Anemia

Anemia
(including a little introduction to

hematopathology)
Kristine Krafts, M.D.
Pathology for Dental Students
Transfusion Medicine | 2
of 12
Introduction to Hematopathology
Clinical approach
History
• chemical exposures
• drug history
• diet
• blood loss
• fever
• family history
Physical examination
• skin (pale or jaundiced; petechiae
or bruises?)
• sclerae (petechiae?)
• tongue (big?)
• nails (spoon-shaped?)
• lymph nodes (enlarged?)
• sternum, other bones (tender?)
• spleen, liver (enlarged?)
koilonychiaangular
koilonychia
stomatitis
glossitis
anemia | 3 of 25 glossitis
angular stomatitis
(fissuring and
(spoon-shaped
(spoon-shaped ulceration of
nails) nails)
the corner of
(beefy-red, the tongue)
painful (beefy-red, painful
(fissuring tongue)
and ulceration of corner of
in a patient with iron-deficiency
patient with mouth)
iron-deficiency anemiain a patient with megaloblastic anemia
patient with megaloblastic mouth)
anemia anemia patient with megaloblastic anemia
Complete Blood Count*
RBC (red blood cell count) = total
number of red blood cells in blood
• Normal range = M 4.5-6.0 x
1012/L, F 3.8-5.2 x 1012/L
Hemoglobin (Hgb) = concentration of
hemoglobin in blood
• Normal range = M 13-18 g/dL; F
12-16 g/dL
Hematocrit (Hct) = volume of “packed”
red blood cells
• Normal range = M 40-52%, F 35-
47%
• Calculated by machine (MCV x
RBC) (rough guideline: Hct should =
Hgb x 3).
MCV (mean red blood cell volume)
• Normal range = 80-100 fL (1 fL =
10-15 L)
*
Most of the time, you’ll only need to use the indices in red.
anemia | 4 of 25
MCH (mean cell Hgb) = weight of Hgb in
the average red blood cell
• Normal range = 26-34 pg (1 pg =
10-12 g)
MCHC (mean cell Hgb concentration) =
concentration of Hgb in the average red
blood cell
• Normal range = 32-36 g/dL
• Calculated by machine (Hgb/Hct).
RDW (red cell distribution width) =
standard deviation of the MCV
• Normal range = 12-13.5%
• Tells you how much the red blood
cells differ from each other in size.
(If they are all pretty similar in size →
low RDW. If some are tiny and some are
huge → high RDW.)
WBC (white blood cell count) = total
number of leukocytes in blood
• Normal range = Adult: 4.5-11 x
109/L
anemia | 5 of 25
Child: 5.0-17.0 x 109/L (the exact
range differs according to age)
Differential = percentages of each cell
type in blood
• Normal ranges:
Adults Children
Neutrophils 45-75% 20-55%
Lymphocytes 20-50% 25-75%
Monocytes 1-8% 0-10%
Eosinophils 0-6% 0-6%
Basophils 0-1% 0-6%
Platelet count (Plt) = total number of
platelets in blood
• Normal range = 150-450 x 109/L
MPV (mean platelet volume)
• Normal range depends on the
platelet count! (Normally, if the platelet
count falls, the body
• compensates a little by trying to
make bigger platelets.)
anemia | 6 of 25
How to examine a blood smear
Look at the red blood cells
• Estimate number.
• Look for variation in size
(anisocytosis).
Oval macrocytes (B12/folate
•
deficiency)
Microcytes (iron deficiency anemia,
•
thalassemia)
The size range can often help you
•
narrow down which type of anemia is

present!
• Look for variation in shape
(poikilocytosis).
• Schistocytes (microangiopathic
hemolytic anemia)
• Spherocytes (hemolytic anemia,
hereditary spherocytosis)
• Teardrop cells or dacryocytes
(myelofibrosis or myelophthisic
processes)
anemia | 7 of 25
• Target cells or codocytes
(hemoglobinopathies, thalassemias,
liver disease, the post-splenectomy
state)
• Sickle cells (sickle cell anemia)
• Echinocytes and acanthocytes
(liver disease)
• Estimate the average amount of
hemoglobin in each cell (chromasia).
• Normochromic – Zone of
central pallor comprises ≤ 1/3 of the
cell diameter.
• Hypochromic – Zone of central
pallor comprises >1/3 of the cell
diameter.
• Estimate number of reticulocytes
(look for polychromatophilic cells*).
• Normal: one or two
polychromatophilic cells per field
*
Reticulocytes and polychromatophilic cells are the same thing – immature red cells that still
contain a little ribosomal RNA. When you do a supravital stain on a blood smear, the RNA stains
blue, and the cells are called “reticulocytes”. When you do a normal Wright-Giemsa stain, the cells
look big and slightly basophilic, and they are called “polychromatophilic cells.” This is one of those
fine points that, when casually mentioned on rounds your third or fourth year, will make you look
very smart.
anemia | 8 of 25
• The lower the Hgb, the higher
the reticulocyte count should be.
• Look for anything else weird.
• Nucleated red blood cells
• Inclusions (Howell-Jolly bodies,
Pappenheimer bodies, bugs)
Look at the platelets
• Check morphology (size,
granulation).
Look at the white blood cells
• Check morphology.
• Do a differential count.
anemia | 9 of 25
Anemia
INTRODUCTION
Definition: anemia is a
reduction below normal in
hemoglobin or red blood cell
number.
Causes
Blood loss
Increased red blood cell
destruction
• Extracorpuscular
hemolytic disease
(autoimmune disorders,
infection (e.g. malaria),
hypersplenism, trauma to red
blood cells)
• Intracorpuscular
hemolytic disease (hereditary
membrane or globin synthesis
abnormalities)
hematopathology | 10 of 25
Decreased red blood cell
production
• Bad diet (not enough
iron, B12, or folate)
• Decreased number of
erythroblasts (as in aplastic
anemia)
• Bone marrow full of
other stuff besides
hematopoietic precursors (e.g.,
tumor)
• Chronic disease (e.g.,
renal disease, inflammatory
diseases)
• Cirrhosis
Morphologic groups
Abnormal size
Red
• cells too small
(microcytic)
iron-deficiency anemia
•
thalassemia
•
•Red cells too big (macrocytic)
• megaloblastic anemia
• non-megaloblastic anemia
Abnormal shape
• Round red cells (spherocytes)
• hereditary spherocytosis
• autoimmune hemolytic
anemia
Elongated red cells
•
• sickle cell anemia (sickles)

• anemia associated with
splenomegaly or myelophthisis
(teardrops)
Pointy red cells
•
• glucose-6-phosphate
dehydrogenase deficiency (bite
cells)
• microangiopathic hemolytic
anemia (schistocytes)
Normal size and shape
• Increased reticulocytes
hemorrhage (onset >3
•
days ago)
• No increase in reticulocytes
• hemorrhage (onset <3 days
ago)
• anemia of chronic disease
• iron deficiency anemia (early
stages)
• anemia of chronic renal
disease
• aplastic anemia
• anemia due to bone marrow
infiltration
IRON-DEFICIENCY ANEMIA (IDA)
Iron Facts IDA:

1. Microcytic,
hypochromic anemia.
Absorption 2. Increased
anisocytosis and
• Occurs in 3.
poikilocytosis
Abnormal iron studies.
duodenum/proximal jejunum
• In mucosal cell, iron is
bound to either ferritin (for
storage) or transferrin (for
circulation).
Circulation
•Iron is bound to transferrin.
•Transferrin carries iron to
red blood cell precursors in
bone marrow, and to other
organs.
Distribution
storage
hemoglobin
transport
Metabolism
• Most of the circulating iron is
taken up by red cell precursors
and incorporated into heme
(which is then combined with
globin chains to make
hemoglobin).
• The rest of the iron is stored in
macrophages in the marrow,
spleen, and liver.
Storage
• Ferritin: Labile iron storage
form (quick in, quick out). Used
for heme synthesis.
• Hemosiderin: Stable storage
form (but iron less available).
Contains ferritin and cell
debris.
Causes of Iron Deficiency

Decreased iron intake
• Dietary deficiency (rarely
the sole cause of iron
deficiency anemia!)
• Decreased absorption (e.g.,
achlorhydria, gastric surgery)
Increased iron loss
• GI bleeding (e.g., from
gastric ulcer, colon cancer)
• Excessive menstrual flow
(menorrhagia) (most common
cause of IDA in females)
• Acute blood loss (e.g.,
massive trauma, childbirth)1
Increased iron requirement
(e.g., pregnancy)
It all boils down to this:
1. IDA in Premenopausal women:
First things to consider are
menorrhagia and/or repeated
pregnancies.
2. IDA in Men and
postmenopausal women: First
thing to consider is GI blood loss.
Clinical Features
Symptoms
1
Note: the patient's hemoglobin will appear normal during and immediately after blood loss!
That's because the patient has lost not just red cells (containing hemoglobin), but plasma. So, the
blood that's left in the body has the same concentration of hemoglobin as it did before the blood
loss. After a while, plasma volume is restored (either artificially or by the body itself), and the
hemoglobin (now diluted) is decreased.
• fatigue, palpitations, dizziness,
breathlessness
• patients might have NO symptoms if:
• the anemia is mild or moderate
(hemoglobin >8 or so)
• the anemia is chronic (long-standing,
slowly-progressing).
Signs
• Skin, mucous membranes: pallor.
• Nails: thinning, flattening, koilonychia
(spoon-shaped nails).
• Tongue: atrophy of lingual papillae
leaves tongue smooth, shiny.
Pica
• Hippocrates: a "craving to eat the
earth" associated with "corruption of the
blood."
• Patients crave (and often really eat)
dirt, ice, cardboard.
Morphology
Blood
• Hypochromic, microcytic anemia
• Increased anisocytosis
• Increased poikilocytosis
• Decreased reticulocyte number
• Platelet count usually increased
Bone marrow
• Erythroid hypoplasia
• Dyserythropoiesis.
iron-deficiency
anemia
Iron studies
• ↓ serum iron
• ↑ TIBC (total iron binding capacity)
iron-deficiency anemia after iron
therapy
↓population
ferritin (but
normal red blood cell
• remember: ferritin is an
iron-deficiency anemia
acute phase reactant!)
Treatment
• Figure out why patient is iron deficient
(don't just treat the
anemia, or you might miss something
really important).
• Then give iron (orally).
MEGALOBLASTIC ANEMIA
Macrocytic anemia Megaloblastic anemia:

1. Macrocytic anemia with
oval macrocytes and
Definition: MCV > 100. hypersegmented

neutrophils.
2. Defective DNA synthesis
Two categories: leads
to nuclear/cytoplasmic
1. Megaloblastic (most common)

asynchrony.
3. Almost always due to ↓
Almost always caused by ↓ B12/folate.

B12/folate
•
Specific “megaloblastic”
•
morphologic changes (see

morphology, below).
2. Non-megaloblastic (much less
common)
• Usually caused by alcoholism;
sometimes cause is unexplained.
• No “megaloblastic” changes.
Pathogenesis
Retarded DNA synthesis (causing cells
to divide more slowly), but unimpaired
RNA synthesis (allowing cytoplasm to
mature at normal speed) leads to big
cells
with immature nuclei but mature
cytoplasm (nuclear/cytoplasmic
asynchrony).
Vitamin B12 and/or folate deficiency
is most common cause of retarded DNA
synthesis.
You need both B12 and folate to make
DNA:
Methyl FH4
B12
FH4
Methylene FH4 FH2
dUMP dTMP DNA
Vitamin B12
Sources
• Meat, dairy products, breakfast cereal
(added as a supplement)
• Not in plants!
How does B12 get to red cells?
• Ingested B12 binds to intrinsic factor
(secreted by gastric parietal cells)
• B12 /IF is absorbed in the distal ileum
• B12 is transported by transcobalamin II
to organs and erythroblasts.
What else do you need B12 You need B12 to convert

homocysteine into
for?
methionine, and you need
methionine for myelin
maintenance.
• B12 is also necessary for

conversion of homocysteine to
methionine.
• You need methionine for
myelin maintenance (patients
with untreated B12 deficiency
eventually get an irreversible
demyelinating disease of the
spinal cord called “subacute
combined degeneration”).
• So…even if you know a
patient has a folate deficiency,
always check for a
concurrent B12 deficiency!
Causes of B12 deficiency
• Diet (rare!). If you stopped
eating B12 completely, it would
take a few years to become
anemic.
• Lack of IF
1) Pernicious anemia
• Patients have
autoantibodies to their parietal
cells (as these are destroyed,
less IF is produced).
• Once dreaded and lethal
(“pernicious”), now easily
treated with B12 injections.
• To see how well a patient
absorbs B12, you can do a
Shilling test2.
2) Other causes (gastrectomy)
Pancreatic damage (lack of
•
pancreatic enzymes →can’t

liberate B12 in the stomach →
B12 can’t bind to IF.)
Ileal disease/resection (B12-IF
•
can’t be absorbed).
Bugs (tapeworms, bacterial
•
overgrowth) in the small

intestine (these compete for
B12).
2
Shilling’s test:
1. Give “flushing” dose of intramuscular B12.
2. Give small oral dose of radioactive B12.
• Healthy patients will excrete radioactive B12 in urine.
• Patients who can’t absorb B12 via gut will not excrete radioactive B12 in urine.
3. If urine has low radioactivity, give another oral dose of radioactive B12 with intrinsic factor.
• If patient now excretes radioactive B12, patient lacks intrinsic factor.
• If patient still doesn’t excrete radioactive B12, the defect is not in intrinsic factor
(probably, something else is wrong with absorption.).
Folate (“folic” = (green)
“leafy”)
Sources
• Lots!
• Green leafy vegetables, but
also yeast, organ meats, fruit,
breakfast cereals, dairy
products.
How does folate get to red
cells?
• Absorbed mostly in jejunum.
• Converted to methyl-FH4
during absorption.
• Transported freely (mostly)
to liver, red blood cells.
Causes of folate deficiency Folate stores are small!
• Diet. Folate stores are

relatively small! If you stopped
eating folate completely, it
would only take a few months
to become anemic.
• Alcohol abuse (malnutrition,
poor absorption of folate,
inhibition of folate
metabolism).
• Jejunal disease (sprue,
inflammatory bowel
disease)/resection.
• Drugs (especially
chemotherapeutic drugs,
many of which are folate
antagonists!).
Morphology
Megaloblastic anemia:
Blood •
•
oval macrocytes
hypersegmented
Macrocytic anemia.
neutrophils
•
• Oval macrocytes.
• Hypersegmented
neutrophils.
Bone marrow
•Megaloblastic
erythroblasts (BIG
cells with big,
immature nucleus but
maturing cytoplasm).
•Megaloblastic neutrophils
and precursors.
•Giant metamyelocytes.
•Hypersegmented
neutrophils.
megaloblasticmegaloblastic anemia
anemia oval macrocytes megaloblastic
megaloblastic anemia
hypersegmented hypersegmented neutrophil anemia
giant metamyelocyte
Blood smear morphology
neutrophil, oval megaloblasts
HEMOLYTIC ANEMIAS
Causes Hemolytic anemias:

1. Increased rate of red cell
destruction.
Inherited 2. Bone marrow responds (usually)

by
• Defects in red blood cell membrane increasing red cell production.
• hereditary spherocytosis
• hereditary elliptocytosis
• Enzyme deficiencies
• Glucose-6-phosphate dehydrogenase
deficiency
• Defects in globin structure/synthesis
• hemoglobinopathies (e.g., sickle cell
anemia)
• thalassemias
Acquired
• Immune-related
• autoimmune hemolytic anemia
• Microangiopathic hemolytic anemia
• Infection-related (e.g., malaria or
clostridium infection)
• Drug-related
Clinical features
Chronic hemolytic anemias
• Usually congenital.
• Sometimes well-compensated,
with few symptoms!
• Jaundice (↑ unconjugated
bilirubin).
• Crises (due to fragile
equilibrium between red cell
destruction and bone marrow
compensation)
• Usually precipitated by
infection (especially common:
parvovirus B19).
• Parvovirus attacks red cells;
the already maxed-out bone
marrow cannot
compensate!
• Splenomegaly.
• Gallstones (unclear
pathophysiologic reasons).
Acute hemolytic anemias
•Usually acquired.
•Aching back, abdominal,
and/or limb pain.
•Headache, malaise, fever.
•Pallor, jaundice, tachycardia.
Laboratory findings
Signs of excessive red cell
destruction
•Hemoglobinemia/hemoglobi
nuria (when hemolysis is
intravascular, or so brisk
extravascularly that
macrophages cannot keep up).
•↑ serum unconjugated
bilirubin (unless liver can keep
up with excretion!).
•↑ lactate dehydrogenase
(LDH) (a red cell enzyme).
•↓ haptoglobin (a protein that
binds free Hgb).
• ↓ red cell lifespan (label
51
cells with Chromium,
measure t1/2; rarely done
because expensive, time-
consuming).
Signs of accelerated
erythropoiesis: reticulocytosis
• Reticulocyte count = percentage
of red blood cells that are
reticulocytes (normal=1-3%).
This doesn’t take into account the
patient’s Hgb (at lower Hgb, should
have more retics!).
• “Corrected” reticulocyte count =
reticulocyte % x Hgb/15 (or
reticulocyte % x Hct/45).
This doesn’t take into account the
fact that when the blood is
desperate for red cells, it
prematurely releases
reticulocytes into the blood (these
are called “shift” reticulocytes).
• “Reticulocyte production index” =
(reticulocyte %/reticulocyte
maturation time) x Hgb/15.
• at Hgb of 15, it takes 1 day
for reticulocytes to mature
• “ 12 “ 1.5 days ”
• “ 8 “ 2 days “
• “ 5 “ 2.5 days “
Morphology
• Normochromic, normocytic
(usually) anemia.
• Spherocytes (can be found in
almost any hemolytic process).
• Other more specialized
poikilocytes:
• Target cells (thalassemias and
hemoglobinopathies)
• Elliptocytes (hereditary
elliptocytosis)
• Sickle cells (sickle cell anemia)
• Schistocytes, helmet cells, other
fragmented red cells
(microangiopathic hemolytic
anemia)
•Signs of increased
erythropoiesis:
• Polychromatophilia (or, if
stained with supravital stain,
reticulocytosis)
• Basophilic stippling (RNA
remnants not yet removed from
cell)
• Nucleated red blood cells
(bone marrow hurrying to get
red cells out as quickly as
possible)
Important lab test

Direct antiglobulin test (DAT)
• Also called the Coomb's test.
• Mix patient's red cells with
anti-IgG and anti-IgM antibodies.
• If the red cells are coated with
antibodies (as they are in some
immune processes, see later), the
anti-IgG or anti-IgM will attach to
those antibodies, bridging the red
cells and making them clump
together.
• So, a positive result (red cell
clumping) means the patient's
red cells are coated with
antibodies, and the hemolysis is
probably immune-related.
Diagnosis
1. Is there hemolysis? Look for:
Signs of increased red cell
•
destruction
Signs
• of increased
erythropoiesis (if hemolysis has
been around long enough)
2. What's causing the
hemolysis? Using the history,
DAT, and blood smear, you can
categorize patients into five
groups:
• Patients with known
exposure to infectious or
chemical agents.
• Patients with positive DAT
(diagnosis: immune-related
hemolytic anemia).
• Patients with negative DAT
but lots of spherocytes
(probable diagnosis: hereditary
spherocytosis).
and other specific, morphologic
abnormalities (e.g., sickle cells).
and no specific morphologic
abnormalities (do Hgb
electrophoresis).
HEREDITARY SPHEROCYTOSIS
Hereditary spherocytosis:
1. Lots of spherocytes
Clinical features
2. Spectrin defect.
3. Splenectomy is curative.
• Classic triad: mild

anemia, intermittent
jaundice, splenomegaly.
• Relatively common (1
in 5000 people of northern
European descent).
• Variable age of onset,
severity.
• Anemia often
exaggerated during
"crises", most often
precipitated by infection
with parvovirus B19 (fifth
disease).
Pathogenesis
• Basic defect: membrane
cytoskeleton has defective
spectrin content or
function.
• Leads to: altered
membrane properties (loss
of surface area, altered
membrane lipids/proteins).
• Intrinsic red cell defects
cause red cell destruction -
but only in the presence of
the spleen!
Morphology
• Mild normochromic, hereditary
spherocytosis
normocytic anemia. spherocytes
• Numerous spherocytes.
• Evidence of accelerated
hematopoiesis
(polychromatophilia,
normoblasts).
Therapy
• Splenectomy (curative).
• If splenectomy not
possible, may need red cell
transfusions during crises.
Other hemolytic anemias

due to inherited membrane
abnormalities
Hereditary elliptocytosis
• Pathogenesis: Spectrin
abnormality (mutation
different than that of HS).
• Clinical Features: Mild
anemia, usually fully
compensated.
May have exacerbations
during crises, however.
Homozygotes have
chronic, transfusion-
dependent anemia,
which is responsive to hereditary
spherocytosis
splenectomy (like patients spherocytes
with HS).
• Morphology: Numerous
elliptocytes.
Hereditary
pyropoikilocytosis
• Pathogenesis: Mutant
spectrin won't stick to
itself, gets degraded too
rapidly.
• Clinical Features: Mild
anemia with crises, like HS
and HE.
• Morphology: Bizarrely-
shaped red cells! (look like
red cells that have been
exposed to heat – thus the
name "pyro".)
hereditary
elliptocytosis
elliptocytes
GLUCOSE-6-PHOSPHATE
DEHYDROGENASE DEFICIENCY
Pathogenesis G6PD Deficiency:

1. ↓ G6PD → ↑ peroxides → cell lysis.
• G6PD catalyzes the 2. Self-limited; follows exposure to

oxidant agent.
initial step in the pentose 3. Bite cells present (from removal of

Heinz bodies).
phosphate pathway of
glycolysis.
• Need G6PD to reduce
NADP to NADPH, which
keeps glutathione in the
reduced state (reduced
glutathione detoxifies
hydrogen peroxide and
other organic peroxides).
• Gene for G6PD is on the
X chromosome (therefore,
males usually have full
disease expression;
heterozygous females are
clinically normal).
• Very common in certain
populations (10% of black
men in US have the gene!).
Highest incidence is in
populations in which
malaria was endemic. G6PD
deficiency thought to confer
a selective advantage
against malaria infection:
• Malaria bug infects the red
cell, but then both red cell
and bug die.
• G6PD-deficient red cells
lack the ribose derivatives
bugs need to grow.
• Why are G6PD-deficient
cells destroyed
prematurely?
• Red cell can't reduce the
H2O2/other nasties made
during cell life
• Sulfhydryl groups/disulfide
bonds are attacked
• Heme is liberated from
globin
• Globin is denatured
(making Heinz body); sticks
to red cell membrane
• Membrane plasticity
compromised
• Red cells detained in
passage through liver/spleen,
where macrophages
remove Heinz bodies.
Clinical findings
In most affected individuals,
severe hemolysis occurs only
after exposure to oxidizing
agents (antimalarial drugs,
sulfonamides, H2O2, even
aspirin in some patients) or
infection (unknown
mechanism).
Morphology
• In absence of exposure
to offending agents, most
patients have no anemia.
• After exposure, get
acute hemolytic episode:
• Cell fragments,
microspherocytes, and bite
cells (caused by recent
pitting of Heinz bodies).
• Supravital staining will
reveal Heinz bodies (these
decrease in number as
Hgb bottoms out, because
younger cells have greater
G6PD activity!).
• In 5 days, start seeing
reticulocytes.
• Hemolysis is self-limiting,
with spontaneous resolution
in 1 week (kill off old red
cells first; younger ones have
greater G6PD activity).
Therapy
• Avoid taking offending
drugs or drinking H2O2.
• Rare patients may
require more active
intervention (e.g., red cell
transfusion).
SICKLE-CELL ANEMIA
Hemoglobinopathies Hemoglobinopathies:
1. Qualitative abnormality in
• Group of inherited hemoglobin (structurally

abnormal
α or β chains).
disorders in which 2. Sickle-cell anemia most
important.
structurally abnormal 3. Sickle cells → chronic
hemolysis,
hemoglobin is made. Some vaso-occlusive disease.
of these abnormal
hemoglobins function like
normal hemoglobin, but
some have abnormalities
that lead to hemolysis.
• Hgb S (which produces
the disease called sickle-
cell anemia) is the most
common abnormal
hemoglobin.
Pathogenesis
• Point mutation in β
chain gene leads to
substitution of valine for
glutamate.
• Resultant abnormal
hemoglobin, Hgb S, has
abnormal physical and
chemical properties:
• On deoxygenation, Hgb S
molecules aggregate and
polymerize.
• Red cell shape is distorted
into sickle shape.
• After many episodes, red
cell becomes permanently
sickle-shaped.
• Results:
• Chronic hemolytic anemia
(sickle cells not as
deformable as normal
biconcave disks).
• Occlusion of small blood
vessels leading to ischemic
tissue damage.
Clinical Features
• Occurs predominantly in
blacks. Eight percent of
blacks in US are
heterozygous; one black
child in 600 is homozygous.
• Patients who are
heterozygous rarely have
significant clinical or
hematologic
manifestations.
• Severity of disease is
very variable, for unknown
reasons.
• Increased susceptibility
to infection (after
autosplenectomy,
encapsulated organisms
like Streptococcus
pneumoniae and
Hemophilus influenzae pose
big risk).
• Chronic hemolysis
(Hgb=6-10).
• Vaso-occlusive disease
• Usually occurs as an acute
crisis, precipitated by
infection, hypoxia, or
unidentified causes.
• Children: pain in hands,
feet often first symptom.
All ages: pain common in
bones, lungs, abdomen.
• Spleen may undergo
massive enlargement (due to
red cell sequestration) in
early childhood; by early
adulthood, spleen is reduced
to small, fibrotic
remnant (due to recurrent
hemorrhage, infection).
Morphology
• Sickle cells.
• After autosplenectomy
occurs, see a "post-
splenectomy blood picture":
nucleated red blood cells,
targets, Howell-Jolly bodies,
Pappenheimer bodies,
slightly increased platelet
count.
Treatment
• Prevent triggers:
infection, fever,
dehydration, hypoxemia.
• Take extra precautions
to prevent infections due to
encapsulated bugs
(vaccinate, give
prophylactic antibiotics).
• Blood transfusions
during severe crises
(maybe also regularly, in
certain patients).
• Bone marrow
transplantation.
sickle cell anemia

sickle cells
THALASSEMIA
General
Thalassemias:
1. Quantitative defect in
hemoglobin
Normal hemoglobin (decreased or absent α or β

chains).
composition 2. Degree of anemia varies.

3. Anemia is often microcytic,
• Before 6 months of age: hypochromic with ↑ RBC and

targets.
• most of the circulating

hemoglobin is fetal
hemoglobin (HgbF: α 2γ 2).
• Around 6 months of age,
hemoglobin composition
starts switching to adult
pattern:
• 96% HgbA (α 2β 2)
• 3% HgbA2 (α 2δ 2)
• 1% HgbF (α 2γ 2)
α - and β -chain genes
There are four α -chain genes
and two β -chain genes.
α - vs. β -thalassemia
α -thalassemia = decreased
amount of α chain.
β -thalassemia = decreased
amount of β chain.
Disease severity depends
on how many genes are
defective (or absent).
In β -thalassemia, the defect
is in transcription,
translation, or processing of
mRNA.
• β 0 gene: produces no β
chains.
• β + gene: produces some
β chains (but amount is
less than normal).
• β gene: produces
normal amount of β chains.
• if genotype is:
disease is:
β 0/β 0 or β 0/β + β -
thalassemia major (severe)
β 0/β or β +/β + β -
thalassemia intermedia (less
severe)
β 0/β or β +/β β -
thalassemia minor (mild or
asymptomatic)
In α -thalassemia, the
"defect" is really gene
absence.
• if genotype is:
disease is:
-α /α α silent
--/α α or -α /-α α-
thalassemia trait
(asymptomatic)
--/-α HbH disease
(severe)
--/-- Hydrops fetalis
(fatal in utero)
Pathogenesis
α -thalassemia
• Problem is deletion of gene(s).
• Anemia results from:
• insufficient α chains (leading to
insufficient Hgb A)
• excess unpaired β , γ , and δ chains
(leading to premature destruction of the
red cell)
- Newborns have higher % of HbF, so
they make γ 4 tetramers (Hb Barts).
- Adults have mostly HbA, so they
make β 4 tetramers (HbH).
β -thalassemia
• Problem is in transcription,
translation, or processing of mRNA.
• Anemia results from:
• insufficient β chains (leading to
insufficient Hgb A)
• excess unpaired α chains (leading to
premature red cell destruction)
Morphology
α -thalassemia
• Silent carrier state and
α -thalassemia trait: no
anemia.
• HbH disease: moderately
severe anemia. Supravital
staining reveals HbH
inclusions.
β -thalassemia
• β -thalassemia minor
• Mild anemia.
• Abnormal-looking smear:
hypochromasia, microcytosis,
basophilic stippling,
and target cells.
• Note: Iron-deficiency
anemia is also microcytic and
hypochromic.
However, in β -thalassemia
minor, the MCV is very
decreased compared to the
relatively mild decrease in
Hgb; also, the RBC is
increased (why?)!
• β -thalassemia
intermedia and β -
thalassemia major:
• Severe anemia (Hgb=3-6).
• Very abnormal-looking β -thalassemia minor
smear: marked anisocytosis hypochromasia, basophilic
stippling
and poikilocytosis
(small, very hypochromatic
cells, target cells, and
fragmented red blood
cells), nucleated red blood
cells.
Clinical findings
α -thalassemia
• More common in Asians,
blacks.
• Silent carrier state and α -
thalassemia trait: no
symptoms.
• HbH disease: moderately
severe anemia.
• Hydrops fetalis: fatal in
utero.
β -thalassemia
• More common in
Mediterraneans, blacks,
Southeast Asians.
• β -thalassemia minor:
patients almost always
asymptomatic, with mild or
no anemia.
• β -thalassemia major:
• Anemia very severe,
starting at 6-9 months of
age.
• Without therapy, children
suffer growth retardation and
die at a young age
from profound anemia.
• Therapy is repeated
transfusions (with iron
chelation to avoid iron
overload).
• Unless bone marrow
transplant is performed,
many patients die in their
20s.
WARM AUTOIMMUNE
HEMOLYTIC ANEMIA
Causes Warm AIHA:

1. IgG.
• Primary/idiopathic (2/3 of 2. Spleen.

3. Spherocytes.
cases)
• Secondary to:
• Lymphoma/leukemia
• Other malignancies
• Autoimmune disorders
• Infections
• Drugs (methyl-dopa,
penicillin)
Pathogenesis
• IgG Ab (to Rh blood group
Ag, to a drug, etc.).
• Binds to red cell best at 37°
C.
• Macrophages in spleen
nibble out bits of the IgG-
coated red cells, which
become spherocytes.
Spleen eventually eats up
the spherocytes entirely.
Clinical Features
• Any age, either sex.
• Variably severe anemia.
• Splenomegaly.
Morphology
• Prominent spherocytosis.
• Other signs of hemolysis
(polychromasia,
normoblasts).
Diagnosis warm AIHA
• Direct antiglobulin spherocytes
(Coombs') test (DAT), in

which you use animal anti-
IgM,
-IgG, etc. to look for Ab
bound to red cells.
• Patients with warm AIHA
usually are positive for IgG.
Treatment
• Treat underlying cause, if
there is one.
• Give steroids.
• Splenectomy.
COLD AUTOIMMUNE
HEMOLYTIC ANEMIA
Causes Cold AIHA:
1. IgM, complement.
2. Liver/intravascular
• Primary/idiopathic (Ab often hemolysis.
3. Agglutination.
monoclonal!)
• Secondary to:
1. Infections
• Mycoplasma
pneumoniae (most common).
• Infectious
mononucleosis.
• Ab usually polyclonal.
• Usually self-limited.
2. Lymphoproliferative
disorders
• Ab usually monoclonal.
Pathogenesis
• IgM (usually against "I"
antigen on red cell surface),
complement.
• Bind to red cell best at 4° C
(in distal, colder body parts).
• IgM causes agglutination
(bridges adjacent red cells),
but falls off in warmer body
parts.
• Complement stays on red
cell; causes:
• Intravascular hemolysis
(via complement cascade)
• Extravascular hemolysis
(Liver, and to lesser extent,
spleen, gobble up C'-
coated red cells)
Clinical Features
• Idiopathic type and
lymphoproliferative-disorder-
related type: mostly elderly
patients. Infection-related
type: younger and older
patients.
• Chronic, usually mild
hemolytic anemia
aggravated by the cold.
• Pallor/cyanosis in colder
body parts (vascular
obstruction from red cell
agglutinates).
Morphology
• Red blood cell agglutination
(large clumps) on blood
smears made at room
temperature. *Note: unless
the blood specimen is
warmed before running
through machine, RBC will
be off (low).
• Spherocytes present, but
less numerous than in warm
AIHA.
• Other signs of hemolysis
(polychromasia,
normoblasts).
Diagnosis
• Direct antiglobulin cold AIHA
(Coombs') test red cell agglutination
• Patients with cold AIHA

usually are positive for IgM
and complement.
Treatment
• Treat underlying cause, if
there is one.
• Keep patient warm.
• Splenectomy and steroids
not helpful.
MICROANGIOPATHIC HEMOLYTIC
ANEMIA
MAHA:
1. Schistocytes.
Pathogenesis 2. Find out underlying cause!
Red cells are ripped apart

by physical trauma (fibrin
strands snag them or
mechanical devices bash
them).
Causes
Narrowing/obstruction of
microvasculature
1. Disseminated
intravascular coagulation
(DIC)
• See in sepsis, abruptio
placentae, many other
clinical settings.
• Widespread clotting
and bleeding.
• Get microthrombi,
fibrin strands in vessels.
2. Thrombotic
thrombocytopenic purpura
(TTP)
• Syndrome consisting
of MAHA,
thrombocytopenia, CNS
dysfunction, renal failure
and fever.
• Get microthrombi in
vessels.
3. Hemolytic-uremic
syndrome (HUS)
• Occurs usually in
children, following
infection with E. coli
0157 (symptoms:
vomiting, bloody
diarrhea).
• Syndrome consisting
of acute MAHA and renal
failure (toxin produced
by the bug damages
endothelial cells).
• Get microthrombi in
vesssels.
4. Malignant hypertension
(narrowed arterioles).
5. Systemic lupus DIC
fibrin strands snagging red
erythematosus (necrotizing cells
arteritis).
6. Disseminated
malignancies (fibrin strands
in vessels).
Heart/great vessel
abnormalities
1. Artificial heart valves.
2. Coarctation of aorta.
Morphology
• Schistocytes! Also, helmet
cells, few spherocytes (from
"rounding up" of
schistocytes).
• If also see thrombocytopenia, worry
about DIC, TTP, or HUS.
Clinical features
• Symptoms vary according to cause of
MAHA.
• The important thing is
usually not the anemia
itself, but the underlying
disorder! (Don't miss this
one!)
MAHA
schistocytes
ANEMIA OF CHRONIC DISEASE
ACD:
1. Bland looking!
Definition: a mild to
2. Accompanies some
Infectious Infectious
infections,
conditions conditions
inflammatory conditions,
• Pulmonary • Pulmonary
moderate
infections
• Subacute bacterial
anemia
infections
• Subacute bacterial
malignancies.
3. Disturbed iron metabolism
accompanying
endocarditis
• Pelvic inflammatory
disease
endocarditis
• Pelvic inflammatory
disease
(iron doesn't get into
normoblasts).
infections,
• Osteomyelitis
• Chronic urinary
• Osteomyelitis
• Chronic urinary
tract tract
inflammatory
infection
• Meningitis
infection
• Meningitis
conditions
disorders
Inflammatory or
Inflammatory
conditions
malignant diseases
• Rheumatoid
arthritis
• Rheumatoid
arthritis
• Systemic lupus • Systemic lupus
(see box at left) that
erythematosus
• Severe trauma
erythematosus
• Severe trauma
Malignant
conditions
persist more than 1-2
Malignant
conditions
months.
• Carcinoma
• Lymphoma It's the
• Carcinoma
• Lymphoma
• Leukemia • Leukemia
second-most-
• Multiple myeloma • Multiple myeloma
common
Not included:
• Anemias due to
other
anemia
Not included:
• Anemias due to
other
(after IDA) and it's

mechanisms, such mechanisms, such
characterized by hypoferremia,
despite lots of macrophage
storage iron.
Clinical Features
• Symptoms are those of the
underlying disease, not of the
anemia.
• Anemia develops during the
first 2 months of the chronic
disease; doesn't progress
thereafter.
Pathogenesis
• Disturbance in iron metabolism
(iron never makes it into
normoblasts!)
• Mucosal cells absorb iron okay,
but don't release it into plasma.
• Macrophages take up iron but
release it very slowly.
• Shortened red blood cell survival
• Cells of patients with ACD have
normal lifespan when
transfused into normal
patients; but cells of normal
patients have shortened
lifespan when transfused into
patients with
ACD.
• Probably due to increased
phagocytosis of red cells by
macrophages.
• Impaired bone marrow response
to anemia
• Not enough iron available to
make enough red blood cells.
• Not enough erythropoietin
around, and bone marrow can't
respond to what little there is.
Morphology
anemia (usually).
• Some cases (about 25%) are
microcytic (but MCV rarely gets
below 72 fL).
• Minimal anisocytosis and
poikilocytosis.
Iron studies
• ↓ serum iron
• ↓ TIBC (total iron binding
capacity)
• ↓ transferrin saturation
• ↑ ferritin (remember: ferritin is
an acute phase reactant!)
• ↑ bone marrow storage iron
Diagnosis
• Usually symptoms of underlying chronic
disease will be present.
• Mild, usually normochromic, normocytic
anemia.
• Abnormal iron studies (see V., above).
Treatment
• Treat underlying disease!
• ACD is usually so mild that treatment of
anemia is not required.
ANEMIA OF CHRONIC RENAL
DISEASE
Definition: anemia due to

Anemia of chronic renal disease:
1. Bland looking.
decreased erythropoietin.
2. Decreased erythropoietin.
May be complicated by iron

deficiency anemia
(secondary to hemodialysis),
anemia of chronic disease
(secondary to concurrent
chronic infection or
inflammation), or
microangiopathic hemolytic
anemia (secondary to
changes in renal
microvasculature).
Clinical findings
• Patients are usually in final
stages of severe renal
disease with all attendant
symptoms (anemia is
usually an incidental finding).
• Rough correlation exists
between severity of anemia
and degree of renal
insufficiency.
Morphology anemia of chronic renal

disease
echinocytes
• Normocytic, normochromic
anemia.
• Minimal anisopoikilocytosis;
may see some echinocytes
("burr" cells).
Iron studies
• Normal in mild renal
disease.
• As disease progresses and
complications occur, serum
iron may increase (due to
multiple transfusions) or
decrease (due to blood loss,
chronic infection).
Pathogenesis
• Decreased erythropoietin
(due to decreased excretory
function of kidney) is most
important factor!
• Extracorpuscular hemolysis
(due to unknown factors -
possibly caused by some
toxic substance usually
metabolized or excreted by
the kidney).
Management
• If mild, requires no
treatment.
• Eventually, renal failure
requires:
1. Kidney transplant
(anemia then corrects).
2. Dialysis (may help
anemia a little - but doesn't
increase erythropoietin.
May need to give
recombinant erythropoietin).
ANEMIA OF CHRONIC LIVER
DISEASE
Definition: a mild to Anemia of chronic liver disease:

1. Acanthocytes, targets.
moderate anemia due to the 2. Usually complicated by other

factors.
shortened red blood cell

survival and impaired bone
marrow response seen in
chronic liver disease (see III.,
below); particularly in
alcoholic cirrhosis.
Many other factors contribute
to anemia in patients with
alcoholic liver disease:
• Folate deficiency (→
megaloblastic anemia)
• Impaired heme synthesis (→
sideroblastic anemia)
• Hemorrhage from upper GI
varices/hemorrhoids (→ iron
deficiency anemia)
"Uncomplicated" anemia
(without the above factors) is
actually uncommon.
Clinical
• Three-fourths of patients
with liver disease are
anemic!
• Alcohol abusers with mild
liver disease can get
episodes of hemolysis which
resolve when alcohol is
withdrawn.
Pathogenesis
• Decreased red blood cell
lifespan (possibly due to
congestive splenomegaly).
• Decreased bone marrow
response
• Ethanol inhibits
erythropoiesis
• Liver normally secretes a
small amount of
erythropoietin; in liver
disease, secretion is
decreased.
Morphology (of
"uncomplicated" cases)
(usually) anemia.
• Some cases are macrocytic.
• Increased poikilocytosis.
• Target cells (increased
cholesterol and lecithin in red
cell membrane leads to
increased cell surface area).
• Acanthocytes ("spur" cells
- 5-10 spiky projections) - if
numerous, can lead to
hemolytic anemia
(acanthocytes are fragile,
non-deformable).
• Increased reticulocyte
count (especially after
alcohol is withdrawn; since
alcohol suppresses
reticulocyte formation).
APLASTIC ANEMIA
Etiology Aplastic anemia:

1. Pancytopenia.
Acquired 2. Empty marrow.

3. Nothing else responsible for 1.
1. Chemical agents and 2.
• Agents with predictable,

dose-related effects (e.g.,
chemotherapeutic drugs)
• Agents with unpredictable,
non-dose-related effects
(e.g., chloramphenicol)
2. Other causes
• viral infection (e.g., EBV,
hepatitis, HIV)
• pregnancy
• radiation
3. Idiopathic
Familial
• Fanconi's anemia
(characterized by skeletal
abnormalities, chromosomal
instability, pancytopenia
and increased risk of
leukemia) is the most
common
familial cause.
Clinical features
Incidence
• Rare! Death rate = 1-13
people/1,000,000 per year.
• Not age- or sex-related.
Signs/symptoms are
related to cytopenias.
• Anemia → pallor, dizziness,
fatigue
• Leukopenia → recurrent
infection
• Thrombocytopenia →
bleeding, bruising
Morphology
Blood
• Pancytopenia.
• Bland anemia (normochromic,
normocytic with minimal
anisopoikilocytosis).
Bone marrow
• Markedly hypocellular ("empty").
• Bone marrow aspirate specimen
consists mostly of lymphocytes!
Differential diagnosis
(given only blood findings)
• Disorders infiltrating the
bone marrow (e.g.,
"aleukemic" leukemia,
myelofibrosis, metastatic
carcinoma).
• Disorders involving the
spleen (e.g., congestive
splenomegaly, lymphoma).
• Miscellaneous disorders aplastic
anemia
(e.g., overwhelming infection, empty marrow
refractory anemia).
megalobl
asts
Treatment and prognosis

• Avoid further exposure, if
anemia is result of known
noxious agent.
• Transfuse specific blood
components as needed (red
blood cells, platelets).
• Drug therapy: stimulate
hematopoiesis (G-CSF,
steroids, androgens) and
suppress immune system
(anti-thymocyte globulin or
ATG).
• Bone marrow transplant if
above approaches fail.
• Prognosis (with treatment):
3-year survival = 70%.

Anemia

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Anemia

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Anemia

(including a little introduction to

narrow down which type of anemia is

•Red cells too big (macrocytic)

• sickle cell anemia (sickles)

IRON-DEFICIENCY ANEMIA (IDA)

Iron Facts IDA:

Causes of Iron Deficiency

acute phase reactant!)

Macrocytic anemia Megaloblastic anemia:

Definition: MCV > 100. hypersegmented

1. Megaloblastic (most common)

Almost always caused by ↓ B12/folate.

morphologic changes (see

Methylene FH4 FH2

dUMP dTMP DNA

What else do you need B12 You need B12 to convert

• B12 is also necessary for

pancreatic enzymes →can’t

overgrowth) in the small

• Diet. Folate stores are

Causes Hemolytic anemias:

Inherited 2. Bone marrow responds (usually)

• Defects in red blood cell membrane increasing red cell production.

Important lab test

• Classic triad: mild

normocytic anemia. spherocytes

Other hemolytic anemias

splenectomy (like patients spherocytes

Pathogenesis G6PD Deficiency:

• G6PD catalyzes the 2. Self-limited; follows exposure to

initial step in the pentose 3. Bite cells present (from removal of

• Group of inherited hemoglobin (structurally

sickle cell anemia

Normal hemoglobin (decreased or absent α or β

composition 2. Degree of anemia varies.

• Before 6 months of age: hypochromic with ↑ RBC and

• most of the circulating

Causes Warm AIHA:

• Primary/idiopathic (2/3 of 2. Spleen.

Diagnosis warm AIHA

• Direct antiglobulin spherocytes

(Coombs') test (DAT), in

• Patients with cold AIHA

Pathogenesis 2. Find out underlying cause!

Red cells are ripped apart

(after IDA) and it's

Definition: anemia due to

May be complicated by iron

Morphology anemia of chronic renal

Definition: a mild to Anemia of chronic liver disease:

moderate anemia due to the 2. Usually complicated by other

shortened red blood cell

Etiology Aplastic anemia:

Acquired 2. Empty marrow.

• Agents with predictable,

(e.g., overwhelming infection, empty marrow

Treatment and prognosis

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