Essentials in Hematology and Clinical Pathology Ramadas Nayak, Sharada Rai
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Disorders of Red Cells
  1. Introduction
  2. Classification of Anemia
  3. Iron Deficiency Anemia
  4. Megaloblastic Anemia
  5. Introduction and Classification of Hemolytic Anemia
  6. Hemolytic Anemias due to Red Cell Membrane Disorders
  7. Thalassemia Syndromes
  8. Sickle Cell Disease
  9. Hemolytic Anemias due to Red Cell Enzyme Deficiencies
  10. Immunohemolytic Anemia
  11. Fragmentation Syndrome
  12. Paroxysmal Nocturnal Hemoglobinuria
  13. Aplastic Anemia
  14. Pure Red Cell Aplasia
  15. Miscellaneous RBC Disorders
  16. Sideroblastic Anemia
  17. Approach to Anemias

IntroductionCHAPTER 1

Chapter Outline
  • □ Definition
  • □ Hematopoiesis
Hematology is defined as the study of normal and pathologic aspects of blood and blood cells. Hematopoiesis (hemopoiesis) is the continuous, regulated process of blood cell production or formation.
Hematopoietic (hemopoietic) system: It consists of all organs and tissues involved in hematopoiesis, and these are divided into myeloid tissue and lymphoid tissue. The pluripotent hematopoietic stem cell (HSC) is the progenitor of all the cells in blood and gives rise to cells of both myeloid and lymphoid system.
  1. The myeloid tissue consists of bone marrow (medullary cavity) and the cells derived from it, which include:
    • Red blood cells (RBCs/erythrocytes)
    • White blood cells (WBCs/leukocytes, except lymphocytes): WBCs consist of:
      • Granulocytes: Neutrophils, eosinophils and basophils are collectively called granulocytes because of their different types of cytoplasmic granules. However, the term granulocyte is often referred to only neutrophils.
      • Monocytes
      • Lymphocytes (even though included under WBCs; they are lymphoid derived).
    • Platelets (thrombocytes)
      Compensatory hyperplasia: In adults during pathological states, whenever there is an increased demand for blood cells, the bone marrow undergoes compensatory hyperplasia. This results in replacement of the fatty marrow by hematopoietic tissue.
    • Extramedullary hematopoiesis:
      • Normally, the cells of the myeloid lineage arise in the central bone marrow (medullary cavity). If the increased demand of blood cells is not met with compensatory hyperactivity of marrow alone, hematopoietic islands appear in liver and spleen (resulting in hepatosplenomegaly) and even in lymph nodes.
      • 4The myeloid lineage blood cells arising outside the marrow elsewhere in the body are designated as extramedullary hematopoiesis (agnogenic myeloid metaplasia).
  2. The lymphoid tissue consists of thymus, lymph nodes and spleen. The common lymphoid progenitor cell gives rise to B cell, T cell and natural killer (NK) cell precursors. They mature to form respective lymphoid cells.
The above division of hematopoietic elements as myeloid and lymphoid tissue is mainly for understanding their pathology. It is not always possible to draw clear demarcation between the diseases affecting them.
Functions of Blood Cells
Formed elements of blood are red cells, white cells and platelets. The main functions of blood cells are presented in Table 1.1.
Table 1.1   Main functions of formed elements of blood
Type of blood cell
Main function
Red blood cells
Delivery of oxygen to tissues
White blood cells
Defence against infectious organisms
Immune regulation
  • As the mature blood elements become old, they are destroyed and constantly produced to maintain normal peripheral blood cell counts.
  • In addition, each cell line has the ability to respond appropriately to increased demand like; increased red cell production after blood loss, leukocytosis during infection, wound healing and increased platelet production during chronic bleeding.
  • Despite the wide functional diversity of blood cells, all myeloid and lymphoid cells originate from common precursor; pluripotent hematopoietic stem cells (HSC).
Sites of Hematopoiesis
Different sites of hematopoiesis during various phases of life are shown in Table 1.2.
Table 1.2   Different sites of hematopoiesis during various phases of life
Yolksac (mesoblastic) phase
First 3 months of gestation
Yolk sac
Hepatic phase
4–9 months of gestation
Liver (chief site till birth), spleen (minor site)
Medullary (myeloid) phase
By 3rd week after birth up to puberty
Bone marrow throughout the skeleton
Active marrow is limited to the ends of long bones and flat bones
Terminology Used in Hematopoiesis
The meaning of the terms used with reference to hematopoiesis is shown in Table 1.3.
Normal Development of Blood Cells (Hematopoiesis)
The hematopoietic system is a hierarchy of cells in which pluripotent hematopoietic stem cells proliferate and differentiate. After several steps, HSCs finally give rise to mature blood cells. This hierarchy (Figs 1.1 and 1.2) consists of:
  1. Hematopoietic stem cells
Table 1.3   Different terminologies used with regards to hematopoiesis
Ability to generate all mature hematopoietic cells
Ability to produce a limited range of differentiated cell lineages appropriate to their location
Restricted ability to differentiate and generate one specific cell type
  1. Progenitor cells
    1. Multipotent progenitor cells
    2. Committed (unipotent) progenitor cells
  2. Precursor cells
  3. Maturing and mature cells.
Hematopoietic Stem Cells (HSC)
These are small, undifferentiated mononuclear cells that can generate all the blood cell lineages.
HSCs possess two fundamental properties:
  • Self-renewal: HSCs are capable of cell division to give rise to more stem cells.
  • Differentiation: HSCs can differentiate and give rise to two kinds of lineage-specific multipotent progenitor cells, the common myeloid and the common lymphoid progenitors.
Note: Apart from blood cells, the stem cells may be able to differentiate into diverse tissue types (e.g. neuronal, muscle, liver, vascular cells). This change in the differentiation of a cell from one type to another is known as transdifferentiation, and the capacity of a cell to transdifferentiate into diverse lineages is referred to as developmental plasticity.
Stem cell disorders (Box 1.1).
zoom view
Fig. 1.1: Cell hierarchy in hematopoiesis
Progenitor Cells
Upon commitment to development, the HSCs enter the next compartment known as progenitor cell compartment. This compartment consists of mainly two types of cells.
  • Multipotent progenitor (lineage specific) cells
  • Committed (unipotent) progenitor cells
Both multipotent and unipotent cells in the bone marrow possess the ability to give rise to clones (groups) composed of specific kinds of mature cells when grown in culture and are called as colony forming units (CFU).
Multipotent progenitor cells: These are of two types namely: Early progenitor with myeloid potential and early progenitor with lymphoid potential.
  • Early progenitor with myeloid potential further divide to produce mainly two types of multipotent progenitor cells with restricted differentiation. They are:
    zoom view
    Fig. 1.2: Different stages of hematopoiesis(Abbreviations: BFU, burst forming unit; CFU, colony forming unit)
    • CFU b/Mg/E (multipotent) cells which give rise to three types of committed (unipotent) progenitor cells.
      • CFU-E (colony-forming unit-erythrocyte) cells. It is most sensitive to the action of erythropoietin.
      • 7CFU-Mg (colony-forming unit-megakaryocyte) cells
      • CFU-Baso (colony-forming unit-basophil) cells
    • CFU-Mix which differentiate into three types of committed (unipotent) progenitor cells.
      • CFU-G (colony-forming unit-granulocyte) cells, precursors of neutrophils
      • CFU-M (colony-forming unit-macrophage) cells, precursors of monocytes and macrophages.
      • CFU-Eo (colony-forming unit-eosinophil) cells, precursors of eosinophils.
  • Early progenitor with lymphoid potential cell in turn gives rise to three progenitor cells.
    • Pro-T cells which differentiate into T cells.
    • Pro-NK cells which differentiate into NK cells.
    • Pro-B cells which differentiate into B cells.
Lymphocyte development is discussed in Chapter 29.
Morphologically, the progenitor (both multipotent and unipotent) cells and stem cells cannot be distinguished from one another on morphological appearance or cytochemistry except by immunological techniques.
Precursor Cells
When the immature hematopoietic cell acquires recognizable morphological, cytochemical or immunological feature of a single lineage, it is called as precursor cell. The next step in hematopoiesis is maturation of unipotent progenitor cells to precursor cells. The earliest morphologically recognizable precursor cell of each lineage is termed by adding the suffix “blast” to the type of lineage (e.g. lymphoblast to lymphoid lineage).
Mature Cells
The precursor cells finally give rise to mature blood cells, which are released from the marrow into the circulation.
Regulation of Hematopoiesis
The growth of different hematopoietic cells is regulated by a number of hematopoietic growth factors, which in general are called cytokines.
Most important growth factors acting on various cells are mentioned below.
  • Stem cells: Stem cell factor (also called c-KIT ligand), IL-6 and FLT3-ligand.
  • CMP progenitor cells:
    • Multipotent committed progenitors
      • Granulocyte-macrophage colony-stimulating factor (GM-CSF)
      • Thrombopoietin
      • IL-3, IL-5, IL-6 and IL-11
    • Committed progenitors
      • Erythropoietin (EPO): It is a glycosylated protein synthesized mainly by kidney and minor part from liver. It is produced in response to hypoxia. EPO acts on the erythroid precursors through EPO receptors. This stimulates proerythroblasts to proliferate and differentiate to produce RBCs.
      • 8Granulocyte colony-stimulating factor (G-CSF)
      • Thrombopoietin
  • Lymphopoiesis is regulated by several interleukins (most important being IL-1, 2, 4, 5, 6, 7, 9).
Components of bone marrow are listed in Box 1.2. The characteristic morphologic appearances of various cells of hematopoiesis are discussed in Chapter 39.
  • Hematopoiesis is the continuous, regulated process of production of all blood cells.
  • Organs and tissues involved in hematopoiesis are known as hematopoietic organs and are divided into myeloid and lymphoid tissue.
  • The hematopoietic system is a hierarchy of cells and consists of HSC, multipotent and unipotent progenitors, morphologically identifiable precursors (blast cells) and mature cells.
  • Bone marrow is the main site of hematopoiesis after birth and throughout life.
  • Under abnormal conditions blood cells may be produced outside the marrow and such production is known as extramedullary hematopoiesis.
I. Short Notes
  1. Extramedullary hematopoiesis.
  2. Hematopoietic stem cell (HSC).
  3. Erythropoietin.
  4. Components/contents of bone marrow.
II. Multiple Choice Questions
1. In adults, erythropoiesis occurs mainly in:
  1. Small bones of hand and feet
  2. Flat and long bones
  3. Spleen and lung
  4. Kidneys and adrenals
2. The cell which has the capacity for self-renewal and pluripotent differentiation is:
  1. Hematopoietic stem cell
  2. Progenitor cell
  3. Precursor cell
  4. Mature cell
3. The commonest sites of extramedullary hematopoiesis in adult are:
  1. Liver and spleen
  2. Kidney and thymus
  3. Liver and yolk sac
  4. Lymph node and thymus
4. In the adult, the extramedullary hematopoiesis results in:
  1. Splenomegaly
  2. Hyposplenism
  3. Atrophy of liver
  4. Atrophy of lymphnodes
1. B
2. A
3. A
4. A