Hematology is the study of the normal and pathologic aspects of blood and blood elements. Blood is a unique fluid compromised of many cellular elements as well as a liquid portion consisting of proteins, amino acids, carbohydrates, lipids and elements. The hematopoietic system is characterized by turnover and replenishment throughout life. The pluripotent hematopoietic stem cell (HSC) is the progenitor of the cells in blood
Hematopoiesis is the process of the development of blood cell lineages throughout life. Hematopoiesis in necessary to replenish dying cells with new blood cells. The key role of hematopoietic cells in maintaining hematopoietic homeostasis, host immunity and tissue oxygenation requires that they are highly regulated.
The hematopoietic system: the hematopoietic system includes the elements of the blood, marrow, lymph nodes, endothelial cells, thymus and spleen that are involved in the production of all blood lineages. This system further includes cytokine – producing cells and stromal elements of the bone marrow and spleen. In human physiology, the hematopoietic system supplies various cells in the body with oxygen, contributes to the formation of blood clots when needed, and provides protection against infection and pathogens.
Blood cells: Blood cells include red blood cells (erythrocytes, RBCs), white blood cells (leukocytes) and platelets which provide a variety of functions within the body. RBCs carry oxygen, platelets contribute to hemostasis, thrombosis and the inflammatory response, and white blood cells are involved in immunity.
Hematopoietic homeostasis: Hematopoiesis is in a delicate state of homeostasis the process of maintaining balanced production to offset ongoing destruction of blood cells. Some cell lineages such as neutrophils only survive for several hours after release from the bone marrow into the circulation. RBCs can survive longer, lasting 60 to 120 days, and terminally differentiated lymphocytes, plasma cells, may survive for up to 20 to 30 years. Hematopoietic cell production is regulated by cytokines and growth factors and monitored by tissue sensors (tissue oxygenation for red blood cells for example). The specific regulators and sensors for all hematopoietic elements, however, have not been clearly elucidated.
Hematopoiesis during development
The earliest forms of blood cells are observed in the yolk sac. These cells emanate from a primitive precursor population and produce both cells with oxygen – carrying capacity and a small number of primitive lymphocytes. More definitive hematopoiesis takes place later in development in fetal liver, and during the third trimester, production is transferred to the bone marrow in the developing embryo.
RBC production is unique in development because of the complex evolution in the hemoglobin locus resulting in a structured sequence of distinct hemoglobin produced during fetal life. Because of the oxygen requirements in the fetus and the absence of direct air exchange in the lung, different hemoglobins are produced during gestation.
Most significant is fetal hemoglobin or hemoglobin F, a unique tetramer that disappears normally within a few months after birth. It is the main type of hemoglobin in the fetus. It has greater oxygen – affinity than adult hemoglobin A, allowing for the extraction of oxygen from the maternal blood stream. A small percentage of adult hemoglobin or hemoglobin A appears late in gestation and becomes the dominant form within 6 months of birth, reflecting the change in oxygen requirements after birth.
Interestingly, fetal hemoglobin ameliorates the disease manifestations of homozygous hemoglobin S, the cause of sickle cell anemia. For this reason, erythropoietin and hydroxycarbamide (hydroxyurea), which promotes the generation of hemoglobin F, are used to treat sickle cell anemia.
Hematopoiesis in adult
In adults, hematopoiesis mainly occurs in bone marrow and thymus. Myelopoiesis (non – lymphoid) and lymphopoiesis diverge during the early stage of differentiation. The hematopoietic stem cell’s first lineage commitment is to differentiate to a common myeloid progenitor or a common lymphoid progenitor. The common myeloid progenitor produces megakaryocytic, erythroid (RBC), granulocytic and monocytic lineages. The granulocytes, the neutrophils, eosinophils and basophils, are the most phylogenetically related. Monocytes arise from a common granulocyte – monocyte progenitor.
Erythropoiesis is the process of generating RBC. Thrombopoiesis refers to the formation of platelets from their precursor megakaryocytes. Erythrocytes and megakaryocytes both develop from a common precursor cell. RBC production is stimulated by the growth factor, erythropoietin. Megakaryocytes are unusual in that the cell undergoes nuclear division without cytoplasmic division; the generating cell contains a high amount of DNA content, 32n – 64n, compared to 2n of normal diploid cell. Each megakaryocyte can generate large numbers of platelets by “budding” off pieces of cytoplasm. The process is stimulated by thrombopoietin (TPO), a cytokine hormone mainly produced by liver and kidney.
Since leukemias often recapitulate the normal developmental process, it is not uncommon to encounter a leukemia with both granulocyte and macrophage differentiation capable of recapitulating the common granulocyte – macrophage progenitor or less often a leukemia demonstrating erythrocyte and megakaryocyte differentiation simulating the common megakaryocyte – erythrocyte progenitor.
The common lymphoid progenitor cell differentiates into B – cell, T – cell and natural killer cells. B -lymphoid development remains localized in the bone marrow, whereas developing T cells emigrate from the bone marrow to the thymus to undergo terminal differentiation. B and T – lymphoid development requires rearrangement of the DNA in the maturing cells; the immunoglobulin locus for B cells and T – cell receptor locus for T cells. DNA recombination in the developing lymphocytes randomly combines variable, diversity and joining gene segments (VDJ) to generate antibody and T – cell receptor proteins with tremendous diversity ( greater than 1 × 10 7 ) to match potential antigens from a wide variety of infectious or noxious agents.
The DNA rearrangement process is intimately related to T and B – cell survival and maturation as lack of effective DNA recombination results in cell death. B – lymphopoiesis occurs under the infl uence of IL – 7. The effects of IL – 15 and IL – 2 are important later in lymphopoiesis.