Hemoglobin Overview and Functions

Hemoglobin Definition

• Hemoglobin is a specialized conjugated protein.
• It has a molecular weight (M.W) of 64,000.
• It is the oxygen-carrying protein in red blood cells (RBCs).
• Each RBC contains approximately 640 million hemoglobin molecules.
• These molecules make up about 60% of the dry weight of a red blood cell.

Hemoglobin Structure

• Hemoglobin consists of four polypeptide subunits.
• Each subunit includes a heme group.
• The heme group has a porphyrin ring and ferrous iron.
• Hemoglobin has two alpha chains and two beta chains.

Hemoglobin Function

• Hemoglobin carries oxygen from the lungs to the body tissues.
• It removes carbon dioxide (CO2) from the tissues.
• Hemoglobin helps maintain blood pH by acting as a buffer. This is because it changes from oxyhemoglobin (carrying oxygen) to deoxyhemoglobin (without oxygen).

Hemoglobin Synthesis

• Hemoglobin synthesis occurs in the mitochondria of developing red blood cells as they mature in the bone marrow.

• Adequate iron supply and delivery is crucial for normal synthesis.

• Adequate synthesis of protoporphyrins is important.

• Adequate globin synthesis is essential for normal function.

• 65% of hemoglobin is synthesized in erythroblasts, with 35% produced in reticulocytes.

• Hemoglobin synthesis occurs primarily in the mitochondria, while globin production occurs in the polyribosomes.

• The rates of haem and globin synthesis are precisely coordinated for optimal hemoglobin assembly.

• Iron delivery and supply is required. Iron is delivered to reticulocytes via transferrin.

• Protoporphyrins are synthesized in the mitochondria of red blood cell precursors, a process that requires EPO (erythropoietin), vitamin B6.

• Protoporphyrin + iron = heme.

• Globin synthesis depends on genes and the precise amino acid order in the globin chains.

• The synthesis of globins is genetically controlled.

• Humans have two clusters of globin-gene clusters in chromosome 11 (beta-like) and chromosome 16 (alpha-like).

Hemoglobin Reference Ranges

• Adult males have hemoglobin levels between 14 and 17.4 g/dL.
• Adult females have hemoglobin levels between 12 and 16 g/dL.
• Newborn babies have hemoglobin levels between 13.5 and 20.0 g/mL.
• Children aged 6-12 have hemoglobin levels between 11.5 and 15.5 g/mL.

Normal Hemoglobins

• Embryonic hemoglobins include Gower 1 (zeta 2, epsilon 2), Gower 2 (alpha 2, epsilon 2), and Portland (zeta 2, gamma 2).
• Fetal hemoglobin (HbF) is alpha 2, gamma 2.
• Adult hemoglobin (HbA) is alpha 2, beta 2.

Oxygen Transport

• The amount of oxygen bound to hemoglobin and released to tissues depends on the partial pressures of oxygen (PO2) and carbon dioxide (PCO2).
• Oxyhemoglobin is hemoglobin with oxygen.
• Deoxyhemoglobin is hemoglobin without oxygen.
• Oxygen affinity is the ease with which hemoglobin binds and releases oxygen.

Oxygen Affinity

• Oxygen affinity affects the proportion of oxygen released to tissues at a given oxygen pressure.
• Increased oxygen affinity means hemoglobin has a stronger attraction to oxygen, binding more.
• Decreased oxygen affinity causes oxygen to be released more easily

Oxygen Dissociation Curve

• A right-shift in the oxygen dissociation curve shows hemoglobin with less attraction to oxygen, and is more readily released to tissues.
• Factors that shift the curve to the right include anemia and acidosis.
• A left-shift shows greater attraction between hemoglobin and oxygen and is less readily released to the tissue.
• Examples that shift the curve to the left include abnormal hemoglobins and alkalosis,

Carbon Dioxide Transport

• Three mechanisms are involved in CO2 transport: dissolution in plasma, formation of carbonic acid, and binding to carbaminohemoglobin. 

Nonfunctional Hemoglobins

• Nonfunctional hemoglobins include carboxyhemoglobin, methemoglobin, and sulfhemoglobin.
• In carboxyhemoglobin case, oxygen molecules are replaced by carbon monoxide.
• In methemoglobin, iron in hemoglobin is in the ferric state instead of the ferrous state, which prevents oxygen binding.
• Sulfhemoglobin has sulfur in the hemoglobin molecule and cannot revert to oxyhemoglobin.

Normal Red Blood Cell Breakdown

• Aged or damaged red blood cells are broken down.
• Hemoglobin is broken down into heme and globin components.
• Heme is further broken down to iron, protoporphyrin, and CO.
• Globin is broken down into amino acids.
• Iron is recycled and reused.
• Bilirubin is produced from protoporphyrin and processed by the liver.
• Excess bilirubin is excreted in the feces (stercobilin) and urine (urobilinogen).

What Happens to Aged Red Blood Cells

• Aged red blood cells are broken down by macrophages.
• The globin part of hemoglobin is broken down into amino acids, reused for protein synthesis.
• The iron part is released and stored in transferrin
• The heme portion is broken down into biliverdin, then bilirubin, which is processed by the liver and eventually eliminated in bile.

Hemoglobin Abnormalities

• There are primarily two types of hemoglobin abnormalities:
• Quantitative abnormalities (e.g. thalassemia). These involve reduced production of specific globin types.
• Qualitative abnormalities (e.g. sickle cell anemia). These cause abnormal hemoglobin.