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Hematology Introduction

Organization of blood and blood


forming organs
What is hematology?
• Hematology is the study of blood which is composed
of plasma (~55%), and the formed elements which
are:
– The erythrocytes (RBCs) (~45%)
• Contain hemoglobin
• Function in the transport of O2 and CO2
– The Leukocytes (WBCs) and platlets (thrombocytes)
(~1%)
• Leukocytes are involved in the body’s defense against the invasion
of foreign antigens.
• Platlets are involved in hemostasis which forms a barrier to limit
blood loss at an injured site.
What is hematology?
• Hematology is primarily a study of the formed
cellular elements.
• Alterations in the formed elements in the blood are
usually a result of disease rather than being the
primary cause of disease.
– In fact, variations in the formed elements in the blood are
often the first sign that disease is occurring in the body.
– The changes caused by disease may be detected by lab tests
that measure deviations of the blood constituents from the
normal values. These lab test may include:
What is hematology?
• RBC count
• WBC count
• Platlet count
• Hematocrit (packed cell volume)
• Mean corpuscular volume (MCV)
• Mean corpuscular hemoglobin concentration (MCHC)
• Under normal conditions the production, release, and
survival of blood cells is a highly regulated process.
Quantitative and/or qualitative hematologic
abnormalities may result when there is an imbalance
between cell production, release, and/or survival.
What is hematology?
– Age, sex, and geographic location are involved
in physiologic changes in normal values of the
formed cellular elements
– Pathologic changes in the values of the formed
cellular elements occur with disease or injury.
– Normal values for a group are determined by
calculating the mean for healthy individuals of
the group and reporting the normal range as the
mean +/- 2 standard deviations
What is hematology?
• Hematopoiesis is a term describing the formation and
development of blood cells.
– Cells of the blood are constantly being lost or destroyed. Thus, to
maintain homeostasis, the system must have the capacity for self
renewal. This system involves:
• Proliferation of progeny stem cells
• Differentiation and maturation of the stem cells into the functional cellular
elements.
• In normal adults, the proliferation, differentiation, and maturation of the
hematopoietic cells (RBCs, WBCs, and platlets) is limited to the bone marrow
and the widespread lymphatic system and only mature cells are released into the
peripheral blood.
Marrow-derived
Blood cells

• Neutrophils: inflammation, anti-bacterial


• Monocytes: inflammation, anti-fungal
• Eosinophils: anti-parasitic, hypersensitivity
• Basophils: IgE-mediated hypersensitivity
• Erythrocytes: hemoglobin
• Platelets: coagulation
Blood cell replacement
• Neutrophils: ~ 10 hours
• Platelets: ~10 days
• Erythrocytes: ~ 110 days in circulation

• Marrow replaces 1011 blood cells/day


during health
• Increase replacement rate when
needed
Marrow status during changes
in blood cell numbers?

• RBCs: polycythemia, anemia

• Neutrophils: neutrophilia, neutropenia

• PLTs: thrombocytosis, thrombocytopenia

• Leukemias
Embryonic-fetal-adult
sites of hematopoiesis
• Yolk sac
• Mesonephros
• Liver*
• Spleen*
• Marrow

*EMH sites in adult


Hematopoiesis in adults
• Restricted to marrow of axial skeleton and epiphyses of long
bone (mammals)

• Inactive sites fill with adipocytes that reserve this space in


event of increased hematopoiesis

• Additional sites if needed (EMH): spleen, liver


Marrow collection
sites

• Iliac crest
• Long bones
• Ribs
• Sternum
Sinusoidal marrow structure
Extravascular site of hematopoiesis, BMB
Blood cell exit
from marrow

• Retraction of reticular cell processes and transendothelial


migration to blood
• Loss of receptors to adhesion proteins
– Fibronectin: erythrocytes
– Hemonectin: neutrophils
• Close proximity to sinus lumen (megakaryocyte, RBC)
“Inappropriate”
release of
precursors (NRBCs)
into blood

• Marrow damage (e.g. Pb, hypoxia)


• Altered marrow structure by infiltrative
lesion (myelophthisis): fibrosis, neoplasm
• Proliferation of abnormal precursors
(hematopoietic neoplasm = leukemia)
Hematopoiesis & Growth Factors
Regulation of Hematopoiesis (cont.)
Apoptosis : programmed cell death
Necrosis : forced cell death
Erythropoietin

• Site of synthesis: Renal peritubular cells


• Stimulus: Decreased arterial O2 up-
regulates EPO gene expression.
• Action: Prevents apoptosis (promotes
survival) of erythroid precursors
• Paraneoplastic? Renal disease?
Erythropoiesis
• Nuclear condensation, then loss
• Decreasing cell and nuclear size
• Loss of mitotic activity
• Cytoplasm less basophilic, more
eosinophilic
Reticulocytes
(NMB stain)

• Stage after loss of nucleus


• Final Hb synthesis from ribosomes
• Released into blood and undergo maturation in
spleen (except horses!)
• Clinical application
Erythrocyte Maturation

100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
80 60 40 20 0
Maturation (nuclear area)
Hgb
RNA
Colony stimulating
factors
(GM-CSF, G-CSF)

• Inflammatory cytokine
• Inhibits apoptosis
• Enhance function of
mature cells
Granulopoiesis
• Nuclear shape change
• Nuclear condensation w/o pyknosis
• Cytoplasm: loss of basophilia, appearance then
loss of granules
• Loss of mitotic activity
Maturation
pool*

Proliferation
pool

*Storage pool = segmenters within maturation pool


Monocytopoiesis

monoblast promonocyte monocyte

• Short marrow transit time of monocytes


(~3 days)
• No storage pool in marrow
• Marker of marrow recovery
Monocytes become
tissue macrophages
• Pulmonary macrophages
• Intestinal macrophages
• Langerhans cells (skin)
• Osteoclasts (bone)
• Kupffer cells (liver)
• Microglial cells (CNS)
• Peritoneal, splenic, lymph node, etc.
macrophages
Thrombopoiesis

• Megakaryocytes: nuclear replication


(endomitosis) without cell division.
Favors larger cytoplasmic volume?
• Cytoplasmic fragmentation producing
large “proplatelets”
• Proplatelets fragment into platelets
Thrombopoietin
• Site of synthesis: Liver

• Produced at constant rate and binds to


platelets and megakaryocytes.

• Increased “free” TPO occurs with fewer


platelets, stimulating megakaryocyte
proliferation.
Stages of Lymphopoiesis
• Hematopoietic stem cells (HPSCs): All the blood cell
lineages.
• No CD3 on T cells.
• No CD19 on B cells.
• CD34+
• Embryos : Liver and the bone marrow.
• Growth factors CSFs induces differentiation.
• HSCs→ progenitor cell → Mature cells.
Lymphoid cells development
• Occurs in the thymus gland.
• Lymphoid progenitor, IL-7, Thymocyte, mature T
cell.
• Lymphoid progenitor, Pre-B cell, B cell.
• NK cells.
• SCID→IL-2, IL-7 and IL-7 receptors are missing.
• Stem Cell Transplantation.
• Gene therapy.
Lymphoid cell types
• B cells: Ab production, BCR, MHC II,
CD19, APC, Plasma cell.
• T cells: Same morphology, CD4+, CD8+,
TCR, viruses and other intracellular
infections.
• NK cells: Same morphology, No Ag
receptor, innate, lyse virally infected cells
and tumor cells.
Blood cell kinetics
An example: Regulation of Hematopoiesis

Hematopoietic
Stem Cells
Engagement (HSCs) Totipotency
Self-renewal

Myeloïde Bone Marrow


progenitor Lymphoid
progenitor

BFU-E BFU-Meg CFU-Eo CFU-Baso CFU-GM


Thymocyte

Multiplication and Differentiation


Monocytes LT4 LT8
LB
Erythrocytes Plaquettes Eosinophiles Basophiles Neutrophiles Macrophages
Regulation of Hematopoiesis