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CLINICAL HEMATOLOGY

ENRICO E. TUY, MD, FPCP, FPSHBT

COURSE OBJECTIVES
To acquire knowledge in the basic principles underlying normal and abnormal hematologic phenomena. To understand blood disorders in the context of the structural and functional features of the hematopoietic-lymphoid system. To apply principles of basic sciences (biochemistry, immunology, molecular biology and genetics) in understanding blood disorders

References
Hematology in Clinical Practice; Hillman RS et al(Paperback) McGraw-Hill Professional; 4th edition (June 1, 2005)

Essential Haematology; Hoffbrand V et al, Wiley-Blackwell; 6th edition (2011) Harrisons Textbook of Internal Medicine; Fauci et al (eds); McGraw Hill, 18th edition, 2012 Haematology An Illustrated Colour Text; Howard MR, Hamilton PJ, 3rd Ed (2008) Churchchill Livingstone Elsevier

INTRODUCTION
THE BLOOD

Composition of the Blood


Cellular element
Red blood cells White blood cells
Granulocytes
Neutrophils Eosinophils Basophils

Monocytes Lymphocytes

Platelets

Fluid elements

RBCs

NEUTROPHILS

BASOPHILS and EOSINOPHILS

MONOCYTES

MONOCYTES

LYMPHOCYTES

PLATELETS

Composition of the Blood


Fluid elements
Water Electrolytes Proteins
Albumin Immunoglobulins and complements Transport proteins
Transferrin Transcobalamin Haptoglobin

Serum electrophoresis

HEMATOPOIESIS
Origin and Development of Blood Cells

Hematopoiesis
Refers to the process of formation, development, and differentiation of the formed elements. The process originates from the hematopoietic stem cells (HSCs)

Hematopoietic Stem Cells (HSCs)


Essential Attributes
Self-renewal Mutilineage differentiation Reconstitution of hematopoietic system of a lethally irradiated host HSCs are rare, occurring at a frequency of 1 stem cell per 10,000 to 100,000 bone marrow (BM) cells. Under steady state, HSCs are quiescent (noncycling) and only a fraction enter into the cell cycle. Deregulation of hematopoiesis may lead to malignancies or bone marrow failure syndromes

Stem and Progenitor Cells


Characteristic Proliferative potential Renewal Differentiated characteristi Functional characteristics Stem Cell Tremendous On a population basis Minimal-lineage negative Progenitor Cell More limited Probably none Restricted Progressively increases Potential for differentiation All lineages

Rapid directed motility and Less defined expression of proteopodia; homing Dormant Large number of cytokines needed Cycling Restricted

Cycle status Cytokine responsiveness

Cell of origin
Rhodamine and Hoechst dyes stain Adheres to marrow stroma

Unknown
Stains dimly Yes

Stem cell
Bright No or limited

HEMATOPOIETIC STEM CELLS

Site of Hematopoiesis

Figure 20-03
Copyright 2005 Elsevier Inc. (USA) All rights reserved.

Marrow Structure

Bone Marrow Microenvironment

Marrow Microenvironment

Marrow Microenvironment

Role of Marrow Microenvironment in Hematopoiesis


Provide a source of growth factors Important in the trafficking of immature HSCs into and out of the marrow and the blood. (Homing and Mobilization)

The Hematopoietic Hierarchy

Figure 17-01
Copyright 2005 Elsevier Inc. (USA) All rights reserved.

Characterization of HSCs
Surface markers Dye exclusion In vitro culture Enumeration of HSCs by transplantation models

Sources of HSCs
Bone marrow The peripheral circulation after mobilization by chemotherapy and cytokines (mPB), Umbilical cord blood

Hematopoiesis

Operational Components of Hematopoiesis


Anatomical structure of the marrow The stroma or marrow microenvironment Hematopoietic stem cells

HEMATOPOIETIC STEM AND PROGENITOR CELLS


Characteristic
Proliferative potential Renewal

Stem Cell
Large Yes

Progenitor Cell
More limited Probably none

Potential for differentiation


Differentiated characteristics Cycle status

All lymphohematopoietic lineages


Minimal-lineage negative Dormant

Restricted
Progressively increases to lineage specific cell Cycling

Cytokine responsiveness

Large number of cytokines needed for expression of phenotype


Unknown Yes

Restricted

Cell of origin Adheres to marrow stroma

Stem cell Limited to none

The Humoral Regulation of Hematopoiesis


Cytokines

Characteristics of Cytokines
Are glycoproteins Act on cell surface receptors Initiate complex second messenger and posttranslational regulation May act on stem cells, progenitor cells, and differentiated cells of the same lineage May act on multiple different lineages Stimulate or inhibit proliferation, apoptosis, differentiation, or function Usually act on neoplastic counterpart of normal target cell

Varying Tissue Origin of Cytokines


No Caption Found

Metcalf, D. Blood 2008;111:485-491

Copyright 2008 American Society of Hematology. Copyright restrictions may apply.

Metcalf, D. Blood 2008;111:485-491

Copyright 2008 American Society of Hematology. Copyright restrictions may apply.

Metcalf, D. Blood 2008;111:485-491

Copyright 2008 American Society of Hematology. Copyright restrictions may apply.

No Caption Found

Metcalf, D. Blood 2008;111:485-491

Copyright 2008 American Society of Hematology. Copyright restrictions may apply.

Cytokines with Hematopoietic Activities

Colony-stimulating factors
Granulocyte colony-stimulating factor (G-CSF) Granulocyte-macrophage colony-stimulating factor (GM-CSF) Macrophage colony-stimulating factor (M-CSF) Interleukin-3 (IL-3) Erythropoietin (EPO) Thrombopoieitin (TPO) Interleukin-5 (IL-5)

Figure 19-01
Copyright 2005 Elsevier Inc. (USA) All rights reserved.

HEMATOPOIETIC PROGENITORS ASSAYED IN VITRO

Cell Type
CFU-GEMM CFU-GM CFU-M CFU-G CFU-EOS BFU-E CFU-E BFU-meg CFU-meg

Lineage
Neutrophil, erythroid, macrophage, T cell, megakaryoctes Neutrophil, monocytes-macrophages Monocyte-macrophage Neutrophil Eosinophil Erythroid Erythroid Megakaryocytes Megakaryoctes

Primary Cytokines
IL-3,GM-CSF, EPO GM-CSF M-CSF (CSF-1) G-CSF IL-5, IL-3, GM-CSF IL-3, KIT Ligand, GM-CSF, IL-4, EPO EPO IL-3, GM-CSF,c-mpl ligand IL-3, GM-CSF, c-mpl ligand, IL-11, IL-6, LIF, G-CSF, KIT ligand, IL-4 IL-3, KIT ligand, GM-CSF

CFU-baso

Mast cell, basophil

Table 19-01
Copyright 2005 Elsevier Inc. (USA) All rights reserved.

Table 19-02
Copyright 2005 Elsevier Inc. (USA) All rights reserved.

The Bone Marrow


The Hematopoietic Microenvironment

Cellular Components of the Marrow Microenvironment

Metcalf, D Hematopoietic cytokines Blood, 15 January 2008, Vol. 111, No. 2, pp. 485-491.

THROUGHOUT THE CENTURIES THERE WERE MEN (WOMEN) WHO TOOK FIRST STEPS DOWN NEW ROADS ARMED WITH NOTHING BUT THEIR OWN VISION
AYN RAND THE FOUNTAINHEAD

HEMATOPOIESIS II

Erythropoiesis (Progenitor Compartment)

Erythropoiesis (Precursor Compartment

Granulocytopoiesis

Granulocyte Maturation

Thrombocytopoiesis

CLINICAL HEMATOLOGY
ENRICO E. TUY, MD, FPCP
Diplomate Philippine Society of Hematology & Blood Transfusion

COURSE OBJECTIVES
To acquire knowledge in the basic principles underlying normal and abnormal hematologic phenomena. To understand blood disorders in the context of the structural and functional features of the hematopoietic-lymphoid system. To apply principles of basic sciences (biochemistry, immunology, molecular biology and genetics) in understanding blood disorders

References
Hematology in Clinical Practice; Hillman RS et al(Paperback) McGraw-Hill Professional; 4th edition (June 1, 2005)

Essential Haematology; Hoffbrand V et al, Wiley-Blackwell; 5th edition (October 30, 2006) Harrisons Textbook of Internal Medicine; Fauci et al (eds); McGraw Hill, 17th edition, 2008 Haematology An Illustrated Colour Text; Howard MR, Hamilton PJ, 3rd Ed (2008) Churchchill Livingstone Elsevier

INTRODUCTION
THE BLOOD

Composition of the Blood


Cellular element
Red blood cells White blood cells
Granulocytes
Neutrophils Eosinophils Basophils

Monocytes Lymphocytes

Platelets

Fluid elements

RBCs

NEUTROPHILS

LYMPHOCYTES

MONOCYTES

MONOCYTES

BASOPHILS and EOSINOPHILS

PLATELETS

Composition of the Blood


Fluid elements
Water Electrolytes Proteins
Albumin Immunoglobulins and complements Transport proteins
Transferrin Transcobalamin Haptoglobin

Serum electrophoresis

HEMATOPOIESIS
Origin and Development of Blood Cells

Hematopoiesis Refers to the process of formation, development, and differentiation of the formed elements of blood.

Hematopoietic Stem Cells (HSCs)


Essential Attributes
Self-renewal Multilineage differentiation Reconstitution of hematopoietic system of a lethally irradiated host

HSCs are rare, occurring at a frequency of 1 stem cell per 10,000 to 100,000 bone marrow (BM) cells HCSs are quiescent (ie, noncycling), and only a fraction enter into the cell cycle to proliferate and differentiate

Embryology
Hematopoietic cells originates from mesodermal tissue migrates to the extraembryonic yolk sac primitive hematopoiesis composed of erythroid cells and endothelial cells --- common precursor hemangioblasts Definitive hematopoiesis ---- aortic-gonadmesonephros (AGM) ---- fetal liver and spleen ---- bone marrow

HEMATOPOIETIC STEM CELLS

Derivation and Fate of HSCs

Models of HSC self-renewal and differentiation

Hierarchical organization of hematopoiesis

Stem and Progenitor Cells


Characteristic Proliferative potential Renewal Differentiated characteristi Functional characteristics Stem Cell Tremendous On a population basis Minimal-lineage negative Progenitor Cell More limited Probably none Restricted Progressively increases Potential for differentiation All lineages

Rapid directed motility and Less defined expression of proteopodia; homing Dormant Large number of cytokines needed Cycling Restricted

Cycle status Cytokine responsiveness

Cell o f origin
Rhodamine and Hoechst dyes stain Adheres to marrow stroma

Unknown
Stains dimly Yes

Stem cell
Bright No or limited

Site of Hematopoiesis

Figure 20-03
Copyright 2005 Elsevier Inc. (USA) All rights reserved.

Marrow Structure

Bone Marrow Microenvironment

Marrow Microenvironment

Role of Marrow Microenvironment in Hematopoiesis


Provide a source of growth factors Important in the trafficking of immature HSCs into and out of the marrow and the blood. (Homing and Mobilization)

The Hematopoietic Hierarchy

Figure 17-01
Copyright 2005 Elsevier Inc. (USA) All rights reserved.

Characterization of HSCs
Surface markers Dye exclusion In vitro culture Enumeration of HSCs by transplantation models

Sources of HSCs
Bone marrow The peripheral circulation after mobilization by chemotherapy and cytokines (mPB), Umbilical cord blood

Hematopoiesis

Operational Components of Hematopoiesis


Anatomical structure of the marrow The stroma or marrow microenvironment Hematopoietic stem cells

HEMATOPOIETIC STEM AND PROGENITOR CELLS


Characteristic
Proliferative potential Renewal

Stem Cell
Large Yes

Progenitor Cell
More limited Probably none

Potential for differentiation


Differentiated characteristics Cycle status

All lymphohematopoietic lineages


Minimal-lineage negative Dormant

Restricted
Progressively increases to lineage specific cell Cycling

Cytokine responsiveness

Large number of cytokines needed for expression of phenotype


Unknown Yes

Restricted

Cell of origin Adheres to marrow stroma

Stem cell Limited to none

The Humoral Regulation of Hematopoiesis


Cytokines

Characteristics of Cytokines
Are glycoproteins Act on cell surface receptors Initiate complex second messenger and posttranslational regulation May act on stem cells, progenitor cells, and differentiated cells of the same lineage May act on multiple different lineages Stimulate or inhibit proliferation, apoptosis, differentiation, or function Usually act on neoplastic counterpart of normal target cell

Varying Tissue Origin of Cytokines


No Caption Found

Metcalf, D. Blood 2008;111:485-491

Copyright 2008 American Society of Hematology. Copyright restrictions may apply.

Metcalf, D. Blood 2008;111:485-491

Copyright 2008 American Society of Hematology. Copyright restrictions may apply.

Metcalf, D. Blood 2008;111:485-491

Copyright 2008 American Society of Hematology. Copyright restrictions may apply.

No Caption Found

Metcalf, D. Blood 2008;111:485-491

Copyright 2008 American Society of Hematology. Copyright restrictions may apply.

Cytokines with Hematopoietic Activities

Colony-stimulating factors
Granulocyte colony-stimulating factor (G-CSF) Granulocyte-macrophage colony-stimulating factor (GM-CSF) Macrophage colony-stimulating factor (M-CSF) Interleukin-3 (IL-3) Erythropoietin (EPO) Thrombopoieitin (TPO) Interleukin-5 (IL-5)

Figure 19-01
Copyright 2005 Elsevier Inc. (USA) All rights reserved.

HEMATOPOIETIC PROGENITORS ASSAYED IN VITRO

Cell Type
CFU-GEMM CFU-GM CFU-M CFU-G CFU-EOS BFU-E CFU-E BFU-meg CFU-meg

Lineage
Neutrophil, erythroid, macrophage, T cell, megakaryoctes Neutrophil, monocytes-macrophages Monocyte-macrophage Neutrophil Eosinophil Erythroid Erythroid Megakaryocytes Megakaryoctes

Primary Cytokines
IL-3,GM-CSF, EPO GM-CSF M-CSF (CSF-1) G-CSF IL-5, IL-3, GM-CSF IL-3, KIT Ligand, GM-CSF, IL-4, EPO EPO IL-3, GM-CSF,c-mpl ligand IL-3, GM-CSF, c-mpl ligand, IL-11, IL-6, LIF, G-CSF, KIT ligand, IL-4 IL-3, KIT ligand, GM-CSF

CFU-baso

Mast cell, basophil

Table 19-01
Copyright 2005 Elsevier Inc. (USA) All rights reserved.

Table 19-02
Copyright 2005 Elsevier Inc. (USA) All rights reserved.

The Bone Marrow


The Hematopoietic Microenvironment

Cellular Components of the Marrow Microenvironment

THROUGHOUT THE CENTURIES THERE WERE MEN (WOMEN) WHO TOOK FIRST STEPS DOWN NEW ROADS ARMED WITH NOTHING BUT THEIR OWN VISION
AYN RAND THE FOUNTAINHEAD

HEMATOPOIESIS
Part 2

Erythropoiesis

Erythron

Granulocytopoiesis