Red Blood Cells: Formation, Function & Blood Types

• These notes are for Haematology focusing on red blood cells

Learning Objectives

• Explain where red blood cells come from
• Explain the nutrients needed to form red blood cells
• Describe the steps that form the red blood cells
• Describe the stages of how red blood cells become specialized
• Describe how tissues get oxygen and its role in making red blood cells
• Describe how hormones control red blood cell production
• Understand how long RBCs live
• Understand how RBCs are recycled
• Describe how hemoglobin is formed
• Understand the role of iron in hemoglobin
• Know the major O-A-B Blood Types
• Define anemia and polycythemia

Composition of Blood

• Average blood volume for an adult is 5 liters
• Blood is ~ 55% Plasma
• Blood is ~45% Red blood cells (RBCs)
• Blood contains < 1% Buffy coat, made of platelets and white blood cells

Red Blood Cells (Erythrocytes)

• RBC's transport hemoglobin
• Hemoglobin carries O₂ from the lungs to the tissues

Where are RBCs produced?

• Erythrocytes made in the bone marrow
• After age 20 bone marrow of the long bones (humeri and tibiae) becomes fatty and RBC production stops
• RBCs production continues mainly from vertebrae, sternum, ribs, and ilia in individuals > 20-years

Nutrients Required to Form Mature RBCs

• Maturation of RBCs needs Vitamin B12 and Folic Acid
• B12 and Folic Acid are essential for DNA synthesis by forming thymidine triphosphate
• A deficiency causes abnormal DNA and RBC maturation failure
• Erythoblastic cells fail to proliferate and enlarge RBCs into megaloblasts = Megaloblastic Anemia
• Macrocyte can transport O₂ but have fragile cell membrane that rupture easily, resulting in a short life span

Poor GIT absorption of Vitamin B12- Anemia

• Vitamin B12 absorbed in the GIT is stored mainly in the liver
• It is released when bone marrow requires it for RBC production
• Pernicious anemia - Poor absorption of vitamin B12 from the gastrointestinal tract
• It results in RBC maturation failure
• Pernicious anemia can be caused by atrophic gastric mucosa that fail to make intrinsic factor
• Intrinsic factor binds Vitamin B12 and protect it from digestion
• Lack of intrinsic factor decreases the availability of vitamin B12 because of faulty GIT absorption.
• Pernicious anaemia is an autoimmune disease
• Plasma cells in the gastric mucosa secrete antibody against intrinsic factor

Poor GIT absorption of Folic Acid

• Folic acid is sourced mainly from green vegetables, fruits and meats (liver)
• Folic acid can be easily destroyed when cooking
• Gastrointestinal absorption abnormalities, such as sprue impair absorption of both folic acid and vitamin B12.

Formation of RBCs

• Formation of RBCs is called Erythropoiesis
• Multipotent haematopoietic stem cells in the bone marrow give rise to erythroblasts
• Erythrocytes are derived from committed stem cells called colony-forming unit-erythrocyte (CFU-E)
• Growth and production of RBCs is modulated by growth inducer e.g. erythropoietin

Differentiation of RBCs

• The proerythroblast is the 1st RBC formed from CFU-E stem cells during Erythropoiesis
• Basophil erythroblast is the 1st generation
• Polychromatophil erythroblasts form haemoglobin
• Orthochromatic condenses the nucleus
• haemoglobin occupies the intracellular space
• Reticulocytes enter circulation through capillaries by diapedesis and mature to erythrocyte (RBCs) within 1 – 2 days

The Role of Tissue Oxygenation in RBC Production

• High altitudes reduce O₂ in the air
• Insufficient O₂ is transported to the tissues
• RBC production increases to compensate
• Congestive heart failure and lung diseases causes tissue hypoxia and increase RBC production
• Renal disease causes the person to invariably becomes very anaemic

Erythropoietin Secretion

• Cells in the cortex and outer medulla of the kidneys synthesize erythropoietin
• Erythropoietin is then released it into the bloodstream
• Approx. 90% of erythropoietin is synthesized by the kidneys
• The liver synthesizes ~ 10% of erythropoietin

Hormonal Control of RBC Production

• Low tissue O₂ signals mainly kidneys to secrete hormone called erythropoietin
• Erythropoietin then stimulate RBC production by stimulating
• Low renal tissue O₂ (hypoxia) that increase tissue levels of hypoxia-inducible factor-1 (HIF-1)
• (HIF-1) is a transcription factor for many hypoxia-inducible genes, including the erythropoietin gene.
• HIF-1 binds to a hypoxia response element in the erythropoietin gene and inducing transcription of messenger RNA.

Recombinant Erythropoietin

• Kidneys do not produce enough erythropoietin in kidney disease
• This causes deficiency in RBCs
• The liver fails to produce enough erythropoietin
• People with severe kidney malfunction are injected recombinant erythropoietin to stimulate RBC production

Lifespan of RBC's and Metabolic Product of RBC

• RBCs have a life span of ~120 days before being destroyed
• RBC membranes become fragile
• Narrow capillaries and spleen rapture RBC membrane
• Raptured RBCs are ingested by monocyte-macrophage cells and releases haemoglobin
• Macrophage metabolizes haemoglobin to form bilirubin
• Iron released by macrophage is stored mainly in ferritin to be used for new haemoglobin

Haemoglobin Formation

• There are four clinically important types of globin chains- α, β, γ, and δ
• All types of haemoglobin contain 4 globins chains per molecule
• Common haemoglobins are Haemoglobin A (α2β2) and haemoglobin F (α2γ2)
• Haemoglobin synthesis begins in polychromatophil erythroblasts and continues into the reticulocyte stage of the RBCs production

Sickle Cell Anaemia

• Abnormalities of the globin polypeptide can change physical characteristics of the hemoglobin molecule
• An amino acid substitution occurs on the 2β chains.
• Amino acid is substituted for valine at one point in each of the 2 β chains
• This abnormal haemoglobin forms elongated crystals when is exposed to low O₂
• Causes crystals rupture the cell membranes and lead to sickle cell anaemia

RBCs in the Blood

• Average number of RBCs in 1 µL is ~ 5 million/µL in healthy men
• The number of RBCs is ~ 4.7 million/µL in healthy women
• Healthy men have about 15 grams of Hgb per 100 ml of blood
• Women have 14 g Hgb/100ml
• 1 gram of Hgb can bind with a maximum of 1.34 ml of O₂
• 15 X 1.34 ml = 20.1 ml
• On average, the 15 grams of Hgb in 100 ml of blood can carry ~ 20 ml of O₂ if the Hgb is 100% saturated

Blood Typing

• RBCs have antigens A and B on the surface
• Antigens, or agglutinogens, cause blood transfusions
• ABO blood group system different kinds of blood groups exist
• When neither A nor B agglutinogen is present it is type O
• When only A agglutinogen is present it is type A
• When only B agglutinogen is present it is type B
• When both A and B agglutinogens are present it is type AB
• When blood samples are mismatched, the RBCs agglutinate into clumps
• The Rh system is an important factor during blood transfusions
• Types are Rh neg (-) and Rh pos (+)

Anaemia

• Is defined as an abnormally low RBC concentration in the blood
• Anaemia can be caused by Insufficient RBCs production, in cases of Renal disease
• It can also be caused by Premature loss of RBCs, such as bleeding and short RBCs life-span

Types of Anaemia

• Blood loss anaemia - RBC concentration usually returns to normal within 3 to 6 weeks after haemorrhage
• Aplastic anaemia - Can be caused by Bone marrow dysfunction due to radiation or cancer treatment or autoimmune disorders
• Megaloblastic anaemia - Is due to vitamin B12 or folic acid deficiency. Results in Large, abnormally developed RBC.
• Haemolytic anaemia: -Sickle cell anaemia - Is an abnormal type of haemoglobin -It is called haemoglobin S and it contains faulty β chains.

Polycythaemia

• Is having an abnormally high RBC concentration in the blood
• Secondary Polycythemia occurs when tissues become hypoxic because of failure of oxygen delivery to the tissues e.g. cardiac failure or due to Dehydration
• Physiological polycythemia occurs when a reduction of oxygen happens in the breathed air, such as at high altitudes
• Heavy smoking causes carbon monoxide to binds to Hgb and decreases Hgb capacity to transport O₂
• This leads to increased RBC production due to inadequate oxygenation of tissues
• Primary Polycythaemia : Polycythaemia Vera (Erythremia) is caused by
• A genetic aberration in the haemocytoblastic cells (RBC stem cells) that don't stop producing RBCs even when too many cells are already present
• The hematocrit increase causes blood viscosity increase