Approach to anemia (destruction and sequestration): Clinical sciences

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Introduction0:00–0:23

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.

Unstable Patient0:23–1:42

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.

Stable Patient1:42–3:14

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.

Normal/Low Reticulocyte Count3:14–3:36

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.

Elevated Reticulocyte Count3:36–4:05

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.

Palpable spleen4:05–4:48

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.

Nonpalpable spleen4:48–5:44

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.

Anemia due to RBC destruction5:44–6:00

Sickle cell disease6:00–6:25

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.

Thalassemia 6:25–8:02

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.

G6PD deficiency8:02–8:44

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.

Parasitic infection8:44–9:31

If the peripheral blood smear reveals intraerythrocytic rings, consider parasitic infections. If the patient has a fever and a history of travel to a malaria-endemic area, like Africa or South Asia, diagnose malaria.
On the other hand, your patient may have a history of fever with travel to the Northeast or Midwest United States, with a possible recent tick bite.
If the peripheral blood smear reveals exoerythrocytic rings in addition to the intraerythrocytic rings, with or without a Maltese cross formation, diagnose babesiosis.Let’s move on to our next finding.
Let’s say that the peripheral blood smear reveals schistocytes. These are fragments of red blood cells indicating that the damage occurred within small blood vessels, which is known as microangiopathic hemolytic anemia, or MAHA for short.

MAHA9:31–11:28

To assess the cause, revisit the patient’s history, physical exam, and labs. If the patient’s history includes fever, neurological deficits, and renal dysfunction; the physical exam reveals petechiae, purpura, or ecchymosis; and labs show thrombocytopenia, consider thrombotic thrombocytopenic purpura or TTP.
Next, obtain an ADAMTS13 activity assay, and if there’s severe deficiency of ADAMTS13, diagnose TTP. Now, here’s a high-yield fact!
Deficiency of ADAMTS13 results in von Willebrand factor and platelet aggregation. This results in the formation of microthrombi, which occlude the small blood vessels and cause red blood cell destruction.
On the flip side, your patient may have a history of fever, diarrhea, decreased urine output, and hematuria; and labs may show thrombocytopenia, proteinuria, or hematuria.
In this case, you should consider hemolytic uremic syndrome, or HUS for short. Next, order a stool culture and shiga-toxin assay to confirm.
If the culture grows E. coli O157:H7 or the shiga-toxin assay is positive, diagnose HUS.
Let’s go back once more. If the blood smear reveals spherocytes, which are small, round red blood cells that lack the typical central pallor, consider an immune-mediated process as the cause of hemolysis.
In these individuals you need to order a direct antiglobulin test, also called a Coombs test, to confirm.Now, if your patient has been exposed to certain medications, such as methyldopa, penicillins, cephalosporins, or NSAIDs; and the Coombs test comes positive, diagnose drug-induced immune hemolytic anemia.

Drug-induced/Autoimmune hemolytic anemia11:28–12:59

This occurs when medication triggers the immune system to attack red blood cells. On the flip side, if the patient has no history of exposure to a triggering medication, and the Coombs test comes back positive, you should consider autoimmune hemolytic anemia or AIHA.
Next, obtain warm and cold agglutinin testing. If the antibodies react at or above 37 degrees Celsius, diagnose warm autoimmune hemolytic anemia, which is generally IgG-mediated.
Alternatively, if the antibodies react below 37 degrees, diagnose cold autoimmune hemolytic anemia, which is generally IgM-mediated.
Alright, let’s take one step back to assess the causes of hemolysis related to red blood cell membrane defects. The peripheral blood smear may show spherocytes, but the Coombs test could be negative.
In this case, consider hereditary spherocytosis, especially if your patient reveals family history of hemolytic anemia. Next, test for osmotic fragility, and if it reveals increased red blood cell fragility, diagnose hereditary spherocytosis.Moving on to our next case.

Hereditary Spherocytosis12:59–13:36

The peripheral blood smear may show stomatocytes, which are red blood cells with a defective membrane causing a mouth-shaped central pallor, target cells, as well as macrocytosis.
In these cases, your patient’s history will likely provide your answer. For example, if there’s a history of heavy alcohol use without liver disease, you can diagnose anemia due to alcohol use disorder.

Alcohol use / Liver disease13:36–14:18

Alternatively, if your patient has signs and symptoms of liver disease, such as jaundice and ascites, diagnose anemia due to liver disease.Okay, lety’s wrap this up!Finally, the peripheral blood smear may reveal acanthocytes or “spur cells,” which have spike-like protrusions on the red blood cell membrane due to excess cholesterol.
Target cells with macrocytosis could also be present. The patient may have a history of abetalipoproteinemia, causing an inability to fully absorb dietary fats through the intestines; or they may have advanced liver disease or liver failure.

Spur cell anemia14:18–15:06

These findings are highly suggestive of spur cell anemia.One last high-yield fact! Macrocytic anemia is most often not caused by destruction or sequestration, but rather by underproduction due to a deficiency of vitamin B12 or folate.Alright, as a quick recap… If a patient presents with low hemoglobin and elevated reticulocyte count, diagnose anemia due to sequestration or destruction of red blood cells.
To differentiate between the two, assess the spleen size. A normal-sized spleen is consistent with the destruction of red blood cells, but don’t forget to order additional lab workup to confirm the diagnosis.
Finally, obtain a peripheral blood smear to determine if hemolysis is caused by an internal defect of the RBCs, like sickle cell disease, thalassemia, and G6PD deficiency; a cause external to the RBCs, like parasitic infections, microangiopathic hemolytic anemias, or immune-mediated processes; or a RBC membrane defect, like hereditary spherocytosis, alcohol use or liver disease, and spur cell anemia.

Review15:06–16:01

to confirm the diagnosis Finally obtain a peripheral blood smear to determine if hemolysis is caused by an internal defect of the rbcs like sickle cell anemia thalassemia and G six PD deficiency A cause external to the RBC S like parasitic infections microangiopathic hemolytic anemias or immune mediated processes or an RBC membrane defect like hereditary spherocytosis alcohol use or liver disease and sper cell