Extramedullary Hematopoiesis in Health and Disease - An Overview

Introduction

Hematopoiesis is a process in which cellular blood components and immune cells are formed from hematopoietic stem cells. The hematopoietic process mainly occurs in the liver, spleen, and bone marrow. However, hematopoiesis may occur in organs other than bone marrow in infants or in specific pathological states of chronic anemia, myeloproliferative disorder, or infection. This article discusses the location, pathological causes, and treatment of extramedullary hematopoiesis.

What Is Extramedullary Hematopoiesis?

Extramedullary erythropoiesis is a process in which erythroid or myeloid progenitor cells are formed outside the bone marrow. For example, extramedullary hematopoiesis occurs in the liver and spleen in hypoxia due to elevated erythropoietin formation. Extramedullary hematopoiesis forms blood cells like antigen-presenting cells, natural killer cells, red blood cells, and platelets to promote the survival of the individual. Extramedullary occurs due to insufficient erythrocyte production or their destruction. However, the exact etiology of the condition is unknown.

When Does Extramedullary Hematopoiesis Occur?

This phenomenon is seen during:

1. Healthy Individuals

• Normal Fetal Development: During fetal development, extramedullary hematopoiesis occurs before the development of bone marrow. The common sites for extramedullary hematopoiesis in the fetus are in the yolk sac, fetal liver, and spleen. During the end of the second trimester, extramedullary hematopoiesis occurs in the bone marrow and continues throughout life. Extramedullary hematopoiesis is considered an essential component of normal fetal development.

2. Pathological Conditions: In pathological conditions, many hematopoietic stem cells and progenitor cells are released into the bloodstream, which migrates to other organs.

• As compensatory mechanisms of secondary anemia where primary sites fail to produce adequate blood cells. Deficiency of vitamin B12, folate, or pluripotent stem cells can result in anemia development.

• Patients with abnormal red blood cell morphology like thalassemia.

• Patients with abnormal red blood cell shape like hereditary spherocytosis.

• Prolonged hypoxia leads to kidneys generating erythropoietin that stimulates erythropoiesis extramedullary.

• Extramedullary hematopoiesis is a unique and predominant feature of myelofibrosis.

• In myeloproliferative conditions like lymphoma and leukemia, bone marrow fails to produce hematopoietic cells.

• In rare instances, sickle cell disease can cause extramedullary hematopoiesis. In sickle cell disease, abnormally shaped red blood cells are destroyed, leading to chronic anemia. Therefore, extramedullary hematopoiesis is initiated to compensate for destroyed red blood cells.

• Extramedullary erythropoiesis can occur in the liver and spleen during immune response post-infection.

Where Does Extramedullary Hematopoiesis Occur?

The most frequent sites of extramedullary hematopoiesis are:

1. Adults: In adults, most of the hematopoiesis occurs in the bone marrow. The presence of extramedullary hematopoiesis is due to underlying medical conditions.

• Liver: Under specific circumstances, the liver works to compensate for deficient blood cells caused by improper functioning of bone marrow. Liver hematopoiesis is seen in hepatic tumors or sepsis.

• Spleen: The spleen works with the liver to compensate for deficient blood cells.

• Lymph Nodes: Extramedullary hematopoiesis occurs in the pathological state of myeloproliferative disorders.

2. Fetus: The fetus has two stages of extramedullary hematopoiesis. Primitive hematopoiesis occurs during the early stage of the fetus in the yolk sac. The definitive extramedullary hematopoiesis occurs first in the aorta-gonad mesonephros region and later in the fetal liver until four to five months of pregnancy. Post 20 weeks, bone marrow becomes the primary site for hematopoiesis.

Any other body tissue may also be involved in extramedullary hematopoiesis. Although rare, there were reports of extramedullary hematopoiesis in the bowel, pleura, breast, brain, thymus, heart, skin, and kidneys. If involved epidural space can cause spinal cord compression and significantly increase morbidity.

What Are the Symptoms of Extramedullary Hematopoiesis?

Extramedullary hematopoiesis may be asymptomatic in individuals and can be diagnosed incidentally. However, symptoms may occur when adjacent organ functions are compressed due to extramedullary hematopoiesis.

The symptoms are splenomegaly and hepatomegaly. When hematopoiesis occurs in the spleen, the individual may experience fullness in the upper spleen region or under the ribs. Pain may also be felt in the upper area of the left shoulder. If hematopoiesis occurs in the liver, the individuals may experience fullness in the right upper liver and under the ribs. Pain may be felt in the upper part of the right shoulder. In a few patients, fibro hematopoietic tumors may also develop.

Rarely, pleural effusion (fluid build-up between lung and chest), massive hemothorax (collection of more than 1000 milliliters of blood in pleural space), spinal cord compression, or respiratory failure may develop.

How Is Extramedullary Hematopoiesis Diagnosed?

The diagnosis of extramedullary hematopoiesis can be made based on clinical features, laboratory findings, and imaging studies.

Magnetic resonance imaging (MRI) is a preferred mode of imaging to accurately determine the extent of the extramedullary hematopoiesis mass without inducing any radiation exposure. Computed tomography scans or ultrasound may also be used for diagnosis. Extramedullary hematopoietic groups may appear posterior to the mediastinum if developed in the thorax region. The extramedullary hematopoietic masses can be unilateral, bilateral, sharp, smooth, or lobulated. A biopsy is not preferred but may be performed for a definitive diagnosis.

What Is the Differential Diagnosis for Extramedullary Hematopoiesis?

The differential diagnosis for extramedullary hematopoiesis can be neurofibroma (peripheral nerve sheath tumor), neurogenic tumors, malignant nerve sheath tumors, or chordoma (slow-growing tumor in the spine).

How to Treat Extramedullary Hematopoiesis?

The treatment of extramedullary hematopoiesis depends on its location and symptoms. Extramedullary hematopoiesis in healthy individuals or infants does not need any treatment. However, individuals with pathological states require therapy, and the modes of treatment are:

• Surgery: Excision with surgery is recommended if the extramedullary hematopoiesis mass is greater than six centimeters. In the case of spinal cord compression, surgical approaches such as decompression may be considered.

• Local Radiation: Hematopoietic cells are susceptible to radiation, and a low dosage of local radiation can induce their rapid shrinkage.

• Blood Transfusion: Multiple blood transfusion is performed to reduce the rate of extramedullary hematopoiesis. Blood transfusions stop the efforts of the body to make blood.

• Hydroxyurea Treatment: Due to its myelosuppressive properties, it may be used as an adjuvant treatment. This treatment modality is effective among thalassemia patients where blood transfusions cannot be performed.

• Hypertransfusion: It is a newer treatment option that reduces the risk of developing extramedullary hematopoiesis due to bone marrow suppression.

Conclusion

Extramedullary hematopoiesis is normal in infants until bone marrow develops and takes over the function of blood formation. In adults, various pathological hematology or bone marrow diseases give rise to this condition. The condition is often asymptomatic and is diagnosed based on a high degree of suspicion. Different treatment modalities are available to overcome the disease.