PATHOLOGY
Anemia
Definition ↓RBC/Hb [] in blood
Causes - Blood loss (e.g. hemorrhage)
- Impaired RBC production
- ↑destruction (hemolysis)
- Fluid overload (e.g. HF)
Type Acute & chronic
Classification 1. Normochromic, normocytic (Normal MCHC & MCV):
- Anemia of chronic disease (e.g. cancer, SLE)
- Hemolytic anemia
- Acute hemorrhage
- Aplastic anemia
2. Hypochromic, microcytic (↓ MCHC & MCV):
- Iron deficiency anemia
- Thalassemia
- Chronic disease anemia
3. Normochromic, macrocytic (Normal MCHC, ↑ MCV):
- Vitamin B12 deficiency
- Folate deficiency
- Macrocytic anemia can be megaloblastic or non-megaloblastic
Morphological type - Hereditary spherocytosis
- Sickle cell anemia
S&S - Dizziness, headache, impaired cognition, fatigue, loss of appetite
- Dyspnea, tachypnea, tachycardia
- Reduced exercise tolerance
- Peripheral edema, cold/clammy skin
- Brittle nails
Iron deficiency anemia (IDA)
Definition ↓ Hb due to ↓ iron availability for hemoglobin synthesis
Causes - Chronic blood loss (e.g. GI bleed, menorrhagia)
- ↑ demand (e.g. pregnancy, growth)
- ↓ intake (malnutrition)
- ↓ absorption (e.g. celiac disease, gastrectomy)
Morphology Histology
- Pale & smaller RBC
- Tear drop shape (dacrocytes)
- Pencil shape (elliptocytes
Clinical - Fatigue
- Dyspnea
- Pallor
- Glossitis
- Conjunctiva pallor
- Koilonychia (spoon nails)
- Pica (craving non-food items)
Complication - Delayed growth and development (in children) –
- Poor pregnancy outcomes
- ↓ exercise tolerance
Dx - ↓ Hb, ↓ MCV, ↓ MCHC
- ↓ serum ferritin, ↓ serum iron
- ↑ TIBC (total iron-binding capacity)
- Blood film: microcytic, hypochromic RBCs
Tx - Oral iron supplements (ferrous sulfate)
- IV iron if malabsorption or intolerance
- Treat underlying cause (e.g. bleeding source)
Fe overload
Definition Condition where there is ↑ iron in the body
Causes Primary:
- Genetic (e.g. hereditary hemochromatosis)
Secondary:
- Oral or parenteral iron overload
- Ineffective erythropoiesis
, - Transfusion-dependent (e.g. thalassemia)
- Chronic liver disease
Types 1. Hemochromatosis:
- Excessive Fe absorption stored in parenchymal organs (liver, pancreas)
- Leads to tissue damage & liver cirrhosis
2. Hemosiderosis:
- Excess Fe stored as hemosiderin in liver, spleen, bone marrow
3. Hemosiderin:
- Complex aggregate of partially denatured ferritin
4. Sideroblastic anemia:
- RBC precursors fail to use Fe → accumulation in sideroblasts
Features - Liver cirrhosis
- Cardiomyopathy
- Bronze diabetes (pancreatic damage + DM)
- Bronze skin pigmentation
- Polyarthropathy
- Hypogonadism → infertility
Tx Iron chelation therapy
- Deferoxamine – IV/subcutaneous infusion (older but effective)
- Deferasirox – oral, more convenient
- Deferiprone – also oral, used if others aren’t enough
Limit transfusions (if possible)
Monitor iron levels
- Ferritin levels
- Liver iron concentration (MRI)
Liver protection – monitor for fibrosis or cirrhosis in long-term case
Macrocytic anemia
Type & Macrocytic non-megaloblastic (normoblast)
Cause - Liver cell disorder
- Chronic alcoholism
- Aplastic anemia
Macrocytic megaloblastic (megaloblast – large & immature RBC)
- Vit B12 deficiency / pernicious anemia
- Folate deficiency
Pernicious Anemia
Definition Type of macrocytic megaloblastic anemia
Cause Vitamin B12 deficiency due to autoimmune destruction of intrinsic factor-producing gastric cells
Etiology - ↓ intake (strict vegan, rare)
- Pernicious anemia (autoimmune destruction of parietal cells → ↓ IF)
- Malabsorption (Crohn’s disease, gastrectomy)
- Fish tapeworm, bacterial overgrowth
- Pregnancy, hyperthyroidism, cancer
Morphology Histology
- Hypersegmented neutrophils (6–8 lobes)
Pathogenesis ↓ IF → ↓ vitamin B12 absorption
- ↓ DNA synthesis
- Delayed nuclear maturation & division → megaloblasts → macrocytosis
- Ineffective hematopoiesis → apoptosis in marrow → pancytopenia
Clinical Features - Pallor, fatigue, dyspnea
- CHF, mild jaundice
- Neuropathy: symmetrical numbness, tingling, burning feet
Folic Acid Deficiency - Alcohol, malabsorption
- Hemodialysis, pregnancy, cancer
- Drugs: methotrexate (folate antagonist)
- Folate destroyed by cooking; needs fresh uncooked veggies/fruits
Dx - ↓ serum vitamin B12
- Normal/high serum folate
- Achlorhydria
- Serum anti-IF antibodies
- Abnormal Schilling test – radiometric test w B12 absorption
,Tx Lifelong vitamin B12 replacement
- IM injection of hydroxocobalamin or cyanocobalamin (Usually 1 mg IM every day for 1 week, then weekly for 1 month, then
monthly for life)
Monitor for response:
- Reticulocyte count ↑ in a few days
- Hemoglobin normalizes in ~2 months
- Neurological symptoms may take longer or may not fully reverse if late
Hemolytic anemia (HA)
Definition Anemia caused by ↑ rate of premature red blood cell (RBC) destruction
Sites of Hemolysis Intravascular (in bloodstream):
- ↑ Plasma Hb (hemoglobinemia) → hemoglobinuria
- Causes: mechanical trauma (e.g. defective valve), biochemical/physical agents
Extravascular (in spleen/liver, RES):
- Heme converted to bilirubin & recycled
- Plasma Hb not significantly raised unless ↓ haptoglobin
Clinical Features - Pallor
- Mild jaundice (hyperbilirubinemia)
- Dark urine (↑ urobilinogen)
- Splenomegaly (chronic HA)
- Pigment gallstones
- Positive family history
Lab Tests 1. ↑ RBC Production Evidence:
- ↑ Reticulocytes
- Macrocytosis, normoblasts in blood film
- Marrow erythroid hyperplasia
- X-ray: marrow expansion
2. RBC Damage Tests:
- Abnormal RBC morphology
- ↑ Osmotic fragility
- Autohemolysis test, Coombs, electrophoresis
- G6PD/sickle screening
3. ↓ RBC Lifespan (Cr labelling):
- Normal: 120d
- Moderate: 20–40d
- Severe: 5–20d
4. ↑ Breakdown Evidence:
- ↑ Bilirubin, urobilinogen (urine), stercobilinogen (feces)
- ↑ Plasma LDH, hemoglobinemia, hemoglobinuria (intravascular)
Tx - Treat underlying cause – e.g. stop offending drugs, treat infections
- Folic acid supplementation – to support increased erythropoiesis
- Blood transfusion – for severe anemia or crisis
- Corticosteroids – if autoimmune (like in warm AIHA)
- Immunosuppressants – in refractory autoimmune cases
- Splenectomy – in some chronic or autoimmune cases (esp. hereditary spherocytosis)
- Plasmapheresis – for some severe autoimmune types (like cold AIHA)
- Avoid triggers – for things like G6PD deficiency (e.g. fava beans, oxidant drugs)
Hereditary spherocytosis
Definition HA due to inherited RBC membrane defect
Formation of spheroidal, non-deformable cells prone to sequestration and destruction in the spleen.
Inheritance - Autosomal dominant (75%) → mild/no symptoms
- Autosomal recessive (25%) → more severe
- Homozygous = severe anemia, heterozygous = milder form
Morphology - Microcytic (↓ MCV)
- Hyperchromatic (↑ MCHC)
- Lack of central pallor
Pathogenesis Mutation affects membrane skeleton proteins (spectrin, ankyrin, band 3) → weakens vertical linkage → membrane vesicle loss → ↓ surface
area-to-volume ratio → spherocyte formation.
Spleen’s Role Spherocytes are less deformable → trapped in splenic cords → phagocytosed by macrophages.
Splenectomy corrects anemia, but spherocytes remain.
Clinical Features - Variable anemia
- Splenomegaly
- Jaundice
- Pigment gallstones, cholelithiasis
, - Systemic hemosiderosis
- Aplastic crisis (Parvovirus B19 infection)
Dx - Blood film: spherocytes, hyperchromatic microcytes, no central pallor
- ↑ Reticulocytes
- ↑ Serum bilirubin
- Erythroid hyperplasia
- ↑ Osmotic fragility (in hypotonic solution)
Hereditary elliptocytosis (ovalocytosis)
Definition Autosomal dominant disorder of RBC membrane involving spectrin–actin interaction due to band 4.1 defect
Acquired Causes - Iron deficiency
- Myeloproliferative disorders
Morphology - Elliptical or oval-shaped RBCs
- Less fragile compared to HS
- Milder hemolysis on peripheral blood film
Pathogenesis Disruption in spectrin–actin linkage caused by mutation in band 4.1 protein → impairs membrane stability and flexibility.
Similar to hereditary spherocytosis but milder.
Dx - Blood smear: elliptocytes
- Family history
- Mild anemia or asymptomatic in many cases
Tx Often not required; usually benign. Severe cases may consider splenectomy
Hereditary stomatocytosis
Definition A rare genetic disorder characterized by a defect in the membrane protein stomatin
- Leading to ↑permeability of RBCs to Na+ and K+.
Epidemiology Rare; occurs in both children and adults; can present in different populations, often in individuals of European descent.
Cause/Etiology Mutation in the gene coding for stomatin, a membrane protein
This defect results in abnormal RBC membrane permeability to sodium and potassium ions.
Morphology RBCs take on a distinctive "stomatocyte" shape (cup-shaped), with one concave and one convex surface.
Pathophysiology The defect in stomatin leads to altered ion channels, causing increased permeability to Na+ and K+, resulting in swollen RBCs due to
overhydration.
Pathogenesis The loss of ion regulation in RBCs causes water influx, swelling of RBCs, and the stomatocyte morphology.
Clinical Features - Anemia (due to hemolysis)
- Splenomegaly
- Fatigue
- Jaundice
- Mild hepatomegaly
Complications - Hemolytic anemia
- Splenomegaly
- HF
Diagnosis - Blood smear showing stomatocytes
- Genetic testing for stomatin mutations
- Assessment of RBC osmotic fragility.
Treatment No specific treatment for hereditary stomatocytosis
Management focuses on treating anemia (e.g., folate supplementation, blood transfusions if necessary).
Glucose-6-phosphate deficiency
Definition Hereditary RBC enzyme deficiency in the hexose monophosphate shunt, leading to vulnerability to oxidative stress and HA
Epidemiology Higher frequency in Mediterranean countries, Southeast Asia, and Africa
More common in Africa due to providing resistance to Falciparum malaria.
Cause/Etology - X-linked recessive inheritance
- Deficiency in G6PD enzyme (which is responsible for protecting RBCs from oxidative damage by maintaining glutathione in its
reduced form)
Type Type A
- Africa
Type B
- Western
Morphology - Heinz bodies (denatured hemoglobin) precipitate in RBCs
- Bite cells form as phagocytes remove Heinz bodies → resulting in further destruction of RBCs.
Pathophysiology Deficiency of G6PD impairs the reduction of NADP to NADPH
- preventing RBCs from combating oxidative damage, leading to hemolysis.
- Heinz bodies form when oxidized hemoglobin precipitates.
- Over time, RBCs become less deformable and are destroyed in the spleen, causing intravascular and extravascular hemolysis.
Pathogenesis 1. G6PD deficiency reduces NADPH, impairing the protection of RBCs from oxidative stress.
2. Oxidative stress damages RBC membranes, forming Heinz bodies.
Anemia
Definition ↓RBC/Hb [] in blood
Causes - Blood loss (e.g. hemorrhage)
- Impaired RBC production
- ↑destruction (hemolysis)
- Fluid overload (e.g. HF)
Type Acute & chronic
Classification 1. Normochromic, normocytic (Normal MCHC & MCV):
- Anemia of chronic disease (e.g. cancer, SLE)
- Hemolytic anemia
- Acute hemorrhage
- Aplastic anemia
2. Hypochromic, microcytic (↓ MCHC & MCV):
- Iron deficiency anemia
- Thalassemia
- Chronic disease anemia
3. Normochromic, macrocytic (Normal MCHC, ↑ MCV):
- Vitamin B12 deficiency
- Folate deficiency
- Macrocytic anemia can be megaloblastic or non-megaloblastic
Morphological type - Hereditary spherocytosis
- Sickle cell anemia
S&S - Dizziness, headache, impaired cognition, fatigue, loss of appetite
- Dyspnea, tachypnea, tachycardia
- Reduced exercise tolerance
- Peripheral edema, cold/clammy skin
- Brittle nails
Iron deficiency anemia (IDA)
Definition ↓ Hb due to ↓ iron availability for hemoglobin synthesis
Causes - Chronic blood loss (e.g. GI bleed, menorrhagia)
- ↑ demand (e.g. pregnancy, growth)
- ↓ intake (malnutrition)
- ↓ absorption (e.g. celiac disease, gastrectomy)
Morphology Histology
- Pale & smaller RBC
- Tear drop shape (dacrocytes)
- Pencil shape (elliptocytes
Clinical - Fatigue
- Dyspnea
- Pallor
- Glossitis
- Conjunctiva pallor
- Koilonychia (spoon nails)
- Pica (craving non-food items)
Complication - Delayed growth and development (in children) –
- Poor pregnancy outcomes
- ↓ exercise tolerance
Dx - ↓ Hb, ↓ MCV, ↓ MCHC
- ↓ serum ferritin, ↓ serum iron
- ↑ TIBC (total iron-binding capacity)
- Blood film: microcytic, hypochromic RBCs
Tx - Oral iron supplements (ferrous sulfate)
- IV iron if malabsorption or intolerance
- Treat underlying cause (e.g. bleeding source)
Fe overload
Definition Condition where there is ↑ iron in the body
Causes Primary:
- Genetic (e.g. hereditary hemochromatosis)
Secondary:
- Oral or parenteral iron overload
- Ineffective erythropoiesis
, - Transfusion-dependent (e.g. thalassemia)
- Chronic liver disease
Types 1. Hemochromatosis:
- Excessive Fe absorption stored in parenchymal organs (liver, pancreas)
- Leads to tissue damage & liver cirrhosis
2. Hemosiderosis:
- Excess Fe stored as hemosiderin in liver, spleen, bone marrow
3. Hemosiderin:
- Complex aggregate of partially denatured ferritin
4. Sideroblastic anemia:
- RBC precursors fail to use Fe → accumulation in sideroblasts
Features - Liver cirrhosis
- Cardiomyopathy
- Bronze diabetes (pancreatic damage + DM)
- Bronze skin pigmentation
- Polyarthropathy
- Hypogonadism → infertility
Tx Iron chelation therapy
- Deferoxamine – IV/subcutaneous infusion (older but effective)
- Deferasirox – oral, more convenient
- Deferiprone – also oral, used if others aren’t enough
Limit transfusions (if possible)
Monitor iron levels
- Ferritin levels
- Liver iron concentration (MRI)
Liver protection – monitor for fibrosis or cirrhosis in long-term case
Macrocytic anemia
Type & Macrocytic non-megaloblastic (normoblast)
Cause - Liver cell disorder
- Chronic alcoholism
- Aplastic anemia
Macrocytic megaloblastic (megaloblast – large & immature RBC)
- Vit B12 deficiency / pernicious anemia
- Folate deficiency
Pernicious Anemia
Definition Type of macrocytic megaloblastic anemia
Cause Vitamin B12 deficiency due to autoimmune destruction of intrinsic factor-producing gastric cells
Etiology - ↓ intake (strict vegan, rare)
- Pernicious anemia (autoimmune destruction of parietal cells → ↓ IF)
- Malabsorption (Crohn’s disease, gastrectomy)
- Fish tapeworm, bacterial overgrowth
- Pregnancy, hyperthyroidism, cancer
Morphology Histology
- Hypersegmented neutrophils (6–8 lobes)
Pathogenesis ↓ IF → ↓ vitamin B12 absorption
- ↓ DNA synthesis
- Delayed nuclear maturation & division → megaloblasts → macrocytosis
- Ineffective hematopoiesis → apoptosis in marrow → pancytopenia
Clinical Features - Pallor, fatigue, dyspnea
- CHF, mild jaundice
- Neuropathy: symmetrical numbness, tingling, burning feet
Folic Acid Deficiency - Alcohol, malabsorption
- Hemodialysis, pregnancy, cancer
- Drugs: methotrexate (folate antagonist)
- Folate destroyed by cooking; needs fresh uncooked veggies/fruits
Dx - ↓ serum vitamin B12
- Normal/high serum folate
- Achlorhydria
- Serum anti-IF antibodies
- Abnormal Schilling test – radiometric test w B12 absorption
,Tx Lifelong vitamin B12 replacement
- IM injection of hydroxocobalamin or cyanocobalamin (Usually 1 mg IM every day for 1 week, then weekly for 1 month, then
monthly for life)
Monitor for response:
- Reticulocyte count ↑ in a few days
- Hemoglobin normalizes in ~2 months
- Neurological symptoms may take longer or may not fully reverse if late
Hemolytic anemia (HA)
Definition Anemia caused by ↑ rate of premature red blood cell (RBC) destruction
Sites of Hemolysis Intravascular (in bloodstream):
- ↑ Plasma Hb (hemoglobinemia) → hemoglobinuria
- Causes: mechanical trauma (e.g. defective valve), biochemical/physical agents
Extravascular (in spleen/liver, RES):
- Heme converted to bilirubin & recycled
- Plasma Hb not significantly raised unless ↓ haptoglobin
Clinical Features - Pallor
- Mild jaundice (hyperbilirubinemia)
- Dark urine (↑ urobilinogen)
- Splenomegaly (chronic HA)
- Pigment gallstones
- Positive family history
Lab Tests 1. ↑ RBC Production Evidence:
- ↑ Reticulocytes
- Macrocytosis, normoblasts in blood film
- Marrow erythroid hyperplasia
- X-ray: marrow expansion
2. RBC Damage Tests:
- Abnormal RBC morphology
- ↑ Osmotic fragility
- Autohemolysis test, Coombs, electrophoresis
- G6PD/sickle screening
3. ↓ RBC Lifespan (Cr labelling):
- Normal: 120d
- Moderate: 20–40d
- Severe: 5–20d
4. ↑ Breakdown Evidence:
- ↑ Bilirubin, urobilinogen (urine), stercobilinogen (feces)
- ↑ Plasma LDH, hemoglobinemia, hemoglobinuria (intravascular)
Tx - Treat underlying cause – e.g. stop offending drugs, treat infections
- Folic acid supplementation – to support increased erythropoiesis
- Blood transfusion – for severe anemia or crisis
- Corticosteroids – if autoimmune (like in warm AIHA)
- Immunosuppressants – in refractory autoimmune cases
- Splenectomy – in some chronic or autoimmune cases (esp. hereditary spherocytosis)
- Plasmapheresis – for some severe autoimmune types (like cold AIHA)
- Avoid triggers – for things like G6PD deficiency (e.g. fava beans, oxidant drugs)
Hereditary spherocytosis
Definition HA due to inherited RBC membrane defect
Formation of spheroidal, non-deformable cells prone to sequestration and destruction in the spleen.
Inheritance - Autosomal dominant (75%) → mild/no symptoms
- Autosomal recessive (25%) → more severe
- Homozygous = severe anemia, heterozygous = milder form
Morphology - Microcytic (↓ MCV)
- Hyperchromatic (↑ MCHC)
- Lack of central pallor
Pathogenesis Mutation affects membrane skeleton proteins (spectrin, ankyrin, band 3) → weakens vertical linkage → membrane vesicle loss → ↓ surface
area-to-volume ratio → spherocyte formation.
Spleen’s Role Spherocytes are less deformable → trapped in splenic cords → phagocytosed by macrophages.
Splenectomy corrects anemia, but spherocytes remain.
Clinical Features - Variable anemia
- Splenomegaly
- Jaundice
- Pigment gallstones, cholelithiasis
, - Systemic hemosiderosis
- Aplastic crisis (Parvovirus B19 infection)
Dx - Blood film: spherocytes, hyperchromatic microcytes, no central pallor
- ↑ Reticulocytes
- ↑ Serum bilirubin
- Erythroid hyperplasia
- ↑ Osmotic fragility (in hypotonic solution)
Hereditary elliptocytosis (ovalocytosis)
Definition Autosomal dominant disorder of RBC membrane involving spectrin–actin interaction due to band 4.1 defect
Acquired Causes - Iron deficiency
- Myeloproliferative disorders
Morphology - Elliptical or oval-shaped RBCs
- Less fragile compared to HS
- Milder hemolysis on peripheral blood film
Pathogenesis Disruption in spectrin–actin linkage caused by mutation in band 4.1 protein → impairs membrane stability and flexibility.
Similar to hereditary spherocytosis but milder.
Dx - Blood smear: elliptocytes
- Family history
- Mild anemia or asymptomatic in many cases
Tx Often not required; usually benign. Severe cases may consider splenectomy
Hereditary stomatocytosis
Definition A rare genetic disorder characterized by a defect in the membrane protein stomatin
- Leading to ↑permeability of RBCs to Na+ and K+.
Epidemiology Rare; occurs in both children and adults; can present in different populations, often in individuals of European descent.
Cause/Etiology Mutation in the gene coding for stomatin, a membrane protein
This defect results in abnormal RBC membrane permeability to sodium and potassium ions.
Morphology RBCs take on a distinctive "stomatocyte" shape (cup-shaped), with one concave and one convex surface.
Pathophysiology The defect in stomatin leads to altered ion channels, causing increased permeability to Na+ and K+, resulting in swollen RBCs due to
overhydration.
Pathogenesis The loss of ion regulation in RBCs causes water influx, swelling of RBCs, and the stomatocyte morphology.
Clinical Features - Anemia (due to hemolysis)
- Splenomegaly
- Fatigue
- Jaundice
- Mild hepatomegaly
Complications - Hemolytic anemia
- Splenomegaly
- HF
Diagnosis - Blood smear showing stomatocytes
- Genetic testing for stomatin mutations
- Assessment of RBC osmotic fragility.
Treatment No specific treatment for hereditary stomatocytosis
Management focuses on treating anemia (e.g., folate supplementation, blood transfusions if necessary).
Glucose-6-phosphate deficiency
Definition Hereditary RBC enzyme deficiency in the hexose monophosphate shunt, leading to vulnerability to oxidative stress and HA
Epidemiology Higher frequency in Mediterranean countries, Southeast Asia, and Africa
More common in Africa due to providing resistance to Falciparum malaria.
Cause/Etology - X-linked recessive inheritance
- Deficiency in G6PD enzyme (which is responsible for protecting RBCs from oxidative damage by maintaining glutathione in its
reduced form)
Type Type A
- Africa
Type B
- Western
Morphology - Heinz bodies (denatured hemoglobin) precipitate in RBCs
- Bite cells form as phagocytes remove Heinz bodies → resulting in further destruction of RBCs.
Pathophysiology Deficiency of G6PD impairs the reduction of NADP to NADPH
- preventing RBCs from combating oxidative damage, leading to hemolysis.
- Heinz bodies form when oxidized hemoglobin precipitates.
- Over time, RBCs become less deformable and are destroyed in the spleen, causing intravascular and extravascular hemolysis.
Pathogenesis 1. G6PD deficiency reduces NADPH, impairing the protection of RBCs from oxidative stress.
2. Oxidative stress damages RBC membranes, forming Heinz bodies.
