1.

Red blood cell disorders Anemia Anemia is a laboratory diagnosis Classification of anemias on the basis of
etiology and pathogenesis
Male Female
Decreased red cell mass and hemoglobin
Hemoglobin (g/L) 135-175 120-160
• Anemia of blood loss
Anemia Polycythemia Hematocrit (%) 41-53 36-46
– Acute or chronic bleeding
Anemia is a laboratory diagnosis RBC Count (1012/L) 4.5-5.9 4.0-5.2
• Hemolytic anemia
Ferritin (µg/L) 30-300 10-200 – Intrinsic (corpuscular defect)
Red blood cell parameters determined with hematology Reticulocytes (%) 0.5-2.5 – Extrinsic (antibody or mechanical)
analyzers: MCV (fL) 78-100 • Anemia due to impaired RBC production
– Mean corpuscular volume (MCV)
– Mean corpuscular hemoglobin (MCH) MCH (pg/RBC) 26.0-34.0 – Stem cell defect (aplastic anemia)
– Mean corpuscular hemoglobin concentration (MCHC) MCHC (g/L of RBC) 310-370 – Defective DNA, hemoglobin synthesis etc
– Red cell distribution width (RDW), variation in red blood RDW (fL) 39-46
cell size or red blood cell volume RDW (%) 11.6-14.6

Morphologic classification of Blood loss anemia (1) Blood loss anemia (2)
anemias Acute posthemorrhagic anemia – after rapid loss (during 1 day)
more than 1 liter of blood.
• Microcytic hypochromic Acute blood loss is accompanied by a loss of vascular volume Chronic blood loss does not affect blood volume but instead leads
– Iron deficiency, thalassemia and carries with it a risk of hypovolemia and shock. to iron-deficiency anemia when iron stores are depleted.
• Normocytic, normochromic
– Anemia of chronic disease, hemolytic anemia Hydremic phase – 2-3 days after hemorrhage. The red cells are Because of compensatory mechanisms, patients commonly have
• Macrocytic normal in size and color. Hemodilution caused by movement of no symptoms until the hemoglobin level is less than 80 g/L. The
fluid into the vascular compartment produces a fall in red blood red cells that are produced have too little hemoglobin, giving rise
– Megaloblastic (B-12 and folate deficiency) to microcytic hypochromic anemia.
cell count, hemoglobin, and hematocrit.
• Anemias characterized by abnormal red blood
shapes The hypoxia that results from blood loss stimulates red cell
– elliptocytosis, spherocytosis, sickle cell anemia production by the bone marrow. If the bleeding is controlled and
sufficient iron stores are available, the red cell concentration
returns to normal within 3 to 4 weeks.

Hemolytic anemia (1) Hereditary spherocytosis Sickle cell anemia (1)

Intracorpuscular defects Extracorpuscular defects • Sickle cell disease and its variants are genetic disorders
structural abnormalities antibodies, infectious agents, or resulting from the presence of a mutated form of
• The primary defect in the genes encoding either ankyrin, hemoglobin, hemoglobin S (substitution of glutamic
mechanical factors
or α or β chain of spectrin acid by valine, synthesis of an abnormal beta chain)
• The most common hereditary disease of red blood cells • Most prevalent among blacks
(sickle cell anemia, (autoimmune hemolytic anemia,
hemolytic disease of the newborn, in whites • Multiple infarcts in various organs
thalassemia, or hereditary
spherocytosis) transfusion reactions, malaria, • Autosomal dominant disease neurologic defects, sharp pain in the bones, spleen
hemolytic anemia caused by • Peipheral blood: spherocytes, anisocytosis (autosplenectomy), and extremities, retinal infarcts
cardiac valve prosthesis, DIC) • Hemolytic or aplastic crises – splenomegaly and • Hyperbilirubinemia and jaundice (bile stones)
Hemolytic anemia (2) jaundice
• Splenectomy • Retarded intellectual development and neurologic
• anemia (i.e., low erythrocyte count)
deficits
• compensatory erythroid hyperplasia of the bone marrow
• Cardiopulmonary insufficiency
• hyperbilirubinemia and jaundice
• Recurrent infections

Sickle cell anemia (2) Thalassemia (1) Thalassemia (2) Inherited enzyme defects
• Genetic defect in the synthesis of HbA that reduces The most common inherited enzyme defect that results in
the rate of globin chain synthesis hemolytic anemia is a deficiency of glucose-6-phosphate
• Hypochromic anemia dehydrogenase (G6PD). The gene that determines this enzyme
• No abnormal hemoglobin is produced is located on the X chromosome, and the defect is expressed
• Thalassemia beta - reduced synthesis of the beta chain • Splenomegaly, hemosiderosis, and hepatomegaly
only in males and homozygous females.
• Thalassemia alpha - reduced synthesis of the alpha chain • Bone marrow - compensatory hyperplasia
of globin • Hyperbilirubinemia and jaundice The disorder makes red cells more vulnerable to oxidants and
• Thalassemia minor or thalassemia trait • Chronic anemia retards the growth of children causes direct oxidation of hemoglobin to methemoglobin and
– heterozygotes • Impairment of normal intellectual development the denaturing of the hemoglobin molecule to form Heinz
• Cardiorespiratory insufficiency bodies, which precipitate within the red blood cell. Hemolysis
– mild and nonspecific symptoms usually occurs as the damaged red blood cells move through
• Thalassemia major the narrow vessels of the spleen.
– homozygotes
– severe and serious disease The hemolysis is short-lived, occurring 2 to 3 days after the
trigger event.
 Heinz bodies
• Alloantibodies come from an exogenous source and are
• Autoantibodies
inclusions within red blood cells
composed of denatured hemoglobin
Iron deficiency anemia
• The most common form of anemia
• Hypochromic microcytic anemia
• Low serum iron and ferritin levels
• Epithelial tissue atrophy is common and
results in waxy pallor, brittle hair and nails,
smooth tongue, sores in the corners of the
mouth, and sometimes dysphagia and
decreased acid secretion.
Causes of vitamin B12 deficiency (2)
Immune mediated chronic
atrophic gastritis is a disorder that
destroys the gastric mucosa, with
loss of parietal cells and
production of antibodies that
interfere with the binding of
vitamin B12 to the intrinsic
factor. Other causes of vitamin
B12 deficiency anemia include
gastrectomy, ileal resection, and
malabsorption syndromes.
Immune mediated hemolytic anemias Autoantibodies
Anemia due to impaired RBC production
Warm-reacting antibodies of the immunoglobulin G (IgG) type,
which are maximally active at 37 C. 50% are idiopathic, and 50%
are drug induced or are related to cancers of the lymphoproliferative
system or collagen diseases. They react with antigens on the red cell
• Defective DNA, hemoglobin synthesis (deficiency of iron,
membrane, causing destructive changes, with subsequent phagocytic
responsible for transfusion reactions and hemolytic vitamin B12, folic acid)
destruction in the spleen.
• Stem cell defect (aplastic anemia)
disease of the newborn
Cold-reacting antibodies of the immunoglobulin M (IgM) type,
which are optimally active at or near 4 C. They activate
complement. Chronic hemolytic anemia caused by cold-reacting
antibodies occurs with lymphoproliferative disorders and as an
idiopathic disorder of unknown cause. Vascular obstruction by red
cells results in pallor, cyanosis of the body parts exposed to cold
temperatures, and Raynaud’s phenomenon
Megaloblastic anemia
• Caused by abnormal nucleic acid synthesis that results in enlarged
Normal peripheral smear Iron deficiency anemia
red cells (MCV >100 fL) and deficient nuclear maturation.
• Cobalamin (vitamin B12) and folic acid deficiencies are the most
common cause of megaloblastic anemias.
Vitamin B12 and folic acid
• Essential for the synthesis of DNA
• Vitamin B12 is involved in a reaction that prevents abnormal fatty
acids from being incorporated into neuronal lipids. This
abnormality may predispose to myelin breakdown and production
of the neurologic complications
Causes of vitamin B12 deficiency (1)
Vitamin B12 is found in all foods of animal origin. Dietary
deficiency is rare and usually found only in strict vegetarians
who avoid all dairy products as well as meat and fish.
Megaloblastic anemia
Causes of folic acid deficiency Aplastic anemia
Folic acid is found in vegetables (particularly the green leafy • Anemia, leukopenia, thrombocytopenia
types), fruits, cereals, and meats. However, much of the vitamin is
• Aplastic hypocellular bone marrow
lost in cooking.
• Causes:
The most common causes of folic acid deficiency are malnutrition Idiopathic (2/3 of cases)
or dietary lack, especially in the elderly or in association Acquired (secondary)
with alcoholism, and malabsorption syndromes such as sprue – Cytotoxic drugs
or other intestinal disorders – Chemicals (benzene)
– Infection (HIV, EB virus)
Pregnancy increases the need for folic acid 5- to 0-fold, a
deficiency commonly occurs Inherited (Fanconi anemia)
Low / High hepcidin
Polycythemia Primary polycythemia
polycythemia vera, Vaquez disease (1)
An abnormally high total red blood cell mass with
a hematocrit greater than 54% in males and 51%
in females.
Proliferative disease of the pluripotent cells of
Relative - hematocrit rises because of a loss of plasma the bone marrow characterized by an absolute
volume without a corresponding decrease in red cells.
increase in total red blood cell mass
Absolute accompanied by elevated white cell and
platelet counts.
Primary Secondary
 Secondary polycythemia (1) 2. White blood cell disorders Leukocyte formula
Primary polycythemia
hypoxia => erythropoietin White blood cells
polycythemia vera, Vaquez disease (2)
Neutrophils
• Most commonly is seen in men between the ages of 40
and 60 years
• Increased blood volume and viscosity
• Headache, dizziness, and some difficulty with hearing
and vision because of decreased cerebral blood flow
• Hypertension • High altitudes
• Venous stasis gives rise to a plethoric appearance • Chronic heart disease
• Thrombosis • Chronic lung disease
• Smoking

Eosinophils Basophils Physiological leucocytosis Eozinophilic leukocytosis > 0.4 x 109/L

• Newborns and chldren < 1 year Allergic reactions Neutropenia (Agranulocytosis)
• Pregnancy Parasitic infections
• Physical activity Due to redistribution of leukocytes Neutropenia: circulating neutrophil count < 1.5 x 109/L
• Emotions from marginal to circulating pool Basophilic leukocytosis > 0.1 x 109/L Agranulocytosis: circulating neutrophil count < 0.2 x 109/L
• After meals
• After blood loss Chronic myeloleukemia

Pathological leucocytosis Monocytosis > 0.8 x 109/L

Chronic infections (tuberculosis)
Polyclonal Monoclonal (leukemias)
Causes of neutrophilic leukocytosis Lymphocytosis > 3.5 x 109/L
>7.5 x 109/L
• Bacterial infections
• Destruction of tissues (trauma, myocardial infarction, Viral infections (hepatitis A, cytomegalovirus, Epstein-Barr virus),
surgery) lymphoid leukemia
• Malignant tumors

Functional defects of phagocytes Acute vs. chronic leukemia Plasma cell tumors Lymphomas
Acute Chronic
• Hodgkin’s Disease
§ Multiple myeloma
Chronic granulomatous disease (CGD) is a rare (∼1:250,000 § Waldenström macroglobuinemia • Non-Hodgkin’s Lymphomas
births) disease caused by mutations in any one of the five Myeloid Acute myeloid leukemia Chronic myeloid leukemia
components of the nicotinamide adenine dinucleotide phosphate Hodgkin’s lymphoma Non-Hodgkin’s
(NADPH) oxidase in phagocytes. This enzyme generates superoxide
and is essential for intracellular killing of pathogens by phagocytes.
Acute lymphoblastic leukemia Chronic lymphocytic leukemia Lymphomas
(B or T) Hairy cell leukemia
Other circulating B cell
CGD is a primary immunodeficiency that affects phagocytes of the lymphomas
innate immune system and leads to recurrent or persistent Lymphoid Multiple myeloma (1)
Adult T lymphocytic leukemia Sezary Syndrome
intracellular bacterial and fungal infections T-cell LGL Leukemia Adult T lymphocytic leukemia
T-Prolymphocytic leukemia T-cell LGL Leukemia
Aggressive NK/T leukemia T-Prolymphocytic leukemia

Reed-Sternberg cells (derived

from B lymphocytes ?)

Infectious mononucleosis

Epstein-Barr virus (EBV) induced non-malignant proliferation of B

lymphocytes