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.
- No nucleus, cell organelles, or granules
- Biconcave shape
- Contain hemoglobin, which leads to acidophilic cytoplasm
- Anisocytosis: the presence of RBCs of varying sizes
- Poikilocytosis: the presence of RBCs of abnormal shapes
(teardrop cells, teardrop erythrocytes)
| Sickle cells |
| Schistocytes |
| Macrocytes |
| Echinocytes |
|Target cells |
Stomatocytes (mouth cells)
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|Degmacytes (bite cells)|
RBCs with inclusion bodies
|Pappenheimer bodies|| |
|Ringed sideroblasts|| |
|Howell-Jolly bodies|| |
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
Indirect (unconjugated) bilirubin is insoluble in water.
- 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 → release of oxygen into tissue
- 2,3-BPG binds with greater affinity to deoxygenated hemoglobin than oxygenated hemoglobin.
- 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 “ ” below for details).
- For more information about disorders of Hb, see “ .”
- 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).
|Cytoplasm|| || |
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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 polypeptide 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); each subunit is able to bind one O2 molecule
- 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|| || |
|Overview of hemoglobin variants|
|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
Bicarbonate buffer system
- 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.
- For more details on the buffering mechanisms of the body, see “.”
- 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.
- Relationship between saturation and partial pressure of O2 is not linear
- Reflected in the sigmoidal shape (S-shape) of the curve, which begins flat, then rises steeply before plateauing.
- Due to positive cooperativity (the phenomenon by which, e.g., binding of one O2 molecule to a single heme increases the O2 affinity of hemoglobin, facilitating the binding of subsequent O2 molecules).
- Myoglobin is composed of a single polypeptide chain that is associated with a monomeric heme molecule.
- Therefore, it cannot show positive cooperativity and its curve is not sigmoidal.
- 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).
|Differences between the hemoproteins myoglobin and hemoglobin|
|Associated with|| || |
|Binds to|| || |
|Affinity for O2|| || |
Shift to the right of the oxygen dissociation curve
- ↓ Hb affinity for O2 → ↑ O2 dissociation from Hb → ↑ tissue oxygenation → ↑ P50 (the partial pressure of oxygen needed to maintain 50% of Hb saturated)
- Causes of shift to the right include:
Shift to the left of the oxygen dissociation curve
- ↑ Hb affinity for O2 → ↓ O2 dissociation from Hb → ↓ tissue oxygenation → ↑ erythropoietin synthesis (due to renal hypoxia) → compensatory erythrocytosis
- Causes of shift to the left include:
Oxygen transport and conditions that affect oxygenation
|Overview of factors that affect oxygenation|
|Hb concentration|| |
|Anemia (e.g., due to chronic blood loss)||↓||↓|| |
Arterial oxygen content (CaO2)
- 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.
Oxygen delivery (DO2)
- 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 “”
- 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
- 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