Approach to anemia (underproduction): Clinical sciences

Anemia is a condition characterized by a decrease in healthy red blood cells, indicated by low levels of hemoglobin and hematocrit or red blood cell count. Anemia can be caused by red blood cell sequestration, destruction, or underproduction of red blood cells.

Now, if you suspect anemia, you should first perform an ABCDE assessment to determine if the patient is unstable or stable.

If the patient is unstable, stabilize the airway, breathing, and circulation. Next, obtain IV access, give IV fluids, and if necessary, consider blood products, such as packed red blood cells. If needed, provide supplemental oxygen, and don’t forget to put your patient on continuous vital sign monitoring, including blood pressure, heart rate, and pulse oximetry.

Now that we're done with unstable patients, let’s go back to the ABCDE assessment and look at the stable ones.

In this case, obtain a focused history and physical examination, and order labs, including CBC with indices, and a reticulocyte count.

The history could reveal fatigue, malaise, palpitations, and dyspnea; while physical exam might show tachycardia and conjunctival pallor.

However, these findings are non-specific, so you need to check labs. If the labs reveal low hemoglobin and hematocrit, only then can you diagnose anemia.

Here’s a clinical pearl! After confirming that your patient has anemia, you need to find what’s causing it by looking at additional clues in the lab results. Here, our approach is based on assessing reticulocyte count first, followed by the MCV; some people instead start from the MCV. Both approaches are valid! The important thing is to use a reliable approach that will make sure you consider all the appropriate causes and help you narrow your differential.

So let’s assess the reticulocyte count. Reticulocytes are young red blood cells, and if their count is above the reference range, it suggests that the body is actively producing new red blood cells to compensate for the loss. In this case, the underlying cause of anemia is the loss of red blood cells, either through destruction, such as hemolysis, or sequestration in the spleen.

On the other hand, if the reticulocyte count falls within or below the reference range, diagnose anemia due to the underproduction of red blood cells. The next step is to classify the anemia based on the size of the red blood cells using the mean corpuscular volume, or MCV for short. Depending on the value of the MCV, you can classify anemia as either microcytic, normocytic, or macrocytic.

First, let's focus on a patient with an MCV under 80. We call this microcytic anemia because the red blood cells are smaller than normal. To investigate the cause, order iron studies. Check the levels of serum iron and ferritin to assess iron availability in the blood. Next, check transferrin saturation or TSAT to evaluate the iron-binding sites on transferrin; and serum total iron binding capacity or TIBC to determine if the body is trying to compensate by capturing any available iron.

Let’s take a look when the studies reveal low serum iron, ferritin, and TSAT levels, along with a high serum TIBC.

In this case, you should consider iron deficiency or lead poisoning as potential diagnoses. To determine which one it is, order a blood lead level test and a peripheral blood smear.

If the blood lead level test is negative and the peripheral blood smear shows microcytic and hypochromic red blood cells, the diagnosis is iron deficiency anemia. Remember, iron deficiency is the most common cause of microcytic anemia.

On the other hand, if the blood lead level test is positive and the peripheral blood smear shows basophilic stippling of the red blood cells, diagnose anemia due to lead poisoning. Also be sure to keep an eye out for hints in the patient's history, such as potential occupational or environmental lead exposure.

Here’s a high-yield fact! Lead poisoning can cause microcytic anemia via two mechanisms. The fist one can clinically resemble iron deficiency because lead interferes with iron absorption in the intestines;

while the second mechanism involves the inhibition of enzymes that are involved in heme synthesis, resulting in sideroblastic anemia.

Speaking of sideroblastic anemia, let's go back to the iron studies and take a look at a patient with high serum iron, ferritin, and TSAT levels, and a normal serum TIBC.

In this case, you should consider sideroblastic anemia, so make sure to order a peripheral blood smear, as well as a bone marrow aspirate with Prussian blue staining. If the peripheral smear shows basophilic stippling of the red blood cells, and the aspirate reveals erythrocytes with a ring of iron around the center, known as ringed sideroblasts, you can confirm the diagnosis of sideroblastic anemia.

The most common causes include chronic alcohol use, and heavy metal poisoning such as arsenic or even lead!

Lastly, let’s say iron studies show low levels of serum iron, TSAT, and TIBC, and high ferritin levels.

If that’s the case, consider anemia of chronic disease, also known as anemia of chronic inflammation. This type of anemia occurs when the inflammatory response in chronic disease prevents iron release from its stores, so serum iron levels are low, while ferritin is high because iron stores are full.

To confirm your suspicion, take a closer look at the history and look for an underlying chronic condition. Some examples include infections, malignancy, and rheumatologic diseases.

Here’s a clinical pearl! Keep in mind that anemia of chronic disease may initially present as normocytic, and over time becomes microcytic if the underlying condition isn’t resolved.

Speaking of normocytic anemia, let's turn our attention to those with normal MCV, which ranges from 80 to 100.

In such cases, diagnose normocytic anemia, meaning that despite being anemic, the size of red blood cells is within the normal range. To determine the cause, you need to revisit the patient's history.

One of the most important causes you should consider is chronic kidney disease, or CKD.

Normally, the kidneys produce erythropoietin or EPO, which in turn signals the bone marrow to produce red blood cells. But, in CKD, the kidneys can't make enough EPO, leading to insufficient red blood cell production and anemia.