18.3 Erythrocytes

Erythrocyte Structure and Function

Erythrocytes (red blood cells, or RBCs) are the most abundant formed elements in blood, and their sole job is gas transport. They carry oxygen from the lungs to tissues and assist in moving carbon dioxide back to the lungs for exhalation. Understanding their structure, lifecycle, and the hemoglobin they carry is central to understanding blood physiology.

Structure of Erythrocytes

The shape of an erythrocyte is a biconcave disc, meaning it's thinner in the center and thicker at the edges. This shape isn't random. It maximizes surface area relative to volume, which makes gas exchange across the membrane faster and more efficient. It also gives the cell flexibility to squeeze through narrow capillaries.

• Erythrocytes lack a nucleus and most organelles. During maturation, the nucleus is ejected. This frees up internal space so the cell can be packed with hemoglobin instead.
• Each erythrocyte contains roughly 250 million hemoglobin molecules, making it an extremely efficient oxygen carrier.
• The plasma membrane is highly permeable to $O_2$ and $CO_2$, allowing rapid gas diffusion.
• Glycoproteins and glycolipids on the membrane surface determine blood type (A, B, AB, or O). These surface antigens are clinically important for transfusion compatibility.

Because erythrocytes lack mitochondria, they generate ATP through anaerobic glycolysis only. This means they don't consume any of the oxygen they carry.

Lifecycle of Erythrocytes

Erythropoiesis is the production of new erythrocytes, and it takes place primarily in the red bone marrow. The process is regulated by erythropoietin (EPO), a hormone released by the kidneys in response to low blood oxygen levels (hypoxia). When tissues aren't getting enough oxygen, the kidneys ramp up EPO secretion, which stimulates the bone marrow to produce more RBCs.

The maturation stages from stem cell to circulating RBC are:

1. Proerythroblast — the earliest recognizable erythroid cell, committed to the red cell lineage
2. Basophilic erythroblast — actively synthesizing ribosomes for hemoglobin production
3. Polychromatophilic erythroblast — hemoglobin accumulation begins, giving the cell a mixed color on staining
4. Orthochromatic erythroblast — the nucleus condenses and is ejected at this stage
5. Reticulocyte — an immature erythrocyte that still contains some residual RNA; released into the bloodstream where it matures within 1–2 days
6. Mature erythrocyte — fully functional, anucleate cell

Mature erythrocytes circulate for about 120 days. As they age, their membranes become fragile and less flexible. Macrophages in the spleen and liver recognize and phagocytize these old or damaged cells. During breakdown, the hemoglobin is split apart:

• Iron is salvaged and recycled back to the bone marrow via the transport protein transferrin, where it's reused in new hemoglobin synthesis.
• The heme group (minus iron) is converted to biliverdin, then to bilirubin, which is processed by the liver and excreted in bile.
• The globin chains are broken down into amino acids that re-enter the body's amino acid pool.

Hemoglobin and Oxygen Transport

Hemoglobin Structure

Hemoglobin is a quaternary protein made of four polypeptide chains: two alpha (α) and two beta (β) subunits. Each subunit contains a heme group, which is an iron-containing porphyrin ring. The iron atom ($Fe^{2+}$) at the center of each heme is the actual binding site for one $O_2$ molecule. Since there are four heme groups per hemoglobin molecule, one hemoglobin can carry up to four oxygen molecules.

Cooperative Binding and the Dissociation Curve

Oxygen binding to hemoglobin is cooperative, meaning the binding of the first $O_2$ molecule changes the shape of hemoglobin in a way that makes it easier for the remaining subunits to bind oxygen. This is why hemoglobin exists in two conformational states:

• Tense (T) state — lower oxygen affinity (deoxyhemoglobin)
• Relaxed (R) state — higher oxygen affinity (oxyhemoglobin)

Cooperative binding produces the characteristic sigmoidal (S-shaped) oxygen-hemoglobin dissociation curve, rather than a simple linear relationship. This curve is worth understanding well because it explains how hemoglobin loads oxygen efficiently in the lungs (where $PO_2$ is high) and unloads it efficiently in the tissues (where $PO_2$ is low).

Factors That Shift the Dissociation Curve

The $P_{50}$ is the partial pressure of oxygen at which hemoglobin is 50% saturated. Changes in $P_{50}$ reflect shifts in hemoglobin's affinity for oxygen.

A helpful way to remember the right shift: think about exercising muscle tissue. It's warmer, more acidic (from lactic acid and $CO_2$), and produces more 2,3-BPG. All of those conditions push hemoglobin to release oxygen right where it's needed most.

Erythrocyte Assessment and Disorders

Clinicians use several lab values to evaluate erythrocyte status:

• Hematocrit — the percentage of total blood volume occupied by erythrocytes. Normal ranges are approximately 42–52% for males and 36–48% for females. A low hematocrit can indicate anemia; an abnormally high value may suggest dehydration or polycythemia.
• Red blood cell count — the number of erythrocytes per microliter of blood (normal is roughly 4.5–5.5 million/µL). This helps assess whether erythrocyte production and lifespan are within normal limits.
• Hemoglobin concentration — measured in g/dL, this directly reflects oxygen-carrying capacity.

Key Disorders

Anemia is a reduction in the number of erythrocytes, hemoglobin concentration, or both, resulting in decreased oxygen delivery to tissues. Common symptoms include fatigue, pallor, and shortness of breath. Anemia has many causes, including iron deficiency, vitamin B12 deficiency, chronic blood loss, and bone marrow disorders.

Sickle cell disease is a genetic disorder caused by a point mutation in the gene for the beta globin chain. The abnormal hemoglobin (hemoglobin S, or HbS) polymerizes when deoxygenated, distorting erythrocytes into a rigid, crescent (sickle) shape. These misshapen cells can obstruct small blood vessels, causing pain crises, tissue ischemia, and organ damage. Sickle cells also have a shorter lifespan (about 10–20 days vs. the normal 120), contributing to chronic hemolytic anemia.