[HEMATOLOGY] CHAPTER 7: HEMATOPOIESIS

▪ Primary site of hematopoiesis from the 6th week until 1st or 2nd
week after birth
BLOOD
o Hematopoiesis occurs in the aorta-gonad-mesonephrons (AGM)
• Physical Characteristics o Other sites of hematopoiesis
o pH:7.4 ▪ Spleen: B cell production
o 3-4 times thicker than water ▪ Kidney: B cell production
o Makes up 7.8% (75-85mL/kg) of the total body component ▪ Thymus: first fully developed organ; T cell production
o ̴ 6-5 liters ▪ Lymph nodes
o ̴ 20 g of solid/100 mL of blood o Hb F: predominant hemoglobin
• Composition o Hb A also detected
o Liquid portion
▪ Plasma – with fibrinogen • Myeloid (Medullary) Period
▪ Serum – no fibrinogen, factor II, V, VIII o Bone and Bone marrow
o Solid portion o Start at 5th month of gestation
▪ RBC o Bone Marrow
▪ WBC ▪ Chief site of normal hematopoiesis at 24th week
▪ Platelets ▪ Highly specialized tissue comprising a range of cells
• Hematopoietic cells
HEMATOPOIESIS • Stromal cells (e.g., endothelial cells and reticular adventitial
cells); support the developing cells
• Mesoblastic Period (intravascular)
• Osteoblasts and osteoclasts
o Begins during embryonic development
o Adult Hb is produced with 2α and 2β global chains
o Start: 19-20 days
o In children
o End: 8-12th week of gestation
▪ Flat bones of the skull
o Fetus: 2.25 – 5mm in size
▪ Clavicle
o Yolk Sac
▪ Sternum
▪ Ovoid structure joined to the embryo by a stalk
▪ Ribs
▪ Chief site of hematopoiesis
▪ Vertebrae
▪ Contains haemangioblasts (mesoderm derived cells) which
▪ Pelvis
differentiates to form nucleated RBCs and endothelial cells which
▪ Long bones (arms and legs)
generate capillary system (plexus) within the yolk sac
o > 18 years old (confined to flat bones only)
▪ Capillary plexus is joined by the aorta and circulation occurs
▪ Red bone marrow
▪ Disappears in the hepatic period
▪ Remaining marrow is replaced by fat cells (yellow marrow)
• Hepatic Period (extravascular)
o Responsible for erythropoiesis
o Minimal leukopoiesis and megakaryopoiesis ADULT HEMATOPOIETIC TISSUE
o Start: 5-6th week of gestation (5-7th week: book)
• Located in the BM, lymphoid tissue, spleen, liver, thymus
o Primitive erythrocyte formed 3rd month of gestation
• Primary lymphoid tissue: BM, thymus
o Definitive normoblasts replaced PE when dies out
• Secondary lymphoid tissue: Spleen, lymph nodes
o Liver
[HEMATOLOGY] CHAPTER 7: HEMATOPOIESIS

Bone Marrow • Other functions

o Protein synthesis and degradation
• Located within cavities of cortical bones o Coagulation factor synthesis
• Red marrow o Carbohydrate and lipid metabolism
o Haematopoietically active o Drug and toxin clearance
o Consist of developing blood cells and their progenitors o Iron recycling and storage
• Yellow marrow o Hemoglobin degradation
o Haematopoietically inactive o Bilirubin conjugation
o Composed of adipocytes (fat cells), undifferentiated mesenchymal cells • Kupffer cells
and macrophages o Located in the lumen of the sinusoids
• 5-7 years of age: adipocytes become abundant o Macrophages that remove senescent cells and foreign debris from the
• Retrogression blood
o Red marrow to yellow marrow • Porphyrias
• Sites with active marrow in adults o hereditary or acquired defects in the enzymes involved in heme
o Sternum, vertebrae, scapulae, pelvis, ribs, skull, and proximal portion of biosynthesis resulting to accumulation of porphyrins which can cause
long bones damage to hepatocytes, erythrocyte precursors, and other tissues
Red Marrow Spleen
• Composed of hematopoietic cells and macrophages arranged in extravascular • Largest lymphoid organ
cords • White pulp, Red pulp and Marginal zone (contain blood vessels, macrophages,
Marrow Circulation memory B cells, and CD4+ T cells
• Culling – phagocytosed with subsq degradation of cell organelles
• Nutrient artery (supplies blood only to the marrow)--- central longitudinal vein • Pitting – splenic macrophages remove inclusions
(passes along the bone canal)--- (artery divides into ascending and descending • 30% of platelets are sequestered in the spleen
arteriole)--- inner lining of cortical bone (endosteum)--- sinusoid (endosteal • Splenomegaly - spleen becomes enlarged and palpable
bed)--- periosteal capillaries--- periosteal arteries--- osseous bone • Hypersplenism -enlargement of spleen resulting in some degree of
• Periosteal arteries (supplies nutrients for the osseous bone and the marrow)--- pancytopenia despite the presence of a hyperactive bone marrow
venous sinuses in endosteal bed---central longitudinal vein--- foramina
Lymph Nodes
Hematopoietic Microenvironment
• Bean Shaped Structure
• Semifluid matrix • Cortex – B Cell Proliferation (germinal centers)
• Stromal cells • Paracortex – T Cells and Macrophages
• ECM • Medulla – B Cells and Plasma Cells
o Proteoglycans for progenitor binding • Adenitis – infection of the lymph node
o Fibronectin, laminin, collagen, hemonectin, thrombospondin for
adhesion of HSCs to the ECM Thymus

Liver • Cortex
o Waiting zone for progenitor T cells
• Major site of blood cell production during the second trimester of fetal
development
[HEMATOLOGY] CHAPTER 7: HEMATOPOIESIS

o Characterized by a blood supply system that is unique in that it consists

only of capillaries
• Medulla
o Contains 15% mature T cells and
o Holds the mature T cells until they are needed by the peripheral
lymphoid tissues.

HEMATOPOIETIC STEM CELLS AND CYTOKINES

Hematopoietic Stem Cells

• Reside in the medulla of the bone (bone marrow)

• Parental cell type for all blood cells and probably also endothelium
• Self-renewing
• Other daughters of HSCs (myeloid and lymphoid progenitor cells) cannot self-
renew
• Three possible fates of HSCs
o Self-renewal
o Differentiation
o apoptosis
• Stochastic model – HSC randomly commits to self-renewal and differentiation
• Instructive model – the microenvironment in the BM determines the fate of HSC
• Division of HSCs
o Symmetric – CLP and CMP
o Asymmetric – CLP or CMP
• Rare (<0.1%) cell present in BM expressing the antigen CD34+
• HSC niche
o Endosteum (Endosteal niche) – contains long-term, slowly dividing HSCs
which maintain the vascular niche HSCs
o Perivascular region around vascular sinusoids (vascular niche) – more
actively dividing and progenitor cells are produces

• Totipotential – develops into a whole organism; placenta and amniotic sac

• Pluripotential – can’t produce placenta and amniotic sac
• Multipotent – produces all cell types in one organ system
• Oligopotent – lymphoid tissues
• Uni/Monopotent – one cell type
[HEMATOLOGY] CHAPTER 7: HEMATOPOIESIS

PRINCIPLES OF NORMAL CELL MATURATION

• Cytoplasmic Differentiation
o Loss of basophilia
o Cytoplasmic granules
o Elaboration of hemoglobin for RBC
• Nuclear Maturation
o Structure and cytochemistry
▪ Round or oval nucleus – younger cells
▪ Large nucleus/cytoplasmic ration – younger cells
o Changes in shape
▪ More lobulations mean mature cells
• Reduction in Cell Size
o The smaller the size, the mature the cell is

HOW CELLS ARE RELEASED FROM BM INTO THE CIRCULATION

• RBC – by hypoxia and erythropoietin

• WBC – by the presence of chemotaxins
• Platelets – by shedding of megakaryocytic cytoplasm

PROGENITOR CELL GROWTH AND DIFFERENTIATION

• Growth factors and cytokines are needed to drive both proliferation and
differentiation of cells
• Growth factors or cytokines act both in paracrine (they diffuse from the
producer cell to the responder cell) and in a juxtracrine fashion (they remain on
the cell surface of the producer cell and so the responder cell must be
juxtaposed-touching
• Infection increases the amount of growth factors – increased hematopoiesis
• Adhesion interaction especially via integrins are also important in hematopoiesis
(not only for growth and differentiation but also to prevent apoptosis)

ERYTHROCYTES AND PLATELETS

• Common pathway (MEP: megakaryocyte/erythrocyte precursor

ERYTHROPOIESIS
[HEMATOLOGY] CHAPTER 7: HEMATOPOIESIS

• Erythrocyte clearance
o Removed by the spleen and liver after 120 days
o As RBC ages, surface proteins particularly band 3 are progressively
oxidized – this provides a target for phagocytosis by macrophages lining
liver and spleen sinuses

THROMBOPOIESIS

• Stimulated by thrombopoietin (TPO) & other non-specific growth factors

• TPO produced constitutively mostly by liver
• Inflammation can double production by liver via cytokine IL-6
• In thrombocytopenia (reduced platelets) BM stromal cells also produce TPO
• Platelets have TPO receptors and so remove TPO from circulation (negative
feedback)

• Platelet clearance
o Removed by the spleen and liver after app. 7 days
LYMPHOPOIESIS
GRANULOCYTES AND MONOCYTES
• Two pathways:
• Granulocytes (N.E.B. and mast cells) and monocytes share the same pathway – o T cells
Granulocyte/monocyte precursor (GMP) o B cells and NK cells
• Formation of GMP from CMP is driven by granulocyte/monocyte colony • Both from CLP
stimulating factor (GM-CSF) • Initial stages in BM: B & NK cells complete maturation in BM, immature
• Most are relatively short-lived and are lost by apoptosis T cells migrate to thymus and mature there
o The fragments of the dead cells are phagocytosed by cells lining sinuses
• The process of lymphopoiesis is driven initially by the growth factor IL-7
of spleen and BM or in tissues, by epithelial cells
• Lymphocytes are long lived cells unless they are activated (by cognate
antigen).---- They then become immune effector cells (most will die after
a few days by apoptosis; some will become memory cells which are very
long lived (decades)).