Quiz

Yourself
Hematology
Please note that this was put together by a UNC MS2
for other UNC MS2s. If you find any mistakes or have
any feedback, let us know especially if this was
remotely helpful in any way!

Characteristics of
Normal Adult Bone Marrow

Consists of approximately 50% fat cells;

Has more myeloid cells than erythroid cells

(myeloid:erythroid ratio 2:1 to 7:1)
Megakaryocytes are 2-5 per high power field
Plasma cells <3%
Lymphocytes <20%

Peripheral Blood
Morphology
1.
2.

Erythrocytes
Granulocytes
1.
2.
3.

3.
4.
5.

Neutrophils
Eosinophils
Basophils

Platelets
Monocytes
Lymphocytes (B & T cells)

Erythropoiesis what is the order?

Proerythroblast Basophilic
erythroblast

Orthochromatophilic
erythroblast

Reticulocyte

Polychromatophilic
erythroblast

Mature RBC

Granulopoiesis what is the order?

Myeloblast

Metamyelocyte

Promyelocyte

Band

Myelocyte*

Neutrophil

Identify the Type of Cell

Basophil

Eosinophil

Monocyte

Neutrophil

Anemia: When do you

give a transfusion right
away?
.Angina pectoris coronary insufficiency
.Shock
.Surgery

Iron kinetics as a function of

time

1. Childhood building both the hemoglobin

and storage iron by the intake and
conservation of iron- years

2. Adolescent and adult males full

complement of hemoglobin and storage iron

3. Adolescent and adult females iron content

is challenged by menses and childbirth

Causes of iron deficiency

1.
2.
3.
4.

inadequate intake
Malabsorption
diversion of iron during pregnancy
blood loss

RBC Characteristics in Iron

Deficiency Anemia?

Microcytic small RBCs

Hypochromatic pale RBCs

Ways to diagnose iron

deficiency anemia?
1)

Serum ferritin will be decreased.

2)
3)

Bone Marrow - staining

Treatment the simplest!

Careful, itll also be low in diseased/ill

patients (an acute phase reactant)

Causes of Macrocytic
Anemia

B12 deficiency
Folate deficiency

Uses of B12 & Folate

DNA synthesis

B12 = co-factor
Folate = transfer single carbon groups

How do we get folate and

B12?

Folate

In leafy green veggies, liver, yeast

Destroyed by cooking
Need 100-200 micrograms daily

Vitamin B12

In animal products
Unaffected by cooking
Need 1-2 micrograms daily

Folate Deficiency
3 major causes
Dietary
Malabsorption
Increased usage

3 ways to diagnose
folate deficiency
Morphology

macrocytic RBCs and

hypersegmented neutrophils

Serum folate
Red cell folate

Whats This?

Megaloblastic Anemia
Possible Causes?
B12 or folate deficiency

B12 Deficiency
3 major causes
Pernicious Anemia
Pancreatic Insufficiency
Malabsorption

3 ways to diagnose
B12 deficiency
Morphology
Serum B12
Neurologic findings
Demyelination of spinal cord,
cerebral cortex

Treating B12 & Folate

Deficiencies

B12

IM B12 supplementation for life

Folate

Daily folate supplement (1mg/day)

What do you see in the RBCs

below? How would we quantitate
this?

Anisocytosis refers
to red cells which
vary widely in size.
The RDW
mathematically
measures the
range of red cell
sizes.

What do you see in the RBCs

below? What diseases might
they be associated with?

Microcytosis refers to
red cells that are small.
You can use the
lymphocyte nucleus as
a visual reference, or
you can use the MCV
Associated with

Iron deficiency
Thalassemias
Sideroblastic anemia

What do you see

in the top slide?
Characterizes
what diseases?

Macrocytosis refers to
large red cells.
Associated with

Elevated reticulocyte count

B12/folate deficiency
Liver disease
Thyroid disease
Chemotherapy
Anti-retrovirals (AZT)

Whats wrong with these RBCs?

Measured how? A likely cause?

Hypochromasia
refers to red cells
that have too little
hemoglobin.
The area of central
pallor is more than
1/3 the total red cell
diameter.
This is measured by
the MCH (mean
cellular hemoglobin)
Iron deficiency

What do you see on this

slide?

Poikilocytosis
refers to red cells
that vary widely in
shape.
Remember that
anisocytosis refers
to red cells that
vary widely in size.

What do you see here?

Diseases?

Target cells look like

bulls-eyes.
Associated with

Liver disease
Thalassemias
Hemoglobin C
After splenectomy

What do you see here?

Diseases?

Spherocytes have a
loss of central pallor.
Can be seen in

Hereditary
spherocytosis
Autoimmune
hemolysis

If due to autoimmune
hemolysis, the cells
are smaller (i.e.
microspherocytes)

What do you see here?

Diseases?

Schistocytes are
red cell fragments
with sharp edges.
They are a
hallmark of
Microangiopathic
Hemolytic Anemia
(MAHA)

What do you see here?

Sickle Cells are

seen in sickle cell
anemia.
Notice that this
slide has target
cells as well as a
sickled cell.

What RBCs are

here? How do you
distinguish the
two? Associated
disease?

Echinocytes, or burr
cells, have small,
regular projections.
Seen in renal disease
Acanthocytes, or spur
cells, have larger,
irregular projections,
and are seen in liver
disease.

What do you see here?

What causes it?

Teardrop cells
Seen in
myelophthisic
processes, or
diseases of marrow
infiltration.
Deformed as it tries
to squeeze out of
the bone marrow

And what
have we
here?
What
causes
them?

Howell-Jolly bodies are peripheral, small,

round, purple inclusions within red cells that
represent nuclear remnants.
They are seen after splenectomy, or in
cases of splenic hypofunction.

What do you
see here?
Causes?

Rouleaux are linear arrangements of red cells

typically described as piles of coins on a plate
They are typically seen in disorders with
increased levels of immunoglobulin, such as
Multiple Myeloma or Waldenstroms
macroglobulinemia.
Severe hypo-albuminemia can also lead to
reouleux formation

What do you
see here?

Red cell agglutination occurs when the

red cells are coated with IgM. IgM is
large enough to bridge two red cells and
cause agglutination.
Unlike rouleaux, the red cell clumps are
not orderly and linear.

General Clinical Features of

Hemolytic Anemias

Splenomegaly is generally present

Patients have an increased incidence of
pigmented gallstones.
Dark urine (tea-colored or red), jaundice,
scleral icterus
Patients may have chronic ankle ulcers.
Aplastic crises associated with Parvovirus
B19, may occur
Increased requirement for folate

Post-splenectomy blood
findings

Howell-Jolly bodies - small round blue DNA

remnants in periphery of RBCs
Red cell abnormalities: target cells,
acanthocytes, schistocytes, NRBCs

Hemolytic Anemias Sites of Red Cell Destruction

Extravascular Hemolysis

Macrophages in spleen, liver, and marrow

remove damaged or antibody-coated red
cells

Intravascular Hemolysis

Red cells rupture within the vasculature,

releasing free hemoglobin into the
circulation
(and the circulation does NOT like this!)

Evidence for increased

red cell production

In the blood:
Elevated reticulocyte count
May be associated with high MCV
Circulating NRBCs may be present
In the bone marrow:
erythroid hyperplasia
reduced M/E (myeloid/erythroid) ratio
In the bone:
Deforming changes in the skull and long bones
(frontal bossing)

Evidence for Increased Red

Cell Destruction

Biochemical consequences of hemolysis in

general

Morphologic evidence of red cell damage

Elevated LDH
Elevated unconjugated bilirubin jaundice, scleral icterus
Lower serum haptoglobin
Hemoglobinemia
Hemoglobinuria
Hemosiderinuria
Schistocytes
Spherocytes
Bite/blister cells

Reduced red cell life-span

Hemolytic Anemias Classification by Etiology

Congenital

Defects in membrane skeleton proteins

Defects in enzymes involved in energy
production
Hemoglobin defects

Acquired

Immune-mediated
Non-immune-mediated

Most common defect leading to anemia?

Frequency?

Defect is in proteins of the membrane skeleton, usually

spectrin or ankyrin
Lipid microvesicles are pinched off in the spleen and other
RE organs, causing decreased MCV and spherocytic
change.

Diagnosing?

Autosomal dominant

Pathophysiology?

Affects 1/5000 Europeans

Transmission?

Hereditary spherocytosis

Increased osmotic fragility

Treatment?

Supplemental folate
Splenectomy (but carefully consider timing in children)

 Functions of GP6D?

Detoxification of metabolites of oxidative stress

Elimination of methemoglobin

NADPH
Reduced glutathione

Heinz bodies
Causes the formation of bite/blister cells

Type B is more prevalent

Type A is in 20% of healthy Africans
In 10-14% of African American men
Also prevalent in the Mediterranean
X-linked

Important Products of GP6D?

Diagnostic methemoglobin precipitate?

Epidemiology of GP6D Deficiency?

G6PD Deficiency
Agents to avoid
For SKAND

Fava beans
Sulfa drugs
Vitamin K
Anti-malarials
Naphtha
compounds
(mothballs)
Dapsone

What cell is below?

Blister cell

Sorry Skand at least your girlfriend thought it was funny!

How will you

diagnose an
autoimmune cause
of hemolytic
anemia?

Coombs Test

The Direct Coombs = DAT (Direct

Antiglobulin Test) - tests for IgG or C3
DIRECTLY ON THE RED CELLS. Youre
adding patient RBCs!
The Indirect Coombs - tests for IgG or
C3 in the serum which react with
generic normal red cells. This is also
known as the antibody screen in bloodbanking. Youre adding patient serum!

Warm-Antibody Hemolytic
Anemias
Clinical Features

Splenomegaly, jaundice usually present.

Depending on degree of anemia and rate of fall in
hemoglobin, patients can have VERY symptomatic
anemia
Lab Dx reticulocytes, bili, LDH,
positive Coombs test - both direct and indirect.
SPHEROCYTES are seen on the peripheral
smear.

Warm-Antibody Hemolytic
Anemias Treatment

Immunosuppressive Treatment

First line is corticosteroids (i.e. prednisone).

If steroids fail to work, or if patient relapses after
steroid taper, splenectomy may be necessary.
Immunosuppressives such as cyclophosphamide
(Cytoxan) or azathioprine (Immuran) may be
required as third-line therapy.

Folate repletion
Transfusion determining factors:

Heart failure, shock?

Inadequate reticulocyte count?

Drug-Induced Immune Hemolysis

Three general mechanisms

Innocent bystander

Hapten

the Ab was directed at the drug, but it cross reacted

w/ RBCs
Drug must be present for hemolysis to occur
Quinine, Quinidine, Isoniazide
Drug binding to RBC Abs that react to this complex
Penicillins, Cephalosporins

True autoimmune

You dont need the drug in the body any more to get
the hemolysis
Alpha-methyldopa, L-DOPA, Procainamide

Cold Agglutinin Disease

IgM antibodies bind to I antigens of RBCs when

cold (falls off when warm)
Causes agglutination cyanosis & ischemia of
extremities
Direct Coombs test + for C3, but not IgM!
Has both intravascular and extravascular
hemolytic components
Primary, or associated w/ Mycoplasma,
Mononucleosis, or lymphoproliferative disease
Treat by avoiding cold & folate repletion
Corticosteroid and splenectomies uneffective (big
difference from warm antibody-mediated
hemolysis)

Non-Immune Hemolytic
Anemia
Classification

Mechanical trauma to red cells

Microangiopathic Hemolytic Anemia

Abnormalities in heart and large vessels
March Hemoglobinuria

Infections
Drugs, Chemicals, and Venoms

Chemical & Physical Agents

Causing Hemolysis
BAr CoIns

Severe Burns
Arsenic
Copper
Insect and spider bites

Infections Causing
Hemolysis

Malaroa
Babesia microti
Clostridium welchii
Bartonella bacilliformis

Basic Structure of All

Human Hemoglobin

Each hemoglobin molecule is composed of:

4 iron-containing, tetrapyrrole heme rings

4 polypeptide globin chains

2 alpha chains
2 non-alpha chains

Each globin chain has 141 amino acids

All non- chains have 146 amino acids

There is considerable structural homology

among the non-alpha chains

Normal Human
Hemoglobins

Gower Hemoglobin (Embryonic)

Fetal Hemoglobin (HbF)

2 2

Major Adult Hemoglobin (HbA)

2 2

2 2

Minor Adult Hemoglobin (HbA2)

2 2

Heme Synthesis

Begins with condensation of glycine & succinyl

Co-A -amino levulinic acid ( -ALA).

The rate-limiting step in heme synthesis

Requires intra-mitochondrial enzyme ALAsynthase

-ALA travels to cytoplasm; converted to

porphobilinogen (PBG), a monopyrrole.

PBG converted from monopyrrole to biologically

active form protoporphyrin IX, a tetrapyrrole.

Iron inserted into tetrapyrrole ring n the

mitochondria

Heme synthesis stimulated by iron & repressed

when iron is inadequate (e.g., iron deficiency)

Location of the Globin Genes

Genes for the non- chains are located on

Chromosome 11. This is referred to as the globin gene cluster

Chain genes are located on Chromosome

16

There is duplication of the genes for:

Globin
Globin (G and A ) *

and A differ from one another only at position 136

where they have glycine & alanine respectively
G

Synthesis of the non- chains involves a

coordinated switching that proceeds from
embryonic () to fetal ( ) to adult ( ) globin
chains

Yolk sac () liver/spleen ( ) marrow ( )

Structure of the
Hemoglobin Molecule

Each Hb is comprised of 4 subunits: 2 identical

chains & 2 identical non- chains
Each chain is arranged in the form of an -helix with
8 individual helical segments (labeled A - H)
Each globin molecule has both hydrophobic &
hydrophilic areas
The iron-containing heme ring is buried within a very
hydrophobic region of the globin that is called the
Heme Pocket
The hydrophobic nature of this region protects the
iron residue from oxidation, thereby maintaining it in
the active, reduced form
Each iron atom in the center of the heme residue is
held in place and kept in the active, reduced Fe++
state by two histidine residues

Possible Consequences of a
Hemoglobinopathy

No detectable effect

Instability of the hemoglobin molecule

An increase or a decrease in oxygen

affinity

Inability to maintain the heme iron in

its active, reduced state
(methemoglobinemia)

Decreased solubility of the

hemoglobin molecule

Unstable
Hemoglobinopathies

Most of the unstable hemoglobinopathies

involve a mutation in the region of the heme
pocket
These mutations enable water to gain access to
this very hydrophobic region of the molecule
The end result is heme instability, denaturation,
and release of heme from its binding site
The demonstration of Heinz Bodies in these red
cells is evidence of the presence of an unstable
hemoglobin mutant

Hemoglobinopathy Altering
Oxygen Affinity

Increased Oxygen Affinity

Stabilization of the Oxy conformation increases the

oxygen affinity of the hemoglobin molecule

The presence of such an effect can be confirmed by

demonstrating a left shift in the Oxygen Saturation
Curve

Individuals with an increase in oxygen affinity typically

exhibit erythrocytosis
Decreased Oxygen Affinity

Stabilization of the Deoxy conformation produces a

decrease in the the oxygen affinity of the hemoglobin
molecule

The presence of such an effect can be confirmed by

demonstrating a right shift in the Oxygen Saturation
Curve

Individuals with a decrease in oxygen affinity are

typically somewhat anemic

Hemoglobin M
Diseases

The Hemoglobin M disorders are seen when a

substitution has occurred at the locus of either
the proximal or distal histidine
Typically, this involves a his
tyr substitution
which then forms an iron-phenolate complex
Hemoglobin with its iron in the oxidized Fe+++
state is incapable of binding oxygen
This form of hemoglobin (called Methemoglobin)
has a brownish appearance
Patients with Hemoglobin M disease are typically
cyanotic

The Sickle Cell Diseases:

Inheritance, Appearance of
Symptoms, Diagnosis

The most common sickle cell disease (SCD) is called sickle

cell anemia (HbSS)

However, there are a number of other SCD genotypes compound heterozygous states

The sickle mutation is inherited in an autosomal codominant fashion

Individuals with sickle cell trait (AS) have roughly equal

amounts of HbA & HbS and are generally asymptomatic

Compound heterozygotes (e.g., SC or S- Thalassemia)

generally express a significant sickle cell disease

We dx/ with electrophoresis:

-

Hb C has a positive; HbS is neutral, HB A is negative.

Movement: HbA > HbS > HbC

Sickle Cell Anemia

Pathophysiology
presence of the abnormal (or sickle)

The presence of the abnormal (or sickle)

hemoglobin (HbS) within the cells of the affected
individuals
The decreased solubility & the tendency of this
abnormal hemoglobin to polymerize when it
assumes the deoxy conformation
In HbS, the negatively charged glutamic acid at 6
position is replaced by an uncharged valine residue
In deoxy conformation, the valine at 6 position
approaches the phenylalanine at 85 position on
adjacent HbS molecule.
Multiple critical contact points that enable the
hemoglobin molecules to attach to one another
The polymer begins as a small nucleus of
hemoglobin molecules aligned polymer with a
total of 7 anti-parallel pairs (or 14 individual
hemoglobin chains)

SICKLE CELL DISEASE

Clinical Features

Painful Vaso-occlusive Crises

Strokes
Retinopathy
Acute Chest Syndrome
Pulmonary Hypertension
Sickle Cell Nephropathy
Biliary Tract Disease
Leg Ulcers
Avascular Necrosis of the Large Joints

SICKLE CELL DISEASE

Therapeutic Approaches

Reactivate Fetal Hemoglobin

Production using Hydroxyurea!

Chemical inhibition of Hb S
polymerization
Increase in intracellular hydration

Altering RBC/Endothelial cell interactions

Bone marrow transplantation
Gene therapy

What is this an
example of?
Typical
Diseases?
Megaloblastic
Anemia

Red cells are

macrocytic.
Hypersegmented
neutrophils can be
seen.
Vitamin B12 or
folate deficiency

Sickle Cell Anemia

What Disease?

Target Cell

Sickled Cell

Platelet Function in Hemostasis what is it called?

Primary Hemostasis!
What are the functions?

(1) Adhesion
exposure to
collagen;
binding to von
Willebrand
factor via GPIb
receptor
(4) Aggregation and
Surface Coagulation

(2) Accumulation and

Shape Change

(3) Granule
Content
Release
ADP released,
integrin
activation,
fibrinogen binding

Main Types of Coagulation Factors

Zymogens/active enzymes:

Vitamin K-dependent -- factors II, VII, IX, X

Vitamin K-independent-- XI, XII, and XIII

Cofactors:

factor V, factor VIII, tissue factor, and

von Willebrand factor

Non-protein cofactors:

calcium and phospholipid surfaces

Fibrinogen:

fibrinogen is converted to fibrin by thrombin

Laboratory Assays to Monitor Coagulation Parameters

Prothrombin Time (PT)
Activated Partial Thromboplastin Time (APTT)
Thrombin Clot Time (TCT)
Appropriate tube to use for specimen?

Citrate solution as anticoagulant.

Stops clotting by binding calcium.
Blood to additive ratio 9:1
Plasma, NOT Serum!

Prothrombin
Time (PT)

XII

Extrinsic
Pathway

XI
IX

VII

VIII
X
Common
Pathway

V
Prothrombin (II)

Fibrinogen

PT
what
does it do?

Test plasma + tissue

thromboplastin (source
of tissue factor) + CaCl2
Fibrin clot
Tests extrinsic
pathway:
Formation of tissue
factor-factor VII
complex to
formation of fibrin.
Prolonged PT:
Deficiencies of
factors II
(prothrombin), VII, X,
V, and fibrinogen.

Activated Partial
XII
Thromboplastin
Time (APTT)
XI
IX
Intrisic
Pathway

VII

VIII
X

Common
Pathway

V
Prothrombin (II)

Fibrinogen

APTT What does

it do?
Test plasma + partial
thromboplastin (lipid) +
particulate activator +
CaCl2 Fibrin clot
Tests intrinsic pathway:
Activation of factor
XII to formation of
fibrin
Prolonged APTT:
Deficiencies of
factors XII, XI, IX,
VIII, X, V, II,
fibrinogen (and
kallikrein and
HMWK).

Thrombin Clot
Time (TCT)

XII
XI

TCT What does

it do?
Test plasma + thrombin
Fibrin clot

IX
VII

VIII
X
V

Prothrombin (II)

Fibrinogen

Measures conversion of
fibrinogen to
polymerized fibrin
Sensitive to
quantitative and
qualitative fibrinogen
deficiencies.

Hemophilia A
Factor VIII
(VIII)

Hemophilia B

Factor X

IXa
(IX)

VIIIa
Factor Xa
Fibrinogen

Prothrombin

Va

Xa

Thrombin
Fibrin

Thrombus

Roles of Von Willebrand Factor

von Willebrand
Factor VIIIFactor (vWF)

Primary Hemostasis

Secondary Hemostasis

von Willebrand Disease (vWD)

How does it differ from classic hemophilia?
(1) Suffer from mucocutaneous hemorrhage rather
than hemarthroses like in hemophilia.
(2) Autosomal inheritance trait, so men and women have
similar prevalence, rather than X-linked like hemophilia.
(3) Consistently had prolonged bleeding times unlike the
normal bleeding times in hemophilia.

Virchows Triad
Virchow (1845) thought that
thrombosis was the result of
abnormalities in:
A) the vessel wall;
B) blood flow, and
C) the properties of blood.

Thrombosis: 2 Types
Arterial: Injury to the
endothelium; platelets adhere and
a dense platelet aggregate is
formed, and coagulation system
activated.
White thrombus
Venous: Related to decrease blood flow (stasis);
venous thrombosis is dominated by the
coagulation system, the production of fibrin-rich
thrombi.
Red thrombus

Regulators of Blood Coagulation:

3 useful systems
Protein C Anticoagulant System:
Thrombin-Thrombomodulin
Protein C and S [Activated Protein C (APC) and Protein S]
Protease Inhibition by Antithrombin with Heparin:
Antithrombin (ATIII)
Heparin (drug)/Heparan Sulfate (naturally-occurring on
vessel wall)
Fibrinolytic System:
Tissue plasminogen activator (tPA)
Plasminogen/Plasmin
Plasminogen activator inhibitor-1 (PAI-1)/Antiplasmin

How does the Protein C

Anticoagulant System Work?

Thrombin binds to thrombomodulin on

vessel wall
Thrombin, once bound to thrombomodulin,
can no longer cleave fibrinogen into fibrin
or activate factor V or platelets
Thrombin-thrombomodulin complex
activates Protein C (vit K dep) APC
APC associates with Protein S
APC + S cleaves/inactivates factors Va and
VIIIa

How Does the Antithrombin

Anticoagulant System Work?

Antithrombin = serine protease

inhibitor (serpin)
Circulates freely in the plasma
Inhibits thrombin, IXa, Xa, XIa
Activity increased by:

Heparan sulfate (basement membrane)

Heparin (drug)

How does the Fibrinolysis/Clot

Lysis Anticoagulant System
Work?

Plasminogen freely circulates in the plasma

Endothelium secretes tissue-type
plasminogen activator (tPA)
tPA converst plasminogen plasmin
Plasmin lyses clots
Plasminogen activator inhibitor-1 (PAI-1) is
secreted by endothelium
PAI-1 downregulates tPA activity
Its another fine balancing act!

Thrombosis
Why heparin therapy?
Inhibits further thrombus formation almost immediately.
Why warfarin therapy?
Depletes vitamin K-dependent factors to impair procoagulant
function.
Why tissue plasminogen activator therapy?
Degrades thrombus to re-establish blood flow.
Family history?
Necessary to determine if familial or acquired clinical scenario.
Common hereditary cause of venous thrombosis?
factor V Leiden: a plasma protein resistant to inactivation by
the protein C system

Some Acquired Causes of Venous Thrombosis

Surgery and trauma
Prolonged immobilization
Older age
Cancer
Myeloproliferative disorders
Previous thrombosis
Pregnancy
Use of contraceptives or hormone-replacement therapy
Anti-phospholipid antibodies

Anticoagulant Therapy: Medications

Heparin-

Heparin binds to antithrombin, which

converts it to a very potent and immediate inhibitor of
thrombin, factor Xa and other proteases in the clotting
cascade. IV

Warfarin (or Coumadin)-

Oral anticoagulants
produce their effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K
epoxide).

Fibrinolytic enzymes-

Induction of a fibrinolytic
state by the infusion of plasminogen activators is used in
massive pulmonary embolism and to restore the patency of
acutely occluded arteries.

Benefits of Low Molecular Weight Heparins (LMWH)

LMWHs have a higher affinity for antithrombinfactor Xa.
Longer plasma half-life.
Safe and effective for venous thromboembolism, and
with unstable angina or acute thrombotic stroke.
Convenient, given subcutaneously without laboratory
assay monitoring (allowing for patient and home care
options).
GENERAL Heparin Targets
-Thrombin
-IXa, Xa, XIa, XIIa
-Measure efficacy with APTT

Vitamin K Cycle and Effect of Warfarin

Vitamin K antagonists exert their anticoagulant effect by
inhibiting vitamin K epoxide reductase and vitamin K reductase
activities.
All vitamin K-dependent coagulant proteins are impaired:
prothrombin,
factor VII,
factor IX,
factor X,
anticoagulant protein C and protein S
Oral anticoagulants cause hepatic production and secretion of
partially and fully de--carboxylated and dysfunctional proteins.
Can reverse effects with emergency administration of Vitamin K
Monitored by PT; most closely reflects VII (shortest K-dep
life)
Must avoid use during pregnancy!
PO administration

Treatment of Venous Thromboembolism

Treatment strategy differ between arterial from
venous circulation.
Objective of treating/preventing venous thrombosis:
-prevent extension of thrombus;
-prevent thrombus from embolizing;
-render fibrin more susceptible to fibrinolysis.
(standard in threat of massive PE)
-standard tx in acute venous thrombosis & PE
heparin + oral vitamin K antagonists

Arterial Thrombosis

Main pathogenic mechanism for acute MI,

unstable angina, sudden coronary death
Tx: heparin, LMWH, warfarin, anti-platelet
cmpds, fibrinolytics, ASPIRIN
Clopidogrel and Ticlopidine inhibit platelet
aggregation by blocking ADP receptor on
platelet and inhibiting activation of GPIIb/IIIa.

But Ticlopidine may cause TTP!

Abciximab (ReoPro), Eptifibatide (Integrilin),

Tirofiban (Aggrastat) bind GPIIa/IIIa receptor
on platelets preventing fibrinogen binding

What is this? What will it give rise

to?
A Megakaryocte that will shed off Platelets!

Platelet Plug Formation

Adhesion

Aggregation

Platelets stick to each other via fibrinogen bridges.

GPIIb/IIIa to fibrinogen
Activators: ADP, collagen, 5HT, Epi, TXA2, thrombin

Providing a phospholipid
Secretion
scaffold
for coagulation
Platelets release granular
contents and potentiate
clotting
reactions,
like
generation
Spits out pro-clotting
materials:
ADP, Epi, factor V,
vWF, fibrinogen
of Xa and thrombin!

And another role of platelets?

Platelets stick to injured vessel wall.

GPIb/IX to vWF and collagen

Thrombocytopenia
three broad categories of
causes
Underproduction
Peripheral Destruction
Splenic sequestration

If you saw this in a blood sample and

were told the patient has too few
platelets, what would you say?

WRONG!!!

Its Pseudothrombocytopenia!
Or in Dr. Mas words, you
could say damn, theres more
than one platelet on this field

YIKES! Whats this?

Whats the
ACK, and this?

Petechia
e
difference?

Purpura are formed

when Purpura
petichiae coalesce

Thrombocytopenia
Underproduction Causes

Marrow failure: myelodysplasia, aplastic

anemia, vitamin deficiencies (B12/folate)
Marrow infiltration: tumor,
granulomatous diseases, fibrosis,
leukemias, lymphomas
Marrow toxins: drugs (esp. alcohol),
radiation, infections
Congenital: Wiskott-Aldrich Syndrome,
Thrombocytopenia Absent Radius
Syndrome (TAR), May-Hegglin

DIC- Diagnosis

Elevated PT - due to consumption of Factor

VII, which has the shortest half-life (4 hrs)
of all clotting factors.

Low platelets
Low/falling fibrinogen
Elevated fibrin degradation products

When advanced, the APTT can be prolonged as

well, as the other clotting factor levels fall.

(FDPs/FSPs) or D-Dimers

Can see a few schistocytes on the

peripheral smear in most cases. (MAHA)
Low clotting factor levels

DIC - Etiologies and

Treatment

Can be associated with:

gram negative sepsis,

severe burns,
obstetrical disasters,
certain leukemias or tumors,
shock,
insect or snake venoms

TREAT THE UNDERLYING CAUSE!!!

Supportive measures can include:

transfusion of platelets
clotting factors, fibrinogen
+/- low dose heparin to halt thrombin generation.

Low dose heparin can slow down the forest fire

TTP - Diagnostic Features

(aka The Pentad)

Whats normal in TTP thats

NOT in DIC?

Microangiopathic Hemolytic Anemia (MAHA) MUST

BE PRESENT
Elevated LDH, elevated bilirubin
Schistocytes on the peripheral smear
MUST BE PRESENT
Low platelets - MUST BE PRESENT
Fever
Neurologic Manifestations
- headache, sleepiness, confusion, stupor, stroke,
coma, seizures
Renal Manifestations
hematuria, proteinuria, BUN/Creatinine

PT, fibrinogen levels,

FDPs/D-dimers

TTP - etiology

Associated with an antibody against or a deficiency of

the protease (ADAMTS-13) that cleaves the very high
molecular weight multimers of von Willebrands factor
vWF accumulates abnormal platelet adhesion and
activation
Can be induced by drugs, including

ticlopidine,
quinine,
cyclosporine,
FK-506,
mitomycin C

Increased incidence with pregnancy or HIV

TTP - Treatment

Treatment relies on PLASMA EXCHANGE.

Remove all inciting agents (ultra-high MW

multimers of vWF)
Restoring ADAMTS-13
Adjunct therapies, including glucocorticoids
and anti-platelet agents can be used but are
of uncertain benefit.

Secondary measures if no response to

plasma exchange include splenectomy,
vincristine.

AVOID PLATELET TRANSFUSIONS

- THEY FUEL THE FIRE

Thrombocytopenia Drugs/Immune Mechanism

Drugs can lead to immune-mediated

thrombocytopenia by a variety of mechanisms.
1) directly stimulating anti-platelet
antibody production
2) a hapten mechanism
3) innocent bystander phenomenon.

Thrombocytopenia Drugs/Immune Mechanism

Qua BASH (dont ask me, Im sleepy)
Quinine/quinidine
Beta-lactam antibiotics
Abciximab (ReoPro)
Sulfa drugs like Trimethoprimsulfamethoxazole
Heparin

ITP - Therapy

Initial therapy relies on use of

corticosteroids (e.g. prednisone).
These can take 48-72 hrs to take
effect.
If platelet count is <10K or if patient is
bleeding, need more rapid therapy-use IVIg
If patient is Rh positive, can use Anti-D
(WinRho) in place of IVIg. (need a
spleen)
2nd line splenectomy
3rd line - immunosuppression

Compare TTP, DIC, ITP

Low platelets
Schistocytes

TTP
DIC
Must have Usually
Must have Maybe

PT/FDP/
Fibrinogen

Normal

Low

Transfuse
platelets?

NEVER

Maybe

Treatment

Plasma
Tx underexchange lying
cause

ITP
Must have
Never
n/A
Only if pt is
bleeding

Steroids,
IVIG,
AntiD

Qualitative Platelet Disorders Differential

Congenital -

Glanzmanns thrombaesthenia - defect in

IIb/IIIa
Bernard-Soulier - defect in Ib/IX

Acquired

uremia
Drugs - ASA, NSAIDs, antibiotics, ReoPro,
Herbs - ginkgo, garlic, Vitamin E
Myeloproliferative diseases

Diagnosis?
Normal APTT/PT/TCT, prolonged bleed time

Anti-Platelet Drugs

Aspirin

Thienopyridine Derivatives

Inactivates COX-1, decreasing TXA2 (a platelet

agonist)
Prevent stroke, MI, CAD, peripheral arterial
occlusion
Ticlopidine, Clopidogrel
Blocks ADP (platelet agonist)
Ticlopidine may cause TTP

GPIIb/IIIa inhibitors

Abcizimab (ReoPro), Eptifibitide (Intergrillin),

Tirofiban (Aggrastat)
Blocks platelet aggregation by blocking fibrinogen
receptor on platelets

Donor screening criteria:

Allogeneic (volunteer)

Hgb >12.5
BP, pulse: healthy
Uniform Donor screening questionnaire
Infectious Disease Screening of donor

Hepatitis B
Hepatitis C
HIV I/II
HTLV I/II
Syphilis

Autologous (for self): Less stringent criteria

Parts Collected Out of a

Whole Blood Collection
pRBC
Platelet

rich plasma (platelet

concentrate)
Plasma (FFP)

pRBC Storage

RBCs suspended in
anticoagulant (citrate based) and,
Additive Solution - AS
Provides nutrients to support RBC
metabolism
42 days = Shelf life
Volume= 250 to 300 mL
65% RBCs, 35% plasma and AS
contains WBCs and some platelets
may be frozen w/ glycerol (cryoprotectant) for
10 yrs

pRBC Transfusion

1 unit = 1 g/dL Hb; 3% hematocrit

Decide w/ clinical judgement NOT lab values

Transfuse slowly, so you can catch adverse rxn
RBCs should be infused alone or with 0.9% NaCl
through a 170m clot-screen filter
NEVER mixed with :

Calcium containing solutions

Dextrose

May cause clumping or clots

Hypotonic,may cause hemolysis or clumping

Medications
Hypertonic solutions

AVOID infusing with Lactated Ringers

Fresh Frozen Plasma:

Storage, Contents, Tx?
Frozen w/in 8hrs of collection
Stored -20 C for up to 1 year
Once thawed, can be kept at 1-6 C for 24 hrs
Contents:
1 unit/mL of all clotting factors including labile Factors V and VIII
~400 mg fibrinogen
Citrate as anticoagulant
No platelets
Treatment of multiple coagulation factor deficiencies
Massive transfusion
Trauma
Liver disease
DIC
Unidentified deficiency

Platelets: Storage, Dosing, Treatment,

Matching

Pooled platelet concentrates (PCs) from several

whole blood donations or apheresis
Suspended in citrated plasma
Stored @ 20-24 C for 5 days only highly
susceptible to shortages!!!
One therapeutic dose platelet count 30-50k
PLT surface

Trace amts RBCs Rh type important

ABO antigens but not Rh

Platelet specific Ags
HLA- A and HLA-B
Rh- female gets Rh- PLT

Tx: thrombocytopenia, qualitative defects

Monitor efficacy of transfusion via PLT count
w/in 1hr of transfusion conserve resources

Cryoprecipitate: Contents,
How to Get it, Tx, Dosing?

Cold insoluble white precipitate

Forms when FFP is thawed at 1-6 C
Removed from FFP by centrifugation, then refrozen at 20 C
CONTAINS:
80 to 150 IU Factor VIII:C (antihemophilic factor)
150 mg fibrinogen
Von Willebrand Factor
Tx:
Deficiency of fibrinogen, Factor VIII
Improve platelet function in uremia
Dose calculation based on
Patients weight and hematocrit : plasma volume
Desired increase in Factor level

ABO Blood Group: Population

Frequency

O
A
B
AB

45%
41%
10%
4%

What is ABO?

specific terminal sugar residues on a

large glycolipid backbone on the RBC
membrane
The ABO genes

Codominant inheritence
Encode for a glycosyl transferase enzyme
Adds the specific terminal sugar to the
glycolipid backbone
Convey immunogenicity
O = fucose
A = N-acetyl galactosamine
B = galactose

ABO Discrepancy

when the front and back types do not match

Front = antigen on cells

Back = antibody in serum

Must resolve prior to transfusion

Common Causes:

Cold agglutinin
Weak or absent antibodies in elderly or infants
Interfering substance: protein, dextran
Weak subgroup of A or B

RECIPENT
BLOOD
TYPE

O
A
B
AB

RED CELLS

PLASMA

AB, A, B, O

AB

Whose
Whose
RBCs
Plasma
O
O,
A, B, AB
A, they
O
A, AB
Can
Can
they
B, O
B, AB
Take?
Take?

ABO Antibodies

ABO Antibodies anti A , anti B

Predominantly IgM >> IgG > IgA

IgM reacts at room temperature

Can bind complement intravascular

hemolysis
Naturally occurring

Anti A and B form due to similar antigens in

nature

(bacteria, pollen, etc)

Transfusion exposure or pregnancy NOT required

IgM pentamer can agglutinate RBCs

Immediate transfusion reactions possible

Rh Blood Group: the 2 nd most

impt
Rh System : family of 51 antigens

Integral membrane proteins, well formed during fetal development

Rh Antigens of routine importance: D, C, c, E, e
Rh null are individuals lack all Rh proteins
Clinically significant in:

Transfusion practice
Transfusion reactions
Hemolytic disease of newborn

D Antigen (Rh Type)

D+ 85% prevalence
D- 15%

= Rh+
= Rh-

Highly immunogenic
Clinically significant with RBC transfusion & platelet transfusion

Females of child bearing potential need Rh- blood

Immune sensitization required to develop Rh system antibodies

Transfusion or pregnancy

IgG , react at 37 C - must incubate in the lab to demonstrate them

Typically cause extravascular hemolysis, if present
Some may activate complement and cause intravascular
hemolysis

Comparison b/tw ABO and Rh

Blood Groups

ABO

IgM >> IgG > IgA

Test at room temp
Causes intravascular
hemolysis
Naturally occurring

Bacteria, pollen

Rh

IgG
Test at body temp
Causes extravascular
hemolysis
Sensitization required

Pregnancy, transfusion

RBC Blood Groups and

Antibodies

Other protein blood groups

K
Fy a , Fy b
Jk a, Jk b

Integral membrane proteins are well formed at

birth
Antibodies predominantly IgG
Delayed Transfusion Reactions

Kell
Duffy
Kidd

Extravascular hemolytic reactions

Intravascular hemolysis more likely with Kidd Jka, Jkb
due to complement binding

Hemolytic disease of newborn

Front & Back Types

FRONT TYPE whats on the cells?

BACK TYPE whats in the serum?

Mix 2 drops of patient cells with 2 drops of

reagent antibodies to A, B and D antigens
in different test tubes, Agglutination
indicates presence of antigen
Mix 2 drops patient serum with both A and B
reagent cells. Agglutination indicates
presence of antibody

Front and back types should match

Antibody Screen

Determines if patient has antibodies to the other

major blood groups
Requires

Combining pt serum with 3 different RBCs with known

blood group phenotype
Incubate at 37 C to detect IgG antibodies
Addition of Coombs serum

Anti-human IgG : enables in vitro agglutination if IgG present

due to monomeric structure of IgG

If screen is +, antibody specificity is determined

by a more extensive panel of testing RBCs

Types of Crossmatch

Immediate Spin Crossmatch

Full Crossmatch

Rapid, room temp mixing of patient serum with

donor RBCs to confirm ABO compatibility
For patients with antibodies
Requires incubation and Coombs serum to confirm
the patients IgG will not react with donor RBCs

Electronic Crossmatch

Alternative for Immediate spin crossmatch for

patients without antibodies

Special Circumstances

Emergency Release

When delaying transfusion poses risk of

death
Insufficient time to perform type screen and
crossmatch
Requires MD signature

Conditional Release

Blood may be crossmatch compatible

however, blood bank testing is incomplete
or cannot completely resolve antibody
testing (ex: warm auto antibody)
Requires MD signature

Component Modifications

Leukocyte reduction
Filtration with specialized leukocyte removing filters 3 log leukocyte
reduction

Prevent CMV transmission

Prevent alloimmunization to leukocyte antigens for those w/ chronic
transfusion
Prevent recurrent febrile non-hemolytic transfusion reactions

Washing
Removal of plasma by washing RBC or platelets with saline

For prevention of severe allergic reactions

Anaphylaxis
IgA deficiency

Time consuming , labor intensive, delays transfusion, decreases

transfusion increment slightly
Does not substitute for leukocyte reduction
Irradiating
Prevent graft versus host disease GVHD ( Transfusion is a transplant)
Indicated in severe immunodeficiency settings

BMT
Hematopoietic malignancies undergoing chemotherapy
Premature infants
Severe combined immunodeficiency

Blood products from relatives must also be irradiated due to HLA antigens

Adverse Effects of Transfusion

Acute Immune Transfusion Reactions < 24 hours

Allergic
Hemolytic
Febrile, non-hemolytic
Anaphylactic
Transfusion related acute lung injury (TRALI)

Delayed Immune Transfusion Reactions > 24 hours

Hemolytic
GVHD
Platelet refractoriness
Post transfusion Purpura (development of anti-platelet antibodies)

Acute Non-Immune Transfusion Reactions

Circulatory Overload (Volume excess)

Septic shock from bacterial contamination of blood product

Delayed Non-Immune Transfusion Reactions

Iron Overload
Infectious Disease transmission

Suspected Transfusion
Reaction
Hemolytic reaction symptoms are not specific
and include:

Fever
Chills
Hypotension
Oozing from IV site
Back pain
Hemoglobinuia red urine

If any of these occur STOP transfusion, provide

appropriate supportive care, notify blood bank
Send repeat samples for blood bank evaluation
DO NOT restart the unit

Exceptions: mild urticaria that responds to antihistamine

White Cells
What are the cell types?

Granulocytes

Neutrophils
Band forms
Eosinophils
Basophils

Lymphocytes
Monocyte/Macrophages

ID the cell!
Band Cell

Eosinophil
Basophil

Monocyte
Lymphocyte

Neutrophil

What is this? What does it

do?

Neutrophils!

PMNs (polymorphonuclear neutrophils)

polys
segs (short for segmented neutrophils)

Most common white cell

Pale pink granular cytoplasm with
condensed, segmented nucleus
7 hr life
Functions include

chemotaxis,
phagocytosis,
killing of phagocytosed bacteria

What is this? What does it

do?

Eosinophil
Granulocytes with large, refractile,
orange-pink granules.
Nucleus is typically bilobed.
Functions include all PMN functions,

Chemotaxis
Phagocytosis
Killing of phagocytosed bacteria

serving as effector cells for antibodydependent damage to parasites,

regulation of immediate-type
hypersensitivity reactions

inactivation of histamine and

leukotrienes released by basophils and
mast cells

What is this? What does it

do?
Basophils
Large, dark blue granules which
overlie the nucleus.
The most uncommon of all
granulocytes
Functions include

mediation of immediate-type
hypersensitivity
modulation of inflammatory
responses by releasing heparin and
proteases
Precursor of tissue mast cells

What is this? What does it

do?

Lymphocyte
Lymphocytes have an oval nucleus,
with a thin rim of blue cytoplasm.
There may be a few very fine
purplish-red granules.
The nuclear border is smooth.
Functions in immune regulation
and production of hematopoietic
growth factors.
Functions in

immune regulation and

production of hematopoietic growth
factors.

What is this? What does it

do?
Monocyte

Largest white cell normally found in

the periphery
Has a folded nucleus with uneven
countour
Slate grey cytoplasm--there may be
vacuoles
Functions Include:

chemotaxis,
phagocytosis,
killing of some microbes,
antigen presentation,
release of IL-1 and TNF, which
stimulates bone marrow stromal cells
to produce growth factors, including:
GM-CSF, G-CSF, M-CSF, and IL-6.
Precursors of tissue macrophages

Causes of Elevated Neutrophil

Count
Physiologic

exercise,
pregnancy,
lactation,
neonates

Acute infections
Acute inflammation surgery, burns, infarcts,
crush injuries, acute gout, rheumatoid arthritis
Acute hemorrhage
Non hematologic malignancies
Myeloproliferative disorders, esp CML
Drugs: corticosteroids, G-CSF, lithium
Misc: seizures, electric shock, post-splenectomy,
Leukocyte Adhesion Deficiency

Causes of Neutropenia

Physiologic - in African-Americans
Drugs

anti-psychotics,
anti-epileptics,
anti-thyroid, and
some antibiotics (gold, sulfa)

Chemotherapy
Infections: viral, overwhelming bacterial
sepsis, TB, fungal
Immune - lupus, rheumatoid arthritis (Felty
syndrome)
Familial
Hypothyroidism, hypopituitarism

What is Agranulocytosis? Major

Sxs?
This is the complete or near-complete

absence of neutrophils in the peripheral

blood, with a normal platelet count and hgb
Almost always drug-induced

Clozaril (and other newer antipsychotics)

Propythiouracil (antithyroid)
Anti-convulsants
Sulfa and chloramphenicol antibiotics

Causes severe necrotizing ulcers in the

mouth and throat

What is basophilia a major symptom of?

chronic myeloproliferative diseases

Causes of Eosinophilia

Differential Diagnosis for elevated

eosinophil count NAACP:

Neoplasm,
Allergy/asthma,
Addisons disease,
Collagen vascular disease
Parasites

Causes of Lymphocytosis

Viral infections
Bacterial infections - whooping cough
(pertussis), TB, syphilis, brucellosis
Chronic Lymphocytic Leukemia (CLL)
Lymphomas and Waldenstroms
macroglobulinemia

Causes of Lymphocytopenia

Immunodeficiencies, including HIV/AIDS

Immunosuppresive drugs, including
corticosteroids
Lymphomas
Granulomatous diseases, including sarcoid,
TB
Alcoholism, malnutrition, zinc deficiency

Causes of Monocytosis

Bacterial infex: TB, syphilis, subacute

bacterial endocarditis, typhoid, brucellosis
Protozoal infex: malaria
Rickettsial infex: RMSF, typhus
Myelodysplastic syndromes (just one of them)
Leukemias
Inflammatory bowel disease

Normal Neutrophil Function

Adherence

Chemotaxis

Moving along a concentration gradient to higher

[ ]s

Recognition/Phagocytosis

Rolling mediated by selectins

Adhesion mediated by beta-2 integrins

Via complement and IgG

Once it eats, its got a phagosome

Degranulation

Granules are released INTO the phagosome

NADPH oxidase: O2 O2Superoxide dismutase: O2- H2O2

MPO: H2O2 HOCl

Oxidative Metabolism and Bacterial Killing

Defects in Neutrophil
Function

Acquired Defects

Corticosteroid Use Alcoholism

Leukemias
Myelodysplasia
Myeloproliferative disorders

Congenital Defects

Leukocyte Adhesion Deficiency

Chronic Granulomatous Disease
Myeloperoxidase Deficiency
Chediak Higashi Syndrome

Erythrocytosis What is it?

An increase in the number of circulating RBCs per

volume of blood.
Reflected as an elevated hemoglobin and hematocrit.

Relative Erythrocytosis (Gaisbocks syndrome)

Depressed plasma volume, RBC mass is normal

Common in middle age men w/ HTN, smoking hx

Secondary Erythrocytosis

>60% in man, >57% in woman = true erythrocytosis

Red cell mass study if elevated but not quite these levels

Erythropoietin production increased by kidney/liver

Tissue hypoxia, tumors, genetic disorders, drugs for
athletics will all increase Epo

Primary Erythrocytosis

The bone marrow is going crazy without outside input

Why is erythrocytosis bad?

Hyperviscosity Syndrome

Your blood gets too sludgy

Symptoms include:

Headaches
Visual changes
Tinnitus
Dizziness
Paresthesias
Decreased mental acuity

Erythrocytosis due to
appropriate increases in epo

Life at high altitude

High affinity hemoglobins
Cardiopulmonary disease
Obesity-Hypoventilation syndrome
Obstructive sleep apnea
High carboxyhemoglobin levels

What are the Myeloproliferative

Diseases? Definition? Associated
sxs?
Includes:

Myeloproliferative disorders are Stem Cell

Disorders leading to autonomous production of
hematopoietic cells from ALL THREE LINEAGES
(red cells, white cells, platelets).
All of these disorders are clonal (except for a
subset of ET cases)
Associated sxs:

Polycythemia vera
Essential Thrombocythemia
Myelofibrosis
Chronic Myelogenous Leukemia

Basophilia
Splenomegaly

Potential to develop into AML

Polycythemia vera
Most of cells in circulation are derived from a single,
neoplastic stem cell
Does not need Epo to produce more cells
Diagnosis based on low/absent levels of Epo
Natural History 4 phases:
Latent phase - asymptomatic
Proliferative phase -pts may have sxs of:

Hypermetabolism
Hyperviscosity
Thrombosis

Spent phase - red cell mass, anemia, leukopenia,

secondary myelofibrosis, increasing HSM. 20% of pts
Secondary AML aka when the body says screw it, Im not differentiating anymore

1-2% of pts treated with phlebotomy alone

Symptoms of Polycythemia
Vera
Those common to ALL erythrocytosis

Pruritis after bathing

Hypermetabolic sxs
Erythromelalgia
Thrombosis
Hemorrhage
PE findings

Headache
Decreased mental acuity
Weakness

Facial plethora
Splenomegaly
Hepatomegaly
Retinal vein distension

Lab findings

BASOPHILIA
Low EPO levels
Increased Hbg/HCT, WBCs, platelets, uric acid, B12, leukocyte alkaline
phosphatase score

P vera - Treatment

Phlebotomy Draw 500 cc blood 1-2x/wk to target Hct 45%; maintain BP w/ saline
Generally, the best initial treatment for P vera rapid onset
Downsides:
Increased risk of thrombosis
No effect on progression to spent phase
May be insufficient to control disease
Myelosuppressive agents
Hydroxyurea
can be used in conjunction with phlebotomy
May increase the risk of leukemic transformation from 1-2% to 4-5%
32P kills some of the proliferating cells!
increase the risk of leukemic transformation from 1-2% to 11%
Single injection may control hemoglobin and platelet count for a year or
more.
Alkylating agents such as busulfan
Interferon alpha
Benefits
No myelosuppression
No increase in progression to AML
No increase in thrombosis risk
Drawbacks
Must be given by injection up to daily
Side effects may be intolerable in many pts: flu-like symptoms, fatigue,
fever, myalgias, malaise

So what disease are you

thinking?

Arrow indicates a giant platelet, larger than

the red cells or lymphocyte

Essential Thrombocythemia

Essential Thrombocythemia

Increased megakaryocyte production of platelets

Must exclude secondary causes of thrombocytosis
and other myeloproliferative disorders
Major complications:

Thrombosis: 20-30% of all patients; Budd-Chiari

Microvascular thrombi/digital ischemia
Pruritis & erythromelalgia
Acquired von Willebrands disease

Will see clusters of abnormal megakaryocytes on

smear
Platelet morphology will be big and odd-shaped
Treatment:

Anagrelide platelet lineage specific

Hydroxyurea
Interferon alpha

Myelofibrosis

Clonal stem cell disorder affecting megakaryocytes

predominantly
All myeloproliferative disorders can result in a
spent phase which can be difficult to distinguish
from primary MF
Myeloid metaplasia refers to earlier proliferative
phase where extramedullary hematopoiesis
predominates.
WILL become AML median survival is 5yrs
Splenomegaly and hepatomegaly
Aspirate is a dry tap
Peripheral blood smear: leukoerythroblastic

Teardrop RBCs
Nucleated RBCs
Early granulocytes/precursors

Myelodysplastic Syndromes

Definition: disordered maturation in 1 or more cell lines

producing cytopenias: anemia, leucopenia,
thrombocytopenia or combos
More common in the elderly
Based on cytogenic abnormalities
Peripheral cell abnormalities

Macrocytic RBCs
Large platelets
Hypogranular or bilobed nuclei neutrophils

Megaloblastic erythropoeisis
Ringed sideroblasts
Abnormal nucleus of RBC precursors (dyserythropoiesis)
Small megakaryocytes with abnormally hypolobate
nuclei
Blast cells should account for <30% of marrow cells