Extramedullary 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 objective of the production of these cells will be the facilitation of tissue oxygenation to support rapid embryonic growth. This primitive phase is transitory and the cells that are produced express embryonic globins, aren't pluripotent, and aren't capable of self-renewal.

Definitive hematopoiesis differs from the primitive phase through the production of hematopoietic stem cells. The formation of these cells occurs in the AGM later in development. Later, they migrate to the fetal liver where the majority of physiologic EMH takes place. Finally, once the bone marrow has developed, they migrate there. They can also migrate to the spleen and lymph nodes where hematopoiesis can occur, but to a lesser degree.

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

Sites of EMH can be widespread however, most common localizations are in the spleen, liver, and lymph nodes. Other manifestations occur in the thymus, heart, breast, prostate, broad ligaments, kidneys, adrenal glands, pleura, retroperitoneal tissue, skin, peripheral and cranial nerves, and the spinal canal.[6][7]

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

It is normal for infants have hepatic EMH as they are developing up until roughly 5 weeks of age.[9] On the other hand, hepatic EMH in adults can indicate a pathological state. This includes transplantation, hepatic tumors, hepatic disorders, or sepsis. Hepatoblastoma, adenomas and hepatocellular carcinomas can also lead to EMH in adults.[10][11] Additionally, EMH is often observed within the hepatic sinusoids.

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

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