General Characteristics of Anemia
Anemia. We’re all familiar with it. It’s been around for more than 4000 years, and it affects approximately 660 million people worldwide – which is 8.8% of the population! We will discuss all the intricacies of the different types of anemia later, but for now, what can we say generally about anemia?
Identifying Anemia Based on Red Blood Cell Mass
Anemia can be defined as a reduction of total circulating red cell mass below normal limits. Sadly however, it is pretty difficult to measure red cell mass, and instead, anemia is diagnosed based on a reduction in hematocrit (ratio of packed red blood cells to the total blood volume) and the hemoglobin concentration for the patient’s age and sex, of the blood to levels that are lower than normal levels.
Just for reference, hematocrit, also referred to as packed cell volume (PCV) or erythrocyte volume fraction (EVF) refers to the percentage of blood volume that comprises of red blood cells. It is usually 40% for women, and 45% for men, but of course, there are ranges over which values are normal.
Although values vary between laboratories, a normal range of hemoglobin is: For men, 13.5 to 17.5 grams per deciliter. For women, 12.0 to 15.5 grams per deciliter. Thus, a value used for diagnosing anemia would usually be hemoglobin concentration below 13.5g/dL for males, and below 11.5g/dL in females. From the age of 2 years to puberty, hemoglobin concentration below 11.0g/dL specifies anemia. In contrast, since newborns have a high hemoglobin level at birth, a lower limit of 14.0g/dL is taken.
However, it should be noted that values of hematocrit and hemoglobin concentration may not always be indicative of anemia. For example, in conditions of severe dehydration, where fluid volume is reduced, the hematocrit percentage would appear to be elevated due to reduced plasma concentration. This can give the appearance of the patient suffering from polycythemia (thus termed pseudo-polycythemia), when in fact, the patient may have anemia. In contrast, in conditions of fluid retention such as pregnancy and splenomegaly, when plasma volume is increased, the hematocrit would appear to be lower, giving an impression of anemia despite normal red blood cell mass and hemoglobin concentration.
Identifying Anemia Based on Red Blood Cell Morphology
Another useful method of classifying anemia depends on the structural morphology of red blood cells.
Morphologic characteristics of red blood cells that are vital to diagnosis of anemia are:
- Red Cell Size
- Normal size: Normocytic
- Smaller than normal: Microcytic
- Larger than normal: Macrocytic
- (Remember the suffix -cyte means, “cell.” Thus the terms simply mean either normal cell, smaller cell, enlarged cell)
- Degree of Hemoglobinization
- This is reflected in the color of red cells.
- They can be of two types:
- Normal colour: Normochromic
- Pale colour: Hypochromic
- Sickle Shaped : Sickle Cell Anemia
In general, microcytic hypochromic anemias are caused by abnormalities in hemoglobin synthesis, the most common of which is a deficiency in iron. You can picture it as a factory. Imagine the machinery that makes red blood cells operating inefficiently due to a lack of iron for making hemoglobin. Thus, red blood cells appear smaller, and paler due to lower materials (such as hemoglobin) to build with.
Notice how much paler they are.
In contrast, macrocytic anemias stem from abnormalities involving the maturation of erythroid precursors, which are the cells that develop into the red blood cells. Often, although the cells are larger, the overall cell number and hemoglobin content per cell is reduced, leading to anemia.
On the other hand, normocytic, normochromic anemias, where the red cell morphologies do not contribute to anemia, have various etiologies that we will discuss in detail further down.
Anemias of Blood Loss
Next, we will discuss the significance of blood loss to anemia. Blood loss in two forms can cause anemia over time: Acute and Chronic
Acute Blood Loss
In a scenario of acute blood loss, there is massive loss of intravascular volume, both red blood cells and blood plasma. If extreme, it can lead to shock, cardiovascular collapse and death.
The clinical features depend on the rate of hemorrhage and whether the blood loss in internal or external.
If the patient survives the acute blood loss, then there must be some way for the body to replace the lost fluid. It does this using the fluid stored in the interstitial fluid compartment. There is thus an intravascular shift of water from the interstitial fluid compartment. Thus, the hematocrit of the blood is reduced, due to the increase in fluid relative to the decrease in red blood cells.
A reduced oxygenation of the kidneys promotes the release of erythropoietin, which promotes the proliferation of committed erythroid progenitors (CFU-E) from the bone marrow. It takes about 5 days for the CFU-E to cause proliferation and division to form newly formed red blood cells. These newly formed red blood cells are called reticulocytes, and still contain some nuclear matter within them.
However, if blood loss occurs into the external environment or into the gut, there is iron loss, and you know what happens when there is iron loss, right? A possible abnormality in formation of red blood cells – possible microcytic hypochromic anemia. If blood loss occurs into the tissues, then it is possible to extract iron from the blood and allow for formation of proper reticulocytes.
If the blood loss is extreme, then the body may also overcompensate, and excessive leukocytes, platelets and even reticulocytes are formed. This results in leukocytosis, thrombocytosis and reticulocytosis.
Chronic Blood Loss
Chronic blood loss induces anemia only when the rate of blood loss exceeds the regenerative capacity of the marrow or when iron reserves are depleted and iron deficiency anemia appears (which will be discussed later).
Anemia in the Hospital
Clinical Features of Anemia
The major adaptations of the body to anemia occur in the cardiovascular system and the hemoglobin O2 dissociation curve. There are 4 important factors that determine how the body responds to anemia:
- Speed of onset
- This is simply a matter of preparation. If something approaches you quickly, you barely have time to react, whereas if something approaches you very slowly, you can plan and act accordingly.
- Similarly, rapidly progressing anemia causes more symptoms than mild anemia, simply because the body has more time to adapt by adjusting the cardiovascular system and the hemoglobin O2 dissociation curve.
- The severity of anemia can be defined by how low the individual’s red blood cell mass, hematocrit or hemoglobin concentration falls. Extremely severe anemia, when the hemoglobin levels falls below 9-10g/dL, usually shows more symptoms than mild anemia, where hemoglobin is subnormal only by a small amount.
- The elderly tolerate anemia less well than a younger individual. This is simply because elderly bodies are not able to adapt as efficiently as a younger, healthier body.
- Haemoglobin O2 Dissociation Curve
- In general, anemia is associated with an increased production of 2,3-DPG and a shift of the dissociation curve to the right to allow oxygen to be given up more readily to the tissues. This, in one way attempts to compensate for the lower amount of oxygenated blood being delivered to the tissues. This adaptation is particularly marked in some anaemias that either affect red cell metaboism directly (e.g. pyruvate kinase defi- ciency which causes a rise in 2,3-DPG concentra- tion in the red cells) or that are associated with a low affinity haemoglobin (e.g. Hb S)
(Note, COHb is Carboxyheamoglobin.)
Symptoms of Anemia
The most classic symptoms of anemia, if they are present, is a weakness in the body due to lack of oxygenation. There may also be shortness of breath, lethargy, palpitations (due to tachycardia to increase heart rate to allow increased rate of delivery of oxygen as a compensatory mechanism – this is increasing cardiac output) and headaches.
In older patients, anemia may also present with angina pectoris, symptoms of cardiac failure and intermittent claudication (a condition in which cramping pain in the leg is induced by exercise, typically caused by obstruction of the arteries).
Occasionally, in very severe circumstances, retinal haemorrhages may occur and visual problems may occur, especially in severe anemia of rapid onset.
Signs of Anemia
Before we begin to discuss signs of anemia, let us get into mind, the normal red cell values for human beings.
So any value outside these ranges indicates some pathology.
Here is a graphical representation of values that indicate anemia.
The signs of anemia can be divided into general and specific signs.
General Signs of Anemia:
General signs of anemia are present in all types of anemia. They include:
1) Pallor of Mucous Membranes, such as the conjunctival mucosa.
Notice the paleness of the conjunctival mucosa in the anemic patient when compared to the non-anemic patients.
2) Skin Colour, but this is not a reliable sign. Generally, skin appears to become paler and more yellow due to buildup of biliirubin in the skin due to liver problems associated with anemia.
3) Tachycardia, Bounding Pulse, Cardiomegaly, Systolic Flow Murmur at the Apex. These are all associated with the heart attempting to increase heart rate to improve cardiac output to compensate for the lack of oxygenation.
4) In the elderly, features of congestive cardiac failure may be present.
5) In very extreme cases, retinal hemorrhages may occur.
Specific Signs of Anemia:
Specific signs of anemia occur in response to particular subtypes of anemia. Thus, they are very useful as diagnostic features of illness, and can be used to deduce what type of anemia the patient is suffering from. These include:
1) Koilonychia (spoon nails) with Iron Defiency Anemia.
Yep, definitely spoon shaped.
2) Jaundice with Megaloblastic Anemia and Hemolytic Anemia.
3) Leg Ulcers with Sickle Cell Anemia and other Hemolytic Anemias
4) Bone deformities with Thalassemia Major.
We will discuss all these anemias individually in a series of blog posts.
Classification and Laboratory Findings In Anemia
The most important method of classifying anemias is based on red cell indices, which provide information on the red blood cell size and hemoglobin content.
We have already spoken about the three sizes of a red blood cell – microcytic, normocytic and macrocytic. Thus, as previously described, there can be microcytic anemia, normocytic anemia and macrocytic anemia.
However, when does a cell become microcytic or macrocytic? To answer this question, the two red blood cell indices must be explored: Mean Corpuscular Hemoglobin (MCH) and Mean Corpuscular Volume (MCV).
Mean Corpuscular Hemoglobin (MCH): The average mass of hemoglobin per red blood cell in a sample of blood. It is calculated by dividing the total mass of hemoglobin in the entire sample by the number of red blood cells. Like a simple average, really. A normal value in humans is 27 to 31 picograms/cell. To put it really simply, MCH is really the amount of hemoglobin per cell. So when would MCH drop? In conditions where hemoglobin is reduced, such as hypochromic anemias.
Mean Corpuscular Volume (MCV): The average volume of a corpuscle, or of one red blood cell. It is simply reflective of the size of a red blood cell. The higher the MCV, the higher the volume of the corpuscle, and thus the size. Thus, when the MCV is low, the red blood cell is small and indicates microcytic anemia when the MCV is high, the red blood cell is large, and thus indicates macrocytic anemia. The normal reference range is typically 80-95 fL.
There is also an additional RBC index, known as the mean corpuscular hemoglobin concentration (MCHC), a measure of the concentration of hemoglobin in a given volume of packed red blood cells. It is measured by dividing the mass of hemoglobin in a sample by the hematocrit. MCHC is diminished (“hypochromic”) in microcytic anemias, and normal (“normochromic”) in macrocytic anemias (due to larger cell size, though the hemoglobin amount or MCH is high, the concentration remains normal).
In order to classify an anemia as microcytic, normocytic or macrocytic, a combination of MCH and MCV must be reported.
A Microcytic Anemia occurs when MCV is below 80fL.
A Macrocytic Anemia occurs when MCV is above 95fL.
A Normocytic Anemia occurs when MCV is between 80fL and 95fL.
A Hypochromic Anemia occurs when MCH is below 27 pg/cell.
Different combinations of anemia would follow more than one criteria. For example, a microcytic hypochromic anemia has an MCV below 80 and MCH below 27.
Don’t worry, we will discuss all the different causes of each when we speak individually of each type of anemia.
There are also other important laboratory findings that can help obtain information about the type of anemia the patient is suffering from.
Importance of Leukocyte and Platelet Counts
These factors help to distinguish between actual anemia, where red blood cell mass, hematocrit or hemoglobin concentration decrease, and pancytopenia. Pancytopenia is a deficiency of all three cellular components of blood, namely red blood cells, white blood cells and platelets. Thus, measuring for leukocytes and platelet counts aids in understanding whether pancytopenia is present, or if it is in fact, pure anemia. Pancytopenia is usually indicative of a problem in body systems that produce cells of the blood, namely the bone marrow and the spleen. Thus pancytopenia is indicative of a general marrow defect (eg. marrow hypoplasia), or general destruction of cells (e.g. hypersplenism).
In contrast, in anemias caused by haemolysis or haemorrhage, the neutrophil and platelet counts are often raised; in infections and leukaemias, the leucocyte count is also often raised and there may be abnormal leucocytes or neutrophil precursors present.
As discussed above, the normal reticulocyte count is 50-150 x 10^9/L, or 0.5 – 2.5% of blood. Reticulocytes are the immediate precursors to red blood cells that still have some RNA matter or nuclear matter within them.
The reticulocyte number rises during anemia, primarily because the body attempts to compensate for lower oxygenation by increasing the number of red blood cells that can reach the tissues. This is done by the kidney’s release of erythropoietin during times of low oxygenation. Thus, by increasing the production of reticulocytes, eventually the production of red blood cells will increase as well.
After an acute major haemorrhage there is an erythropoietin response in 6 hours, the reticu- locyte count rises within 2–3 days, reaches a maximum in 6–10 days and remains raised until the haemoglobin returns to the normal level. If the reticulocyte count is not raised in an anaemic patient this suggests impaired marrow function or lack of erythropoietin stimulus. These impaired systems can be:
(Tables courtesy Essential Haematology 6th ed – Hoffbrand).
A brief introduction to cells under the blood film will also be done here. A blood film is extremely important. Even though a CBC will give information on the number of all the cells within the blood, there is no way to understand or know how the cells appear – their morphology and red cell inclusion bodies. Thus, blood films allow us to understand the morphological patterns of cells under the microscope and determine pathological processes occurring in the blood. Knowing how the cell looks helps us to know which disease is occurring in the body.
To summarise, there may either be variations in size, termed anisocytosis, or variations in shape, termed poikilocytosis.
To understand anisocytosis, we must understand red blood cell distribution width (RDW or RCDW). This is a measure of the range of variation of red blood cell (RBC) volume that is reported as part of a standard complete blood count. Usually red blood cells are a standard size of about 6-8 μm in diameter. Certain disorders, however, cause a significant variation in cell size. Higher RDW values indicate greater variation in size. Normal reference range in human red blood cells is 11.5-14.5%.
Deficiencies of Vitamin B12 or folate produce a macrocytic anemia (large cell anemia) in which the RDW is elevated in roughly two-thirds of all cases. However, a varied size distribution of red blood cells is a hallmark of iron deficiency anemia, and as such shows an increased RDW in virtually all cases. In the case of both iron and B12deficiencies, there will normally be a mix of both large cells and small cells, causing the RDW to be elevated. An elevated RDW (red blood cells of unequal sizes) is known as anisocytosis.
Below is a diagram illustrating the common anisocytoses and poikilocytoses.
Notice the several changes that can occur within the red blood cell, and what disease they are caused by.
Similarly, there are a host of inclusion bodies that can occur in red blood cells and can be indicative of pathologies under a blood film. These are:
That’s all for now guys! Remember, this was meant to simply introduce you into hematology in the form of anemias. I will definitely to separate posts about the different types of anemias, in detail, the variations of Red blood cells under the microscope and the inclusion bodies of red blood cells. Hope this was useful!