Formation of Blood

Mr. Topesh Patle

Formation of blood or hematopoiesis is the process by which all types of blood cells are produced and developed from a common precursor, the hematopoietic stem cell (HSC). It occurs primarily in adult bone marrow and the yolk sac, liver, and spleen during embryonic and fetal development. This intricate process ensures the continuous renewal of blood cells, essential for oxygen transport, immunity, and clotting functions. Below is a detailed description of hematopoiesis.

Phases of Hematopoiesis

  1. Embryonic Hematopoiesis (Yolk Sac Phase)
    • Timing: Begins around the 3rd week of gestation.
    • Location: In the yolk sac (an extra-embryonic structure).
    • Products: Primitive red blood cells and macrophages.
  2. Fetal Hepatic Phase (Liver and Spleen)
    • Timing: Around six weeks of gestation, blood formation shifts to the fetal liver and the spleen.
    • Location: The liver becomes the primary hematopoietic organ, followed by some hematopoietic activity in the spleen.
    • Products: Red blood cells (RBCs), white blood cells (WBCs), platelets, and fetal hemoglobin.
  3. Bone Marrow Phase (Myeloid Phase)
    • Timing: Around the 5th month of gestation and continues throughout life.
    • Location: Blood production shifts to the bone marrow, which remains the adults’ primary site of hematopoiesis.
    • Process: The bone marrow’s hematopoietic stem cells (HSCs) give rise to all blood cells (RBCs, WBCs, and platelets) through complex differentiation pathways.

Hematopoietic Stem Cells (HSCs)

  • HSC Characteristics:
    • Pluripotency: HSCs can differentiate into all blood cell types.
    • Self-renewal: They can divide and produce more HSCs, ensuring a constant supply throughout life.
    • Lineage Commitment: HSCs can commit to the myeloid or lymphoid lineage, further differentiating into specific blood cells.

Differentiation of Hematopoietic Stem Cells

Hematopoiesis is divided into two main lineages:

  1. Myeloid Lineage: Gives rise to:
    • Erythropoiesis: Formation of red blood cells.
    • Thrombopoiesis: Formation of platelets.
    • Granulopoiesis: Formation of granulocytes (neutrophils, eosinophils, and basophils).
    • Monocytopoiesis: Formation of monocytes and macrophages.
  2. Lymphoid Lineage: Gives rise to:
    • Lymphopoiesis: Formation of lymphocytes (T cells, B cells, and natural killer (NK) cells).

1.  Erythropoiesis

Erythropoiesis is the process by which red blood cells (RBCs) are produced. It takes place primarily in the bone marrow in adults, and its main purpose is to maintain a sufficient number of erythrocytes to ensure proper oxygen transport from the lungs to tissues.

Stages of Erythropoiesis

Erythropoiesis begins with hematopoietic stem cells (HSCs) and proceeds through several stages, each marked by changes in cell size, nuclear structure, and cytoplasmic composition until mature, enucleated erythrocytes are produced.

1. Hemocytoblast (Stem Cell)

  • A multipotent stem cell is found in the bone marrow.
  • Role: It is the precursor to all blood cell types, including red blood cells (RBCs), white blood cells, and platelets.
  • Specialization: When erythropoiesis is needed (due to low oxygen levels or blood loss), the hemocytoblast is stimulated to become an RBC by specific growth factors and hormones, especially erythropoietin (produced by the kidneys).
  1. Proerythroblast
  • The first committed precursor in the red blood cell line.
  • Role: This cell is destined to become a red blood cell and undergoes rapid division.
  • Appearance: The proerythroblast is a large, round cell with a prominent nucleus and a basophilic (blue-staining) cytoplasm due to the presence of RNA for protein synthesis.
  1. Basophilic Erythroblast
  • The cell continues to divide, and at this stage, it starts synthesizing haemoglobin, the protein that will carry oxygen.
  • Role: The key focus is haemoglobin production.
  • Appearance: The cytoplasm becomes even more basophilic due to increased ribosomes actively producing haemoglobin. The nucleus remains large.
  1. Polychromatic Erythroblast
  • Haemoglobin production intensifies, and the cytoplasm changes colour as the haemoglobin accumulates.
  • Role: The cell prepares for final maturation, and haemoglobin dominates over ribosomal RNA, making the cytoplasm greyish.
  • Appearance: The cell shrinks, and the nucleus condenses further. The cytoplasm takes on a mix of colours: pinkish from the haemoglobin and bluish from the remaining RNA.
  1. Orthochromatic Erythroblast (Normoblast)
  • The cell is almost filled with haemoglobin at this stage, and the nucleus is ejected.
  • Role: The cell undergoes final maturation, and the nucleus shrinks until expelled.
  • Appearance: The cytoplasm is now pink due to the high haemoglobin concentration. The nucleus becomes very condensed (pyknotic) and is finally ejected, leaving the cell almost mature.
  1. Reticulocyte
  • Size: Slightly larger than mature RBCs.
  • Nucleus: None (anucleate).
  • Cytoplasm: Mostly eosinophilic, still contains residual ribosomal RNA.
  • Location: Reticulocytes are released from the bone marrow into the bloodstream, where they mature into erythrocytes over 1-2 days.
  • Function: Reticulocytes are a marker of recent erythropoiesis and contribute to oxygen transport, though they are not fully mature.
  • Next Step: Mature into a mature erythrocyte.
  1. Mature Erythrocyte
  • Size: Biconcave, disc-shaped cell (7-8 µm diameter).
  • Cytoplasm: Contains no organelles; filled with haemoglobin.
  • Nucleus: None (anucleate).
  • Function: Mature erythrocytes circulate in the blood, transporting oxygen from the lungs to tissues and carbon dioxide back to the lungs for exhalation.
  • Lifespan: Approximately 120 days in circulation.

2.  Thrombopoiesis

Thrombopoiesis produces platelets (thrombocytes) from hematopoietic stem cells (HSCs) in the bone marrow. Platelets play a critical role in blood clotting and maintaining vascular integrity. Like erythropoiesis, thrombopoiesis involves several stages of cell differentiation and is regulated by various growth factors, primarily thrombopoietin (TPO).

  1. Megakaryoblast
  • A large, immature cell in the bone marrow.
  • Role: This cell is the precursor to megakaryocytes, which eventually produce platelets.
  • Appearance: It has a large nucleus and moderate cytoplasm.
  1. Promegakaryocyte
  • An intermediate stage in the development of megakaryocytes.
  • Role: The cell continues to mature and grow larger. It begins to develop the characteristics necessary for platelet production.
  • Appearance: The nucleus becomes more lobulated, and the cell grows.
  1. Megakaryocyte
  • A large, mature cell in the bone marrow.
  • Role: This cell is responsible for the production of platelets.
  • Appearance: It has a large, multi-lobed nucleus and an extensive cytoplasm. The cytoplasm extends into long, branching extensions known as proplatelets.
  1. Platelet (Thrombocyte)
  • The functional end product of thrombopoiesis.
  • Role: Platelets are small, disc-shaped cell fragments that play a crucial role in blood clotting by adhering to damaged blood vessels and aggregating to form a clot.
  • Appearance: Platelets are much smaller than the precursor cells and lack a nucleus. They have a disc shape and contain granules essential for clotting.

3.  Granulopoiesis

Granulopoiesis is the process by which granulocytes, a type of white blood cell (WBC), are produced from hematopoietic stem cells in the bone marrow. Granulocytes play a crucial role in the immune response, particularly in fighting bacterial infections and inflammation. The granulocyte lineage includes three main types of cells:

  • Neutrophils
  • Eosinophils
  • Basophils

Each type of granulocyte has specific functions in the immune system, and granulopoiesis involves a multistep process of differentiation and maturation regulated by growth factors and cytokines.

Stages of Granulopoiesis

Granulopoiesis begins with hematopoietic stem cells (HSCs) and progresses through various stages, where cells differentiate into different types of granulocytes.

  1. Hematopoietic Stem Cell (HSC)
  • Location: Bone marrow.
  • Function: Multipotent stem cell that can give rise to all blood cells, including granulocytes.
  • Next Step: Differentiate into a common myeloid progenitor (CMP).
  1. Common Myeloid Progenitor (CMP)
  • Characteristics: CMPs give rise to all myeloid lineage cells, including erythrocytes, monocytes, and granulocytes.
  • Next Step: Commits to the granulocyte-macrophage lineage, becoming a granulocyte-macrophage progenitor (GMP).
  1. Granulocyte-Macrophage Progenitor (GMP)
  • Characteristics: GMPs have the potential to differentiate into either granulocytes or monocytes. Under specific cytokine signalling, they become granulocyte progenitors.
  • Next Step: The GMP further differentiates into myeloblasts, the first recognizable precursors in granulopoiesis.
  1. Myeloblast
  • Size: Large cells with a large nucleus, fine chromatin, and multiple nucleoli.
  • Cytoplasm: Basophilic with no granules.
  • Function: Myeloblasts are the first morphologically identifiable cells in granulopoiesis. They undergo multiple rounds of cell division.
  • Next Step: Mature into a promyelocyte.
  1. Promyelocyte
  • Size: Larger than myeloblasts, with a prominent, round nucleus and the appearance of primary (azurophilic) granules in the cytoplasm.
  • Function: Promyelocytes synthesize granules that will eventually contain the enzymes and substances necessary for granulocyte function.
  • Next Step: Mature into a myelocyte.
  1. Myelocyte
  • Characteristics: Myelocytes are smaller than promyelocytes and have a round to oval nucleus that begins to condense. Based on the granules produced, they can now be recognized as neutrophilic, eosinophilic, or basophilic myelocytes.
  • Granules: Secondary (specific) granules appear, which define the type of granulocyte:
    • Neutrophilic myelocytes: Produce neutral-staining granules.
    • Eosinophilic myelocytes: Produce large, eosinophilic granules.
    • Basophilic myelocytes: Produce basophilic granules.
  • Next Step: Mature into a metamyelocyte.
  1. Metamyelocyte
  • Size: Slightly smaller than myelocytes with a kidney-shaped nucleus.
  • Function: Metamyelocytes are the last stage where the cell is still dividing. Granulocytes become more functionally specialized at this stage based on their granule content.
  • Next Step: Mature into a band cell (stab cell).
  1. Band Cell (Stab Cell)
  • Characteristics: The nucleus is now curved or band-shaped, and the cell is close to its final differentiation into a fully mature granulocyte.
  • Clinical Relevance: Band cells are immature neutrophils, and their presence in peripheral blood often indicates an ongoing infection or inflammation.
  • Next Step: Mature into a fully functional granulocyte.
  1. Mature Granulocyte
  • Characteristics: Fully developed granulocytes with a lobulated nucleus and specific granules that define their function.
    • Neutrophils: Multi-lobed nucleus, granules stain neutral, involved in phagocytosis and killing of bacteria.
    • Eosinophils: Bi-lobed nucleus granules stain red with eosin, involved in allergic reactions and defence against parasitic infections.
    • Basophils: Bi-lobed nucleus, granules stain dark purple with basic dyes, involved in hypersensitivity and inflammatory reactions.
  • Function: Granulocytes are released into the bloodstream and tissue, where they perform immune functions, particularly in response to infection and inflammation.

4.  Monocytopoiesis

Monocytopoiesis produces monocytes, a type of white blood cell (leukocyte), from hematopoietic stem cells in the bone marrow. Monocytes are part of the body’s innate immune system, and their primary function is to become macrophages and dendritic cells in tissues, where they help with phagocytosis, antigen presentation, and immune regulation.

Stages of Monocytopoiesis

Monocytopoiesis follows a well-defined sequence of cell differentiation from hematopoietic stem cells to mature monocytes:

  1. Hematopoietic Stem Cell (HSC)
  • Location: Bone marrow.
  • Function: Multipotent stem cells that give rise to all blood cells, including monocytes.
  • Next Step: Differentiate into a common myeloid progenitor (CMP).
  1. Common Myeloid Progenitor (CMP)
  • Characteristics: Gives rise to various myeloid lineages, including granulocytes, erythrocytes, and monocytes.
  • Next Step: Differentiate into a granulocyte-monocyte progenitor (GMP).
  1. Granulocyte-Monocyte Progenitor (GMP)
  • Characteristics: This progenitor has the potential to differentiate into both granulocytes and monocytes.
  • Next Step: Differentiates into a monoblast, the first committed precursor in the monocytic lineage.
  1. Monoblast
  • Characteristics: Large cells with a large nucleus and a basophilic cytoplasm, similar in appearance to myeloblasts, but committed to becoming monocytes.
  • Next Step: Mature into a promonocyte.
  1. Promonocyte
  • Characteristics: Promonocytes are slightly smaller than monoblasts, with an indented or kidney-shaped nucleus and cytoplasm that contains some granules. They undergo several rounds of division and maturation.
  • Next Step: Mature into a monocyte.
  1. Monocyte
  • Characteristics: Monocytes are large, mononuclear cells with a kidney-shaped or U-shaped nucleus and abundant cytoplasm. They circulate in the bloodstream for 1-3 days before migrating into tissues.
  • Next Step: Upon entering tissues, monocytes differentiate into macrophages or dendritic cells, key players in the immune response.

Clinical Significance of Hematopoiesis

Disorders in hematopoiesis can lead to a variety of medical conditions:

  • Anaemia: A deficiency in red blood cell production or haemoglobin.
  • Leukaemia: Uncontrolled proliferation of abnormal white blood cells.
  • Thrombocytopenia: A reduced number of platelets, leading to bleeding disorders.
  • Aplastic Anemia: Bone marrow fails to produce sufficient blood cells.
  • Myelodysplastic Syndrome (MDS): Ineffective hematopoiesis leading to defective blood cells.

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