- Clinical science
Erythrocytes, or red blood cells (RBCs), are the most common blood cells. They are filled with hemoglobin (Hb), which is responsible for transporting oxygen throughout the body. If Hb's binding site for oxygen is blocked, this transport mechanism will be impaired, resulting in decreased oxygen transportation and therefore tissue oxygenation. This can occur, for instance, after inhaling carbon monoxide or exposure to substances that increase methemoglobin levels such as nitrates. Particular disorders or abnormalities often involve characteristic changes to RBC morphology. For example, the presence of schistocytes is an important factor for diagnosing hemolytic uremic syndrome. For this reason, the microscopic analysis of RBCs, either in a blood smear or in urine samples, is a valuable tool for diagnosing erythrocyte pathologies.
- 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 oxygenated state), which influence how it binds and releases O2 and CO2.
- Deficient or defective Hb can ultimately affect the transport of O2.
- For more information about disorders of Hb, see the learning card on .
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|Mitochondria|| || |
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Sideroblastic anemia (with possible basophilic stippling) has different etiologies, of which three are part of heme synthesis: X-linked defect in the δ-ALA synthase gene, vitamin B6 deficiency and lead poisoning (and sequential inhibition of δ-ALA dehydratase and ferrochelatase).
Porphyrins: derivatives include protoporphyrin
- Composed of 4 rings with a central iron
- O2 binds to ferrous iron (Fe2+)
- Iron binds to globin via histidine residues
Globin is an integral part of the Hb molecule. It is composed of amino acids that fold to form eight alpha helices. Throughout the lifespan of an individual, different types of globin chains are present in Hb, particularly during embryonic, fetal, and early life.
|Chromosomes||Hb genes||Globin chains||Time of physiologic expression|
|Chromosome 16||HBA1||α||fetal + adult|
- Embryonic Hb: ζ and ε
- Fetal Hb
- Adult Hb: synthesized in bone marrow
: Defective α chain production results in tetramer formation → tetramer have heightened affinity for O2 → decreased O2 release
- HbH: 4 β-chains form a tetramer
- Hb-Barts: 4 γ-chains form a tetramer
- : Defective β-chain formation results in increased HbA2 and HbF formation.
See “” for more information.
- O2, CO2, and protons all bind Hb and influence each other's affinities to Hb, which is important for gas exchange.
- CO2 is mainly carried in three forms in the body:
- RBCs carry carbonic anhydrase, which converts HCO3- and H+ to H2O and CO2 in the following formula: HCO3− + H+ ⇄ H2CO3 ⇄ H2O + CO2
- Ultimately, excess H+ during acidic states can be eliminated by being converted to CO2, which can be exhaled.
During basic states, the reversal can occur 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 and accounts for 50% of the blood buffer capacity.
- For more details on the buffering mechanisms of the body, see in .
- 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 ODC → ↓ O2 affinity for Hb → ↑ O2 dissociation from Hb → ↑ tissue oxygenation
Shift to the left of the ODC → ↑ O2 affinity for Hb → ↓ O2 dissociation from Hb → ↓ tissue oxygenation
Causes of shift to the left
- ↓ Partial pressure of carbon dioxide (PCO2)
- ↓ Body temperature
- ↓ H+ (↑ pH)
- Causes of shift to the left
|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 )||High (sigmoidal curve)|
|Function|| || |
- amino acids. chains are released and converted into
Process: heme (red) → (green pigment) → bilirubin (yellow pigment)
- Heme is converted to biliverdin by .
Biliverdin is converted to by biliverdin reductase.
- Requires NADPH + H+
Heme breakdown is responsible for the color changes in hematomas!
- 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 enzyme in the liver.
- Bilirubin diglucuronide excreted in bile is broken down by GI bacteria to 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 (allosteric effector)
- Mature RBCs are unable to generate energy via the Krebs cycle because they lack mitochondria
- Important biochemical pathways available in RBCs:
| Dacryocytes |
(teardrop cells, teardrop erythrocytes)
| Sickle cells |
| Schistocytes |
| Macrocytes |
| Echinocytes |
Smooth, rounded, and evenly spaced cytoplasmic projections
| Target cells |
| Acanthocytes |
Slit-like central pallor most often caused by changes in membrane permeability
|Degmacytes (bite cells)||One more semicircular portions removed ("bitten off") from the cell margin|
RBCs with abnormal contents
|Heinz bodies||Denaturated hemoglobin|| |
|Basophilic stippling||RNA|| |
|Howell-Jolly bodies||DNA|| || |
|Pappenheimer bodies||Iron|| |
Hemoglobin undergoes conformational changes as it travels in the blood, and takes up oxygen in the lungs to deliver it to tissues. Also, changes in iron state (from Fe2+ to Fe3+) causes a change in the structure of hemoglobin within the RBC. The affinity and ability of hemoglobin to carry oxygen are dependent on its configuration.
- Oxyhemoglobin: hemoglobin with oxygen bound to its heme component (oxygenated) → red color
- Deoxyhemoglobin: hemoglobin with no oxygen bound to its heme component (deoxygenated) → dark red, purple colors → "cyanosis"
- Hemoglobin that is removed from oxygen transportation because its oxygen binding site is occupied by carbon monoxide (→ )
- Methemoglobin contains iron in its oxidized (ferric = Fe3+) rather than its reduced state (ferrous = Fe2+) and cannot bind oxygen.
- 0–3% of total hemoglobin: physiological
- > 3%: visible cyanosis (a brownish-blue or greyish coloration of the skin and membranes)
- > 20%: clinical symptoms of oxygen deprivation, brown blood ("chocolate-colored blood")
- > 70%: fatal
Causes of methemoglobinemia
- Exposure to substances that increase methemoglobin levels (most common cause)
- Congenital (hereditary) methemoglobinemia
- Glucose-6-phosphate dehydrogenase deficiency
- Dark brown coloration of blood
- Reduced oxygen saturation and total oxygen content with normal PaO2 on despite clinical signs of cyanosis
- Confirm with CO-oximeter
- Methylene blue: In lower concentrations, it is very effective in reducing methemoglobin to hemoglobin.
- Reducing agents such as ascorbic acid (vitamin C) and riboflavin may help reduce methemoglobin to hemoglobin, although they are not always effective.
- In cases of acquired methemoglobinemia: Investigate pharmaceutical causes and cease therapy with agents they may at fault.
- Last resort: Exchange transfusion