Transcript Hematopoiesis, immunity, hypoproliferative anemias

WHAT ARE THE COMPONENTS OF THE
BLOOD, AND WHERE ARE THEY MADE?
Plasma: proteins made mainly in liver
Serum is the fluid that remains after blood clots
Red cells, neutrophils and platelets made in bone
marrow
lymphocytes made in bone marrow, lymph nodes,
spleen
BONE MARROW
BONE MARROW
WHAT HAPPENS IN BONE MARROW?
1.
2.
3.
4.
5.
Neutrophils, red cells and megakaryocytes all
descended from common precursor cell called
myeloid stem cell
Stem cells differentiate into primitive cells called
blasts, which are precursors of each cell type
Blasts divide and mature under the influence of
proteins called growth factors; as they mature
they lose the ability to divide
Mature neutrophils and red cells enter the blood
Megakaryocytes break into small fragments
(platelets), which enter blood
What is a stem cell?
• A cell that can reproduce itself indefinitely
– Other cells eventually stop dividing and die
• A cell that can differentiate into one or more types of
functional mature cells
– Other cells are “locked in” to a certain differentiation
pathway
– For example, hematopoietic stem cells can differentiate into
red cells, neutrophils, megakaryocytes, or lymphocytes
• There are many types of stem cells
– Usually they exist in small numbers compared to other cell
types
• In theory a single hematopoietic stem cell could reconstitute an entire bone marrow
E
rbc
M
N
pmn
U
M
megakaryocyte
B
L
L
T
NK
lymphocytes
Stem cells
Blasts
Differentiation
Mature cells
E
rbc
M
N
pmn
U
M
megakaryocyte
B
L
L
T
NK
lymphocytes
Stem cells
Blasts
Differentiation
Mature cells
DIFFERENTIATION OF
NEUTROPHILS AND RED CELLS
A megakaryocyte releasing platelets
Platelets
Blood 2005;106:9
HEMATOPOIETIC GROWTH FACTORS
CONTROL PRODUCTION OF BLOOD CELLS
• Growth factors regulate the growth, differentiation and
function of cells of the hematopoietic and immune
systems
• Examples
– Erythropoietin: stimulates red cell production
– Thrombopoietin: stimulates platelet production
– G-CSF: stimulates granulocyte (neutrophil)
production, activates neutrophil function
• These can be manufactured and given to patients to
boost production of specific blood cells
NORMAL BLOOD COUNTS
White cells
(thousands)
Red cells
(millions)
Hemoglobin
(grams/dl)
Hematocrit (%)
Platelets
(thousands)
Men
Women
3.7-9.5
3.9-11.1
4.3-5.7
3.9-5.0
13-16.7
11.8-14.8
39-55
36-44
150,000 - 350,000
White cell, red cell and platelet numbers are per microliter of blood
HEMATOCRIT TUBES
normal
Anemia
polycythemia
Functions of blood
• transport oxygen, nutrients & waste products
• fight infection
• prevent bleeding
RED BLOOD CELLS (ERYTHROCYTES)
little bags of hemoglobin
top
side
function: carry 02 to tissues, CO2 to lungs
hematocrit: proportion of blood volume occupied
by red cells
Red blood cells
RBC in small blood vessel
Red cells must be very flexible
WHITE BLOOD CELLS (LEUKOCYTES)
Neutrophils
• eat bacteria
• produce inflammatory molecules
Lymphocytes
• make antibodies
• kill foreign or infected cells
• regulate immune system
Monocytes
• eat bacteria and other unwanted things
• regulate immune system
PLATELETS
Smallest formed elements in blood
Not really cells (no nuclei) but fragments of large
cells called megakaryocytes found mainly in
bone marrow
Function: help blood clot, prevent bleeding
CELLS OF THE IMMUNE SYSTEM




B lymphocytes and plasma cells
T lymphocytes
Natural killer (NK) lymphocytes
Monocytes and macrophages
MONOCYTES
LYMPHATIC TISSUE
LYMPH NODE
SPLEEN
THE LYMPHATIC SYSTEM
WHERE LYMPHOMAS COME FROM
or, why good lymphocytes go bad
 Lymphocytes must undergo extensive rearrangement of
their DNA to create a repertoire of cells capable of
responding to many different antigens
 Occasionally this rearrangement is not accomplished
properly and the cell gains a growth advantage over
its neighbors
 Lymphocytes (especially B-cells) must undergo
programmed cell death (apoptosis) when they are no
longer needed
 Occasionally this program is faulty and the cells
continue to divide indefinitely
ANEMIA
Definition: reduced total red cell mass
Hematocrit and hemoglobin concentration usually
low (exception: acute blood loss)
Causes:
1. blood loss
2. red cell destruction (hemolysis)
3. decreased red cell production
ANEMIA
 Macrocytic: big red cells
 Normocytic: normal size red cells
 Microcytic: small red cells
 Reticulocytes: newly made red cells; number in
blood proportional to rate of red cell production
VARIATION IN RED CELL SHAPE
IN ANEMIA
ANEMIA
Classified by cause
1.
2.
Decreased red cell production
a. Stem cell damage - neutrophils,
platelets often affected also
b. Defective red cell maturation
Increased red cell destruction (hemolysis)
a. Intrinsic defect in red cell leading to shortened
lifespan
b. External factors in blood or blood vessels destroy
red cells
3.
Blood loss
Stem cell damage
E
rbc
M
N
pmn
U
M
megakaryocyte
B
L
L
T
NK
lymphocytes
Stem cells
Blasts
Differentiation
Mature cells
Defective red cell maturation
E
rbc
M
N
pmn
U
M
megakaryocyte
B
L
L
T
NK
lymphocytes
Stem cells
Blasts
Differentiation
Mature cells
APLASTIC ANEMIA: a stem cell disorder
 Decreased numbers of pluripotent stem cells
• cytotoxic chemicals
• ionizing radiation
• virus infection
• "idiopathic" - probably autoimmune
 Marrow empty or hypocellular
 Anemia, neutropenia, thrombocytopenia
 Treatment:
• supportive (transfusions, antibiotics etc)
• immune suppression
• bone marrow/stem cell transplantation
APLASTIC ANEMIA
Bone marrow biopsy
Normal
Aplastic
ANEMIA SECONDARY TO OTHER DISEASES
“Anemia of chronic disease”
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Inflammation: infection, rheumatoid arthritis, etc
Kidney failure (kidneys make erythropoietin)
Cancer
Malnutrition
 All associated with decreased stimulus for red cell
production
 Nothing intrinsically wrong with bone marrow
 Anemia resolves if causative disorder cured
 May be treatable with synthetic erythropoietin
IRON DEFICIENCY ANEMIA
 Most common cause of anemia worldwide
 Decreased red cell production
 Microcytic: small cells due to decreased
hemoglobin production (need iron to make
hemoglobin)
 Causes: chronic blood loss, pregnancy, poor
diet
• Premenopausal women: Menstrual blood loss,
pregnancy
• All others: Gastrointestinal bleeding (eg, ulcer,
cancer)
• (Young children): diet of cow's milk
 Treatment: replace iron, rule out/treat bleeding
Normal
Iron deficient
(small, pale cells)
ANEMIA DUE TO VITAMIN DEFICIENCY
 Vitamin B-12 Deficiency
• Macrocytic (big cells): B-12 needed for DNA synthesis, so
cells grow but can’t divide normally
• Usually due to poor absorption of vitamin rather than poor
diet
• Pernicious Anemia = stomach disorder causing lack of
factor which aids B-12 absorption (intrinsic factor)
• May be associated with serious neurologic disorder
• Treatment: B-12 injections
 Folic Acid deficiency
• Macrocytic (folic acid also needed for DNA synthesis)
• Causes: poor diet, alcohol abuse, certain medications
• Treatment: oral folic acid supplements
Normal
Macrocytic
THALASSEMIA
 Inherited disorder of hemoglobin production
 Caused by defect in gene(s) for either of the protein
chains in hemoglobin
• alpha
• beta
 Microcytic anemia
• Severe = thalassemia major
Most patients depend on red cell transfusion to survive
• Mild or moderate = thalassemia minor
Normal
Thalassemia
minor