Introduction
Erythropoiesis is a procedure in which hematopoietic stem cells in bone marrow proliferate and differentiate to form reticulocytes. The reticulocytes are generated and released into the bloodstream, where most of them are transformed into matured erythrocytes within two days. The mature red blood cells (RBC) transport oxygen throughout the body. A higher-than-normal reticulocyte can indicate anemia in most cases. It results in inadequate oxygenation within the body. This article discusses details on causes and diagnostic approaches for reticulocytosis.
What Are Reticulocytes?
Reticulocytes are immature red blood cells formed in the bone marrow and released into peripheral blood, where they become matured red blood cells (RBC) within one or two days. They represent a stage of red cell development immediately after nucleus expulsion. In normal individuals, one percent of reticulocytes are circulating in the bloodstream. Reticulocytes can be differentiated from mature red blood cells due to their high RNA (ribonucleic acid) composition and appearance of a bluish tinge with Ramanowsky stains of peripheral blood smear.
The reticulocyte count in a healthy individual is between 0.5 to 2.5 percent. A higher or lower reticulocyte count can result in various disorders. It is essential to accurately quantify reticulocytes as their count reflects the erythropoietic activity of bone marrow and the rate of reticulocyte release in peripheral blood.
What Is Reticulocytosis?
Reticulocytosis is a medical condition with an abnormal reticulocyte increase in peripheral blood. Reticulocytosis can be an indicator of bone marrow response to anemia. When there is a standard or hyperactive bone marrow response, there is an increase in reticulocytes.
Reticulocytosis can be determined when the reticulocyte index is greater than 3 percent and the reticulocyte count is more significant than 1.5 percent.
What Are the Conditions Causing Reticulocytosis?
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Hemolytic Anemia: Hemolytic anemia results from RBC destruction but the bone marrow functions are intact. In anemic patients, bone marrow tries to compensate for hemoglobin reduction by increasing erythropoiesis and releasing reticulocytes into the peripheral blood. Hemolytic anemia can develop due to immune factors, primary red blood cell membrane defect, enzyme defect, sickle cell anemia, or exposure to toxins.
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Blood Loss: Acute or chronic blood loss can induce erythropoiesis and release of reticulocytes into the peripheral blood. The blood loss can be caused by injury, surgery, or ulcer. The bone marrow tries to recover the blood loss by producing many red blood cells, but they are released before they mature. Reticulocytosis due to blood loss is transient and reverts to normal levels after some time.
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Hemolysis: Increased destruction of red blood cells stimulates the bone marrow to produce more cells faster. Therefore, releasing immature red blood cells into the bloodstream. Red blood cell destruction and reticulocytosis are a feature of sickle cell disease.
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Erythroblastosis Fetalis: A blood disorder in a fetus or newborn can induce reticulocytosis. It is a condition where RBC destruction exceeds their production leading to anemia and tissue hypoxia. The fetus responds to this condition by reticulocytosis.
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Other Causes
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Microangiopathic hemolytic anemia is caused by damage to the red blood cell membrane. Reticulocytosis is one of the disease features.
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Reticulocytosis is observed immediately after splenectomy.
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Hemoglobinopathy: Diseases like sickle cell disease and thalassemia major can induce reticulocytosis.
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After anemia treatment: Treatment with folate, iron, or vitamin B12 supplements can cause reticulocytosis. The bone marrow cannot produce enough red blood cells when nutrients are deficient. Still, when the nutrients become available, the bone marrow produces excessive red blood cells resulting in reticulocytosis.
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There is a natural increase in reticulocytes during pregnancy or in infants.
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Exercising increases reticulocyte count among athletes. Exercise causes the release of cortisol or stress hormones and stimulates the bone marrow to release reticulocytes.
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Exposure to toxins like ethylene glycol ethers present in paint or cleaners can cause reticulocytosis. Lead poisoning can also induce reticulocytosis.
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Individuals with a smoking habit may exhibit reticulocytosis.
How Is Reticulocytosis Diagnosed?
The diagnosis of reticulocytosis can be performed with the following methods:
1) Reticulocyte Count
It is necessary to determine reticulocyte count to monitor bone marrow regeneration potential post-chemotherapy or marrow transplantation. Reticulocyte count must be estimated in patients taking hydroxyurea for sickle cell anemia. Reticulocyte count is analyzed to determine treatment response in individuals with end-stage kidney disease receiving erythropoietin therapy.
The laboratory diagnosis is performed on the principle of high RNA levels in reticulocytes.
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Staining Method
It is one of the earliest methods that use supravital dye or Ramanowsky stain in peripheral blood smear for staining RNA in reticulocytes. The stained cells are then counted under a microscope. However, estimating the reticulocytes manually under a microscope increases inaccuracy and intraobserver variability.
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Flow Cytometry
It is a semi-automated, easy, rapid, and less expensive method for reticulocyte quantification. The estimation is highly accurate and precise. However, the drawbacks of flow cytometry are when immunofluorescent techniques are used, and they can produce abnormally high reticulocyte count due to the inclusion of nucleated RBC or Howell- Jolly (nuclear remnants present in red blood cell) bodies.
2) Other Procedures
Other techniques that can measure reticulocytes are the following:
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Reticulocyte Production Index: It is measured by multiplying the percentage of reticulocyte count by 0.45 fraction of patient hematocrit. This method is helpful for estimation in individuals with anemia where there can be false elevation of reticulocyte count. In this technique, a reduction in RBC causes an increase in reticulocytes, even in the absence of erythropoiesis.
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Absolute Reticulocyte Count: It is an accurate method for reticulocyte estimation.
Absolute reticulocyte count = Reticulocyte count in percentage x red blood cell (RBC/mm3, red blood cell per cubic millimeter).
The absolute reticulocyte count in healthy individuals is between 50,000 and 1,50,000 reticulocytes/ mL (per milliliter).
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Immature Reticulocyte Fraction: It is measured by calculating the ratio of immature reticulocytes to the total number of reticulocytes.
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Reticulocyte Hemoglobin Content: This method is indirectly used to measure iron deficiency anemia. Iron in bone marrow is measured using reticulocytes to produce hemoglobin. Iron deficiency anemia is diagnosed if reticulocyte hemoglobin is less than 28 pg.
How Is Reticulocytosis Treated?
An underlying medical disorder causes reticulocytosis. There are no specific procedures for treating reticulocytosis, but treating the underlying cause can resolve reticulocytosis. Quitting smoking may also prevent the elevation of reticulocytes.
Conclusion
Reticulocytosis is a phenomenon of elevated immature red blood cells in the peripheral bloodstream. The elevation of reticulocytes can be transient or chronic. Pregnancy, anemia treatment, and smoking are some temporary conditions of reticulocytosis. However, newborns' hemolytic anemia, blood loss, or hemolytic disease can induce reticulocytosis for prolonged periods. There are various diagnostic methods to detect reticulocytes. Reticulocytosis does not have any specific treatment except the curing of the underlying cause. The presence of reticulocytosis can help with disease diagnosis.
