Non-hemolytic normocytic anemia: Pathology review

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Case study0:00–0:49

At the family medicine center, Sofia, a 32-year-old black person of African descent, came to visit the doctor because she has been feeling fatigue as well as exertional dyspnea.
Her medical history includes systemic lupus erythematosus. Next to Sofia, a father from Ireland brings his 14-year-old son, John, who’s been less active and has bruised easily for the past month.
John’s medical history includes recurrent upper respiratory tract infections before the onset of the current symptoms. During the clinical examination, his spleen cannot be palpated.
CBC is ordered for both people and they show low hemoglobin with normal MCV and reticulocyte count index lower than 2%. John also has leukopenia and thrombocytopenia.

Pathology0:49–2:57

Both John and Sofia are suffering from anemia, which is defined as lower than average levels of hemoglobin, typically below 13.5 grams per deciliter in adult men and below 12.0 g/dL in adult women.
For children, this level varies based on the age. Now, anemias can be broadly grouped into 3 categories based on mean corpuscular volume, or MCV, which reflects the volume of an RBC.
So, microcytic anemia is where the MCV is lower than 80 femtolitersfL, normocytic is when, the MCV is between 80 and 100 femtoliters, and macrocytic is when the MCV is larger than 100 femtoliters.
Alright, the normocytic anemias can be further classified as hemolytic where there’s increased destruction of red blood cells and non-hemolytic where there’s decreased production of red blood cells in the bone marrow.
When there’s hemolysis, the bone marrow revs up and starts pumping out reticulocytes which are immature red blood cells, but when there’s a bone marrow problem the reticulocyte count is low.
So for your exams, if you run into a normocytic anemia and the reticulocyte production index, or RPI, is higher than 2%, think hemolytic anemia, since the red blood cells are being destroyed and the body compensates by producing more.
If it’s a non-hemolytic anemia, the reticulocyte production index is lower than 2% since the anemia is caused by a decrease in red blood cell production.
Now, in this video, let’s focus on the nonhemolytic normocytic anemias, which are basically anemia of chronic disease and aplastic anemia.
Keep in mind that although anemia of chronic disease is classified as a normocytic anemia, in less than 25% of the cases it could present as microcytic.
Let’s start by looking at anemia of chronic disease, which is also referred to as anemia of inflammation. Whenever there’s inflammation there’s an increase in the release of a protein called hepcidin by the liver.

Anemia of chronic diseas2:57–4:43

Hepcidin binds to a transmembrane protein called ferroportin which can be found on intestinal mucosal cells, blocking iron absorption from the gut and on macrophages where iron is stored, blocking the release of iron in the blood.
So, in anemia of chronic disease, there is iron in the body but it’s trapped in macrophages and cannot be used by the bone marrow to produce the correct amount of red blood cells, which eventually leads to anemia.
Now, the size of red blood cells initially is normal, and so at first, anemia of chronic disease is normocytic. But as the disease progresses, due to the inability to properly incorporate iron into hemoglobin, the bone marrow starts pumping out smaller red blood cells, so anemia of chronic disease can eventually become microcytic.
Another hint that could tip you off is that when compared to other kinds of anemia, like iron deficiency anemia, erythropoietin levels are relatively low.
This means that it’s elevated compared to someone who’s non-anemic, but it’s too low to stimulate the necessary amount of red blood cell production.
Alright, now anemia of chronic disease can be associated with chronic inflammatory conditions like rheumatoid arthritis and systemic lupus erythematosus; neoplasms like hepatocellular and renal cell carcinoma; and chronic kidney disease.
Okay, moving on to aplastic anemia. Aplastic anemia is not really only an anemia but it’s actually a type of pancytopenia, which means that RBCs, WBCs and platelets are no longer produced.

Aplastic anemia4:43–6:09

Aplastic anemia is caused by failure or destruction of the precursor to platelets and blood cells in the bone marrow. It’s important to remember the list of causes for aplastic anemia such as exposure to radiation, environmental toxins like benzene, and medications like chloramphenicol, which is an antibiotic; chemotherapy agents like alkylating agents and antimetabolites; carbamazepine, an anticonvulsant; antithyroid agents like methimazole and propylthiouracil; and NSAIDs.
Other causes of aplastic anemia include viral infections like EBV, HIV, hepatitis viruses, and parvovirus B19; and autoimmune disorders, where white blood cells attack the bone marrow.
Fanconi anemia is also another potential cause, where there is a DNA repair defect causing bone marrow failure and pancytopenia.
However, aplastic anemia can also be idiopathic, meaning it’s not quite clear why there’s bone marrow failure but it’s usually caused by an immune mediated mechanism.

Pure red cell aplasia6:09–8:54

For your exams, you should differentiate aplastic anemia from pure red cell aplasia. This is a rare form of anemia where the bone marrow ceases to produce red blood cells exclusively, while white blood cells and platelets are produced normally.
It may be due to congenital causes, like Diamond- Blackfan anemia, where there is abnormal synthesis of ribosomes. Acquired causes include autoimmune diseases where white blood cells attack red blood cell precursors, tumors and especially thymoma, where antibodies against erythropoietin are produced, and viral infections like HIV, herpes and parvovirus B19.
Once again, pure red cell aplasia can also be idiopathic, where no cause can be identified. Now, all anemias can present with fatigue, pallor and shortness of breath, but other symptoms of the underlying cause can help you identify the specific disease.
In anemia of chronic disease, you may have symptoms like joint pain in rheumatoid arthritis. For aplastic anemia caused by Fanconi anemia, we may see the characteristic clinical features, meaning short stature, increased incidence of tumors and leukemia, cafe-au-lait spots and thumb or radial defects.
Then, there could also be an increased risk of bleeding or bruising due to thrombocytopenia, and a higher risk of infections due to leukopenia.
For your exams, remember that in aplastic anemia, there’s pancytopenia without splenomegaly because there’s a lack of red blood cell precursors.
This will help you differentiate it from other causes of pancytopenia that come with an enlarged spleen, like myelofibrosis where extramedullary hematopoiesis will occur in the spleen, causing it to enlarge, and hairy cell leukemia where there’s infiltration of the spleen by leukemic cells.
For pure red cell aplasia caused by Diamond- Blackfan anemia, the test question will typically describe an infant with characteristic features, like growth retardation, craniofacial abnormalities, like hypertelorism and a flat nasal bridge, and thumb abnormalities.
There’s also predisposition to cancer, especially acute myelogenous leukemia and myelodysplastic syndromes. Whatever the cause, there would be no increased risk of bleeding or bruising since platelets are normal, and no higher risk of infections since white blood cells are also normal.

Diagnosis8:54–11:26

Moving on to diagnosis. Let’s start with anemia of chronic disease.
The best initial test is a CBC with a peripheral blood smear that shows anemia that can be normocytic or microcytic and an RPI that’s lower than 2%.
In your exams, the patient’s history of having a chronic inflammatory condition, a neoplasm, or chronic kidney disease may be a clue to help you identify the disorder.
However, the best clues for identifying anemia of chronic disease are the iron studies values. The serum iron is decreased because it can’t be absorbed in the GI tract and can’t be released by the macrophages, but ferritin, a marker of iron stores, is normal and eventually may be elevated as iron accumulates inside the body.
Now, transferrin, a molecule that transports iron in the blood, is decreased because there’s plenty of iron in the body, and TIBC, total iron binding capacity, which indicates the amount of unbound transferrin in the blood, remains normal.
Alright, moving on to aplastic anemia and pure red cell aplasia. For both, the best initial test is a CBC with a peripheral blood smear showing normocytic anemia, while the reticulocyte production index is lower than 2%.The key here is that aplastic anemia will additionally have low platelets and white blood cells.
Iron studies are normal. There is no specific test for aplastic anemia and pure red cell aplasia.
The diagnosis is basically a diagnosis of exclusion, since pancytopenia or isolated anemia with reticulocytopenia can also be caused by other diseases that infiltrate the bone marrow and decrease the production of cells, like myelofibrosis and cancer, either leukemia or metastatic cancer.
So in order to confirm the diagnosis a bone marrow biopsy must be done. In aplastic anemia, the bone marrow aspiration is referred to as a “dry tap” because the marrow is hypocellular and the precursor cells are replaced by fat cells and fibrous stroma.
In contrast, in pure red cell aplasia, the bone marrow is typically normocellular, with an absence of erythroblasts, but normal maturation of platelets and white blood cells.
Now, treatment of anemia of chronic disease focuses on addressing the underlying cause of inflammation. In certain cases, like chronic kidney disease, erythropoiesis- stimulating agents like erythropoietin, or EPO, for short, are considered.

Treatment11:26–12:43

Blood transfusions should be used with caution. For aplastic anemia, treatment starts with red blood cell or platelet transfusions are, which are often given supportively.
Depending on the cause, it might also include stopping the offending agent, immunosuppressive regimens like antithymocyte globulin and cyclosporine, in case of autoimmune disease or treating the underlying infection.
Bone marrow stimulation with certain agents like granulocyte-macrophage colony-stimulating factor or GM-CSF may also be helpful.
For your exams, keep in mind, though, that the only curative option is a bone marrow transplant. Similarly, for pure red cell aplasia, red blood cell transfusions can be given, and then, depending on the cause, immunosuppressants, thymectomy or treating the infection may be considered.
Okay, to review! Non-hemolytic normocytic anemias include anemia of chronic disease and aplastic anemia.

Review12:43–13:37

Anemia of chronic disease can occur when there’s a chronic inflammatory condition, a neoplastic disorder or chronic kidney disease.
Aplastic anemia can occur when there’s radiation, environmental toxins, medications or infections that are toxic to the bone marrow but can also be idiopathic.
A diagnosis can be made based on the patient’s history, physical examination, and a CBC with a peripheral blood smear, as well as iron studies for anemia of chronic disease and bone marrow biopsy for aplastic anemia and pure red cell aplasia.
Treatment focuses on the source of inflammation in anemia of chronic disease and the underlying disorder in aplastic anemia and pure red cell aplasia.
Now, back to the patients! Both of them have normocytic non-hemolytic anemia.

Summary13:37–14:27

Due to her history of SLE which is a chronic inflammatory disorder, Sofia probably has anemia of chronic disease but it must be confirmed with iron studies which will show decreased serum iron, normal or elevated ferritin, decreased transferrin and normal TIBC.
Now, John has pancytopenia without splenomegaly and may have aplastic anemia. A bone marrow aspiration must be done to exclude diseases that infiltrate the bone marrow such as leukemia.
The aspiration will be a dry tap since the bone marrow is hypocellular and blood precursors are replaced by fat cells and fibrous stroma and so the diagnosis of aplastic anemia will be confirmed.
...And that’s the non-hemolytic normocytic anemia pathology in a nutshell.