Erythrocyte morphology and hemoglobin

Last updated: January 7, 2023

Summarytoggle arrow icon

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.

Erythrocyte morphologytoggle arrow icon

Normal morphology

Dysmorphic RBCs

  • Anisocytosis: the presence of RBCs of varying sizes
  • Poikilocytosis: the presence of RBCs of abnormal shapes
Overview of dysmorphic RBCs
Morphology Associated conditions
(teardrop cells, teardrop erythrocytes)
  • Teardrop-shaped
Sickle cells
  • Sickle-shaped
  • Fragmented
  • Large, spherical
  • Small, spherical, no central pallor

Elliptocytes (ovalocytes)

  • Oval or elliptical
(burr cells)
Target cells
  • Bullseye appearance
(spur cells)
  • Thorny irregular cytoplasmic projections of varying length and width

Stomatocytes (mouth cells)

  • Slit-like central pallor most often caused by changes in membrane permeability
Degmacytes (bite cells)

HALT when you see a Target! Associated etiologies of target cells are: HHemoglobinopathies (HbC/HbS), AAsplenia, LLiver disease, TThalassemia

Dacryocytes (teardrop cells) are formed via extramedullary erythropoiesis: “Don't cry, we can play outside to-marrow.”

RBCs with inclusion bodies

Overview of erythrocyte inclusion bodies
Content Appearance Cause
Heinz bodies
Pappenheimer bodies
Basophilic stippling
Ringed sideroblasts
Howell-Jolly bodies
  • DNA (nuclear remnants)
  • Do not contain iron
Iron granules

Metabolism of erythrocytestoggle arrow icon

The lifespan of RBCs is about 120 days. After this time, macrophages in the reticuloendothelial system of the bone and the spleen phagocytose RBCs. They are then broken down and their parts recycled.

Globin metabolism

Globin chains are released and converted into amino acids.

Hemoglobin metabolism

Process: heme (red) → biliverdin (green pigment) → bilirubin (yellow pigment)

  1. Heme is converted to biliverdin by heme oxygenase.
  2. Biliverdin is converted to bilirubin by biliverdin reductase (requires NADPH + H+)

Heme breakdown is responsible for the color changes in hematomas.

Bilirubin metabolism

  1. Unconjugated bilirubin (insoluble in water) is released into the blood by macrophages binds to albumin and reaches the liver
  2. Unconjugated bilirubin is converted into bilirubin via the enzyme UDP-glucuronosyltransferase in the liver.
  3. Conjugated bilirubin excreted in bile is broken down by GI bacteria into urobilinogen
    • Most urobilinogen is converted to stercobilin excreted in feces (brown color).
    • Part of urobilinogen oxidates to urobilin excreted in the urine (yellow color).

Indirect (unconjugated) bilirubin is insoluble in water.

2,3-bisphosphoglycerate shunt

Energy production

Hemoglobin synthesistoggle arrow icon


Hb is a circulating globular protein composed of a heme moiety with a central iron ion and four subunits of globin.

  • 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 “Hemoglobin variants” below for details).
  • For more information about disorders of Hb, see “Anemia.”

Heme synthesis

Overview of heme synthesis
Location Reaction Enzyme Clinical significance
  • Two molecules of δ-ALA combine → porphobilinogen
  • ALA dehydratase
  • Porphobilinogen deaminase
  • N/A
  • Uroporphyrinogen decarboxylase
  • N/A


  • N/A
  • Ferrochelatase

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 Hb variants.

Hemoglobin patterns

For genetic variants of hemoglobin patterns, see “Hemoglobin variants” below.

Chromosome 16
HBA1 gene HBA2 gene HBZ1 gene HBZ2 gene
α globin ζ globin
Chromosome 11 HBB gene β globin
  • Portland 2 (ζζββ): embryonic Hb
HBD gene δ globin
HBG1 gene γ globin
  • Portland 1 (ζζγγ): embryonic Hb
HBG2 gene
HBE gene ε globin
  • Gower 2 (ααεε): embryonic
  • Gower 1 (ζζεε): embryonic Hb

Sequence of switching from fetal to adult hemoglobin (γ-globin in HbF is replaced by β-globin in HbA, and α-globin is always present in both HbA and HbF): Gamma goes, Beta becomes, Alpha always.

Hemoglobin variantstoggle arrow icon

Overview of hemoglobin variants
Hemoglobin Globin chains


Beta thalassemia Alpha thalassemia Sickle cells Hemoglobin C
Minor (trait)


(Cooley's anemia)

Silent carrier




Hb H disease


Hb Barts disease


Sickle cell trait Sickle cell disease Hemoglobin SC disease (HbSC) HbC carrier HbC disease
HbA ααββ Normal Absent Normal ↓↓ Absent Absent Absent Absent
HbA2 ααδδ Normal ↑↑ Normal ↓↓ Absent Absent Absent
HbF ααγγ Normal ↑↑ Normal Normal ↑/Normal Absent Normal Normal Normal Absent
HbH ββββ Absent Absent Absent Absent ↑↑ ↑↑ Absent Absent Absent Absent Absent
Hb Barts γγγγ Absent Absent Absent Absent Absent ↑↑ Absent Absent Absent Absent Absent
HbS ααββ


Absent Absent Absent Absent Absent Absent ↑↑ Absent Absent
HbC ααββ Absent Absent Absent Absent Absent Absent Absent Absent Absent ↑↑

Oxygen and carbon dioxide transporttoggle arrow icon


  • O2, CO2, and protons all bind Hb and influence one another's affinity to Hb, which is important for gas exchange.
    • Hb releases CO2 more easily with increasing pO2 (Haldane effect).
    • Hb binds CO2 more easily if the pO2 is low.
    • Hb releases O2 easier with increasing H+(Bohr effect).
  • 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 “Compensation.”

Bohr effect

  • 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 O2-Hb dissociation curve is shifted to the right).
    • HbO2 + H+ ⇄ H+Hb + O2
    • HbO2 + CO2 Hb-COO- + H+ + O2

Haldane effect

  • 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):
    • Oxygenated Hb has a decreased affinity for CO2 CO2 that is bound to Hb is released in the pulmonary arteries to diffuse into the alveoli (the O2-Hb dissociation curve is shifted to the left).
    • Hb releases bound H+; → ↑ H+ shifts equilibrium to CO2 production (see equation above) → CO2 is exhaled in lungs

Oxygen-hemoglobin dissociation curvetoggle arrow icon


Differences between the hemoproteins myoglobin and hemoglobin
Myoglobin Hemoglobin
Associated with
  • 1 Heme (monomeric)
Binds to
  • 1 Oxygen molecule
  • 4 Oxygen molecules
Affinity for O2
  • Very high (hyperbolic oxygen-myoglobin dissociation curve)
  • High (sigmoidal curve)
  • Transport of O2 in blood

Shift to the right of the oxygen dissociation curve

Shift to the left of the oxygen dissociation curve

Oxygen transport and conditions that affect oxygenationtoggle arrow icon


Overview of factors that affect oxygenation
Hb concentration CaO2



O2-Hb dissociation curve

Anemia (e.g., due to chronic blood loss)




CO poisoning (carboxyhemoglobin) and methemoglobinemia

Normal Normal Left-shift
Cyanide poisoning Normal Normal Normal Normal Normal
Polycythemia Normal Normal Normal
High-altitude exposure Normal Right-shift

Arterial oxygen content (CaO2)

Oxygen delivery (DO2)

Carbon monoxide poisoning

Methemoglobinemia [5][6]

Because MetHb artificially increases pulse oximeter readings, oxygen concentration measured via pulse oximetry remains high (> 80%) even if methemoglobin levels are very high!

To remember that ferrous iron (Fe2+) is the reduced form of iron, think: “Joe reduced 2 ferocious animals from his iron cage.

Referencestoggle arrow icon

  1. Schuerholz T, Irmer J ,Simon TP, Reinhart K,Marx G. Methemoglobin level as an indicator for disease severity in sepsis. Crit Care. 2008; 12 (2): p.448.doi: 10.1186/cc6669 . | Open in Read by QxMD
  2. Ohashi K, Yukioka H, Hayashi M, Asada A. Elevated methemoglobin in patients with sepsis. Acta Anaesthesiologica Scandinavica. 1998; 42 (6): p.713-716.doi: 10.1111/j.1399-6576 . | Open in Read by QxMD
  3. Rochette J, Craig JE, Thein SL. Fetal hemoglobin levels in adults.. Blood Rev. 1994; 8 (4): p.213-24.doi: 10.1016/0268-960x(94)90109-0 . | Open in Read by QxMD
  4. L. Terrenato, C. Bertilaccio, P. Spinelli, B. Colombo. The Switch from Haemoglobin F to A: the Time Course of Qualitative and Quantitative Variations of Haemoglobins after Birth. Br J Haematol. 1981; 47 (1): p.31-41.doi: 10.1111/j.1365-2141.1981.tb02759.x . | Open in Read by QxMD
  5. Van Wijk R. The energy-less red blood cell is lost: erythrocyte enzyme abnormalities of glycolysis. Blood. 2005; 106 (13): p.4034-4042.doi: 10.1182/blood-2005-04-1622 . | Open in Read by QxMD
  6. Merchant SH, Oliveira JL, Hoyer JD, Viswanatha DS. Molecular Diagnosis in Hematopathology. Elsevier ; 2012: p. 679-726

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