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Disorders of Red Blood Cells. Professor Myat Thandar Department of Physiology University of Medicine 1. Functions of RBCs. O 2 transport (Hb in the RBCs) CO 2 transport Acid-base balance. Functional Importance of the Biconcave Shape of RBCs. Larger surface area for O 2 diffusion

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Disorders of red blood cells

Disorders of Red Blood Cells

Professor Myat Thandar

Department of Physiology

University of Medicine 1

Functions of rbcs
Functions of RBCs

  • O2 transport (Hb in the RBCs)

  • CO2 transport

  • Acid-base balance

Functional importance of the biconcave shape of rbcs
Functional Importance of the Biconcave Shape of RBCs

  • Larger surface area for O2 diffusion

  • Thinness of cell membrane enables O2 to diffuse easily

  • Flexibility of membrane facilitates the transport function

Network of fibrous proteins of rbcs
Network of Fibrous Proteins of RBCs

  • Spectrin and Ankyrin

  • Imparts elasticity and stability to membrane and allows RBCs to deform easily


  • A natural pigment, reddish when oxygenated

  • 4 polypeptide chains (a globin portion and a heme unit)

Haemoglobin f in fetus
Haemoglobin F in Fetus

  • Higher affinity for O2 than adult Hb

  • HbF is replaced within 6 months of birth with HbA

Haemoglobin synthesis
Haemoglobin Synthesis

  • Availability of iron for heme synthesis

  • Amount of iron: 2 g in women and 6 g in men

Clinically, decreased ferritin levels

usually indicate the need for prescription

of iron supplements.

Red cell production
Red Cell Production

  • Until 5, almost all bones; After 20, membranous bones

  • Approximately 1% of total RBC is generated from bone marrow each day

  • Reticulocyte count serves as an index of erythropoietic activity of bone marrow

Disorders of red blood cells

Stages of Erythropoiesis

  • Hematopoietic stem cell (HSCs)

  • Unipotent committed stem cell

  • Proerythroblast (15-20 mm)

  • Early normoblast (12-16 mm)

  • Intermediate normoblast (10-14 mm)

  • Haemoglobinization begins

  • Late normoblast (10-14 mm)

  • Haemoglobinization ++

  • Nuclear disintegration

  • Reticulocyte (7-8 mm)

  • Haemoglobinization ++

  • Nucleus remains only as strands of reticular element

  • Erythrocyte (7.5 mm)

IL-1, IL-6, IL-3 (interleukins)




Red cell maturation
Red Cell Maturation

  • Reduction in the cell size

  • Increase in the amount of haemoglobin

  • Disappearance of nucleus, and

  • Change in staining characteristics of cytoplasm: basophilic to eosinophilic. This is partly due to a fall in content of RNA.

Human erythropoietin
Human Erythropoietin

Produced by recombinant DNA technology

Used for anaemia induced by chemotherapy in cancer patients, and HIV infected persons treated with zidovudine

In severe anaemia, retic count may be as much as 30% (normal about 1%); numerous erythroblasts may appear in the blood

Excretion of bilirubins
Excretion of Bilirubins

Excess bilirubin elimination leads to

bilirubin gallstones

If red cell destruction and bilirubin

production is excessive, yellow discoloration of the skin, jaundice, occurs due to accumulation

of unconjugatedbilirubin


  • Haemoglobin binding protein – Haptoglobin – in the plasma

  • Other plasma proteins – albumin – also binds to Hb

  • Extensive destruction of RBCs (haemolytic transfusion reactions), binding capacity is exceeded

  • Haemoglobinaemia and haemoglobinuria results

Red cell metabolism
Red Cell Metabolism

2,3-DPG decreases affinity of Hb for O2, facilitating the release of O2 at tissue levels

Increased 2,3-DPG occurs in chronic hypoxia such as chronic lung diseases, anemia and residence at high altitude

Inhibition of oxygen haemoglobin binding
Inhibition of Oxygen Haemoglobin Binding

Certain chemicals : nitrates and sulfates

Hb reacts with nitrite to form methaemoglobin

G6PD deficiency predisposes to oxidative denaturation of hemoglobin

with resultant red cell injury and lysis (oxidative stress generated by infection or exposure to certain drugs)

Laboratory tests
Laboratory Tests

  • Using automated blood cell counters: red cell content and indices

  • Red cell indices are used to differentiate type of anemias by size or color of red cells

  • Haemoglobin

  • Hematocrit

  • Mean corpuscular volume (MCV falls in microcytic and rises in macrocytic anemia)

  • Mean corpuscular haemoglobin concentration (normochromic or normal MCHC; hypochromic or decreased color or decreased MCHC)

Laboratory tests1
Laboratory Tests

  • Mean cell haemoglobin

  • A stained blood smear: information about size, color and shape of red cells and the presence of immature or abnormal cells

  • If blood smear is abnormal, bone marrow examination may be indicated

  • Bone marrow aspiration from posterior iliac crest or the sternum

Disorders of red blood cells

Red cell count and Haemoglobin severity of anemia

Red cell characteristics

Size normocytic, microcytic or macrocytic

Color normochromic, hypochromic

Shape the cause of anemia


  • Values of hemoglobin, hematocrit or RBC counts which are more than 2 standard deviations below the mean

    • HGB<13.5 g/dL (men) <12 (women)

    • HCT<41% (men) <36 (women)

Normal Hb Concentration

Western value Myanmar value

Male : 16 g / dL (14 - 17 g/dL) 14.4 g / dL

Female : 14 g / dL (12 - 15.5 g/dL) 12.5 g / dL

Pathophysiology of anemia
Pathophysiology of Anemia

  • Blood Loss

  • Decreased Production (lack of nutritional elements or bone marrow failure)

  • Increased Destruction (haemolysis)

Effects of anemia
Effects of Anemia

  • Manifestations of impaired oxygen transport and the resultant compensatory mechanisms

  • Reduction in red cell indices and hemoglobin levels

  • Signs and symptoms associated with the pathophysiologic process that causes anemia

Manifestations depend on its severity, the rapidity of

its development and the person’s age and health status

Impaired oxygen transport and tissue hypoxia
Impaired oxygen transport and tissue hypoxia

  • Weakness, fatigue, dyspnoea and angina

  • Brain hypoxia results in headache, faintness and dim vision

  • Redistribution of blood results in pallor of skin, conjunctiva, mucous membranes and nail beds

Compensatory mechanisms
Compensatory Mechanisms

  • Tachycardia, palpitations and increased cardiac output

  • A flow type of systolic murmur

  • Ventricular hypertrophy and high output heart failure

  • Accelerated erythropoiesis results in diffuse bone pain and sternal tenderness

Haemolytic anemia : jaundice

Aplastic anemia : petechiae and purpura due to reduced platelet functions

Blood loss anemias
Blood Loss Anemias

  • Depends on rate of haemorrhage and blood loss is external or internal

  • Rapid loss causes circulatory shock and collapse; fall in red cell count, Hb, hematocrit due to fluid shift into vessels

  • Initially red cells are normocytic, normochromic

  • Increased erythropoietin and retic count

  • Slow loss (GI bleeding, menstrual disorders) causes anemia; signs and symptoms develop if the amount of red cell mass loss reach 50% (Hb <8 g/dL)(iron deficiency anemia)

  • External bleeding leads to iron loss and iron deficiency

Haemolytic anemias

  • Characterized by premature destruction of red cells, retention in the body of iron and other products of Hb destruction and increased erythropoiesis

  • Normocytic normochromic red cells

  • Increased retic count in the circulating blood

  • Haemoglobinemia, haemoglobinuria, jaundice, haemosiderinuria

Haemolytic anemias1

  • Intravascular haemolysis is less common, caused by complement fixation in transfusion reactions, mechanical injury or toxic factors

  • Extravascular haemolysis occurs when RBCs are less deformable to traverse splenic sinusoids, characterized by anemia and jaundice

  • Intrinsic : defects of red cell membrane, haemoglobinopathies (sickle cell disease and thalassemias) and enzymes defect

  • Extrinsic or acquired : drugs, bacteria and other toxins, antibodies and physical trauma

Inherited disorders of red cell membrane
Inherited Disorders of Red Cell Membrane

  • Hereditary spherocytosis : abnormalities of spectrin and ankyrin

  • Mild hemolytic anemia, jaundice, splenomegaly and bilirubin gallstones

  • Splenectomy done to reduce red cell destruction and blood transfusion in a crisis

Sickle cell disease
Sickle Cell Disease

  • Haemoglobin S (point mutation in the βchain of Hb, valine for glutamic acid)

  • Haemolytic anaemia, jaundice, gallbladder stones, pain and organ failure (infarction of organs)

  • Hb S becomes sickled when deoxygenated or at a low oxygen

  • Deoxygenated Hb aggregates and polymerizes in the cytoplasm, creating a semisolid gel that changes the shape and deformability of the cell

Red cell sickling
Red Cell Sickling

  • Chronic hemolytic anemia

  • Blood vessel occlusion

  • Associated conditions: cold, stress, physical exertion, infection, illnesses that cause hypoxia, dehydration or acidosis

Diagnosis and treatment
Diagnosis and Treatment

  • Neonates : clinical findings and haemoglobin electrophoresis

  • Prenatal diagnosis : analysis of fetal DNA by amniocentesis

  • Prevention of sickling episodes, symptomatic treatment and treatment of complications (prophylactic penicillin and full immunization)

  • Cytotoxic drug – hydroxyurea – to allow synthesis of more HbF and less HbS

  • Nitric oxide appears to be a promising new drug

  • Bone marrow or stem cell transplantation


  • Inherited disorders of haemoglobin synthesis and decreased synthesis of αorβglobin chains of HbA

  • Heterozygous or homozygous


  • βthalassemias – Cooley anaemia or Mediterranean anemia – common in Mediterranean population of southern Italy and Greece

  • αthalassemias more common among Asians

  • Anemia due to low production of affected chain and continued production and accumulation of unaffected globin chain

  • Reduced Hb synthesis leads to hypochromic microcytic anemia; accumulation of unaffected chain interferes with normal red cell maturation, and membrane changes leading to hemolysis and anemia

β -thalassemias

  • Excess α chains are denatured to form precipitates (Heinz bodies) in the bone marrow red cell precursors

  • Heinz bodies impair DNA synthesis and damage to red cell membrane

  • Coagulation abnormalities, thrombotic events (stroke and pulmonary embolism) in moderate to severe form

Disorders of red blood cells

Pathophysiology of β -thalassemias

Thinning of cortical bones

Treatment of thalassemias
Treatment of β -thalassemias

  • Regular transfusion to maintain Hb at 9 to 10 g/dL

  • Iron chelation therapy to reduce iron load

  • Stem cell transplantation

  • Stem cell gene replacement


  • Synthesis of globin chains is controlled by 4 genes

  • Deletion of single gene : silent carrier; two genes is αthalassemia trait

  • Deletion of three genes leads to unstable aggregates of αchains – HbH

  • Four globin chains are deleted : Hb Bart (extremely high oxygen affinity, cannot release oxygen in the tissues

  • Chronic hemolytic anemia

Inherited enzymes defect
Inherited Enzymes Defect

  • G6PD deficiency

  • RBCs vulnerable to oxidants, direct oxidation of Hb to methaemoglobin, and denaturation of Hb to form Heinz bodies

  • Anti-malaria drug primaquine, the sulfonamides, nitrofurantoin, aspirin, phenacetin, some chemotherapeutics and other drugs cause hemolysis

  • Diagnosed through G6PD assay or screening test

Acquired hemolytic anaemias
Acquired Hemolytic Anaemias

  • By direct membrane destruction or antibody mediated lysis

  • Various chemicals, toxins, venoms, malaria infection, prosthetic heart valves, vasculitis, severe burns, septicaemia, thrombotic thrombocytopenic purpura, renal disease

  • Warm reacting antibodies (IgG) and cold reacting antibodies (IgM)

  • Warm antibodies bind with Ag on red cell membrane (Rh Ag), resulting in spherocytosis and destruction by RE system

  • Cold antibodies activate complements; as in lymphoproliferative disorder and idiopathic

Disorders of red blood cells

Rh incompatibility

Coomb s test
Coomb’s Test

  • Direct Antiglobulin Test (DAT) is positive in autoimmune hemolytic anaemia, erythroblastosis fetalis, transfusion reactions, transfusion reactions and drug induced hemolysis

  • Indirect antiglobulin test is used for antibody detection and crossmatching before transfusion

Anemias of deficient red cell production
Anemias of Deficient Red Cell Production

  • Deficiency of nutrients for hemoglobin synthesis (iron)

  • Deficiency of nutrients for DNA synthesis (Cobalamin or folic acid)

  • Marrow is replaced by nonfunctional tissues

Iron deficiency anemia
Iron Deficiency Anemia

  • Dietary deficiency (vegetarians)

  • Loss of iron through bleeding (peptic ulcer, polyps, cancer, menstrual bleeding)

  • Increased demands (growing children, pregnancy)

Characteristics of iron deficiency anemia
Characteristics of Iron Deficiency Anemia

  • Low haemoglobin and hematocrit

  • Decreased iron stores, low serum iron and ferritin

  • Red cells number decreased and are microcytic and hypochromic

  • Poikilocytosis (irregular shape)

  • Anisocytosis (irregular size)

  • Reduced MCHC and MCV

  • Membrane changes predispose to


Treatment of iron deficiency anemia
Treatment of Iron Deficiency Anemia

  • Prevention and treatment of the cause

  • Ferrous sulfate

  • Parenteral iron (iron dextran or sodium ferric gluconate)

  • Initial test dose to prevent severe anaphylactic reactions

Megaloblastic anemia
Megaloblastic Anemia

  • Impaired DNA synthesis

  • Enlarged red cells (MCV >100 fL)

  • Develop slowly

  • Vitamin B12 and folic acid


Vitamin b 12 deficiency anemia b 12 absorption
Vitamin B12 Deficiency Anemia: B12 Absorption

Pernicious anemia
Pernicious Anemia

  • Atrophic gastritis

  • Autoimmune destruction of gastric mucosa

  • Gastrectomy, ileal resection, inflammation or neoplasms in terminal ileum, malabsorption syndrome

  • MCV elevated; MCHC is normal

Vitamin b 12 containing food
Vitamin B12 Containing Food

Normal body stores of 1000 to 5000 µg provide the daily requirement of

1 µg for a number of years.

Therefore, deficiency develops slowly

Diagnosis of b 12 deficiency
Diagnosis of B12 Deficiency

  • The Shilling test – 24 hour urinary excretion of radiolabelled vitamin B12 administered orally

  • Detection of parietal cell and intrinsic factor antibodies

  • Lifelong intramuscular or high oral doses of vitamin B12 is required

Folic acid deficiency
Folic Acid Deficiency

Total body stores amount to 2000 to 5000 µg and 50µg is required

in the daily diet. A dietary deficiency may result in anaemia in a few months

Pregnancy increases the need for folic acid 5 to 10 fold

Aplastic anemia
Aplastic Anemia

  • Reduction of all 3 hemopoietic cell lines

  • Onset may be insidious but may be abrupt and severe

Therapy in aplastic anemia
Therapy in Aplastic Anemia

Therapy in aplastic anemia1
Therapy in Aplastic Anemia

  • Immunosuppressive therapy with lymphocyte immune globulin

  • Avoid offending agents

  • Antibiotics for infection

  • Red cell transfusion to correct anaemia

  • Platelets and corticosteroid therapy to minimize bleeding

Chronic disease anemia
Chronic Disease Anemia

  • Occur as a complication of chronic infections, inflammation, cancer and chronic kidney diseases

  • Short red cell life span; deficient red cell production; a blunted response to erythropoietin, and low serum iron

  • Mild anemia – normocytic and normochromic – with low reticulocyte counts

  • In chronic renal diseases, uremic toxins and retained nitrogen interfere with actions of erythropoietin; hemolysis and blood loss associated with hemodialysis and bleeding tendencies also contribute to anemia

Therapy in chronic disease anemia
Therapy in Chronic Disease Anemia

  • Short-term erythropoietin therapy

  • Iron supplementation

  • Blood transfusions

  • In future – iron chelating agents and cytokines to stimulate erythropoietin production