Module 4

Blood Disorders
• The anemias and polycythemia
• Leukemias
• Platelet disorders
• Blood clotting disorders
 Erythrocyte function
Anemias
• Anemia = a decrease in the the oxygen carrying capacity
of the blood

• O2 carrying capacity is determined by:

1. the number of red blood cells
2. the amount of hemoglobin in the red blood cells
• A reduction in either or both can produce anemia

Porth p293
 Anemia
produces

Hypoxemia: a reduction in the

oxygen content of the blood

produces

Hypoxia: abnormally low oxygen content

in the tissues
 Anemias
Normal Values:
• Hemoglobin 14-18 g/100 mL
12-16 g/100 mL
• Hematocrit 42-52%
Plasma

37-47%
RBC
• RBC Count 4.7-6.1 106/uL
4.2-5.4 106/uL Hematocrit

• Reticulocytes 0.5-2%
(immature RBCs)
 Some diagnostic criteria

WHO Hb thresholds (g/dl) for anemia

 General signs and symptoms
of anemia
i.e. what happens when the O2 carrying-capacity of the
blood is decreased?
1. Fatigue - Why?
•  aerobic cell respiration =  ATP

2. Dizziness, headaches - Why?

•  ATP in CNS (nerve tissue especially sensitive)

3. Shortness of breath - Why?

• cannot get sufficient O2 to tissues to supply their demands
• worse on exertion
 General signs and symptoms
of anemia
4. Increased breathing rate and depth - Why?
• body’s attempt to correct hypoxemia: respiratory center
response to increase the diffusion rate of O2 in the lungs

5. Rapid and pounding heart beat - Why?

• body’s attempt to correct hypoxemia:

cardiac centre response  HR and  SV to
 blood flow to lungs and tissues (are hypoxic)

SV = stroke volume, HR = heart rate, SV x HR = Cardiac output

 General signs and symptoms
of anemia
6. Vasodilation – which further increases demands on
heart - Why?
• Hypoxia causes release of signaling molecules like nitric
oxide > local vasodilation of tissue capillaries>  TPR > 
venous return
7. Decrease in blood viscosity (thickness) Why?
• reduction in number of blood cells, while the body maintains
total volume of blood
Effect is to  TPR >  venous return to heart

TPR = Total Peripheral Resistance

 General signs and symptoms
of anemia
8. Pale lips, nail beds, mucous membranes- Why?
• blood less oxygenated = less bright red
 The effect of decreasing
oxygen saturation on blood flow

Blood flow increases

due to vasodilation in
the tissues
 Other clinical manifestations
of anemia
Much depends on the underlying cause, but
may include:
• Impaired healing
• Numbness
• Nausea
• GI symptoms
• Low-grade fever
 Some causes of anemia
• i.e. different etiologies
Frequently the – chronic blood loss from whatever cause
same condition
– iron deficiency (often a result of hemorrhage)
– pernicious = vitamin B12 deficiency
– folate anemia = vitamin B9 deficiency
– red bone marrow disorders
(e.g. leukemia)
– sickle cell, thalassemia, many others…
 Anemia through blood loss
• Either through slow / chronic blood loss secondary to
other illness or condition or acute bleeding
• Results in iron deficiency since most iron is bound to
hemoglobin
• 2-4 ml blood loss a day sufficient = 1-2 mg iron
• Secondary to:
– Menorrhagia, ulcerative colitis, bleeding gastric
ulcers, hemorrhoids, medications (aspirin), bleeding
from cancer, excess blood loss in childbirth…
 Iron deficiency anemia
Hemoglobin production is
completely dependent on
iron availability

Where do we store iron?

• 80% bound to hemoglobin in RBCs
• 20% bound to storage protein ferritin in cells
or transferrin in plasma (free iron is toxic)
Porth p299
 Iron deficiency anemia
• Most common world-wide
• Results from
1. Chronic blood loss (as discussed)
2. Lack of sufficient iron in diet
3. Reduced ability to absorb iron - genetic predisposition,
type of diet, inflammatory bowel disease (IBD)
• At risk groups: poverty, women, children, elderly
• Treatment:
– replace lost iron
– identify and treat condition causing loss
 Iron deficiency anemia
Pathogenesis
1. Iron stores deplete
2. Fewer RBCs (low hematocrit) with reduced cell
volume (MCV) and low hemoglobin content per
cell (MCHC) produced
3. These “anemic” blood cells gradually replace
older blood cells
Terminology of lab results:
MCV – Mean cell volume
MCHC – Mean cellular hemoglobin content
 Iron deficiency anemia
Histology
• The anemic blood cells in iron deficiency are
distinctive: described as microcytic (small)
hypochromic (pale)
 Vitamin B12 deficiency anemia
• B12 is essential for
– DNA synthesis / mitosis in RBC
– Myelination of nerves / nerve function
• B12 comes from a diet including meat, fish, and
dairy

• Intrinsic factor from the gastric mucosa enables

vitamin B12 absorption in the small intestine
Porth p300
 Vitamin B12 deficiency anemia
Etiology
– diet
– autoimmune destruction of gastric mucosa =
pernicious anemia
– heavy alcohol ingestion
– cigarette smoking
– gastrectomy
– malabsorption
– aging
• Slow pathogenesis (20-30 yrs)
– undetected progression of gastritis
– slow depletion of B12 stores in liver
 Vitamin B12 deficiency anemia
Diagnosis
• Megaloblastic RBCs
– macrocytic (large) and
– normochromic (normal color)
Signs / Symptoms
• General symptoms of anemia
• Low serum B12 levels
• Neurologic complications: paresthesias in hands/feet
(tingling, numbness), depression, sometimes
dementia
Treatment: Vitamin B12 injections
 Folate deficiency anemia
• Folic acid (vitamin B9) essential for
– nucleic acid synthesis within RBC
– cell growth and mitosis
• Similar features to pernicious anemia, including histology
• Neurological manifestations include peripheral
neuropathies, neural tube defects in the fetus
• Other symptoms: mouth ulcers (stomatitis), watery
diarrhea
• Common in malnutrition, diets low in green veg and meat
• At risk: elderly, children, alcoholism, pregnancy
Module 4
Blood Disorders
• The anemias and polycythemia
• Leukemias
• Platelet disorders
• Blood-clotting disorders
 STOP AND THINK
TRUE OR FALSE?

Only iron deficient anemia, not B12 deficient

anemia, leads to hypoxemia and hypoxia
 STOP AND THINK
TRUE OR FALSE?

Anemia causes vasoconstriction.

 Erythrocyte Function
Polycythemia
• Excessive erythrocyte presence
• Has two forms:
– Relative polycythemia – brought about through
dehydration – minor consequence and easily fixed
– Absolute polycythemia – two types
1. Primary – “polycythemia vera”
- rare non-malignant condition where there is an overabundance of
bone marrow stem cells
2. Secondary – due to hypoxia
– common in those living at higher altitudes, smokers and those with
COPD and/or coronary heart failure
– results in overproduction of erythropoietin in compensation for low
oxygen levels
Porth p305
 Polycythemia Manifestations
• Variable and related to an increase in RBCs,
hemoglobin level, and hematocrit with increased blood
volume and viscosity

– Splenomegaly
– Depletion of iron
– Hypertension ( blood viscosity)
– Disrupted cardiac output
– Decreased cerebral blood flow
– Venous stasis (slow blood flow in veins)
– Thromboembolism
 Leukocyte Function
• As with RBC function, WBC function is
affected if there are too few/too many cells
(quantitative changes), or the cells are
functionally defective (qualitative changes)

Porth p311
 Quantitative changes in WBC Count

• Leukocytosis • Leukocytopenia
• Normal response to stressors • Never a normal response. when
such as infection, surgery, count falls to <1000/mm3, the risk
pregnancy, hormones of infection increases dramatically

• Pathological when caused by • Can occur as a result of radiation,

malignancies or blood disorders chemotherapy, autoimmune
disease (e.g.,SLE)
Individual classes of leukocytes can alter in number
(a) Eosinophil (b) Basophil (c) Neutrophil (d) Lymphocyte(e) Monocyte

Granulocytes:
• Increase usually due to infection
• Decreases can be due to production falling behind need
(in the case of chronic infections)
• Most often seen in neutrophils - because the most
numerous granulocyte with a primary role against infection
• For example:
– Neutrophilia – an early response to infection
(shift to the left)
– Neutropenia – with severe prolonged infections,
production can’t keep up with demand. Other
causes include starvation, autoimmune
disorders, HIV infection, chemotherapy, etc.
– Agranulocytosis (granulocytopenia) – extremely
low counts of granulocytes. Can be caused by
chemotherapy, aplastic anemia
Lymphocytes

• Lymphocytosis usually produced through viral

infection (not bacterial, why?)

• Lymphocytopenia – immune deficiencies,

neoplasia, drugs, no known cause
 Example of a B cell lymphocytosis:
Infectious Mononucleosis (IM)
• Acute viral infection of B lymphocytes (Epstein-Barr virus - EBV)

• Transmission: commonly through saliva (“kissing disease”), also

other body fluids

• Increased number of abnormal lymphocytes - atypical cells

produce heterophile antibodies (used for diagnosis)

• Most commonly observed in individuals 15 -19 years of age

– Asymptomatic EBV infection is common in children, providing immunity
against re-infection
Porth p317
 Infectious Mononucleosis:
Pathophysiology
• Virus (EBV) invades tissue of the oropharynx, nasopharynx and
salivary epithelial cells → lymphoid tissues and B cells

• Symptoms: fever, sore throat, cervical lymph node

enlargement. Can progress to more serious symptoms,
including enlargement of the spleen (rupture is most
common cause of death, but is rare)

• Usually self-limiting
 STOP AND THINK
A prolonged bacterial infection causes ____.

A. agranulocytosis
B. lymphocytosis
C. lymphocytopenia
D. neutrophilia
E. neutropenia
 Alteration in function of WBC
Leukemia
• A malignant disorder of the blood and blood-forming
organs
• Common pathological feature of all leukemias:
pancytopenia - a reduction in all cellular components of
the blood
– Why? Uncontrolled proliferation of malignant leukocytes
“crowd out” bone marrow, causing production of other cell
types to cease
 RECALL: Leukemic Cells
• Are immature and poorly differentiated
• Proliferate rapidly and have a long life span
• Do not function normally
• Interfere with the maturation of normal blood cells
• Circulate in the bloodstream
• Cross the blood–brain barrier
• Infiltrate many body organs
• Risk factors for leukemia:
– Can reappear in families, and is associated with other
hereditary abnormalities (e.g., Down syndrome)
– Increased risk has been linked to cigarette smoke,
ionizing radiation, infections with HIV or HCV, some
drugs (chloramphenicol, some chemotherapies)
 Leukemia is divided into 4 classes
• Leukemias are named for:
1. type of cell line affected
a) lymphocytic or
b) myelogenous
and
2. progression of the disease
a) acute or
b) chronic
– Rapid, with short survival time (if untreated) vs longer
onset, with longer survival time (if untreated)
Formation of blood cells
Acute leukemias
• Rapid growth of immature blood cells
• Abrupt onset of disease; short survival time (untreated)
1. Acute lymphocytic (ALL) - concerns lymphocytes
(85% from B cell line)
• Least common type overall, but most common type in children
– accounts for ¾ cases of childhood cancer

2. Acute myelogenous (AML) - concerns any cells

except lymphocytes (i.e., neutrophils, platelets,
erythrocytes)
• tends to occur more in older adults, but is also seen in children
and younger adults
Porth p323
 Acute leukemias: clinical manifestations
(Why?)
• Fatigue caused by anemia
• Shortness of breath
• Tachycardia
• Bleeding caused by thrombocytopenia
• Infections and fever
• Anorexia
• Weight loss
• Swollen lymph nodes
• Liver, spleen, lymph node enlargement
• Bone pain
• Neurological / CNS manifestations
 Acute leukemias: evaluation and treatment
• Difficult to detect early as symptoms are so general
(easily confused with other diseases)
• Blood tests and bone marrow biopsy
– many immature WBC (60%-100% of cells)
• Treatment: chemotherapy is usual treatment,
blood transfusions and antimicrobial agents (bone
marrow transplant as last resort)
• Good survival rates
– since 1970s, 5 yr survival rate for ALL has increased to
66% for adults and 91% for children
Chronic leukemias
• Slow growth of more mature (differentiated) cells
which do not function normally
• Onset is gradual: longer survival time. Symptoms
appear very slowly
• Clinical manifestations: Fatigue, weight loss, low-grade
fever, splenomegaly

• Account for the majority of cases in adults (increase

significantly over 40 yrs of age)

• As with ALL and AML, two types, based on type of cell

affected:
Porth p326
 Chronic lymphocytic leukemia (CLL):
clinical manifestations
• Accounts for about ½ of all leukemias (generally in older
people – average age is 72)
• CLL involves transformation of primarily B cells
– they refuse apoptosis commands, and accumulate while also
becoming inactive; no antibody (Ab) production
• Increase in infections (due to low Ab)
• Causes anemia, thrombocytopenia and neutropenia
• Can be slow or very aggressive
– If slow, often is asymptomatic for a long time, person may die of
other apparently unrelated disease
 Chronic myelogenous leukemia (CML):
clinical manifestations
• Disease of older people – average age is 67
• Affects stem cells so there are excessive amounts of
marrow granulocytes, RBC precursors and
megakaryocytes
• 3 phases may occur:
1. Chronic: (2-5 yr) may be asymptomatic
2. Accelerated: (6-18 mo) primary symptoms develop, more immature cells in
bone marrow and blood. infections, weight loss, fever, enlargement of
spleen and liver
3. Terminal blast phase: (3-6 mo) more blast cells in blood, increase in
severity of symptoms. Resembles AML. Prognosis poor at this point.
• Philadelphia chromosome is observed in 95% CML cases
Blood smear showing
blast crisis in CML
• Chromosomes 22
and 9 exchange parts
of long ends
• The much smaller 22
that results is known
as the Philadelphia
chromosome (Ph1)
• The new protein that
is made allows cell to
bypass controls of
normal cell growth
and differentiation
Chronic leukemias: evaluation and treatment
• Blood tests and bone marrow biopsy
• Combined treatments
– Bone marrow transplant
– Biologic response modifiers: increase body’s immune
response (e.g. interferon alpha)
– Combination chemotherapy
• CLL survival rate highly variable: many years for
indolent forms, rapid in aggressive forms
• CML survival rate - 90% live 5 yrs or longer
• Death is usually caused by infection or
hemorrhage due to metastatic infiltration of
tissues
 Alteration in function of platelets
• Can be alteration in number or quality of platelets
• Too few platelets: Thrombocytopenia

• Risk of hemorrhage with minor

trauma
• Spontaneous bleeding can
occur without any trauma
(petechiae, purpuric spots;
when platelet # very low)
• Such bleeding can be fatal if in
the GI tract, respiratory tract or
CNS Manifestations
Porth p278
 Thrombocytopenia
• Results from decreased platelet production, increased
consumption, or both
• May occur primary, or secondary to other conditions
• Two examples:
– Heparin-induced thrombocytopenia (HIT): most common drug-
induced condition. Can occur when heparin (an anticoagulant) is
given with surgery. IgG antibodies are produced against a
heparin/platelet factor complex, causing aggregation of platelets
and increased clot formation, leading to stroke, pulmonary
embolism, myocardial infarction, etc.
– Immune thrombocytopenic purpura (ITP): Antibodies complex
with compounds in the platelet membrane, making them more
susceptible to phagocytosis in the spleen. Levels of
thrombopoeitin do not rise in response to lowered levels of
platelets
 Too many platelets: Thrombocythemia
• Primary thrombocythemia
– Platelet production increases, due to defects in thrombopoietin
receptors on platelets (negative feedback effect)
– The defective receptor cannot adequately bind and remove
thromobopoietin from the blood, thus keeping levels of the
hormone high in the blood, resulting in more platelet production
• Secondary thrombocythemia
– Would occur with any disease state that stimulates
thrombopoietin production, including surgery, infection, cancer
and chronic inflammation
• Individuals are at high risk of large-vessel thrombosis
(ischemia in extremities is common)
 Impaired platelet function
• Characterized by increased bleeding time in the presence
of a normal platelet count
• inherited causes (rare)
– e.g. Von Willebrand disease
• acquired causes
– drugs (aspirin, NSAIDs) – decreases platelet aggregation
– secondary to leukemia: “crowding out” effect
→ low quality platelets produced
BLOOD TISSUE
VESSEL DAMAGE
DAMAGE
 Disorders of coagulation
Usually caused by defects or deficiencies in one or more
of the clotting factors

Causes include:
1. Inherited disorders. For example, hemophilia is an
inherited deficiency in one of the clotting factors

2. Acquired disorders: deficient synthesis of clotting

factors by the liver, or due to dietary deficiency of
vitamin K

Porth p280
 Inappropriate coagulation
• Turbulent or reduced blood flow: triggers clotting
cascade (e.g. DVT – deep vein thrombosis)

• Tissue factor induced: TF (thromboplastin) released

from damaged, inflamed or dead tissues

• Important to remember: When

inappropriate clotting is stimulated,
not only is there the problem of
emboli/thrombosis, but this also uses
up clotting factors and platelets
leading to uncontrolled bleeding!

TF – initiates clotting via extrinsic pathway

 DIC – Disseminated Intravascular Coagulation
• Acquired clinical syndrome (not a disease, a complication)
– characterized by widespread activation of coagulation →
resulting in fibrin clots in medium and small vessels throughout
the body

• Widespread clotting may lead to

– Blockage of blood flow to organs, leading to multiple organ
failure
– Consumption of platelets and clotting factors, leading to severe
bleeding

• Can range from severe, life-threatening process (involving

massive hemorrhage and thrombosis) to a chronic, low-
grade condition
Porth p282
DIC – Disseminated Intravascular Coagulation
Etiology
1. trauma
2. obstetric complications
3. bacterial infection: (most frequent cause)
particularly involving sepsis (blood-borne)
4. tumours
• Cause excessive tissue factor release and / or
damage to endothelial lining of blood vessels
• Results in uncontrolled activation extrinsic and
intrinsic clotting pathways → thrombin → fibrin
 DIC – Disseminated Intravascular Coagulation
Manifestations and treatment
• Can present in a variety of ways, depending upon the cause:
– Bleeding at the eyes, nose (epistaxis), gums
• three or more unrelated sites
– Infarctions of kidney, lungs, heart, brain → renal failure,
respiratory failure…. → coma → death

• Treatment involves:
– eliminating the underlying cause
– control of thrombosis – e.g. heparin with care
– replacing clotting components (e.g. plasma transfusions)
– correcting loss of fluid (hypovolemia)
 STOP AND THINK
TRUE OR FALSE?

Too much clotting can lead to bleeding.