Normal Hematopoiesis

Describe the steps of normal hematopoiesis, in fetus, new born, and adults

Hematopoiesis%20timeline.gif

Fetus

  • Yolk sac
    • islands of erythroid cells appear at day 18 (A)
    • Macrophages and megakaryocytes also form here
  • Aorta/gonad/mesonephros (AGM) region
    • provides lymphoid and non-lymphoid stem cells at early stages of hematopoiesis
  • Liver
    • Erythroid progenitors found ~5-6 weeks (B)
    • CFU-G (granulocyte) & CFU-GEMM (granulocyte, erythrocyte, megakaryocyte, and monocyte) found ~7+ weeks
    • Site for meyloid and lympoid lineages production
  • Thymic gland
    • develops ~6th week (C)
    • lymphoid cells migrate within 2-3 weeks to there
  • Spleen
    • Progenitor cells populate ~4 months (E)
  • Liver and spleen centres of erythropoiesis until time of birth, then slowly ceases
  • Bone marrow
    • hematopoietic cells seen at 10-11 weeks (D)
    • because major site after 24th week (F)

New born

  • Bone marrow
    • Packed with hematopoietic cells for the first four years
    • fat content increase with age
    • myelopoisis only in the bone marrow
    • under some pathologic stress conditions, myelopoisis will reappear in liver and spleen (extramedullary hematopoiesis)

Adults

  • All derived from the bone marrow

List the normal sequences of maturation/differentiation of hematopoietic cells in the bone marrow; integrate your knowledge of maturation arrest with the development of myeloid leukemias

Myeloid stem cell differentiates into the following progenitors:

  • granulocytes (myeloid)
  • erythroid
  • monocytic
  • megakaryocytic

Growth factors required for maturation, activation, proliferation, and differentiation - mainly growth factors

General Poiesis steps

Pluripotential stem cell -> Committed myeloid stem cell (GEMM/E/B) or Committed Lymphoid stem cell -> Differentiated cell types
Blasts should NEVER be seen in the normal peripheral blood

Granulopoiesis

Pluripotential stem cell -> committed myeloid stem cell (progenitor stem cell G-CFU) -> Myeloblast -> Promyelocyte -> myelocyte -> Metamyelocyte -> band -> granulocyte

  • If mutation occurs, get acute myeloblastic leukemia
  • If mutation occurs, get chronic myeloblastic leukemia

Erythropoiesis

  • stem cell -> proerythroblast (pronormoblast) -> basophilic erythroblast -> polychromatic erythroblast -> orthochromatic erthroblast -> erythroblasts (nucleated RBCs) -> reticulocyte (first to be out of the marrow) -> erythrocyte

Thrombocpoisis & Monopoiesis

Steps not clear morphologically
Megakaryoblast -> prothrombocyte -> thrombocyte
Monoblast -> Promonocyte -> monocyte

Describe stromal structures of the bone marrow

Microvascular compartment

  • Composed of sinuses, veins, and arteries
  • sinus wall is endothelial cells, underdevelopment basement membrane, and interrupted layer of adventitial reticular cells
  • Endothelium and adventitial cells are sources of hematopoietic cytokins
  • Mature blood travels from the hematopoietic compartment, enter the sinuses, and travel to central veins and systemic circulation

Stromal cells

  • the BM stroma provides environment for stem cell renewal, maturation, differentiation, and survival
  • provides all growth factors except for EPO (kidney) and thrombopoietic (liver)
Reticular cells
* large branched, capable to differentiate into fibroblasts and smooth muscle
* Lie around the endothelial cells of the sinuses
* Regulation cell passage from hematopoietic to vascular compartment
Adipose tissue
likely develop from reticular cells, and express factors promoting hematopoiesis
Bone cells
Osteoblast (screte hematopoietic growth factors including monocyte-colony stimulating factor - M-CSF), and osteoclast
Hematopoietic cells
Consists of erythroid, myeloid, lymphoid, and megakaryocytic elements
mixed with stromal cells of fibroblasts and macrophages
number varies inversely with age (i.e. babies have a lot, seniors don't)

Extracellular matrix

  • proteoglycans, fibronectin, tenascin, collagen (types 1, 3, 4, and 6), laminin, hemonectin, vitronectin, thrombospondin (TPO)
  • Froms part of microinvironment surrounding maturing hematopoietic cells
  • Help maturation and differentiation of different hematopoietic cells
  • Provide attachment of hematopoietic cells and stromal cells

List factors affecting maturation, proliferation, and differentiation of all hematopoietic cell lines

  • stem cell factor (SCF; c-KIT ligand)
  • Colony Stimulating Factors (CSFs)
    • Monocyte CSFs (M-CSF)
    • Granulocyte CSFs (G-CSF)
    • Granulocyte/monocyte CSFs (G/M CSF)
  • Thrombopoietin (TPO)
  • Erythropoietin (EPO)
  • Flt3 ligand
  • Interleukins: IL (1, 3, 5, 6)
  • cytokines that may have a negative effect on hematyopoiesis: transforming growth factor beta, and gamma interferon (TGF-β and γ-interferon)

Explain why bone marrow samples are taken at specific sites; explain reasons for choosing one site

PSIS.jpg
the posterior superior iliac spine
  • Two techniques used: Trephine biopsy, and Aspiration
  • Usually uses the posterior superior iliac spine (PSIS)
  • Trephine Biopsy can be first taken, at the PSIS. Then fixed with formalin, and stained
  • Aspiration punctures ~1cm away from the trephine biopsy, but through the same incision
    • Can be done on the tibia (in infants <1yo) and sternum. However, sternum aspirations may pierce the heart, so will not be used unless the patient is morbidly obese and not highly agitated, or thrombocytopenics whose diagnosis can't be made without the bone marrow. Cannot do core biopsies on the sternum

Comparison between BM and Peripheral Blood Cells Under Normal Conditions

Bone Marrow Peripheral Blood
Megakaryocyte Yes No
Blasts and Promyelocytes Yes <3% No
Myelocytes and Metamyelocytes Yes No
Bands and segmented granulocytes Yes Yes
Erythroblasts and Nucleated RBCs Yes No

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