utilization
– The body is unable to absorb, uptake and use the iron effectively
o E.g. Surgical procedures such as gastric bypass that decrease stomach acidity, intestinal transit time, and/or absorption
o Chronic disease eg renal failure
Nutritional
– Low dietary iron
Pathophysiology
Impaired function of mitochondrial enzymes (dependent on iron as cofactor) leads to impaired metabolism and ATP generation. This explains fatigue
Decreased iron stores (ferritin) combined with increase need for hemoglobin synthesis to compensate for blood loss
Eventually low serum iron
Clinical Manifestations
Early:
– Fatigue, weakness, shortness of breath, pallor
Advanced:
– Brittle, thin, coarsely rigid, and spoon shaped nails (koilonychia)
– Angular stomatitis
o Inflamed and dry mouth, lips, tongue
o Atrophied tongue papillae leading to soreness, redness and burning
o Typically resolves within 1-2 weeks of iron replacement
Other manifestations related to additional physiological processes requiring iron:
– Gastritis
– Neuromuscular changes
– Irritability, headache
– Numbness, tingling, vasomotor disturbances
– Pica: cravings for non-nutritional substances such as clay, dirt and chalk
Main lab data:
Low serum iron
Low ferritin (iron storage protein)
– Medications:
o E.g. Excessive use of Ibuprofen inducing gastritis or ulcer
Defective iron utilization
– The body is unable to absorb, uptake and use the iron effectively
o E.g. Surgical procedures such as gastric bypass that decrease stomach acidity, intestinal transit time, and/or absorption
o Chronic disease eg renal failure
Nutritional
– Low dietary iron
Pathophysiology
Impaired function of mitochondrial enzymes (dependent on iron as cofactor) leads to impaired metabolism and ATP generation. This explains fatigue
Decreased iron stores (ferritin) combined with increase need for hemoglobin synthesis to compensate for blood loss
Eventually low serum iron
Clinical Manifestations
Early:
– Fatigue, weakness, shortness of breath, pallor
Advanced:
– Brittle, thin, coarsely rigid, and spoon shaped nails (koilonychia)
– Angular stomatitis
o Inflamed and dry mouth, lips, tongue
o Atrophied tongue papillae leading to soreness, redness and burning
o Typically resolves within 1-2 weeks of iron replacement
Other manifestations related to additional physiological processes requiring iron:
– Gastritis
– Neuromuscular changes
– Irritability, headache
– Numbness, tingling, vasomotor disturbances
– Pica: cravings for non-nutritional substances such as clay, dirt and chalk
Main lab data:
Low serum iron
Low ferritin (iron storage protein)
Sideroblastic anemia
A group of disorders characterized by anemia of varying severity related to inefficient iron uptake leading to abnormal hemoglobin synthesis, as well as the presence of ringed sideroblasts in the bone marrow
– Sideroblasts = erythrocytes containing iron granules that have not been incorporated into hemoglobin
Causes:
May be hereditary or acquired
Hereditary
– Rare and almost exclusively in males
– Present in infancy or childhood but may not manifest until midlife when other conditions occurring from iron overload (e.g. diabetes, cardiac failure) begin to manifest
Acquired:
– Myelodysplastic syndromes (MDS)
o Usually all stem cell lineage are abnormal; however, in some cases only the erythrocytic line of stem cells is affected
o If all stem cell lineages, impaired platelets = bleeding, and impaired granulocytes = infection will be observed
– Patients are treated with blood transfusions with the risk of iron overload
– Of those who survive, 40% develop Acute myeloblastic leukemia (AML)
Reversible:
– Acquired SA associated with secondary conditions that can be corrected once treatment is initiated to treat underlying cause. Includes:
o Excessive alcohol use resulting in folate deficiencies
– Drug reactions
o E.g. Anti-tuberculous agents which can interfere with B12 metabolism or directly injure mitochondria
– Copper deficiency
– Hypothermia
– Pyridoxine deficiency (vitamin B6)
– Lead poisoning
Pathophysiology
Ineffective iron uptake dysfunctional hemoglobin synthesis
Cell injury due to inflammatory reaction and altered mitochondrial activity
Clinical and lab manifestations
Common signs/symptoms of anemia
Ringed Sideroblasts in bone marrow are diagnostic
– Test with blue stain to see the Sideroblasts
Manifestation of siderosis (depositing excess iron in body)
Can be treated with pyroxidine (B6) if that is the issue
Treatment:
Hereditary SA can be usually treated with pyroxidine (B6) therapy at 50-200 mg/day
Death related to SA is rare and usually occurs from secondary condition
Hemosiderosis (iron overload)
Increased plasma iron leading to deposition in various body tissues
Causes:
Congenital:
– Genetic defect increasing iron absorption
– Known as Hemochromatosis
– Iron is absorbed but not utilized, so level rises
Acquired – Severe chronic hemolysis of any cause
– Iron is released from Hb
– Multiple frequent blood transfusions (thalassemias, sickle cell, MDS)
– Excess parenteral iron supplements (iron poisoning)
Clinical manifestations
Due to deposition of iron in tissues: mainly liver, heart, pancreas, spleen
Hemosiderosis focal iron deposition related to excess iron within an organ that does not
result cause no tissue damage
Hemochromatosis is typically a systemic process in which iron deposition can cause tissue damage
Treatment
Phlebotomy 
Haemoglobinopathies
Hemoglobinopathies are a set of inherited disorders affecting the protein structure and thus function of the hemoglobin molecule
Pathophysiology
Increased RBC destruction due to altered structure
Impaired function of RBCs will affect oxygen carrying capacity and distribution to tissues
Increased destruction combined with altered function leads to manifestations of anemia
Thalassemias
The most common hemoglobinopathy
Hereditary disorder primarily affecting those of African, Middle Eastern, and Mediterranean descent
Defective hemoglobin synthesis due to defects in the alpha or beta chains of the globin molecule
– Results in low intracellular hemoglobin (hypochromic); and
– Relative excess of the unaffected chain
Pathophysiology and symptoms:
Bone marrow hyperplasia
– BM increase synthesis of RBCs to compensate for low levels of Hb
– This hyperactivity leads to abnormal bone (face and skull) structure
Splenomegaly
– Due to increased destruction of old/damaged cells
– Worsens the anemia
Iron overload
– If multiple transfusions are required
Normocytic-Normochromic Anemia
Red cells are relatively normal in size and Hb content but low in number
Causes and classifications:
Bone marrow failure (aplastic anemias)
– Disorder affecting hemopoetic stem cell precursors (located in the bone marrow) and therefore affecting all blood cell lines
– Leads to pancytopenia
– Bone marrow biopsy is required to determine whether cause is pure red cell aplasia or hypoplasia
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Post-hemorrhagic anemia:
Hemolytic anemia:
– Increased hemolysis of cells stemming from hereditary abnormalities in RBCs or acquired disease conditions
– Trauma to RBCs within blood vessels from shear forces against vessel wall cause RBC fragmentation and intravascular hemolysis
o This can occur with prosthetic heart valves
o Conditions with both hemolysis and deposition of fibrin and platelets within the blood vessel that leads to microvascular narrowing (e.g. disseminated intravascular coagulation (DIC), hemolytic uremic syndrome (HUS) – both discussed in later chapters)
Immune destruction of RBCs:
– Antibodies bind to RBCs leading to premature destruction
– Two types:
o Warm antibody disease mediated by IgG
o Cold antibody disease mediated by IgM
Drug induced hemolysis
Chronic inflammation or infection
– e.g. AIDS, rheumatoid arthritis, SLE
– May occur in malignancies
o Decreased RBC lifespan, or a failure of compensatory mechanisms related to progression of disease
Hemoglobinopathies associated with hemolysis
– Sickle cell anemia
o Globin chain deficiency leading to sickle (fragile) RBCs
o Sufficient amounts of hemoglobin is produced, however there is increased destruction of defective (sickled; fragile) cells
o The remaining RBCs being normal in size and structure (hence, normocytic-normochromic classification)
Pathophysiology and manifestations
The pathophysiology and manifestations vary according to disease conditions
Underlying diseases causing hemolysis determines the pathophysiology and subsequent symptoms
– For example, a person who has suffered acute hemorrhage and a person with a bone marrow or autoimmune condition will both have normocytic normochromic anemia, however one results from severe blood loss while the other results from an impaired erythropoiesis
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Generally, conditions with increased hemolysis will lead to splenomegaly and bone marrow hyperplasia (if the bone marrow is able to continue to produce cells)
Macrocytic (megaloblasic) Anemia
– MCV >100 + hyper-segmented neutrophils
Neutrophils are normally bi-lobed, but in macrocytic anemia are multi-lobed due to B12 and B9 deficiency
Cause:
Vitamin B12 (Cobalamin) deficiency
Synthetic form of Vitamin B12 is Cyanocobalamin
Can be caused by low levels of intrinsic factor (IF)
1) IF is produced by parietal cells of the stomach lining
2) Cause of Pernicious Anemia (see below)
Other potential causes include:
1) Insufficient intake (primarily seen in vegans)
2) Malabsorption related to decrease IF follow gastric bypass surgery, autoimmune condition, or other gastric conditions that impact acidity
The manifestations take a long time to develop and are bad once developed
B12 deficiency leads to demyelination of nerves resulting in memory loss, ataxia, dementia
– The relationship between B12 and dementia has led to increased attention to B12 supplements in the treatment of Alzheimer’s disease
Folic acid (B9) deficiency
Vitamin B9 = Folic acid (folate)
More common than B12 deficiency
This deficiency causes impaired DNA and RNA synthesis in bone marrow (erythropoiesis)
Symptoms show once stores are depleted (3-4 months) and include:
1) Cheilosis (dry, cracked mouth)
2) Stomatitis (swelling of mouth)
3) Can cause GI disorders
4) Causes no neuropsychiatric symptoms.
Treatment for deficiency is supplements
Pathophysiology
Vitamins B12 and B9 are coenzymes required for DNA synthesis
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Impaired metabolic reactions involving homocysteine and methylmalonate, as they require B12 and B9 to complete the reactions
– Levels of homocysteine and methylmalonate increase
There is impaired DNA synthesis and nuclear maturation
– Inadequate DNA synthesis leads to defective nuclear maturation and rapidly proliferating cells
– The RBC overproduces hemoglobin during a delayed division leading to macrocytosis
(1) Macrocytosis: Disproportionate growth of nucleus & cytoplasm
(2) This results in a large cell with a small nucleus
Timing of manifestations resulting from B12 and/or B9 deficiency are dependent on body stores.
It is when body stores are depleted that symptoms begin to manifest
– B12 stores last 3-4 years
– B9 stores last 3-4 months
– It is deficiency of both resulting in impaired DNA.
Pernicious Anemia
Autoimmune vitamin B12 deficiency (seen with autoimmune thyroiditis, type 1 DM and vitiligo)
Etiology/Patho:
Lack of intrinsic factor required for B12 absorption (anti-intrinsic factor antibody)
Manifestations:
General manifestations of anemia
– Dyspnea, weakness, fatigue
Neurologic manifestations related to
demyelination of nerves
– Loss of vibration sense
– Ataxia
– Spasticity
Others:
– Loss of appetite
– Abdominal pain
– Beefy red tongue (atrophic glossitis)
– Icterus (jaundice)
– Splenic enlargement = due to wanting to save RBC
Polycythemia
Overproduction of RBCs
Can be classified into:
1. Absolute polycythemia
– Primary (Polycythemia Rubra Vera; PRV)
o Abnormality of stem cells in the bone marrow. High number of RBCs = sticky blood; increase blood viscosity inducing clotting tendency
– Secondary
o Condition of chronic hypoxia:
• Leading to an increase in erythropoietin (EPO) hormone
• Increased EPO leads to increased production of RBCs by the bone marrow
• The body increases RBC production in response to need
o Potential causes:
• High altitude
• Hypoxia associated with respiratory or cardiovascular diseases
• EPO secreting tumor
2. Relative polycythemia
– Results from dehydration
o Clinically manifests with an increase in blood viscosity
– Loss of vibration sense
– Ataxia
– Spasticity
Others:
– Loss of appetite
– Abdominal pain
– Beefy red tongue (atrophic glossitis)
– Icterus (jaundice)
– Splenic enlargement = due to wanting to save RBC
Polycythemia
Overproduction of RBCs
Can be classified into:
1. Absolute polycythemia
– Primary (Polycythemia Rubra Vera; PRV)
o Abnormality of stem cells in the bone marrow. High number of RBCs = sticky blood; increase blood viscosity inducing clotting tendency
– Secondary
o Condition of chronic hypoxia:
• Leading to an increase in erythropoietin (EPO) hormone
• Increased EPO leads to increased production of RBCs by the bone marrow
• The body increases RBC production in response to need
o Potential causes:
• High altitude
• Hypoxia associated with respiratory or cardiovascular diseases
• EPO secreting tumor
2. Relative polycythemia
– Results from dehydration
o Clinically manifests with an increase in blood viscosity