IDA develops slowly through 3 overlapping
stages:
 1body’s iron stores for erythrooesis are
depleted
 2erythropoesis begins to be affected at the
same time that the hemoglobin content of the
RBC’s being formed is lowered
 3when small, Hb deficient RBCs enter the
circulation
Stages of Iron deficient anemia
!
Laboratory tests to confirm
IDA
Microscopic Histopathology
findings for IDA
1. Serum ferritin and iron concentration will be
LOW (but, acute phase reactant, may go up for
other reasons)Serum iron binding capacity is
HIGH
2. Bone marrow—can use storage Fe, but this is
painful, cumbersome
3. Treatment
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Hypochromia refers to lowered Hb content in
RBCs (MCHC)
Microcytic (MCV)
These findings suggest that laboratory tests
should be done to confirm IDA
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Signs of anemia
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Hematopoiesis: Stem cells
Pluripotential, multipotential, progenitor,
precursor
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Cold, pale extremitites
Generalized pallor of skin and mucous
membranes
Jaundice (suggest hemolytic anemia)
Chelosis—fissuring at the angles of the mouth
(can have other causes)
Koilonychia (concave nails)
0.01-0.05% of bone marrow population
self-renew and differentiate
pluri: self-perpetuating pool
multi: can become either lymphoid or
myeloid cells
progen: commited to a cell lineage
precursor: can prolife and develop into
myeloid lineage
Embryology of RBCs
Bone marrow stroma
1. types of cells
2. What else?
Stages of erythropoiesis?
Stages of Granulopoiesis?
1.
2.
3.
4.
5.
begins in fetal yolk sac
shift to liver
later forms in spleen
term, forms in bone marrow
as adult, most occurs in axial skeleton
1. fat cells, macrophages, endothelial cells,
lymphocytes, and fibroblasts
2. Collagen, adhesion proteins, growth factors
such as G-CSF, GM-CSF, EPO
1. proerythrobast—intense blue, round nucleus
2. basophilic erythroblast—intense blue, condensed
chromatin
3. polychromatophilic erythroblast—grayish cytoplasm
due to hb, smaller nuleus
4. orthochromatic erythroblast—reddish, small nucleus
5. reticulocyte—no nucleus, still has mito and RNA
6. mature erythrocyte
1. myeloblast—high N:C ratio
2. promyelocyte—primary (purple) granules
3. myelocyte—nucleus may be eccentric, cytoplasm
may have pink granules
4. metamyelocytes—kidney bean shaped nucleus
5. band—horseshoe shaped nucleus
6. PMN—lobular nucleus
--first line of defense for microorganisms, chemotatic,
opsonins, lysosomal enzymes
KNOW: hydrogen peroxide, superoxide, halides
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Monocytopoiesis
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Monoblasts mature into monocytes. Become
part of mononuclear phagocyte system in
tissue.
Half life is 70h
Chemotaxis, phagocytosis, antigen
presentation, IL-1 and TNF relase (eg due to
endotoxins),
Megakaryocytopoiesis
Eosinophils
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Etoposide (VP-16), teniposide (VM-26)
These mature into multilobed giant cells by
endomitotic divisions. Granular cytoplasm,
with platelet containing ribbons
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Large granules stain red with eosin due to
basic proteins
Bilobed nucleus
In tissue
IgA receptors, toxic cationic proteins, kill
parasites, cause allergic reactions
Chemotaxis, phagocytosis,
Immediate type hypersensitivity
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Basophils
When are transfusions necessary?
What are the risks? What happens?
Anemia with:
1. low reticulocytes
2. normal reticulocytes
3. high reticulocytes
Blue-black granules with histamine
Allergic reactions
Immediate type hypersensitivity
Inflammatory responses
Based on symptoms, NOT numbers
1. shock
2. surgery
3. angina pectoris—cornonary insufficiency, chest
pain on exertion
Risks: Hep B, HIV, Hep C even with testing
Hb increases by 1g and hematocrit rises by 3% with
250mls.
1. marrow problem
2. ditto
3. rbc destruction or blood lossnormal marrow
is accounting for decreased RBCs
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The low down on iron
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Differential diagnosis for
Macrocytic anemia
3 major causes of folate deficiency
How do you diagnose folate
deficiency?
How do you treat it?
In most foods
Absorbed in small intestine
Transferring—carrier protein which delivers it to
the marrow
Ferritin—iron is stored complexed to ferritin in the
liver, spleen.
The body recycles iron!! Adults tend to keep their
iron around 3g: 2 in erythrocytes, 1 in storage
Because storage is full in adulthood, decreased iron
must be due to loss of blood.
1. Folate deficiency
2. B12 deficiency
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Dietary (salads), Malabsorption (illium),
Increased usage (pregnancy)
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Dx:
1. Morphology (macrocytic RBCs,
hypersegmented PMNs
2. Serum folate—look for LOW levels
3. Red cell folate—look for LOW levels
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Treatment:
1. folate supplement, 1mg a day
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3 major causes of B12 deficiency
How do you diagnose B12
deficiency?
How do you treat it?
What is folate very important for?
How long does the body store it
for?
Pernicious Anemia (autoimmune anti-parietal cells,
therefore no IF), Malabsorption (illium), Pancreatic
insufficiency (no secretion, no R/IF switch
 Dx:
1. Morphology (macrocytic RBCs, hypersegmented
PMNs
2. Serum B12—look for LOW levels
2. Neurologic findings—demyelination of spinal
cord (proprioception, cerebral cx (dementia)
 Treatment:
B12 supplement, 1mg a day
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B12 is a cofactor (stored for four mo)
Folic acid to dihydrofolate
Without enough folate you don’t make
DNA!!
Folate stored for years
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B12 absorption
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Hemolytic anemias—increased
RBC degradation, decreased life
span of RBCs. What are clinical
features?
Extravascular vs. intravascular
hemolytic anemai
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Splenomegaly
Jaundice
Icterus (yellow discoloration of sclerae)
Ankle ulcers
Aplastic crisis from Parvo B19 (infect and
lyse RBCs)
Pigmented gallstones composed of bilirubin
Tea colored urine
Increased requirement for folate
1. Extravascular: macs in spleen, liver, marrow
remove damaged RBCs with Abs on them.
Hemolysis occurs in cells of RE system. Little
free Hb released.
2. Intravasc: destroyed directly in vasculature.
Free hb released into circulation.
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Laboratory findings for
increased RBC production
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Laboratory evidence for
increased RBC destructoin
Mech:
MeatB12R factor from salivary glands
binds to B12in duodenum, IF from stomach
switches with R factor—pancreatic secretions
are required for thisB12 is absorbed at
terminal illium
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Elevated reticulocyte count, polychromasia
Elevated MCV, RDW elevated
Erythroid hyperplasia in bone marrow
“frontal bossing;” marrow (skull, ribs, and
long bones) expands because of increased
erthropoiesis
elevated LDH due to cell death
elevated unconjugated bilirubin aka “indirect”
bilirubin
lower levels of serum haptoglobin; it binds to hb and is
rapidly cleared
Hemoglobinemia more hb than can be bound to
haptoglobin
Hemoglobinuria free hb in urine (reddish ur.)
Hemosiderinuria hb in urine taken up by tubular cells and
changed into hemosiderin
Schistocytes, spheerocytes, bite cells or blister cells
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Types of congenital hemolytic
anemia
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Hereditary Spherocytosis
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Red cell metabolic enzyme
defects
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Defects in membrane skeleton proteins—
hereditary spherocytosis
Defects in enzymes involved in energy
production—GP6D deficiency
Defects in hb structure or synthesis--
Defects in spectrin or ankyrin
People tend to be of European background
Blebs are pinched off by macs in
spleendecreased size of cell, lose biconcavity
Symptoms: splenomegaly, ankle ulcers,
pigmented gallstones, INCREASED
OSMOTIC FRAGILITY, increased MCHC
Tx: folate, splenectomy has a risk for OPSS
overwhelming post-splenectomy sepsis
Aerobic metab requires G6PD. This is required for
detoxification of oxidative stress and getting rid of
methemoglobin
Heinz bodies methoglobin that denatures and ppcs out
Type B=most prevelant, Type A=20% of healthy Af-Ams
have this.
Af. Mutant A- unstable and loses activity;
Mediteranian always low base activity
X-linked
Clincal features: triggered by drugs, infections, maximal
7-10d of drug exposure
Tx: avoid oxidant agents, folate repletion
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Oxidant drugs/chemicals which
cause hemolysis
Sulfa drugs, chloramphenicol
Dapsone
Quinine and chloroquine, primiaquine
Vitamin K
Fava beans
Naptha compounds--mothballs
•antibodies bind to red cellsRE system via Fc
R’spherocyte formation
1. warm antibody mediated—drug induced, reacts at 37’,
does not cause red cell agglutination. IgG
2. cold antibody mediated—react best <32’, do cause red
cell agglutination. IgM
Hallmark: positive coomb’s test
Immune mediated hemolysis
Two types? Hallmark?
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Coomb’s test
Causes of autoimmune hemolytic
anemia
Clinical Features of autoimmune
hemolytic anemia? Tx?
 Myeloid
 Looks for antibodies to red cells, comes as a set:
1. Directpt’s RBC’s with goat-anti-human IgG or
C3 inkit
2. indirecttest for IgG or C3 inserum
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Busulfan
Idiopathic
Complication of SLE, lymphoma, or leukemia
Infections can provoke it
Drugs can induce it
Associated with immune platelet destruction—
Evan’s syndrome
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Thiotepa
Fatigue
Pallor
Jaundice
Splenomegaly
Lab: increased reticulocyte, increased bilirubin,
increased LDH, positive coombs, sphereocytes
Tx: immunosuppression1. corticosteroids,
2. splenectomy, 3. cyclophosphamide
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Drug induced hemolytic anemias
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Cold agglutinin
disease/autoimmune hemolytic
anemia. Tx?
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Carmustine (BCNA
Innocent bystander mechanism antibodies +
drug land on RBCsRE system clears; drug
must be present
Hapten mechanism antibodies against durg +
RBC suface
True autoimmune mechansism antibody
production continues even in absence of drug
Dacarbazine—
IgM!! Directed against I or i antigen
Agglutinatecyanosis or ischemia in the cold
extremities.
Coombs is + for C3, negative for IgM
Etiology: IgM, Mycoplasm pneumonia,
Mononucleoisis, lymphoproliferative disease
Tx: cold avoidance, mittens, folate repletion
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Microangiopathic Hemolytic anemia (MAHA)
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Neutorphils
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Lymphocytes
Elevated neutrophil count
Neutropenia
Non-immune
Hallmark: schistocytes-scharp
Chemotaxis, phagocytosis, killing of phagocytosed
bacteria
Fine pink granules
Adherance rolling mediated by selectins, firm adhesion
via beta-2 integrins
Recognition and phagocytosis, make phagosome
Degranulation
Oxidative metabolism and bacterial killing. First NADH
oxidase converts superoxide into hydrogen peroxide.
Within phagosome, myeloperoxidase combines hydrogen
peroxide and chloride to form hydrochlorous acid
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Immune regulation
Hematopoitic growth factors
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Physiologic: Neonate, Exercise, Lactation, Pregnancy
Acute infection or inflammation
Acute hemorrhage
Non-hemolytic malignancies
Myeloproliferative diseases
Metabolic: uremia, acute thyrotixicosis, diabetic ketodosis
Drugs: G-CSF, GM-CSF, corticosteroids, lithium
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Seizures, electric shock
Post-splenectomy
Rebound after neutropenia
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Drugs: antipsycotics, antiepileptics,
propylthiouracil (anti-thyroid), gold salts, sulfa
drugs, chemotherapy
Infections
Immune: SLE, Felty’s syndrome
Familial/congenital
Endocrine hyperthyroidism, hyperpituitarism
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Felty’s syndrome
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Rheumatoid arthritis
Splenomegaly
neutropenia
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Eosinophilia
Neoplasia
Allergic disorders
Addison’s disease
Collagen Vascular disease
Parasites
Basophilia
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Hypersensitivity reactions
Chronic myeloproliferative diseases
Thyroid disease
Lymphocytosis
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Viral infections
Bacterial infections
CLL (chronic lymphocytic leukemia)
lymphomas
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immunodeficiencies
immunosuppressive drugs
lymphomas
granulomatous disease, including TB and
sarcoidosis
alcoholism
malnutrition
zinc deficiency
lymphocytopenia
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monocytosis
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LAD
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Chronic granulomatous disease
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Chediak-Higashi syndrome
Acquired defects in neutrophil function
bacterial infections: TB, syphilis, bucellois, SBE,
typhoid!!
Protozoa infections
Rickettsial infections—incl. rocky mountain
spotted fever
Myelodysplastic features
Leukemias
Other malignancies
Inflammatory bowel disease
Neutorphils lack beta2 integrins for surface
adhesion, unable to leave circulation
Peripheral WBC count is ELEVATED because
they can’t leave
Recurrent infections with lack of pus
X linked defect in components of NADPH
oxidase complex
Recurrent pyrogenic infections with organisms
that are catalase positivedegrades H2O2
Eg staph aureus (has Exotoxin F, TSS)
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Autosomal Recessive defects in granule fusion with
plasma membrane
Defects in leukocyte function, platelet function
Deaths in early childhood
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CALM
Corticosteroid use
Alcoholism
Leukemias
Myelodysplasia
Myeloproliferative syndrome
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