Blood Physiology and Erythropoiesis

Blood Physiology

• Erythropoietin (EPO) is crucial for red blood cell (RBC) production.
• Anephric individuals have a deficiency in EPO production, resulting in severe anemia.
• The kidney is the primary site for EPO production and a small amount is produced in the liver.
• In anephric individuals, residual EPO supports 30-50% of needed RBC production.
• Normal hematocrit (packed cell volume) is 40-45%.
• Anephric individuals may only achieve a hematocrit of 23-25%.
• EPO levels increase rapidly in response to hypoxia (low oxygen).
• RBC production takes longer than EPO level increases (days, weeks, months).
• EPO stimulates the production of proerythroblasts from hematopoietic stem cells.
• EPO accelerates the maturation of proerythroblasts into RBCs.
• EPO production is regulated by a negative feedback mechanism, halting when normal oxygen levels are restored.

Requirements for Erythropoiesis

• Vitamin B12, folic acid, iron, and amino acids are essential for optimal erythropoiesis.
• These nutrients are important after EPO is present.
• Rapid cellular proliferation requires an adequate supply of these vitamins and minerals.
• Vitamin B12 and folic acid are needed for DNA synthesis (thymidine triphosphate) to support cell division.
• Failure in nuclear maturation leads to large, irregular RBCs (macrocytes) and increased fragility, resulting in hemolysis leading to anemia.

Pernicious Anemia

• Pernicious anemia is a type of megaloblastic anemia.
• It's characterized by the production of large, bizarre, and immature RBCs by the bone marrow.
• Causes are a failure to absorb vitamin B12 and/or produce intrinsic factor.
• Atrophic gastric mucosa can lead to intrinsic factor deficiencies resulting in difficulties absorbing Vitamin B12.
• Adequate vitamin B12 stores can delay symptoms of deficiencies

Folic Acid Deficiency

• Folic acid is found in green vegetables, fruits, and meats.
• It is easily destroyed by cooking.
• Deficiencies can arise from poor diet or malabsorptions in the intestine.
• Folic acid deficiency causes similar complications to vitamin B12 deficiencies in DNA synthesis.

Hemoglobin

• Hemoglobin (Hgb) is crucial for transporting oxygen in RBCs.
• Hgb consists of a peptide attached to iron.
• Hemoglobin formation begins before RBC exit bone marrow and continues until maturation.
• Reticulocytes, prior to maturation, contain endoplasmic reticulum and mRNA to allow for continued hemoglobin synthesis.
• Mature RBCs have adequate hemoglobin to support 120 days of life.
• Different types of hemoglobin exist (e.g., Fetal hemoglobin).

Variation in Globin Chains

• Different forms of hemoglobin have slight differences that affect oxygen binding affinities.
• Mutations can result in abnormalities like sickle cell hemoglobin.
• Sickle hemoglobin structure changes when exposed to low oxygen, often resulting in long crystals forming inside RBCs.
• The changes interrupt RBC flexibility, leading to hemolysis (RBC breakdown) and vascular occlusion (blockages).

Oxygen Binding to Hemoglobin

• Loose iron-oxygen binding allows for smooth oxygen uptake in the lungs and release in tissues.
• Oxygen affinity changes based on oxygen pressure and CO2 levels in the body.
• Fetal hemoglobin has a higher oxygen affinity to support the baby's oxygen needs in utero.
• Hemoglobin transfers oxygen as a molecule, not as an ion.

Iron Metabolism

• Iron is vital for hemoglobin, myoglobin and many other enzymes.
• Total body iron is 4-5 grams, mostly in hemoglobin (around 65%).
• Iron is stored in the body, and tightly regulated for maximal absorption.
• Different forms exist in the body as ferritin or hemosiderin.

Iron Transport and Storage

• Transferrin is essential for iron transport in the blood.
• Ferritin stores iron in cells.
• Serum ferritin levels are used to evaluate the body's total iron stores.
• Iron absorption happens in the small intestines.
• Excess iron is stored as hemosiderin to prevent iron overload and toxic conditions.

Iron Balance

• Daily iron loss is approximately 0.6mg daily in men and 1.3mg in women
• Iron is absorbed in the small intestine
• The liver secretes apotransferrin, binds with free iron for transferrin transport.
• Maximal iron absorption occurs at small amounts daily which is modulated by body iron stores.
• RBC lifespan is 120 days

RBC Senescence and Destruction

• RBC lifespan lasts approximately 120 days
• RBCs lack a nucleus, mitochondria, and endoplasmic reticulum, however contain enzymes to support ion transport.
• Enzymes deplete with age, making the RBCs fragile, eventually leading to rupturing in the organs such as the spleen, liver.
• Macrophages (specialized immune cells) phagocytose the ruptured cells for recycling.
• Components (hemoglobin) are recycled to support functions in new cells

Degradation of Hemoglobin

• Hemoglobin is broken down into globin and heme.
• Globin is broken down into amino acids.
• Heme is broken down to form bilirubin.
• Bilirubin is transported to the liver for excretion.
• Iron is released back into the circulation or stored as ferritin.

Anemia

• Anemia is caused by a reduction in RBC count or haemoglobin.
• Causes for anemia include decreased production, blood loss and/or increased destruction of RBCs
• Conditions like iron deficiency and thalassemia are examples of anemia.
• Methods for correcting RBC concentrations may not correct/fix the oxygen capacity of the body