Red Blood Cell (RBC) Morphology

Introduction

The unique red blood cell (RBC) morphology plays an important role in the optimal function of RBC as an oxygen transporter. This biconcave disc-shape offers a high surface area to volume ratio, allowing for efficient diffusion of oxygen molecules into and out of the RBCs.  Any abnormality in RBC shape can significantly impact this process, potentially leading to oxygen deficiency in the body’s tissues.

Approach to Anemia: A Brief Overview

Anemia is a condition characterized by a deficiency in red blood cells (RBCs) or hemoglobin, the oxygen-carrying protein within them. This deficiency leads to reduced oxygen delivery to tissues, causing symptoms like fatigue, weakness, and shortness of breath. Diagnosing anemia involves a multi-step approach, and RBC morphology examination plays a vital role in pinpointing the underlying cause.

Here’s a breakdown of the key steps involved:

Complete Blood Count (CBC)

• The CBC serves as the cornerstone of anemia evaluation. It provides a quantitative assessment of RBC count, hemoglobin concentration, hematocrit (percentage of blood volume occupied by RBCs), and other cellular parameters like Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH), and Mean Corpuscular Hemoglobin Concentration (MCHC).

History, Physical Examination, and Additional Tests

• A detailed medical history and physical examination can provide valuable clues. These include:
  • Dietary habits (pointing towards potential iron or vitamin deficiencies)
  • Menstrual history (heavy periods can contribute to iron deficiency)
  • Family history (certain anemias are hereditary)
  • Presence of chronic illnesses (chronic inflammatory diseases can suppress RBC production)
  • Medication use (some medications can cause drug-induced anemia)
• Depending on the initial findings, further investigations may be warranted:
  • Iron studies: Serum iron, ferritin, transferrin saturation, and total iron binding capacity (TIBC) help differentiate between iron deficiency anemia and other causes.
  • Vitamin B12 and folate levels: Assessed to rule out deficiencies that can lead to macrocytic anemia.
  • Autoimmune workup: Certain autoimmune conditions can target RBCs, requiring specific tests for confirmation.
  • Bone marrow examination: In complex cases, a bone marrow biopsy or aspirate might be necessary to evaluate RBC production.

RBC Morphology Examination

A peripheral blood smear offers a wealth of information about RBC morphology. By examining the size, shape, and color of RBCs, you can gain valuable insights into the underlying cause.

Diagnosis and Treatment

By analyzing the CBC results, medical history, physical examination findings, additional tests, and crucially, the RBC morphology, we can arrive at a specific diagnosis. This paves the way for targeted treatment, which may involve:

• Iron supplementation: The mainstay of therapy for iron deficiency anemia.
• Vitamin B12 or folate replacement: For deficiencies leading to megaloblastic anemia.
• Supportive care: Blood transfusions in severe cases or for specific hemolytic anemias.
• Treating underlying conditions: Addressing chronic illnesses or autoimmune disorders that contribute to anemia.

Key RBC Characteristics Assessed in Morphology

The peripheral blood smear, a simple yet powerful tool, serves as the gold standard for evaluating red blood cell (RBC) morphology.  This readily available and cost-effective test provides valuable information about the size, shape, and color of RBCs, offering crucial clues for diagnosing various RBC disorders, particularly anemias. A trained medical professional, typically a laboratory technician or hematopathologist, examines the stained smear for RBC morphology under a microscope. By analyzing the RBCs under high magnification, the examiner can identify various morphological features, including:

• Size (Normocytosis, Microcytosis, Macrocytosis): A healthy red blood cell (RBC) would fall between 7.2 and 7.9 microns across. This ideal size allows RBCs to squeeze through tiny blood vessels and deliver oxygen efficiently. Mean Cell Volume (MCV) is an average measurement of the volume of RBCs in a blood sample. The MCV helps assess the overall size of RBCs.
  • Normocytic RBCs (80 < MCV < 100 fL): Normocytic RBCs are red blood cells with a normal size. Healthy RBCs fall within this range. However, normocytic RBCs can also be present in certain types of hemolytic anemia.
  • Microcytic RBCs (MCV < 80 fL): These are smaller than normal cells. This can be a sign of iron deficiency anemia or other conditions that affect hemoglobin production.
  • Macrocytic RBCs (MCV > 100 fL): These are larger than normal cells. This can indicate vitamin B12 or folate deficiency, among other causes.
• Color (Normochromia, Hypochromia, Polychromia): Healthy RBCs appear round with a pink-stained rim. This pink color comes from hemoglobin, the protein inside RBCs that carries oxygen. The center of the cell is typically more pale, is called central pallor. The size of this pale area can tell us about the amount of hemoglobin present in RBC morphology. A normal central pallor is about ⅓ in size of the RBC. Mean corpuscular hemoglobin (MCH) is a measurement of the average amount of hemoglobin within a single RBC. A normal MCH range is 27 – 32 pg.
  • Hypochromic Cells:  If an RBC has less hemoglobin than normal, it will have a larger central pallor. These pale cells are called hypochromic (MCH less than 27 pg). This can be a sign of iron deficiency anemia.
  • Polychromatic cells:  These are usually young, immature RBCs (reticulocytes) that are slightly larger than mature RBCs and may have a slight bluish tint due to residual RNA. They are normally present in very small numbers (less than 1%) in the bloodstream.
• Shape (Discocyte, Spherocyte, Elliptocyte, Stomatocyte etc.): The typical biconcave disc shape allows for optimal oxygen transport. Abnormalities like sickle cells, spherocytes, elliptocytes, and fragmented RBCs (schistocytes) can be indicative of specific diseases.
• Distribution: Normally, red blood cells (RBCs) are spread out evenly across the blood smear. This allows for clear examination of their individual size, shape, and color. However, sometimes RBCs can clump together in abnormal patterns:
  • Rouleaux formation: This refers to RBCs stacked together in long rows, resembling a pile of coins. It’s a non-specific finding and can be seen in conditions like increased blood protein levels, particularly in the presence of abnormal proteins called paraproteins. These abnormal proteins can act like a bridge between RBCs, causing them to stick together.
  • Cold agglutination: This is a specific type of clumping where RBCs aggregate due to cold temperatures or the presence of cold agglutinins, which are antibodies that target RBCs at cooler temperatures. This can be a sign of an underlying autoimmune disorder.

Common RBC Morphology Seen in Disorders

Normal Red Blood Cell (RBC) Morphology

The red blood cell (RBC) is approximately 7.2 – 7.9 μm in diameter with a pinkish hue cytoplasm. The central pallor is approximately 1/3 the size of the red cells. The cells are almost all the same shape and size. The red cells are slightly smaller than the small lymphocyte in size.

Microcytosis (Microcytic Red Cells)

Microcytic red blood cells (RBCs) are smaller than their healthy counterparts in terms of RBC morphology. Typically, their diameter falls below 7.2 µm. On a peripheral blood smear, they appear:

• Smaller in size: Compared to normal RBCs, microcytes have a noticeably reduced diameter.
• Maintain biconcave shape: Despite their smaller size, microcytic RBCs usually retain the characteristic biconcave disc shape of healthy RBCs.
• Increased central pallor: Due to potentially reduced hemoglobin content, the central pale area of the cell may appear larger than usual (more than ⅓ in diameter).

Causes of Microcytic Anemia

Microcytic RBCs are a hallmark feature of microcytic anemia, a condition where the body produces abnormally small red blood cells.  Several factors can contribute to this:

• Iron deficiency anemia:  This is the most common cause of microcytic anemia. It occurs when the body doesn’t have enough iron, a crucial component of hemoglobin. Without sufficient iron, the body produces smaller RBCs with less hemoglobin, leading to reduced oxygen-carrying capacity.
• Thalassemia:  This is a group of inherited blood disorders where there’s a defect in globin protein production. Globin chains combine with iron to form hemoglobin. A deficiency in globin production disrupts hemoglobin formation and leads to microcytic RBCs.
• Chronic inflammation:  Long-term inflammatory conditions can suppress red blood cell production and lead to microcytic anemia. The mechanism behind this is not fully understood, but it’s thought to be related to the effects of inflammatory molecules on bone marrow function.
• Sideroblastic anemia:  This is a group of rare anemias where iron gets trapped inside bone marrow cells and isn’t readily available for hemoglobin production. As a result, the body produces microcytic RBCs despite having adequate iron stores.
• Lead poisoning:  Lead can interfere with hemoglobin production, leading to microcytic anemia.

Macrocytosis (Macrocytic Red Cells)

Macrocytic red blood cells (RBCs) are larger than their healthy counterparts in terms of RBC morphology. Typically, their diameter falls above 100 µm. On a peripheral blood smear, they can exhibit varying characteristics:

• Increased size: The most striking feature is their noticeably larger diameter compared to normal RBCs.
• Shape variations: Macrocytes may retain the biconcave disc shape of healthy RBCs, but they can also appear more oval-shaped or even teardrop-shaped.
• Variable central pallor: The size of the central pale area can vary depending on the underlying cause. In some cases, it might be similar to normal RBCs, while in others, it may appear larger due to a potential hemoglobin deficiency.

Causes of Macrocytic Anemia

Macrocytic RBCs are a hallmark feature of macrocytic anemia, a condition where the body produces abnormally large red blood cells. Several factors can contribute to this:

• Vitamin B12 deficiency:  Vitamin B12 is essential for DNA synthesis, which is crucial for proper RBC production. A deficiency can lead to problems with RBC maturation, resulting in macrocytic RBCs.
• Folate deficiency:  Folate, like vitamin B12, plays a vital role in DNA synthesis. A deficiency can also disrupt RBC maturation and lead to macrocytic anemia.
• Alcohol abuse:  Chronic alcohol consumption can interfere with vitamin B12 absorption and metabolism, leading to macrocytosis.  Alcohol can also directly damage bone marrow, further affecting RBC production.
• Liver disease:  Severe liver disease can impair vitamin B12 storage and utilization, leading to macrocytic anemia.
• Certain medications:  Some medications can have side effects that interfere with DNA synthesis or vitamin B12 absorption, potentially causing macrocytosis.
• Rare bone marrow disorders:  In rare cases, certain bone marrow disorders like myelodysplastic syndrome (MDS) can lead to macrocytic anemia.

Normochromic Red Cells

Normochromic RBCs appear pink or red, similar to healthy RBC morphology. The central pallor (pale area) is also typically within the normal range. This indicates that they contain a typical amount of hemoglobin, the protein responsible for carrying oxygen.  However, their normal color doesn’t necessarily rule out anemia.

Causes of Normochromic Anemia

Several factors can contribute to normochromic anemia RBC morphology:

• Chronic Inflammatory Disease: Long-term inflammation can suppress red blood cell production in the bone marrow, leading to normochromic anemia.
• Chronic Kidney Disease: Kidneys play a role in red blood cell production. When kidney function is impaired, anemia can develop.
• Blood Loss: Acute or chronic blood loss can deplete the body’s red blood cell stores, leading to normochromic anemia.
• Bone Marrow Disorders: Certain bone marrow disorders like aplastic anemia or myelodysplastic syndrome (MDS) can disrupt red blood cell production, causing normochromic anemia.
• Nutritional Deficiencies: While deficiencies in iron, vitamin B12, or folate typically cause hypochromic (pale) RBCs, severe deficiencies can sometimes lead to normochromic anemia.

Hypochromic Red Cells

Hypochromic red blood cells (RBCs) appear paler than normal on a peripheral blood smear in terms of RBC morphology. This pale appearance signifies a reduced concentration of hemoglobin within the cell. Hemoglobin, the protein responsible for carrying oxygen, gives healthy RBCs their characteristic pink color. When there’s less hemoglobin, the RBCs appear fainter.

Appearance on Blood Smear

• Pale Color: The most striking feature is the overall paler appearance compared to healthy RBCs. The central pallor, the pale area in the center of the cell, appears significantly larger than normal (more than ⅓ in diameter). In severe cases, the entire cell might appear almost colorless.
• Possible Size Variations: Hypochromic anemia can sometimes co-occur with microcytosis (smaller than normal) RBCs. This combination is frequently seen in iron deficiency anemia. However, the size of hypochromic RBCs can be variable depending on the underlying cause.

Causes of Hypochromic Anemia

The most common cause of hypochromic anemia is

• Iron deficiency anemia: This occurs when the body doesn’t have enough iron, a crucial component of hemoglobin. Without sufficient iron, red blood cells become smaller and paler due to reduced hemoglobin content.

Other potential causes include

• Chronic blood loss: Long-term blood loss, due to conditions like peptic ulcers or heavy menstruation, can deplete iron stores and lead to hypochromic anemia.
• Chronic inflammatory disease: Long-term inflammation can disrupt iron metabolism and contribute to hypochromic anemia.
• Certain inherited blood disorders: Conditions like thalassemia can affect hemoglobin production and lead to hypochromic anemia.

Polychromatic Red Cells

Polychromatic red blood cells (RBCs) appear slightly different on a blood smear compared to their mature counterparts in terms of RBC morphology. These immature cells, also known as reticulocytes, offer a glimpse into red blood cell production within the bone marrow.

Appearance on Blood Smear

• Size Variations: Polychromatic RBCs can be slightly larger than mature RBCs. However, the size variation is usually not as significant as seen in microcytic or macrocytic anemia.
• Bluish Hue: When stained with certain dyes used in blood smears, polychromatic RBCs may exhibit a faint bluish tint. This bluish color is due to the presence of residual ribosomal RNA (ribonucleic acid) within the cells. Mature RBCs typically lack this RNA and appear solely pink due to hemoglobin.

Causes of Polychromatic Red Cells

The presence of polychromatic RBCs in a blood smear is not necessarily a cause for concern.  A small percentage (typically less than 1%) of these immature cells are normally present in the bloodstream. However, an increased number of polychromatic RBCs (reticulocytosis) can indicate:

• Increased red blood cell production: The bone marrow might be ramping up RBC production in response to a condition like blood loss or hemolytic anemia (increased RBC destruction).
• Early recovery from anemia: Following treatment for anemia, the body might be actively producing new RBCs, leading to an elevated reticulocyte count.

Target Cells

Target cells, also known as codocytes, have a distinctive appearance on a peripheral blood smear in terms of RBC morphology.

Appearance on Blood Smear

• Bulls-eye Pattern:  The defining feature of a target cell is its resemblance to a shooting target. It has three distinct zones in the RBC morphology:
  • Central Dense Area: A dark, centrally located disc containing a normal or slightly increased amount of hemoglobin.
  • Pale Ring: A clear or pale zone encircling the central area, lacking sufficient hemoglobin.
  • Peripheral Rim: A darker outer rim containing hemoglobin, similar in intensity to the central area.

Causes of Target Cells

The presence of target cells on a blood smear can be associated with several conditions:

• Liver Disease: Liver dysfunction, particularly obstructive liver disease with jaundice, can lead to macrocytic target cell formation. The exact mechanism is not fully understood, but it’s thought to be related to abnormal cholesterol metabolism in the liver, which affects the RBC membrane.
• Hemoglobinopathies: Certain inherited blood disorders like beta-thalassemia or hemoglobin E trait can cause microcytic target cells.
• Iron Deficiency Anemia: In some cases, mild iron deficiency can be associated with the presence of a few target cells on the blood smear.
• Splenectomy: The removal of the spleen, an organ that filters blood cells, can sometimes lead to an increased number of target cells.
• Lead Poisoning: Exposure to lead can interfere with normal RBC development and contribute to target cell formation.

Stomatocytes

Stomatocytes are a type of red blood cell (RBC) with a distinctive appearance on a peripheral blood smear in terms of RBC morphology. 

Appearance on Blood Smear

• Mouth-Shaped Indentation: The defining feature of a stomatocyte is a centrally located, slit-like indentation that resembles a small mouth. This indentation gives the cell its name (stoma means “mouth” in Greek).

Causes of Stomatocytes

The presence of stomatocytes on a blood smear can be associated with several conditions:

• Hereditary Stomatocytosis: This is a rare group of inherited disorders where the genes responsible for maintaining the structure and function of the RBC membrane are defective. This defect leads to the formation of stomatocytes.
• Liver Disease: Liver dysfunction, similar to the case with target cells, can sometimes lead to stomatocyte formation. The mechanism is likely related to abnormal cholesterol metabolism affecting the RBC membrane.
• Certain drugs: The exact mechanisms by which some drugs induce stomatocytosis are not fully established. Some medications known to be associated with drug-induced stomatocytosis including phenolthiazine and chlorpromazine.
• Alcoholism: The exact mechanism by which alcohol induces stomatocytosis is not fully understood.

Pencil cells

Pencil cells are a type of abnormally elongated thin-shaped red blood cells (RBCs) seen on a peripheral blood smear. 

Appearance on Blood Smear

• Elongated Shape: The defining feature of a pencil cell is its markedly elongated shape, resembling a pencil lead in terms of RBC morphology. The length of the cell can be several times greater than its width.
• Microcytic Tendencies: Pencil cells are often, but not always, microcytic. This means they are smaller than normal red blood cells in diameter despite their elongated form.
• Pale Color: In some cases, pencil cells may also appear pale, suggesting a reduced hemoglobin concentration (hypochromic). This is particularly common when they occur due to iron deficiency.

Causes of Pencil Cells

The presence of pencil cells on a blood smear is most commonly associated with:

• Iron Deficiency Anemia: This is the most frequent cause of pencil cells. When the body lacks sufficient iron, a crucial component of hemoglobin, it produces smaller and more elongated red blood cells. In severe iron deficiency, these cells can take on the characteristic pencil shape.

Other potential, less common causes include

• Thalassemia: A group of inherited blood disorders where there’s a defect in globin protein production. Globin chains combine with iron to form hemoglobin. A deficiency in globin production, independent of iron stores, can sometimes lead to pencil cell formation.
• Lead Poisoning: Exposure to lead can interfere with normal red blood cell development and contribute to the formation of pencil cells, along with other abnormalities.
• Sideroblastic Anemia: This is a rare group of anemias where iron gets trapped inside bone marrow cells and isn’t readily available for hemoglobin production. In some cases, pencil cells can be seen.

Echinocytes (Burr or Crenated Cells)

Echinocytes are a type of red blood cell (RBC) morphology with spiky projections appearance on a peripheral blood smear. 

Appearance on Blood Smear

• Spiky Projections: The defining feature of an echinocyte is the presence of numerous small, evenly spaced projections on the cell surface. These projections resemble the spikes on a sea urchin (echinoderm) or the burrs on a plant, hence the nicknames.

Causes of Echinocytes

The presence of echinocytes on a blood smear can be associated with several conditions:

• Artificially Induced: In some cases, echinocytes can appear due to technical issues during blood smear preparation. This is why proper blood collection and smear processing are crucial for accurate interpretation.
• Kidney Disease: Advanced kidney disease can lead to the accumulation of waste products in the blood, which can damage the RBC membrane and contribute to echinocyte formation.
• Liver Disease: Severe liver dysfunction can also affect the RBC membrane and lead to the appearance of echinocytes.

Acanthocytes

Acanthocytes, also known as thorn cells, are a type of red blood cell (RBC) morphology with spiky projections.

Appearance on Blood Smear

• Irregular Spikes: The defining feature of an acanthocyte is the presence of numerous, irregularly spaced, and often pointed projections on the cell surface. These spikes are larger and more prominent compared to the smaller, evenly spaced projections seen in echinocytes (burr cells).

Causes of Acanthocytes

The presence of acanthocytes on a blood smear can be associated with several conditions:

• Abetalipoproteinemia: This is a rare genetic disorder characterized by a deficiency in apolipoproteins, proteins that help transport fats (lipids) in the bloodstream. This deficiency can affect the RBC membrane and lead to acanthocyte formation.
• Liver Disease: Severe liver dysfunction can disrupt cholesterol metabolism and impair the structure of the RBC membrane, contributing to acanthocytosis.
• Neuroacanthocytosis Syndromes: These are a group of rare neurological disorders where acanthocytes are a prominent feature. The exact cause is not fully understood, but it’s thought to involve abnormal protein interactions with the RBC membrane.
• Certain Medications: Some medications, particularly high doses of drugs like phenytoin (anti-seizure medication) or misoprostol, can induce acanthocyte formation.

Spherocytes

Spherocytes are a type of red blood cell (RBC) morphology with spherical shape seen on a peripheral blood smear. 

Appearance on Blood Smear

• Spherical Shape: The defining feature of a spherocyte is its near-spherical shape, resembling a ball. Healthy RBCs are typically disc-shaped with a central indentation.
• Reduced Size (Usually): Spherocytes are often, but not always, smaller than normal red blood cells (microcytic). This is because the abnormal shape reduces the surface area of the cell.

Causes of Spherocytosis

The presence of spherocytes on a blood smear can be caused by two main factors:

• Hereditary Spherocytosis: This is a genetic disorder where there’s a defect in the genes responsible for producing proteins that maintain the structure and flexibility of the RBC membrane. This defect makes the cells more spherical and more susceptible to destruction by the spleen.
• Acquired Spherocytosis: This is less common and can be caused by:
  • Autoimmune hemolytic anemia: In rare cases, the immune system mistakenly attacks healthy RBCs, leading to spherocyte formation.

Schistocytes (Fragmented Cells)

Schistocytes, also known as fragmented red blood cells (RBCs), have a distinct appearance on a peripheral blood smear. Their fragmented RBC morphology can offer clues about potential underlying conditions that damage or shear RBCs as they travel through the bloodstream.

Appearance on Blood Smear

• Fragmented Cell Pieces: The defining feature of a schistocyte is its fragmented appearance. The cell is broken into pieces of various sizes and shapes, resembling triangles, helmets, or teardrops.
• Variable Size: The fragmented pieces of schistocytes can be small or large depending on the severity of the damage.

Causes of Schistocytes

The presence of schistocytes on a blood smear can be associated with several conditions that put physical stress on RBCs:

• Microangiopathic Hemolytic Anemia (MAHA): This is a general term for a group of conditions where RBCs are damaged and destroyed as they squeeze through narrowed or damaged blood vessels. This can occur in:
  • Thrombotic thrombocytopenic purpura (TTP): A serious condition where blood clots form in small blood vessels throughout the body.
  • Hemolytic uremic syndrome (HUS): A complication of certain infections or kidney problems that can damage blood vessel walls.
  • Preeclampsia: A pregnancy complication characterized by high blood pressure and potential damage to blood vessels.
• Heart Valve Abnormalities: Severe heart valve problems can cause turbulent blood flow that damages RBCs as they pass through the valve.
• Severe Burns: Extensive burns can lead to fluid loss and increased blood viscosity, which can damage RBCs.
• Aortic Stenosis: Narrowing of the aortic valve can increase shear stress on RBCs as they pass through the narrowed opening.
• Sickle Cell Disease: In this inherited blood disorder, abnormal hemoglobin molecules can cause RBCs to become sickle-shaped and prone to fragmentation.

Elliptocytes

Elliptocytes are a type of red blood cell (RBC) with an elongated oval appearance on a peripheral blood smear in terms of RBC morphology.

Appearance on Blood Smear

• Oval Shape: The defining feature of an elliptocyte is its elliptical shape, resembling an oval or elongated ellipse. Unlike oval-shaped footballs, elliptocytes typically lack the pointed ends and have a smoother, more elongated oval form.

Causes of Elliptocytes

The presence of elliptocytes RBC morphology on a blood smear can be associated with two main categories of causes:

• Hereditary Elliptocytosis: This is a group of inherited disorders where there’s a defect in the genes responsible for maintaining the shape and structure of the RBC membrane. This defect leads to the production of oval-shaped RBCs. The severity of elliptocytosis can vary depending on the specific genetic mutation.
• Acquired Elliptocytosis: This is more common and can be caused by:
  • Iron deficiency anemia: In some cases, mild iron deficiency can be associated with the presence of a few elliptocytes on the blood smear. This is thought to be due to changes in RBC membrane composition.

Tear Drop Poikilocytes (Tear Drop Cells)

Tear drop poikilocytes are also known as dacrocytes, with a teardrop shape on the peripheral blood smear in terms of RBC morphology.

Appearance on Blood Smear

• Teardrop Shape: The defining feature of a tear drop poikilocyte is its resemblance to a teardrop. One end of the cell narrows and comes to a point, while the other end is wider and rounder.
• Blunt versus Sharp Ends: It’s important to note that not all pointed RBCs are tear drop poikilocytes. Artificially induced poikilocytosis during blood smear preparation can sometimes create pointed RBCs with sharp, spiky ends. True tear drop poikilocytes typically have blunt or rounded points at the narrowed end.

Causes of Tear Drop Poikilocytes

The presence of tear drop poikilocytes RBC morphology on a blood smear can be associated with several conditions:

• Bone Marrow Infiltration: Conditions that infiltrate or replace bone marrow with abnormal cells, such as myelofibrosis, tumors, or granulomas, can disrupt normal RBC production and lead to the formation of tear drop poikilocytes.
• Vitamin B12 or Folate Deficiency: Deficiencies in these vitamins, crucial for healthy RBC production, can sometimes lead to the formation of tear drop poikilocytes.

Bite Cells

Bite cells, also known as degmacytes, have the characteristic “bite” appearance on the red cells on a peripheral blood smear in terms of RBC morphology. 

Appearance on Blood Smear

• Circular Depressions: The defining feature of a bite cell is one or more round, well-defined depressions on the cell surface. These depressions resemble bites taken out of a cookie, hence the name.
• Smooth or Irregular Edges: The edges of the bite can be smooth or slightly irregular.

Causes of Bite Cells

The presence of bite cells RBC morphology on a blood smear can be associated with several conditions that cause oxidative stress on RBCs:

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency: This is a common inherited enzyme deficiency that hinders the RBC’s ability to protect itself from oxidative damage. The resulting stress can lead to the formation of Heinz bodies (clumps of denatured hemoglobin) within the RBC. The spleen, a filtering organ, then removes these Heinz bodies, leaving behind the characteristic “bite” on the cell surface.
• Other enzyme deficiencies: Deficiencies in other enzymes involved in the pentose phosphate pathway, which plays a role in RBC metabolism, can also contribute to bite cell formation.
• Oxidative drugs and chemicals: Certain medications or exposure to chemicals can generate excessive free radicals, leading to oxidative stress on RBCs and potential bite cell formation. Examples include dapsone (antibiotic) and sulfasalazine (anti-inflammatory).
• Unstable hemoglobins: Some inherited hemoglobin disorders can make RBCs more susceptible to oxidative damage and Heinz body formation, leading to bite cells.

Sickle Cells

Sickle cells are a hallmark feature of Sickle Cell Disease (SCD), a group of inherited blood disorders affecting red blood cells (RBCs). 

Appearance on Blood Smear

• C-Shaped Elongation: The defining feature of a sickle cell is its characteristic sickle or crescent moon shape. This abnormal shape occurs when deoxygenated hemoglobin molecules inside the RBC polymerize (stick together) and form rigid rods. These rods distort the normally round RBC into a C-shaped cell.

Causes of Sickle Cells

The presence of sickle cells is a direct consequence of Sickle Cell Disease, which is caused by a genetic mutation in the beta-globin gene. This mutation alters the structure of hemoglobin, the oxygen-carrying protein within RBCs. When the mutated hemoglobin loses oxygen, it clumps together, forming rigid rods that distort the RBC morphology into the characteristic sickle shape.

Anisopoikilocytosis

Anisopoikilocytosis isn’t a single cell abnormality, but rather a term used to describe the presence of both anisocytosis and poikilocytosis in a RBC morphology blood smear. 

Anisocytosis: This refers to a variation in the size of red blood cells (RBCs) on the smear.

Poikilocytosis: This refers to a variation in the shape of RBCs on the smear. 

Causes of Anisopoikilocytosis

The presence of anisopoikilocytosis indicates an underlying condition affecting RBC production or lifespan. Here are some potential causes:

• Nutritional deficiencies: Deficiencies in iron, vitamin B12, or folate, all crucial for healthy RBC production, can lead to anisopoikilocytosis.
• Bone marrow disorders: Conditions like myelofibrosis or aplastic anemia that affect bone marrow function can disrupt normal RBC production and lead to size and shape variations.
• Hemoglobinopathies: Inherited disorders like thalassemia or sickle cell disease cause abnormal hemoglobin production, leading to misshapen and sometimes different sized RBCs.
• Liver disease: Severe liver dysfunction can impair RBC production and contribute to anisopoikilocytosis.
• Splenomegaly: An enlarged spleen can trap and damage RBCs, leading to fragmentation (schistocytes) and other shape abnormalities.
• Blood loss: Acute or chronic blood loss can trigger the bone marrow to produce RBCs rapidly, leading to a mix of immature and mature cells with varying sizes and shapes.

Dimorphic Picture

A dimorphic blood picture refers to a peripheral blood smear that shows two distinct populations of red blood cells (RBCs) in terms of size and sometimes, color in relation to RBC morphology. 

Appearance on Blood Smear

• Two Distinct Populations: The key feature is the presence of two separate populations of RBCs with clear differences in size and sometimes, color. Here are some possibilities:
  • Macrocytosis and Microcytosis: One population might consist of macrocytes (larger than normal RBCs), while the other consists of microcytes (smaller than normal RBCs).
  • Normochromia and Hypochromia: In some cases, there might also be a difference in color saturation. One population could be normochromic (normal pink), while the other is hypochromic (pale), suggesting a hemoglobin deficiency.

Causes of Dimorphic Blood Picture

Several conditions can lead to a dimorphic blood picture:

• Nutritional Deficiencies: Deficiencies in iron, vitamin B12, or folate, all crucial for healthy RBC production, can manifest as a dimorphic picture. For example, iron deficiency can lead to microcytic, hypochromic cells (small and pale), while a concurrent folate deficiency might also cause macrocytic, normochromic cells (large and pink).
• Bone Marrow Disorders: Conditions like myelodysplastic syndromes (MDS) or aplastic anemia can disrupt normal RBC production, leading to a mix of immature and mature cells with varying sizes and sometimes colors.
• Transfusion in Hemoglobinopathies: The presence of these two distinct populations of RBCs – the patient’s microcytic, hypochromic cells and the larger, normochromic donor cells – creates a dimorphic picture on the blood smear.

Rouleaux Formation

Rouleaux (singular: rouleau) is a term used to describe the stacking or aggregation of red blood cells (RBCs) seen on a peripheral blood smear in terms of RBC morphology. This stacking resembles a stack of coins, hence the name.  

Appearance on Blood Smear

• Stacks of RBCs: Rouleaux appear as elongated rows of RBCs stacked face-to-face, resembling stacks of coins in the RBC morphology. The length of these stacks can vary, with some containing just a few cells and others forming longer chains.
• Variable RBC Distribution: In a normal smear, RBCs are typically evenly distributed with some space between them. However, with rouleaux formation, the RBCs appear clumped together, leaving clear areas devoid of cells in between the stacks.

Causes of Rouleaux Formation

Rouleaux formation is primarily caused by an increase in plasma protein concentration, particularly fibrinogen, which acts like a “glue” between RBCs. Here are some conditions that can lead to increased rouleaux:

• Inflammatory Conditions: Inflammation triggers the liver to produce more acute-phase proteins, including fibrinogen. This can lead to rouleaux formation on the blood smear.
• Dehydration: When the body is dehydrated, the blood becomes more concentrated, including an increase in plasma protein levels. This can contribute to rouleaux formation.
• Autoimmune Diseases: Some autoimmune diseases can lead to increased production of certain proteins, including fibrinogen, potentially causing rouleaux.
• Multiple Myeloma: This cancer of plasma cells can lead to excessive production of abnormal proteins, including ones that can promote rouleaux formation.

Red Cell Clumping (Agglutination)

Agglutination describes the clumping together of red blood cells (RBCs) on a peripheral blood smear. Unlike rouleaux formation, where RBCs stack in a specific pattern, agglutination appears as irregular, dense clusters of clumped cells. This abnormal clumping RBC morphology indicates the presence of antibodies or other molecules coating the RBC surface, causing them to stick together.

Appearance on Blood Smear

• Irregular Clumps: Agglutination manifests as irregular-shaped aggregates of RBCs, often appearing denser and more haphazardly arranged compared to rouleaux formation.
• Variable Size and Distribution: The size of the agglutinates can vary significantly, ranging from small clumps to large aggregates involving numerous RBCs. The distribution of these clumps is also uneven, leaving clear areas devoid of cells in between.
• Loss of Individual Cell Details: Due to the dense clumping, it can be difficult to discern individual RBC morphology (shape) or color on a smear with agglutination.

Causes of Red Blood Cell Agglutination

Agglutination occurs when antibodies or other molecules bind to specific antigens (proteins or sugars) on the RBC surface. This binding triggers the RBCs to clump together. Here are some potential causes:

• Autoimmune Hemolytic Anemia: In this condition, the body produces antibodies that mistakenly attack healthy RBCs. These antibodies bind to the RBC surface, leading to agglutination and subsequent destruction of RBCs.
• Blood Transfusion Reactions: If a blood transfusion is incompatible (blood types are not properly matched), the recipient’s immune system can develop antibodies against the donor’s RBCs, causing agglutination.
• Infections: Certain infections, particularly those caused by Mycoplasma pneumoniae (walking pneumonia) or Epstein-Barr virus (EBV), can trigger the production of cold agglutinins – antibodies that cause RBC agglutination at cooler temperatures.
• Cold Agglutinin Disease: This is a rare autoimmune disorder characterized by the presence of cold agglutinins that cause RBC agglutination, especially in the extremities exposed to cold temperatures.
• Certain Medications: Some medications, like quinine or certain cephalosporin antibiotics, can bind to RBCs and induce agglutination in rare cases.

Disclaimer: This article is intended for informational purposes only and is specifically targeted towards medical students. It is not intended to be a substitute for informed professional medical advice, diagnosis, or treatment. While the information presented here is derived from credible medical sources and is believed to be accurate and up-to-date, it is not guaranteed to be complete or error-free. See additional information.

References

1. Anemia: Diagnosis and Treatment (Willis, 2016).
2. Management of Anemia: A Comprehensive Guide for Clinicians (Provenzano et al., 2018)
3. Goldberg S, Hoffman J. Clinical Hematology Made Ridiculously Simple, 1st Edition: An Incredibly Easy Way to Learn for Medical, Nursing, PA Students, and General Practitioners (MedMaster Medical Books). 2021.