Approach to anemia (destruction and sequestration): Clinical sciences

Anemia is a condition characterized by a decrease in 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, as well as blood loss.

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 consider blood products, such as packed red blood cells. Usually, you want to transfuse patients with hemoglobin below 7 g/dL; unless the patient has cardiac history, in which case you’d transfuse if hemoglobin goes below 8; and lastly, if the anemia is causing severe symptoms like unresponsive tachycardia, or dyspnea at rest, you can transfuse regardless of the hemoglobin level!

Additionally, provide supplemental oxygen if needed, and don’t forget to put your patient on continuous vital sign monitoring, including blood pressure, heart rate, and pulse oximetry.

Here’s a clinical pearl! A very important thing to consider in unstable patients with anemia is if they’re actively bleeding. Be sure to look for evidence of blood loss, such as visible trauma, hematochezia, melena, or hematuria. Additionally, you can search for the active bleed with a CT angiogram.

Now that we're done with unstable patients, let’s look at the stable ones.

Start with 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 the physical exam might show tachycardia and conjunctival pallor. However, these findings are non-specific, so you need to check labs. In biological females, normal hemoglobin lies between 12 and 16 g/dL, and normal hematocrit lies between 36 to 46%; while for biological males, normal hemoglobin lies between 13.5 and 17.5 g/dL, and normal hematocrit lies between 41 and 53%. If labs reveal low hemoglobin and hematocrit, you can 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 reticulocytes count! Reticulocytes are young red blood cells, and if their count is within or below the reference range, it means the bone marrow is not increasing the production to compensate. In this case, anemia is due to the underproduction of red blood cells.

Let’s take a look when the reticulocyte count is above the reference range. If the reticulocyte count is above the reference range, it suggests that the bone marrow is actively producing new red blood cells to compensate. In this case, the underlying cause of anemia is the loss of red blood cells, and so you should consider anemia due to RBC destruction or sequestration in the spleen, like in sickle cell crisis.

Now, to tell if it’s destruction or sequestration, you need to assess the spleen size. A palpable spleen suggests splenomegaly, so diagnose splenic sequestration of red blood cells as the cause of anemia. This is also known as hypersplenism and results from an overactive spleen that prematurely destroys red blood cells. You’ll see this in conditions like cirrhosis, portal vein hypertension, or chronic infections like hepatitis B or C, as well as autoimmune diseases like systemic lupus erythematosus, or malignancy like leukemia and lymphoma.

However, if the spleen is not palpable and is normal in size, you should consider anemia due to red blood cell destruction, so hemolysis.

To confirm, check the labs, including unconjugated or indirect bilirubin; haptoglobin; LDH; and a urinalysis. In hemolysis, there will be a release of LDH and hemoglobin, which is in part metabolized into indirect bilirubin, causing these lab values to increase.

Meanwhile, haptoglobin will be low because it binds to any free hemoglobin in the bloodstream. When the destruction of red blood cells is big, the haptoglobin cannot keep up with the released hemoglobin, and the excess hemoglobin is cleared by the kidneys, causing hemoglobinuria on urinalysis.

At this point, you can diagnose anemia due to red blood cell destruction, or hemolytic anemia. The next step is to assess the causes of hemolysis, and to do so, you need a peripheral blood smear.

First, let’s focus on defects internal to the red blood cell. If the peripheral blood smear reveals sickle cells, diagnose sickle cell disease. This is an autosomal recessive disorder characterized by an abnormality in hemoglobin that leads to fragile red blood cells that are sickled in shape.

Let’s go back now. On the other hand, the peripheral blood smear may show microcytosis; hypochromia; and target cells, which are red blood cells with redundant membranes resembling a target or bullseye.

Here’s a high-yield fact! Target cells can mainly be found in four conditions, which you can easily remember with the mnemonic HALT. This stands for Hemoglobin S and Hemoglobin C disease, Asplenia, Liver disease, and Thalassemia.

In this case, consider thalassemia, another autosomal recessive disorder. This one comes in two flavors, alpha and beta, so don’t forget to order a hemoglobin electrophoresis to distinguish between them. If you see increased HbA2 and HbF, or decreased HbA, consider beta-thalassemia.

To confirm the diagnosis, order genetic testing. Beta globin gene mutation confirms the diagnosis. On the other hand, if hemoglobin electrophoresis is normal, consider alpha thalassemia and again order genetic testing. If genetic testing reveals alpha globin gene mutation, diagnose alpha thalassemia.

Here’s a high-yield fact! If your patient has recently received a transfusion, or if you suspect that the patient specifically has alpha and not beta thalassemia, for instance due to family history, you may skip electrophoresis and go straight to genetic testing.

Let’s go back here once more. Finally, if the peripheral blood smear reveals Heinz bodies, which are collections of denatured hemoglobin within the red blood cell; as well as degmacytes or “bite cells,” which are formed when macrophages remove the denatured hemoglobin from red blood cells, consider glucose-6-phosphate dehydrogenase or G6PD deficiency. Then, order a spectrophotometric assay to assess NADPH production. If it’s decreased, diagnose G6PD deficiency.

Alright, moving on the causes of hemolytic anemia that are external to the red blood cells.

If the peripheral blood smear reveals intraerythrocytic rings, consider parasitic infections.