Extramedullary hematopoiesis

Let’s know about Extramedullary hematopoiesis. Extramedullary hematopoiesis (EMH or sometimes EH) refers to hematopoiesis that occurs outside the marrow ( bone marrow ). It can be physiological or pathological.

Physiological EMH occurs during embryonic and fetal development; The main sites of fetal hematopoiesis during this time are the liver and spleen.

Pathological EMH can occur during adulthood when physiological hematopoiesis cannot function properly in the bone marrow and hematopoietic stem cells (HSCs) have to be transferred to other tissues to continue the formation of blood cellular components Pathologic EMH can be caused by myelofibrosis [3] thalassemia or disorders of the hematopoietic system.

Extramedullary hematopoiesis
Extramedullary hematopoiesis

physical emh

During embryonic development, hematopoiesis occurs primarily in the liver and spleen of the fetus, with subsequent localization in the bone marrow. [4] Hematopoiesis also occurs in many other tissues or organs such as the yolk sac the aorta-gonad mesonephros (AGM) region, the spleen, and lymph nodes During development, vertebrates pass through a primitive and definitive stage of hematopoiesis. The lungs also play a role in platelet production in adults.

primitive hematopoiesis

Primitive hematopoiesis occurs in the yolk sac during early embryonic development It is characterized by the production of erythroid progenitors or nucleated erythrocytes, also known as erythroblasts or megaloblasts. The main purpose of producing these cells would be to facilitate tissue oxygenation to support rapid embryonic development. This primitive stage is transitory and the cells that produce express embryonic globin are not pluripotent and are not capable of self-renewal.

definitive hematopoiesis

Definitive hematopoiesis differentiates from the primitive stage through the production of hematopoietic stem cells These cells are formed in the AGM later in development. Later, they migrate to the fetal liver where most of the physiological EMH occurs. Eventually, after the bone marrow develops, they migrate there. They can also migrate to the spleen and lymph nodes where hematopoiesis can occur, but to a lesser extent.

pulmonary hematopoiesis

Pulmonary hematopoiesis also appears to play an important role in adults. [5] Compared to the bone marrow, where trilineage hematopoiesis occurs, the lungs contribute preferentially to the production of platelets through the resident population of megakaryocytes This is supported by studies showing that blood that drains from the lungs contains more platelets and fewer progenitor cells than blood that enters the lungs. It has been observed that in cases of severe thrombocytopenia pulmonary megakaryocytes migrate from the lungs to the bone marrow, where they help to replenish the depleted bone marrow population.

Pathological EMH

In adults, most hematopoiesis occurs in the bone marrow. Significant production in another organ is usually the result of a pathological process. When the red blood cell (RBC) count is low, the body induces a homeostatic mechanism aimed at increasing the synthesis of RBCs, usually through the production of erythropoietin. If RBC loss becomes severe, hematopoiesis will occur in extramedullary spaces outside the bone. [6]

The cause of pathologic EMH may be one of several hematologic diseases, such as myelofibrosis, or as a result of bone marrow irradiation. Thalassemia and its consequent hemolytic anemia is another important cause of pathologic EMH. EMH has been observed in several other benign hematological disorders such as sickle cell anemia, hereditary spherocytosis, congenital dyserythroblastic anemia, and idiopathic thrombocytopenic purpura. [6] EMH can also be seen as part of a response to systemic inflammation or infection

EMH sites

The sites of EMH can be widespread, however, with the most common localizations being in the spleen, liver, and lymph nodes. Other manifestations occur in the thymus, heart, breast, prostate, broad ligament, kidney, adrenal glands, pleura, retroperitoneal tissue, skin, peripheral and cranial nerves, and the spinal canal.


During the postnatal period, the spleen becomes a frequent site of EMH, whereas, during fetal stages of hematopoiesis, it is only a minor factor. Despite the hypoxic/acidic conditions of the splenic microenvironment, supplied with a set of macrophages that make it inaccessible to HSCs, EMH typically occurs within the red pulp. Among the various organs associated with EMH, the spleen provides a unique site for the evaluation of hematopoietic stem cell (HSC)/niche interactions. [8] [7]


It is common for infants to have hepatic EMH as they continue to develop until about 5 weeks of age. [9] On the other hand, hepatic EMH in adults may indicate a pathological condition. This includes transplants, liver tumors liver disorders, or sepsis. Hepatoblastoma, adenoma, and hepatocellular carcinoma can also cause EMH in adults. [10] [11] Additionally, EMH is often seen within hepatic sinusoids.

lymph nodes

EMH in the lymph nodes is usually associated with an underlying hematopoietic neoplasm. EMH occurs as a result of myeloproliferative neoplasms (MPNs). [12] If EMH is identified in the lymph nodes of an adult or infant, a hematologic evaluation should be performed, including blood cell counts, peripheral blood smear, and possibly a bone marrow biopsy. [7]

other sites

The following tissues may also be associated with EMH: thymus, heart, breast, prostate, fatty tissue, adrenal glands, kidney, periosteum, pleural cavity, para-vertebral region, intra-spinal tissue, retroperitoneal tissue, skin, peripheral and cranial nerves, spinal canal, pre-sacral region, nasopharyngeal region, paranasal sinuses and a variety of benign/malignant neoplasms. The most common sites of EMH associated with neoplastic disorders are the spleen, lymph nodes, skin, bone, small intestine, orbit, breast, cervix, nasal sinuses, mediastinum, and brain. [7] [13] [14] [15]

Microenvironment of EMH

Among the various organs associated with EMH, the spleen provides a unique site for the evaluation of HSC/niche interactions as it is one of the most common sites of EMH, although it does not play a major role in embryonic/developmental hematopoiesis. [7] found higher expression levels of CXCL12 in the human spleen of EMH-positive patients compared to EMH-negative patients  High expression of CXCL12, a candidate marker of bone marrow niche-formation in cells, indicates HSC/niche interactions in the spleen. [16] Studies have shown that CXCL12 is localized in EMH-positive sinus endothelial cells of the red pulp in the spleen; 

Whereas, whereas XCL12 was expressed in vascular endothelial cells of the white pulp in the spleen of EMH-negative and -positive cases.[16] The fact that EMH often occurs in the red pulp is supported by current data that show that splenic sinus endothelial cells expressing CXCL12 can differentiate into hematopoietic precursor cells, forming bone marrow niche-like areas of EMH. Can contribute to circulation and recruitment. In the human spleen.