- Clinical science
Erythrocytes, or red blood cells (RBCs), are the most common blood cells. Normal RBCs have a biconcave shape and contain hemoglobin but no nucleus or organelles. Dysmorphic RBCs (e.g., sickle cells, target cells) have an altered form and are often a sign of an underlying condition. Hemoglobin (Hb) is composed of heme and globin subunits and is responsible for transporting oxygen and carbon dioxide throughout the body. Hb can undergo conformational changes (e.g, depending on its oxygenated state), which influence how it binds and releases O2 and CO2. Deficient Hb (anemia), genetic Hb variants (e.g., HbS, HbC), and certain substances (carbon monoxide, nitrates that form methemoglobin, cyanide) affect the affinity for and ability to transport O2, resulting in decreased tissue oxygenation.
- Biconcave shape: large surface area-to-volume ratio for rapid gas exchange
- No nucleus or organelles
- Contain hemoglobin
(teardrop cells, teardrop erythrocytes)
| Sickle cells |
| Schistocytes |
| Macrocytes |
Small, spherical, no central pallor
|Oval or elliptical|
| Echinocytes |
Smooth, rounded, and evenly spaced cytoplasmic projections
|Target cells |
Slit-like central pallor most often caused by changes in membrane permeability
|Degmacytes (bite cells)||One or more semicircular portions removed ("bitten off") from the cell margin|
RBCs with abnormal content (inclusion bodies)
|Heinz bodies||Denaturated hemoglobin|| |
|Pappenheimer bodies||Iron|| |
|Basophilic stippling||RNA|| |
|Ringed sideroblasts||Iron|| |
|Howell-Jolly bodies||DNA (nuclear remnants)|| || |
chains are released and converted into amino acids.
- Heme is converted to biliverdin by .
Biliverdin is converted to by biliverdin reductase.
- Requires NADPH + H+
- Unconjugated bilirubin (insoluble in water) is released into the blood by macrophages → binds to albumin and reaches the liver
- Unconjugated bilirubin is converted into bilirubin via the enzyme UDP-glucuronosyltransferase in the liver.
- Conjugated bilirubin excreted in bile is broken down by GI bacteria into urobilinogen
- 2,3-bisphosphoglycerate mutase is vital for the formation of 1,3-bisphosphoglycerate (intermediate in glycolysis) → 2,3-BPG
- 2,3-BPG binds to hemoglobin → conformational change → oxygen is released into local tissues
- 2,3-BPG binds with greater affinity to deoxygenated hemoglobin than oxygenated hemoglobin.
- Mature RBCs are unable to generate energy via the Krebs cycle because they lack mitochondria.
- Important biochemical pathways available in RBCs:
- The main function of Hb is to take up O2 from the lungs and deliver it to tissues.
- It can undergo conformational changes (e.g., depending on its state of oxygenation), which influence how it binds and releases O2 and CO2.
- Deficient or defective Hb can ultimately affect the transport of O2 (see Hb variants for details).
- For more information about disorders of Hb, see the article on .
- Heme is synthesized from protoporphyrin, a .
- Porphyrins: a group of intermediates in the heme synthesis pathway that is composed of four subunit rings
- The steps of heme synthesis occur both in the cytoplasm and the mitochondria (the first and final steps occur in mitochondria).
Sideroblastic anemia due to:
Enzyme deficiency causes .
Uroporphyrinogen III → coproporphyrinogen III
Enzyme deficiency causes .
Coproporphyrinogen III oxidase
Protoporphyrinogen III → protoporphyrin IX
Sideroblastic anemia is due to ineffective heme synthesis, which may be congenital (X-linked defect in the δ-ALA synthase gene) or acquired (e.g., vitamin B6 deficiency, or lead poisoning leading to sequential inhibition of δ-ALA dehydratase and ferrochelatase).
- Globin is an integral part of the Hb molecule.
- Tetramer consisting of four individual subunits that bind heme
- Composed of amino acids that fold to form 8 alpha helices
- There are 6 types of globin chains.
- The combination of subunits in the Hb molecule determines the type of Hb (e.g., embryonic, fetal, newborn, or adult Hb).
- Mutations in genes encoding globin results in .
For genetic variants of hemoglobin patterns, see below.
|HBA1 gene||HBA2 gene||HBZ1 gene||HBZ2 gene|
|α globin||ζ globin|
|Chromosome 11||HBB gene||β globin|| |
|HBD gene||δ globin|| |
|HBG1 gene||γ globin|| |
|HBE gene||ε globin|| || |
|Hemoglobin||Globin chains||Beta thalassemia||Alpha thalassemia||Sickle cells||Hemoglobin C|
|Minor (trait)|| |
|Sickle cell trait||Sickle cell disease||Hemoglobin SC disease (HbSC)||HbC carrier||HbC disease|
- O2, CO2, and protons all bind Hb and influence one another's affinity to Hb, which is important for gas exchange.
- CO2 is mainly carried in three forms in the body:
Oxygenation and deoxygenation of Hb
- RBCs carry carbonic anhydrase, which converts HCO3- and H+ to H2O and CO2 in the following steps: HCO3− + H+ ⇄ H2CO3 ⇄ H2O + CO2
- Ultimately, excess H+ during acidic states is eliminated through conversion to CO2, which can be exhaled.
During basic states, the bicarbonate buffer system can reverse so that CO2 is converted to HCO3− + H+.
- Chloride shift: Excess intracellular HCO3− produced this way is released into the plasma in exchange for Cl-.
- This phenomenon makes HCO3- the most important buffer in the body. HCO3- accounts for 50% of the blood buffer capacity.
- For more details on the buffering mechanisms of the body, see in .
- The O2 affinity of Hb is inversely proportional to the CO2 content and H+ concentration of blood.
- High CO2 and H+ concentrations (from tissue metabolism) cause decreased affinity for O2. → O2 that is bound to Hb is released to tissue (the is shifted to the right).
- The CO2 affinity of Hb is inversely proportional to the oxygenation of Hb.
- When Hb is deoxygenated (typically in peripheral tissue), uptake of CO2 is facilitated.
- When Hb is oxygenated (in high pO2, for example, in the lungs):
- The O2-Hb dissociation curve shows the arterial partial pressure of O2 (PaO2) in relation to the percentage saturation of Hb, i.e., the binding affinity of Hb for O2.
- The binding affinity of Hb is influenced by external factors that may lead to a left or right shift of the O2 dissociation curve (ODC).
- Shift to the right of the oxygen dissociation curve → ↓ O2 affinity for Hb → ↑ O2 dissociation from Hb → ↑ tissue oxygenation
- Shift to the left of the oxygen dissociation curve → ↑ O2 affinity for Hb → ↓ O2 dissociation from Hb → ↓ tissue oxygenation
|Differences between the hemoproteins myoglobin and hemoglobin|
|Associated with||1 Heme (monomeric)||4 Hemes (tetrameric)|
|Binds to||1 Oxygen molecule||4 Oxygen molecules|
|Affinity for O2||Very high (hyperbolic oxygen-myoglobin dissociation curve)||High (sigmoidal curve)|
|Function|| || |
|Hb concentration|| |
|Anemia (e.g., due to chronic blood loss)||↓||↓|| |
- Definition: the sum of oxygen bound to hemoglobin and dissolved in plasma within arterial blood
Formula: arterial oxygen content (CaO2, mL of oxygen per 100 mL of blood) = (1.34 x Hb x SaO2) + (0.003 x PaO2)
- Hb (g/dL) = hemoglobin concentration
- SaO2 (%) = arterial oxygen saturation in hemoglobin
- PaO2 (mm Hg) = arterial oxygen saturation in plasma (partial pressure of oxygen)
- 1.34 (mL) = maximum oxygen binding capacity of 1 g of hemoglobin. Normal blood Hb concentration is approximately 15 g/dL. The oxygen binding capacity of blood is therefore: 15 g/dL x 1.34 mL ≈ 20 mL of oxygen per dL of blood.
- 0.003 = solubility coefficient of oxygen in plasma
- Arterial oxygen content is directly proportional to the Hb, SaO2, and PaO2.
- Definition: the rate at which oxygen is transferred from the lungs to the peripheral circulation
- Formula: oxygen delivery (DO2, mL O2/min) = cardiac output (CO) x arterial oxygen content (CaO2)
- Oxygen delivery is directly proportional to cardiac output and arterial oxygen concentration.
- Formation of carboxyhemoglobin: hemoglobin that is removed from oxygen transportation because its oxygen binding site is occupied by carbon monoxide
- See for details.
- A form of hemoglobin that contains iron in its oxidized (ferric = Fe3+) rather than its reduced state (ferrous = Fe2+) and therefore cannot bind oxygen.
- Ferric iron binds less readily to oxygen compared to ferrous iron, leading to a decrease in blood oxygen saturation and total oxygen content (can lead to tissue hypoxia).
- Ferric iron has a high affinity for cyanide; (therefore, in cyanide poisoning, amyl nitrite is given → Fe2+ turns into Fe3+→ formation of methemoglobin → binding of free cyanide in the blood to methemoglobin → less cyanide binding to cytochrome c oxidase)
- Methemoglobin levels
Causes of methemoglobinemia
- Exposure to substances that increase methemoglobin levels (most common cause)
- Drugs: nitroglycerin, sulfonamides, dapsone, inhaled nitric oxide, topical anesthetics such as lidocaine or benzocaine, and aniline derivatives
- Nitro and amino compounds of benzene
- Congenital (hereditary) methemoglobinemia
- Glucose-6-phosphate dehydrogenase deficiency
- Methylene blue: At lower concentrations, it is highly effective at reducing methemoglobin to hemoglobin.
- Reducing agents such as ascorbic acid (vitamin C) and riboflavin may sometimes help to reduce methemoglobin to hemoglobin.
- In acquired methemoglobinemia: Assess for pharmaceutical triggers and cease therapy with any agents thought to be the cause.
- Last resort for patients who do not respond to methylene blue: exchange transfusion