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Micrograph showing nucleated red blood cells (bottom left of image), one of the elements necessary to call extramedullary hematopoiesis, in an endometrial polyp. H&E stain.

Extramedullary hematopoiesis (EH) refers to the hematopoiesis occurring outside of the medulla of the bone (bone marrow).It can be physiologic or pathologic.

The physiologic one occurs during embryonic and fetal development mainly. It has been done in many different locations, depending on the moment or the kind of hematopoiesis that is needed in that moment.

The pathologic EH can occur during adulthood when physiologic hematopoiesis can´t work properly in the bone marrow and the hematopoietic stem cells (HSC) have to migrate to other tissues in order to continue with the formation of blood cellular components. Pathologic EH can be caused by myelofibrosis ,thalassemias or disorders caused in the hematopoietic system.

Physiologic EH

Hematopoiesis has been studied in different mammals like mice and primates, and it has been seen that during fetal development the formation of blood cells happens mainly in the fetal liver and after that in the bone marrow. But it is known that duing fetal development hematopoiesis takes place in many other tissues or organs such as yolk sac, aorta-gonad mesonephros (AGM) regions, spleen or limph nodes.

In order to understand the different locations of the hematopoiesis, it is necessary to know how hematopoiesis works since embryonic periods until adulthood. During development, in vertebrates, we can distinguish two different waves of hematopoiesis:

• Primitive hematopoiesis Primitive wave occurs in the yolk sac in the 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 so that embryo grows rapidly. This primitive wave is transitory and the cells that are produced express embryonic globins, aren´t pluripotent and aren´t able of renew.

• Definitive hematopoiesis Definitive wave differs from the primitive one because through this process HSCs are going to be formed. These cells are going to be the ones which every blood cell will be differentiated from. The formation of these cells occurs in the AGM later in development. Afterwards, they will migrate to the fetal liver where is going to take place the major part of the physiologic EH. When bone marrow is developed, before birth, they will migrate there. It has been seen that they also can migrate to the spleen and lymph nodes where hematopoietic function can happen, but in a less quantity.

To sum up with the Physiologic EH, it is important to take into account that although primitive wave occurs early in development and definitive wave later in development, the time points differs depending on the specie.

• Lung hematopoiesis

Since now, the physiologic EH has been related to the different level of the fetal development. But, researches have realized that there is another organ that during the adulthood plays a very important role in the hematopoiesis; we are talking about lung hematopoiesis. In the hematopoiesis the blood progenitor cells differ in red blood cells, white blood cells and platelets. And the lungs will be the ones that deal with the production of the platelets beside bone marrow. Studies have found that blood leaving the lungs has more platelets and fewer progenitor cells than blood entering the lungs. I has been seen also that in the cases of very low level of platelets, in thrombocytopenia, the megacariocytes (progenitors of platelets) migrate out of lungs into the bone marrow, where they could completely restore production of platelets and other blood cells.

Taking into account all this, it is clear that the lung is a major participant in the platelet biogenesis (%50).

Pathologic EH

In adults the most normal location of hematopoiesis is the bone marrow. So, if it happens in any other organ there will be a pathological reason. In these cases it will be some deficiency in the bone marrow which leads the hematopoiesis to occur in other place.

The cause of EH can be many hematological diseases such as myelofibrosis or bone marrow irradiation. But, nevertheless, thalasemia that causes hemolytic anemia is which causes the highest EH. Depending on the pathology and its gravity many different organs of the body can be affected by the EH such as spleen, liver, lymph nodes, thymus, heart, breasts, prostate, broad ligaments, kidneys, adrenal glands, pleura, retroperitoneal tissue, skin, peripheral and cranial nerves, and the spinal canal. We have to take into account that in spite of having the same disease, there are a lot of different levels where the disease development differs, and that in different person the symptoms will be different.

• Thalasemia: It is a disease where there is some mutation in the gene of alpha or beta globin chain of the hemoglobin, So, there will be an absence or reduced synthesis of these globin chains and it will lead an inefficient erythropoiesis. This insufficient function of the bone marrow will case the migration of the cells of the hematopoietic tissue outside of the bone marrow in order to be able to meet circulatory demands. In this cases most affected organs are spleen, liver, pleura, adrenal glands and spinal canal.

• Myelofibrosis: It is a kind of bone marrow cancer, a kind of leukemia, which leads the replacement of the hematopoietic tissue by the connective tissue (fibrosis). In this way, the hematopoietic function of the bone marrow will be affected and other organs will have to help in the formation the blood cells. In this disease the most affected organ will be the spleen, which is going to take the function of hematopoiesis apart from the bone marrow. That´s why the major symptom of this disease will be splenomegaly that is accompanied by progressive anemia and chronic incapacity symptoms. It has been seen also that in some cases extramedullary hematopoiesis can occur in the pleural fluid.

It also has been seen that in a normal response to an inflammation or infection hematopoietic stem cells populations number decrease in the bone marrow and that this normally is accompanied by the development of extramedullary hematopoiesis in liver and spleen.