Pathology Lecture

(013) RBC and Bleeding Disorders

DRA. REFUERZO| 01/04/22

OUTLINE • Shape (poikilocytosis-different shapes)

I. ANEMIA • In general:
o Microcytic hypochromic anemias are caused by disorders
A. Red Blood Cell Indices
of hemoglobin synthesis (so there is something to do with
B. Anemia of Blood Loss the production of hemoglobin), most commonly iron
C. Haemolytic Anemia deficiency anemia.
a. Hereditary Spherocytosis o Macrocytic anemia often stems from abnormalities that
b. Glucose-6-phosphate impair the maturation of erythroid precursors in the
Dehydrogenase Deficiency (G6PD) marrow. (Megaloblastic anemia)
c. Sickle Cell Disease o Normochromic normocytic anemias have diverse
etiologies (abnormal hemoglobin content but normal size)
d. Thalassemia Syndromes
• Red cells indices which are precisely measured can be used:
e. Paroxysmal Nocturnal o Mean Cell Volume (MCV) - the average volume of a red
Hemoglobinuria (PNH) cell, expressed in femtoliters (fL). NV: 80-100fL
f. Immunohemolytic Anemia ▪ <80 fL: Microcytic >100 f: Macrocytic
g. Hemolytic Anemia from Trauma to o Mean Cell Hgb (MCH) - average content (mass) of Hgb
Red Cells per RBC, expressed in pictograms (pg) NV: 23-35pg
D. Anemia of Diminished Erythropoiesis o Mean Cell Hgb concentration (MCHC) - average
concentration of Hgb in a given volume of packed RBC,
a. Megaloblastic
expressed in grams per deciliter (g/dL)
anemiaMegaloblastic anemia o Red cell distribution width - coefficient of variation of red
b. Pernicious anemia cell volume
c. Folic acid deficiency anemia ▪ The higher red ell distribution width, they are more
d. Iron deficiency anemia associated to aniso or poikilocytosis
e. Anemia of chronic inflammation
f. Aplastic anemia
g. Pure Red Cell anemia
h. Myelophthisic anemia

II. POLYCYTHEMIA
III. BLEEDING DISORDERS
A. Bleeding disorders caused by vessel wall
abnormalities
B. Thrombocytopenia
C. Bleeding disorders with defective
platelet function
D. Hemorrhagic diathesis related to
abnormalities in clotting factors
E. Disseminated Intravascular Coagulation
Table 1.1: Adult Reference ranges for RBC (10th Edition)
F. Complications of TransfusionBLEEDING
DISORDERS
IV. REFERENCES
V. TEST YOURSELF
VI. APPENDIX

I. ANEMIA
• For RBC and bleeding disorders, we assess your RBC of
course, your abnormality with the rbc. Your rbc is one of the
components of our blood. So what are the other components
of the blood? we have plasma, platelets, RBCs and WBCs.
• For bleeding disorders, we assess that with your platelets or
megakaryocytes.
• So your RBCs carry oxygen to the tissues, most common Table 1.2: Adult Reference ranges for RBC (9th Edition)
abnormality is anemia.
• Defined as the reduction of total circulating cell mass.
• It reduces the oxygen-carrying capacity of the blood leading to A. Red Blood Cell Indices
tissue hypoxia (lesser volume to RBCs leads to lesser volume • Used to define the size and hemoglobin content of the red blood
in the tissues leading to hypoxia) cell
• Usually, clinically diagnosed based on: • CONSISTS OF:
o hematocrit - ratio of packed RBC to total blood volume. o MCV- MEAN CORPUSCULAR VOLUME now called
o Hemoglobin concentration- protein that carries O2 mean cell volume
• Anemias can also be classified based on the alterations in red o MCH- MEAN CORPUSCULAR HEMOGLOBIN
cell morphology, which often point to particular cases. o MCHC- MEAN CORPUSCULAR HEMOGLOBIN
• Cell size (normo-, micro-, macrocytic) CONCENTRATION
• Degree of hemoglobinization (normo-, hypochromic)
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 Pathology Lecture

(013) RBC and Bleeding Disorders

DRA. REFUERZO| 01/04/22

A. MEAN CELL VOLUME

The average volume of red cells and is calculated using the
following formula:

𝑯𝒄𝒕 𝒙 𝟏𝟎𝟑 𝒇𝑳
𝑴𝑪𝑽 =
𝑹𝑩𝑪/𝑳

MCV = volume of RBC in Femtoliters (fL) of blood

GIVEN:
Hematocrit = 45% or 0.45L
RBC = 5.0 x 1012/L
1 UL = 109 FL
1L = 1015 FL

Then
𝟎. 𝟒𝟓 𝒙 𝟏𝟎𝟏𝟓 𝒇𝑳/𝑳
𝑴𝑪𝑽 = Figure 3: Normocytic Anemia
𝟓. 𝟎 𝒙 𝟏𝟎𝟏𝟐 /𝑳
𝑴𝑪𝑽 = 𝟎. 𝟎𝟗 𝒙 𝟏𝟎𝟑 𝒇𝑳
B. MEAN CELL HEMOGLOBIN (MCH)
𝑴𝑪𝑽 = 𝟗𝟎 𝒇𝑳 Is the content (weight) of hemoglobin of the average red cell; it
is calculated from the hemoglobin concentration and the red cell
NORMAL Range: 80 to 100 fL
count:
𝑯𝑮𝑩 (𝑮/𝑳) 𝑷𝑮
MCV CLASSIFIES ANEMIA BASED ON RBC SIZE 𝑴𝑪𝑯 =
• <80 FL: MICROCYTIC ANEMIA 𝑹𝑩𝑪(/𝑳)
• 80-100: NORMOCYTIC ANEMIA
𝒘𝒆𝒊𝒈𝒉𝒕 𝒐𝒇 𝑯𝒈𝒃 𝒊𝒏 𝟏 𝑳 𝒐𝒇 𝒃𝒍𝒐𝒐𝒅
• >100: MACROCYTIC ANEMIA 𝑴𝑪𝑯 =
# 𝒐𝒇 𝑹𝒆𝒅 𝑪𝒆𝒍𝒍𝒔 𝒊𝒏 𝟏 𝑳 𝒐𝒇 𝒃𝒍𝒐𝒐𝒅

IF: 1G = 1012 PG
1L = 10 DL

Then:
𝑯𝑮𝑩 𝒙 𝟏𝟎 𝒙 𝟏𝟎𝟏𝟐 𝑷𝑮/𝑳
𝑴𝑪𝑯 =
𝑹𝑩𝑪/𝑳
IF: HGB = 15.0 g/dL
RBC = 5.0 x 1012/L

Then:
𝟏𝟓 𝒙 𝟏𝟎𝟏𝟑 𝑷𝑮/𝑳 𝟏𝟓 𝒙 𝟏𝟎 𝑷𝑮/𝑳
𝑴𝑪𝑯 = = = 𝟑𝟎𝑷𝑮
𝟓.𝟎𝒙 𝟏𝟎𝟏𝟐 /𝑳 𝟓.𝟎 𝒙 𝟏𝟎𝟏𝟐 /𝑳
Figure 1: Macrocytic Anemia
NORMAL RANGE FOR MCH = 27 to 31 PG

C. MEAN CELL HEMOGLOBIN CONCENTRATION (MCHC)

Is the average concentration of Hemoglobin in a given volume
of packed red cells:
𝐻𝐺𝐵 𝑥 100% 𝐻𝐺𝐵 𝑔/𝑑𝐿
𝑀𝐶𝐻𝐶 = 𝑜𝑟
𝐻𝐶𝑇 𝐻𝐶𝑇
𝐻𝐺𝐵 𝑖𝑛 𝑔/𝑑𝐿
𝑀𝐶𝐻𝐶 = 𝑥 100 (𝑡𝑜 𝑐𝑜𝑛𝑣𝑒𝑟𝑡 𝑡𝑜 %)
𝐻𝐶𝑇(𝑣𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝑅𝐵𝐶 𝑖𝑛 𝑔/𝑑𝐿

IF: HGB = 15.0 g/dL

HCT = 45% (0.45)

THEN:
15.0 𝑔/𝑑𝐿 15.0 𝑔/𝑑𝐿
𝑀𝐶𝐻𝐶 = 𝑥 100 = 𝟑𝟑. 𝟑% 𝒐𝒓 = 𝟑𝟑. 𝟑 𝒈/𝒅𝑳
0.45 𝑔/𝑑𝐿 0.45

Therefore, the Formula

Figure 2: Microcytic Anemia 𝐻𝐺𝐵 𝑥 100% 𝐻𝐺𝐵 𝑔/𝑑𝐿
(associated with iron deficiency anemia) 𝑀𝐶𝐻𝐶 = 𝑜𝑟
𝐻𝐶𝑇 𝐻𝐶𝑇

NORMAL RANGE for the MCHC: 31% to 36 % = 31 to 36 g/dL

• <31% = Hypochromia
• 31%-36% = Normochromia
• >36% = Hyperchromia associated to megaloblastic anemia

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Figure 4: Hypochromia
B. Anemia of Blood Loss
• Regardless of cause, severe anemia leads to certain clinical
findings:
o Patients appear pale (Pallor)
o Weakness, Malaise, and Easy Fatigability it’s because of
the decrease oxygen delivery in the body.
o Dyspnea on mild exertion due to decreased 02
o Hypoxia can cause fatty change in liver, myocardium,
kidney
• Fatty changes in the myocardium can cause cardiac failure.
Hypoxia in the myocardium often manifests as angina pectoris
• Acute blood loss and shock, oliguria or anuria can develop as
a result of renal hypoperfusion. (no oxygen in the kidneys)
• CNS hypoxia can cause headache, dimness of vision,
faintness.
1. Acute Blood Loss
• Effects are mainly due to loss of intravascular volume,
which if massive loss of blood, can lead to cardiovascular
collapse, shock, and death.
• Reduction of 02 triggers increased secretion of
erythropoietin from the kidneys, stimulating proliferation of
committed erythroid progenitors.
o It takes 5 days for them to completely mature and
appear as reticulocytes in the peripheral blood.
o If there is increased reticulocytes in the blood, it
signals that there is increase loss of RBCs..The
lifespan of RBCs is 120 days, so if there is increased
reticulocytes in the blood, there is increased turnover
of RBC to shorten their lifespan.
o The iron in hemoglobin is recaptured if red cells
extravasate into tissues, whereas bleeding into the
gut or out of the body leads to iron loss and possible
iron deficiency, which can hamper the restoration of
normal red cell counts.
o Significant bleeding results in predictable
changes in the blood involving not only red cells,
but also white cells and platelets. If the bleeding is
sufficiently massive to cause a decrease in blood
pressure, the compensatory release of adrenergic
hormones mobilizes granulocytes from the
intravascular marginal pool and results in
leukocytosis. Initially, red cells appear normal in size
and color (normocytic, normochromic). However, as
marrow production increases, there is a striking
increase in the reticulocyte count (reticulocytosis),
which reaches 10% to 15% after 7 days.
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Pathology Lecture
(013) RBC and Bleeding Disorders
DRA. REFUERZO| 01/04/22
Reticulocytes are larger than normal red cells and
have blue-red polychromatophilic cytoplasm due to
the presence of RNA, a feature that allows them to be
identified in the clinical laboratory. Early recovery
from blood loss also is often accompanied by
thrombocytosis, which results from an increase in
platelet production.
2. Chronic Blood Loss
• Induces anemia only when the rate of loss exceeds the
regenerative capacity of the marrow.
• It can also cause anemia when iron reserves are depleted
and iron-deficiency anemia (IDA) appears.
C. Hemolytic Anemia
• Hemolysis- Breakdown of RBCs
• Common features of hemolytic anemias:
• Shortened red cell life span below 120 days.
• Elevated erythropoietin levels and compensatory increase in
erythropoiesis.
• Accumulation of Hgb degradation products that are created as
a part of red cell hemolysis
• Persistent hemolysis leads to hyperplasia of phagocytes
manifested by varying degrees of splenomegaly.
• The physiologic destruction of senescent red cells takes place
within macrophages.
• Abundant in the spleen, liver, and bone marrow.
• This process appears to be triggered by age-dependent
changes in red cell surface proteins, which lead to their
recognition and removal by phagocytes.
• In the great majority of hemolytic anemias, the premature
destruction of red cells also occurs within phagocytes, an event
that is referred to as extravascular hemolysis. If persistent,
extravascular hemolysis leads to a hyperplasia of phagocytes
manifested by varying degrees of splenomegaly.
1. Extravascular Hemolysis
• Caused by alterations that render the RBC less
deformable in passing the splenic sinusoids.
• This causes red cell sequestration and phagocytosis.
• Principal features are:
o Anemia (pallor)
o Splenomegaly (increase in size of the spleen)
o Jaundice (yellowing of the skin)
• Some hemoglobin inevitably escapes from phagocytes,
which leads to variable decreases in plasma haptoglobin,
an α2-globulin that binds free hemoglobin and prevents its
excretion in the urine.
2. Intravascular Hemolysis
• May be caused by mechanical injury (trauma to cardiac
valves), complement fixation, intracellular parasites
(malaria), or exogenous toxic factors (clostridial sepsis), it
is also associated with incompatibility in blood transfusion.
• Manifests as:
o Anemia
o Hemoglobinemia (blood plasma will be reddish or
pinkish)
o Hemoglobinuria
o Hemosiderinuria
o Jaundice
• Morphology:
o Increased number of erythroid precursors
(normoblasts) the younger cells of erythropoiesis.
o Compensatory increase in erythropoiesis leading to
prominent reticulocytosis in the peripheral blood.
(Increased number of retics)
o Accumulation of hemosiderin in the spleen, marrow,
liver.
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o Accumulation of this iron pigment is called
hemosiderosis
o Severe anemia can lead to extramedullary
hematopoiesis spleen, liver, or lymph nodes. Usually,
hematopoiesis takes place in the bone marrow but
when there is extravascular hemolysis, there is
hematopoiesis in the spleen, liver or lymph nodes.
o Pigment gallstones can also form due to elevated
biliary excretion of bilirubin in chronic hemolysis.
(black gallstones
o Iron released from hemoglobin can accumulate within
tubular cells, giving rise to renal hemosiderosis.
o Heme groups derived from hemoglobin-haptoglobin
complexes are metabolized to bilirubin within
mononuclear phagocytes, leading to jaundice.
a. Hereditary Spherocytosis
• HS is an inherited disorder caused by intrinsic defects in the
red cell membrane skeleton (spectrin and ankyrin), rendering it
spheroid, less deformable, and prone to splenic sequestration.
• Highest prevalence in Northern Europe (1 in 5,000).
• Autosomal Dominant disorder in 75% of cases.
• Remaining has more severe disease caused by two different
defects, a state known as compound heterozygosity.
Figure 5: Pathophysiology of Hereditary Spherocytosis
• HS is caused by diverse mutations that lead to an
insufficiency of membrane skeletal components.
• As a result of these alterations, the life span of affected red cells
is decreased on average to 10 to 20 days from the normal 120
days.
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Pathology Lecture
(013) RBC and Bleeding Disorders
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• The pathogenic mutations most commonly affect ankyrin, band
3, spectrin, or band 4.2, the proteins involved in one of the two
tethering interactions.
• Most mutations cause frameshifts or introduce premature stop
codons, such that the mutated allele fails to produce any
protein.
• The resulting deficiency of the affected protein reduces the
assembly of the skeleton as a whole, destabilizing the
overlying plasma membrane.
• Because of the spheroidal shape and reduced deformability,
the Shapeless spherocytes are trapped in the splenic cord.
• Splenic environment exacerbates loss of membranes together
with K+ and H20.
• Prolonged splenic exposure (erythrostasis).
• Depletion of glucose and diminished red cell pH. (acidic)
• After splenectomy, anemia is corrected but spherocytes still
persists.
• Spherocytosis apparent on smears as small, dark-staining
(hyperchromie) red cells lacking the central zone of pallor.
• Distinctive but not pathognomonic, as they are also seen in
disorders with membrane loss such as autoimmune hemolytic
anemia
• Other features common to hemolytic anemias
• Hemosiderosis, Reticulocytosis, Marrow erythroid hyperplasia,
mild jaundice.
• Cholelithiasis in 40-50% of adults. (pigmented gallstones)
• Moderate splenomegaly (500-1000g) due to congestion.
• The diagnosis is based on family history, hematologic findings,
and laboratory evidence.
• Characteristic features:
o Anemia
o Splenomegaly
o Jaundice
Clinical signs are usually the same with other anemias so how
are we going to differentiate them? we differentiate them using
CBC, we assess it and further seen in your peripheral blood
smear. So we diagnose anemias manually using your
microscope by their differences in RBC morphology.
• Small population present with marked jaundice at birth
requiring exchange transfusion.
• 20-30% is so mild to be virtually asymptomatic.
• Generally, Stable clinical course is sometimes punctuated by
aplastic crises, triggered by acute parvovirus infection.
o Parvovirus B19 (Erythema infectious) infects and kills red
cell progenitors, causing red cell production to cease until
immune response commences (1-2 weeks).
• Due to decreased life span, anemia can worsen, transfusion
may be necessary until immune response clears infection
• Transfusions may be necessary to support the patient
during the acute phase of the infection.
• Hemolytic Crises produced by intercurrent events leading to
increased splenic destructions (e.g. Infectious mono) but less
significant than aplastic crises.
Figure 6: Hereditary Spherocytosis
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 Pathology Lecture

(013) RBC and Bleeding Disorders

DRA. REFUERZO| 01/04/22

b. Glucose-6-phosphate Dehydrogenase o Since hemolysis is episodic, features to chronic hemolysis

are absent (e.g. splenomegaly, cholelithiasis).
Deficiency (G6PD)
• Abnormalities in the Hexose monophosphate shunt or
glutathione metabolism resulting from deficient or impaired
enzyme function reduce the ability of RBC to protect
themselves from oxidative injury and lead to hemolysis.
• The most important of these enzyme derangements is
hereditary deficiency of glucose-6-phosphate dehydrogenase
(G6PD) activity.
• G6PD reduces nicotinamide adenine dinucleotide phosphate
(NADP) to NADPH while oxidizing glucose-6-phosphate.
NADPH then provides reducing equivalents needed for
conversion of oxidized glutathione to reduced glutathione,
which protects against oxidant injury by participating as a
cofactor in reactions that neutralize compounds such as H2O2.
• G6PD deficiency is a recessive, X-linked disorder, posing
higher risk for males. Several variants, but most are harmless
• Most clinically significant are:
• Designated G6PD-: present in 10% of Americans.
• G6PD Mediterranean: common in Middle East
• Because mature red cells do not synthesize new proteins, as
red cells age G6PD– and G6PD Mediterranean enzyme
activities quickly fall to levels that are inadequate to protect
against oxidant stress.
• Older red cells are much more prone to hemolysis than younger
ones.
• Believed to stem from protective effects against Plasmodium
falciparum malaria
• Episodic hemolysis is characteristic of G6PD deficiency is
caused by exposures that generate oxidative stress.
• Most common triggers:
• Infections
o Radicals produced by macrophages
o Most common.
o Viral hepatitis, pneumonia, typhoid fever so if there is
infection there will be hemolysis.
• Drugs:
o Anti-malarial drugs (primaquine, chloroquine)
o Sulfonamides, Nitrofurantoins, etc.
• Fava beans, most frequently cited oxidant producer
o Uncommonly, G6PD deficiency presents with neonatal
jaundice or a chronic low-grade hemolytic anemia in the
absence of infection or known environmental trigger.
• Oxidants cause both intra- and extravascular hemolysis
• This is not a dangerous deficiency because in can be prevented
it’s just that don’t eat and take drugs that can cause trigger for
hemolysis and this can be evaluated in your newborn screening
so this can be prevented. This can be readily tested upon
delivery of the child.
• Morphologically what we usually see in the blood smear is the
presence of Heinz bodies, Heinz bodies can only be seen using
a supravital stain likewise your reticulocytes we use supravital
stain. Heinz bodies are formed due to exposure of G6PD
deficient cells to high levels of oxidants, causing cross-linking
Figure 7: G6PD Deficiency
of reactive sulfhydryl groups on globin chains that become
denatured c. Sickle Cell Disease
• As the red cells pass the spleen, macrophages pluck out the • A common hereditary hemoglobinopathy caused by a point
Heinz bodies causing membrane damage with partially mutation in the ß-globin that promotes the polymerization of
devoured shape called Schistocytes (Bite cells). deoxygenated hemoglobin, leading to red cell distortion,
• Clinical Features hemolytic anemia, microvascular obstruction, and tissue
o Acute intravascular hemolysis, marked by anemia, damage.
hemoglobinemia, and hemoglobinuria 2-3days following • Sickle cell disease is caused by a missense mutation in the β-
exposure to oxidants. globin gene that leads to the replacement of a charged
o Episode is self-limited: □ Only older cells are at risk for glutamate residue with a hydrophobic valine residue.
lysis, hemolysis stops when only younger cells remain in • The abnormal physiochemical properties of the resulting sickle
the blood. hemoglobin (HbS) are responsible for the disease.
o Recovery Phase is heralded by reticulocytosis. • Occurs primarily in individuals of African descent.

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• The high prevalence of sickle cell trait in certain African
populations stems from its protective effects against falciparum
malaria.
• Sickle Cell trait - about 8-10% of African Americans (2 million)
are heterozygous for HbS, which presents as asymptomatic
• The point mutation in the 6th codon of ß-globin leads to the
replacement of a glutamate residue with a valine residue.
• The abnormal physicochemical properties of the resulting
sickle cell hemoglobin (HbS) are responsible for the disease.
• High frequency stems from protection afforded by HbS against
falciparum malaria, 6 times increase in areas in which malaria
is endemic.
Figure 8: Pathophysiology of Sickle Cell Disease
• G6PD deficiency and thalassemia also protect against
malaria by increasing the clearance and decreasing the
adherence of infected red cells, possibly by raising levels
of oxidant stress and causing membrane damage in the
parasite-bearing cells that leads to their rapid removal
from the bloodstream.
Variable Affecting the degree and Rate of Sickling:
1. Interaction of HbS with other types of haemoglobin
• In heterozygotes with sickle cell trait, 40% are HbS and the
rest is HbA. The HbA interferes with the polymerization of
HbS thus cells do not sickle unless in states of hypoxia.
• HbF inhibits polymerization more than HbA. HbA is your
normal hemoglobin composed of 2 alpha and 2 beta globin
chains.
• HbC, lysine is substituted for glutamate, compounds with
HbS forming HbSC red cells.
2. Mean Cell Hemoglobin Concentration (MCHC)
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• Intracellular dehydration increases MCHC, facilitates
sickling. So if there is dehydration, there is increased
hemoglobin concentration so they are more prone to
hypoxia.
• Conditions that decrease MCHC reduce the disease
severity
3. Intracellular pH
• Decrease in pH reduces 02 affinity, thereby increasing the
fraction of deoxygenated HbS and may augment sickling.
More acidity leads to more sickling
• MORPHOLOGY:
o Peripheral blood demonstrates irreversibly sickled cells,
reticulocytosis, and target cells, resulted from dehydration.
o Howell-Joly Bodies (small nuclear remnants) are also
present due to asplenia.
o There is erythroid hyperplasiam leading to bone marrow
expansion resulting to bone resorption and secondary new
bone formation, resulting to prominent cheek bones and
changes in the skull that resembles a crewcut.
o Extramedullary hematopoiesis
o The increased breakdown of hemoglobin may cause
hyperbilirubinemia and formation of pigment gallstones.
• CLINICAL FEATURES:
o Moderately severe hemolytic anemia (Hct: 18-30%), with
reticulocytosis, hyperbilirubinemia, and irreversibly sickled
cells.
o Vaso-occlusive crises, also called pain crises, are
episodes of hypoxic injury and infarction that cause severe
pain in the affected region
✓ Most commonly involved are bones, lungs, liver,
brain, spleen, and penis.
✓ Frequently manifests as hand-foot syndrome or
dactylitis.
✓ Acute chest syndrome involves lungs, presents as
fever, cough, chest pain, and inflammatory infiltrates.
✓ Stroke
• Aplastic Crises
o Stem from infection of red cell progenitors by
Parvovirus B19, causing transient cessation of
erythropoiesis, leading to anemia.
• Chronic Tissue Hypoxia
o Generalized impairment of growth and development
as well as organ damage
• Increased susceptibility to encapsulated organisms due to
altered splenic function.
• Pneumococcus pneumonia, and Haemophilus influenzae
septicemia and meningitis are common (encapsulated
organisms: S. pneumonia, K. pneumoniae, B. anthracis)
• Mixing a blood sample with an oxygen consuming agent
(metabisulfite) induces sickling of red cells.
• About 90% of patients survive to age 20, and 50% survive
beyond the 5th decade.
• Priapism affects up to 45% of males after puberty and may
lead to hypoxic damage and erectile dysfunction.
• Other disorders related to vascular obstruction, particularly
stroke and retinopathy leading to loss of visual acuity and even
blindness, can take a devastating toll.
• Factors proposed to contribute to stroke include the adhesion
of sickle red cells
• Treatment:
o Mainstay treatment is an inhibitor of DNA synthesis
(Hydroxyurea) which has several benefits.
o Increase in red cell HbF levels.
o Anti-inflammatory effect
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Figure 9: Sickle cell
(they lost already their membrane, the ankyrin and spectrin)
d. Thalassemia Syndromes
o Heterogeneous group of disorders caused by inherited
mutations that decrease the synthesis of either the a-globin or
the ß-globin chains that compose the adult Hgb: HbA (a2ß2).
o 2 a-chains encoded by 2 a-globin genes on chromosome 16.
o 2 ß-chains encoded by 1 ß-globin gene on chromosome 11.
o So when we say a-thalassemia, there is abnormality or missing
in the alpha chain and when we say ß-thalassemia the
abnormality or missing is the beta chain.
o ß-Thalassemia
o Mutations that diminish the synthesis of ß-globin chains
o Pathogenesis:
o Two categories of mutations:
▪ ßo mutations- absent ß-globin synthesis
▪ ß+ mutations - reduced ß-globin synthesis
o 100 different mutations, mostly point mutations:
o Splicing mutations
o Most common cause of ß+ mutations
o Some of these mutations destroy normal RNA splice
junctions and completely prevent the production of
normal β-globin mRNA, resulting in β0 -thalassemia.
o Promoter Region Mutations
o Associated with ß+ mutations.
o Chain Terminator Mutations
o Most common cause of ßO mutations.
o They consist of either nonsense mutations that
introduce a premature stop codon or small insertions
or deletions that shift the mRNA reading frames.
o Impaired β-globin synthesis results in anemia by two
mechanisms.
o The deficit in HbA synthesis produces
“underhemoglobinized” hypochromic, microcytic red
cells with subnormal oxygen transport capacity.
o Even more important is the diminished survival of red
cells and their precursors, which results from the
imbalance in α- and β-globin synthesis.
o Unpaired α chains precipitate within red cell precursors,
forming insoluble inclusions. These inclusions cause a
variety of untoward effects, but membrane damage is the
proximal cause of most red cell pathology.
o Many red cell precursors succumb to membrane damage
and undergo apoptosis.
o In severe β-thalassemia, it is estimated that 70% to 85%
of red cell precursors suffer this fate, which leads to
ineffective erythropoiesis.
o Those red cells that are released from the marrow also
contain inclusions and have membrane damage, leaving
theme prone to splenic sequestration and extravascular
hemolysis.
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o In severe β-thalassemia, ineffective erythropoiesis creates
several additional problems.
o Erythropoietic drive in the setting of severe
uncompensated anemia leads to massive erythroid
hyperplasia in the marrow and extensive extramedullary
hematopoiesis.
o The expanding mass of red cell precursors erodes the
bony cortex, impairs bone growth, and produces skeletal
abnormalities (described later).
o Extramedullary hematopoiesis involves the liver, spleen,
and lymph nodes, and in extreme cases produces
extraosseous masses in the thorax, abdomen, and pelvis.
o The metabolically active erythroid progenitors steal
nutrients from other tissues that are already oxygen-
starved, causing severe cachexia in untreated patients.
o Erythroid precursors secrete a hormone called
erythroferrone that inhibits production of hepcidin, a key
negative regulator of iron uptake in the gut.
o In thalessemia, the marked expansion of erythroid
precursors leads to increased absorption of iron from the
gut, and this together with repeated blood transfusions
inevitably lead to severe iron accumulation (secondary
hemochromatosis) unless preventive steps are taken.
Injury to parenchymal organs, particularly the heart and
liver.
o Clinical Syndromes
o The relationship depends on the severity of anemia
which in turn depends on the genetic defect (ß + or ß)
and the gene dosage (homozygous or heterozygous).
Of course, it is more severe when it is hmomozygous.
o ß-Thalassemia Major (ß+ ß+ or ßOßO or ß+ßO)
o Two ß-thalassemia alleles (Homozygous) have severe
transfusion-dependent anemia.
o Most common in Mediterranean, parts of Africa, and south
East Asia. So in the Philippines, we see patients with
thalassemia.
o Manifests 9 months after birth as HbF switched to HbA.
o PBS: Anisiopoikilocytosis, Reticulocytosis, Schistocytes,
Target Cells.
o It is also included in the newborn screening so as early as
baby upon delivery, you could determine if the patient has
thalassemia unlike before we have to wait until night
months for the manifestations. Prevention is earlier too
now.
o If you notice, their appearances in the blood is the same
so we diagnose your RBC abnormalities/defects using
CBC when you see there is flagging with the use of the
RBC indices and RDW we make smears and view that in
the microscope but they have the same RBC variations
and inclusions so to differentiate them, for thalassemia for
confirmatory we have to undergo electrophoresis which is
a higher and mor sophisticated machine for thalassemia.
o ß-Thalassemia minor/trait (ß+ß or ßOß)
o More common than major, mild, asymptomatic anemia.
o Abnormal PBS, mild erythroid hyperplasia
o ß-Thalassemia intermedia - milder forms of ß+ß+. ß+ßO.
o The peripheral blood smear typically shows hypochromia,
microcytosis, basophilic stippling, and target cells.
o Mild erythroid hyperplasia is seen in the bone marrow.
o Hemoglobin electrophoresis usually reveals an increase in
HbA2 (α2δ2) to 4% to 8% of the total hemoglobin (normal,
2.5% ± 0.3%), reflecting an elevated ratio of δ-chain to β-
chain synthesis.
o HbF levels are generally normal or occasionally slightly
increased.
o Recognition of β-thalassemia trait is important for two
reasons:
1. it may be mistaken for iron deficiency
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2. it has implications for genetic counseling.
o Iron deficiency (the most common cause of microcytic
anemia) can usually be excluded by measurement of
serum iron, total iron-binding capacity, and serum ferritin.
o The increase in HbA2 is diagnostically useful, particularly
in individuals (such as women of childbearing age) who
are at high risk of iron deficiency.
• Blood smear shows severe red cell abnormalities:
o Anisocytosis - change in size
o Poikilocytosis - change in shape.
• It also shows microcytosis and hypochromia.
• Target cells, basophilic stippling, and fragmented RBC
• Diagnosis of ß-Thalassemia Trait/Minor
• Superficially resembles the hypochromic microcytic anemia of
Iron Deficiency.
• Implications for genetic counseling
Figure 10: Jigsaw Puzzle RBC
Figure 11: Codocytes or Target Cells
(most commonly associated to thalassemia)
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a-Thalassemia
• Inherited deletions that result in reduced or absent synthesis of
a-globin chains.
• Normally there are 4 a-globin genes, the severity of a
thalassemia depends on the number of a-globin chains
mutated, it depends on the number of a-globin chains that have
undergone mutations.
• The anemia stems from lack of adequate Hgb and presence of
excess unpaired globin chains.
• In newborns, excess unpaired y-globin forming y4 tetramers
known as Hemoglobin Barts.
• Older children and adults, excess ß-globins form ß4 tetramers
known as HbH.
• If HbH that is your Beta-4 tetramers if hemoglobin Barts, that is
your y-4 tetramers so remember your normal lobin chain is
alpha and beta so ther is a replacement of your globin chains.
• Silent Carrier State
o Deletion of a single a-globin gene, which causes a barely
detectable reduction in a-globin synthesis.
o Completely asymptomatic with slight microcytosis.
o They are just carrier
Hemoglobin H Disease
• Caused by deletion of 3 a-globin genes.
• Most common in Asians.
• With only one normal a-globin gene, synthesis is markedly
reduced, and tetramers of ß-globins form.
• Moderately severe anemia, resembling ß- thalassemia
intermedia. It is severe but does not require blood transfusions
unlike your beta-thalassemia major.
Table 2: Clinical and Genetic Classification of Thalassemias
*See Larger Image in Appendix
Hydrops Fetalis
• Most severe form of a-thalassemia, caused by deletion of all
four a-globin genes.
• In the fetus, y globins form tetramers (Hgb Barts) that also have
high affinity to oxygen causing tissue hypoxia.
• Fetus shows severe pallor, generalized edema, and massive
hepatosplenomegaly.
• Survival in early development is due to the expression of ζ
chains, an embryonic globin that pairs with γ chains to form a
functional ζ2γ2 Hb tetramer.
• Signs of fetal distress usually become evident by the third
trimester of pregnancy.
• With intrauterine transfusion many affected infants are now
saved.
• The fetus shows severe pallor, generalized edema, and
massive hepatosplenomegaly similar to that seen in hemolytic
disease of the newborn
e. Paroxysmal Nocturnal Hemoglobinuria (PNH)
• Results from acquired mutations in the phosphatidylinositol
glycan complementation group A gene (PIGA), an enzyme
essential for the synthesis of certain membrane-associated
complement regulatory protein.
• Thrombosis is the leading cause of disease-related death in
PNH.
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• 40% suffer from venous thrombosis, often involving hepatic
portal or cerebral veins.
• 50% develop acute myelogenous leukemia or myelodysplastic
disorder.
• Diagnosis: Flow Cytometry (Detects GPI-deficient RBC).
Sophisticated machine that diagnose PNH
• Treatments:
o Bone Marrow Transplantation, the only hope for cure
o Infusion of monoclonal antibody inhibitor of C5a that
reduces hemolysis, but can predispose to fatal
meningococcemia due to MAC deficiency.
o Immunosuppressive drugs for those with marrow aplasia
f. Immunohemolytic Anemia
Table 3: Classification of Immunohemolytic Anemias
• Warm Antibody Type
o Most common form.
o This form constitutes approximately 80% of cases of
immunohemolytic anemia. It is caused by antibodies that
bind stably to red cells at 37°C
o 50% are idiopathic (Primary), others are related to
predisposing conditions (refer to table 14-4), or exposure
to a drug.
o Most causative are of the IgG class, less commonly IgA.
Lysis is mostly extravascular.
o Splenomegaly, many cases, antibodies are directed
against the Rh blood antigens.
o As with other autoimmune disorders, the cause of primary
immunohemolytic anemia is unknown.
o In cases that are idiopathic, the antibodies are directed
against red cell surface proteins, often components of the
Rh blood group complex.
o In drug-induced cases, two mechanisms have been
described:
▪ Antigenic drugs. Hemolysis usually follows large,
intravenous doses of the offending drug and occurs 1 to
2 weeks after therapy is initiated. These drugs,
exemplified by penicillin and cephalosporins, bind to the
red cell membrane and create a new antigenic
determinant that is recognized by antibodies. The
responsible antibodies sometimes fix complement and
cause intravascular hemolysis, but more often they act as
opsonins that promote extravascular hemolysis within
phagocytes.
▪ Tolerance-breaking drugs. These drugs, of which the
antihypertensive agent α-methyldopa is the prototype,
break tolerance in some unknown manner that leads to
the production of antibodies against red cell antigens,
particularly the Rh blood group antigens. About 10% of
patients taking α-methyldopa develop autoantibodies, as
assessed by the direct Coombs test, and roughly 1%
develop clinically significant hemolysis.
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• Cold Agglutinin Type
o Caused by IgM antibodies that bind to red cells avidly at
low temperatures (OoC to 4oC).
o Less common than warm, accounts for 15-30% of cases.
o Occurs after certain infections such as Mycoplasma
pneumonia, EBV, CMV, Influenza virus, HIV.
o Chronic cold agglutinin immunohemolytic anemia occurs
in association with certain B-cell neoplasms.
o Occurs in exposed fingers, toes, or ears where vascular
beds’ temperature may fall below 30oC.
o Manifests as pallor, cyanosis, and Raynaud phenomenon
Cold Hemolysin Type
• Autoantibodies that is responsible for an Paroxysmal Cold
Hemoglobinuria, a rare disorder that causes substantial,
sometimes fatal, intravascular hemolysis and hemoglobinuria.
• Autoantibodies are IgGs that bind to the P blood group antigen
in cool peripheral areas
• Most seen in children following viral infections, which recover
within 1 month.
• Treatment:
o Warm - removal of initiating factors such as the drugs,
immunosuppressive drugs and splenectomy.
o Chronic cold - more difficult to treat.
g. Hemolytic Anemia from Trauma to Red Cells
• Most significant is seen in individuals with cardiac valve
prostheses and microangiopathic disorders.
• Artificial mechanical valves are more frequently implicated than
are bioprosthetic porcine valves (from a pig).
• Hemolysis stems from shear forces produced by turbulent
blood flow and pressure gradients across damaged vessels
• Microangiopathic hemolytic anemia is commonly seen in
disseminated intravascular coagulation (DIC), but it can also
occur in:
o Thrombotic thrombocytopenic purpura (TTP)
o Hemolytic uremic syndrome (HUS)
o Malignant HTN, SLE, and disseminated cancer
• These changes produce shear stress that leads to appearance
of red cell fragments (schistocytes), burr cells, helmet cells, and
triangle cells.
Figure 11: Microangiopathic hemolytic anemia. A peripheral blood
smear from a person with hemolytic-uremic syndrome shows
several fragmented red cells
D. Anemias of Diminished Erythropoeisis
• Most common and important anemia associated with red cell
underproduction is those caused by nutritional deficiencies.
• Followed by those that arise form Renal Failure and Chronic
Inflammation.
• Less common disorders that lead to generalized bone marrow
failure:
o Aplastic Anemia
o Primary hematopoietic neoplasm
o Infiltrative Disorder
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a. Megaloblastic Anemia
Table 4: Causes of Megaloblastic Anemia
• Vitamin B12 and B9 are coenzymes required for the
synthesis of thymidine, one of 4 bases of DNA.
• Deficiency or impairment in metabolism results in
defective nuclear maturation due to deranged or
inadequate DNA synthesis, with an attendant delay or
block in cell division.
TWO PRINCIPAL TYPES:
a. Pernicious - major form of Vit. B12 deficiency anemia
b. Folate Acid deficiency anemia
MORPHOLOGY
• Presence of red cells that are macrocytic and oval
(macroovalocytes) with anisopoikilocytosis is highly
characteristic.
• Neutrophils are also larger and show nuclear hyper
segmentation, having >5 segments. (normal: 3-5
segmentations)
• Marrow is markedly hypercellular with megaloblastic red
cell precursors, granulocytic precursors, and
megakaryocytes.
• Ineffective erythropoiesis due to apoptosis of precursor
cells.
• There is marked variation in red cell size (anisocytosis)
and shape (poikilocytosis).
• The reticulocyte count is low.
• Nucleated red cell progenitors occasionally appear in the
circulating blood when anemia is severe.
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• Neutrophils are also larger than normal and show nuclear
hypersegmentation, having five or more nuclear lobules
instead of the normal three to four.
• The marrow is usually markedly hypercellular as a result
of increased numbers of hematopoietic precursors.
• Megaloblastic changes are detected at all stages of
erythroid development.
• The most primitive cells (promegaloblasts) are large, with
a deeply basophilic cytoplasm, prominent nucleoli, and a
distinctive, fine nuclear chromatin pattern.
• As these cells differentiate and begin to accumulate
hemoglobin, the nucleus retains its finely distributed
chromatin instead of developing the clumped pyknotic
chromatin typical of normoblasts.
• Although nuclear maturation is delayed, cytoplasmic
maturation and hemoglobin accumulation proceed at a
normal pace, leading to nuclear-to-cytoplasmic
asynchrony.
• Because DNA synthesis is impaired in all proliferating
cells, granulocytic precursors also display dysmaturation
in the form of giant metamyelocytes and band forms.
• Megakaryocytes also may be abnormally large and have
bizarre, multilobate nuclei.
•
b. PERNICIOUS ANEMIA
• A specific form of megaloblastic anemia caused by an
autoimmune gastritis that impairs the production of
Intrinsic factor, which is required for B12 uptake from the
gut.
• Vitamin B12 requires IF secreted by parietal cells.
• Three types of autoantibodies responsible for the
autoimmune attack in the gastric mucosa:
o Type I - 75% blocks the binding of B12 to IF.
o Type II - Prevents binding of IF-B12 complex to lleal
receptor
o Type III - 85-90% recognize the a and B subunit of
the gastric proton pumps.
MORPHOLOGY
• Bone marrow and blood findings are same for all
megaloblastic anemias.
• Fundic Gland Atrophy, affecting both chief and parietal
cells, there is intestinalization (metaplasia) or replacement
of the glandular epithelium by mucus-secreting goblet cells
that resemble those lining the large intestine, a form of
metaplasia referred to as intestinalization.
• With time, the tongue may take on a shiny, glazed, “beefy”
appearance (atrophic glossitis).
• Because the gastric atrophy and metaplastic changes are
due to autoimmunity, they persist following parenteral
administration of vitamin B12, whereas the “megaloblastic”
changes in the marrow and gut are readily reversible.
• Central nervous system lesions are found in about three-
fourths of all cases of florid pernicious anemia but can also
be seen in the absence of overt hematologic findings.
• The principal alterations involve the cord, where there is
demyelination of the dorsal and lateral spinal tracts,
sometimes followed by loss of axons. These changes may
give rise to spastic paraparesis, sensory ataxia, and
severe paresthesias in the lower limbs.
• Less frequently, degenerative changes occur in the
ganglia of the posterior roots and in peripheral nerves.
CLINICAL FEATURES
• Pernicious anemia is insidious in onset, and the anemia is
often quite severe by the time it comes to medical
attention.
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• The course is progressive unless halted by therapy. The
diagnosis is based on:
1. a moderate to severe megaloblastic anemia
2. leukopenia with hypersegmented granulocytes
3. low serum vitamin B12
4. elevated serum levels of homocysteine and
methylmalonic acid.
• Serum antibodies to intrinsic factor are highly specific for
pernicious anemia.
• The diagnosis is confirmed by an outpouring of
reticulocytes and a rise in hematocrit levels beginning
about 5 days after parenteral administration of vitamin
B12.
• Persons with atrophy and metaplasia of the gastric
mucosa due to pernicious anemia are at increased risk for
gastric carcinoma.
• With parenteral or high-dose oral vitamin B12, the anemia
is cured and the progression of the peripheral neurologic
disease can be reversed or at least halted, but the
changes in the gastric mucosa and the risk of carcinoma
are unaffected.
3. derangements associated with hyperactive
hematopoiesis (e.g., chronic hemolytic anemia)
4. disseminated cancer.
• In all of these circumstances, the demands of increased
DNA synthesis render normal intake inadequate.
• Folic acid antagonists, such as methotrexate, inhibit
dihydrofolate reductase and lead to a deficiency of FH4.
Inhibition of folate metabolism affects all rapidly
proliferating tissues, particularly the bone marrow and the
gastrointestinal tract.
• Many chemotherapeutic drugs used in the treatment of
cancer damage DNA or inhibit DNA synthesis through
other mechanisms, and these also cause megaloblastic
changes in rapidly dividing cells.
CLINICAL FEATURES:
• General Malnutrition
• Cheilosis, Glossitis, Dermatitis
• Folate does not prevent or may even exacerbate
neurologic deficits of Vitamin B12 deficiency.

c. FOLATE ACID DEFICIENCY ANEMIA

• Dependent on dietary source with 50-200 ug daily
requirements
• A deficiency of folic acid (more properly,
pteroylmonoglutamic acid) results in a megaloblastic
anemia having the same pathologic features as that
caused by vitamin B12 deficiency.
• Among the molecules whose synthesis is dependent on
folates, dTMP is perhaps the most important biologically,
because it is required for DNA synthesis.
• It should be apparent from this discussion that
suppressed synthesis of DNA, the common
denominator of folic acid and vitamin B12 deficiency, is the
immediate cause of megaloblastosis.
THREE MAJOR CAUSES:
1. Decreased intake - chronic alcoholics, elderly, indigent
2. Increased requirements
3. Impaired utilization

• Humans depend on dietary sources for folic acid.

• The richest sources are green vegetables, certain fruits
and animal sources contain lesser amounts. The folic acid
in these foods is largely in the form of
folylpolyglutamates. Although abundant in raw foods,
polyglutamates are sensitive to heat; boiling, steaming, or
frying food for 5 to 10 minutes destroys up to 95% of the
folate content.
• Intestinal conjugases split the polyglutamates into
monoglutamates that are absorbed in the proximal
jejunum.
• During intestinal absorption they are modified to 5-
methyltetrahydrofolate, the transport form of folate. The Figure 12: Megaloblastic Anemia
body’s reserves of folate are relatively modest, and a
deficiency can arise within weeks to months if intake is
inadequate. Decreased intake can result from either a d. IRON DEFICIENCY ANEMIA
nutritionally inadequate diet or impairment of intestinal • Most common nutritional disorder in the world.
absorption. • Results in clinical signs and symptoms that are mostly
• Malabsorption syndromes, such as sprue, may lead to related to inadequate Hgb synthesis.
inadequate folate absorption, as may infiltrative diseases • Common in US, particularly in toddlers, adolescent girls
of the small intestine (e.g., lymphoma). (because of menstruation), women of childbearing age
• Certain drugs, particularly the anticonvulsant phenytoin
and oral contraceptives, interfere with absorption.
• Despite normal intake of folic acid, a relative deficiency
can be encountered when requirements are increased.
Conditions in which this is seen include
1. Pregnancy
2. Infancy
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• Disappearance of stainable iron from macrophages using

Prussian Blue stain-smears in the bone marrow.
• Microcytic (small) and hypochromic (pale) cells present.
• Poikilocytosis: small, elongated red cells (pencil cells)

Table 5: Iron Distribution in Healthy Young Adults

• 80% of iron is functional, found in Hgb, myoglobin, and iron

containing enzymes (catalase, cytochromes).
• 15-20% is in the storage pool, in the form of ferritin and
hemosiderin.
• Iron in the body is recycled between the functional and
storage pools. Transported in plasma by an iron-binding
glycoprotein called transferrin, which is synthesized in the
liver.
• Major function is to deliver iron to cells which require it.
• Iron absorption in the duodenum is regulated by hepcidin, Figure 13: Hypochromic microcytic anemia
a small circulating peptide that is synthesized and
released from the liver in response to increases in CLINICAL FEATURES
intrahepatic iron levels. • Non-specific symptoms of anemia.
• Hepcidin inhibits iron transfer from the enterocyte to • Dominating signs and symptoms frequently relate to the
plasma by binding to ferroportin, causing it to be underlying cause.
endocytosed and degraded. • GIT or Gynecologic, Malnutrition, Pregnancy,
• As a result, as hepcidin levels rise, iron becomes trapped Malabsorption
within duodenal cells in the form of mucosal ferritin and is • In severe and long-standing IDA, depletion of iron
lost as these cells slough. containing enzymes in cells throughout the body
• when the body is replete with iron, high hepcidin levels • Depletion from CNS may lead to pica syndrome.
inhibit its absorption into the blood. • Plummer-Vinson Syndrome, a triad of:
• with low body stores of iron, hepcidin levels fall, facilitating o Esophageal webs.
iron absorption. o Microcytic Hypochromic Anemia
• Free iron is highly toxic, there it is sequestered. o Atrophic Glossitis
o Ferritin: a ubiquitous protein-iron complex is found at DIAGNOSIS
highest levels in the liver, spleen, marrow, and • Depressed Hgb and Hct
skeletal muscles bind to iron in storage pools. • Hypochromia, Microcytosis, modest poikilocytosis
o Hemosiderin: partially degraded protein shells of • Serum Iron and Ferritin: LOW
ferritin aggregates, traces amounts principally in • Total Plasma Iron Binding Capacity: HIGH
macrophages. • Low serum iron with increased binding capacity results in
• Plasma Ferritin is derived largely from storage pool, its a transferrin saturation below 15%.
level correlate well with iron stores. So if there is low
plasma ferritin then there is also low iron stores.
ETIOLOGY
e. ANEMIA OF CHRONIC DISEASE
• Dietary insufficiency • Most common cause of anemia among hospitalized patients
• Impaired Absorption (US)
• Increased Requirement (Infants, Pregnant) • Anemia occurs in the setting of persistent systemic
• Chronic Blood Loss inflammation.
• To maintain a normal iron balance, about 1 mg of iron must • Associated with:
be absorbed from the diet every day. o LOW serum iron
• Because only 10% to 15% of ingested iron is absorbed, o DECREASE total iron binding capacity
the daily iron requirement is 7 to 10 mg for adult men and o INCREASE stored iron in tissue macrophages
7 to 20 mg for adult women.
3 categories:
• Chronic blood loss is the most common cause of iron
a. Microbial Infections (Osteomyelitis, Bacterial
deficiency in high income societies.
Endocarditis, Lung Abscess)
PATHOGENESIS
b. Chronic Immune Disorders (Rheumatoid arthritis,
• It produces hypochromic microcytic anemia.
regional enteritis)
• Progressive depletion of the reserves first lowers serum c. Neoplasms - Breast & Lung CA, Hodgkin Lymphoma
iron and transferrin "without anemia".
• Anemia only appears when iron stores are completely PATHOGENESIS
depleted and is accompanied by low serum iron, ferritin, • Certain inflammatory mediators, particularly IL-6 stimulate
and transferrin. Time wherein anemia and pallor can be an increase in hepatic production of hepcidin, which
seen. inhibits iron absorption by
MORPHOLOGY
• Erythropoietin levels are low for the degree of anemia.
• Bone marrow reveals mild to moderate increase in
• Hepcidin can directly or indirectly inhibit erythropoietin
erythroid progenitors.
production.
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• Iron sequestration serves to enhance the body's ability to
fend off certain organisms that require iron (H. influenzae).
CLINICAL LABORATORY FEATURES
• Anemia is usually mild.
• Dominant symptoms are those of the underlying disease.
• Normocytic and normochromic, or microcytic and
hypochromic.
• Increased storage of iron, high serum ferritin, reduced
TIBC.
• Treatment of the underlying condition corrects the
anemia).
f. APLASTIC ANEMIA
• Refers to a syndrome of chronic primary hematopoietic failure
and attendance pancytopenia (anemia, neutropenia, and
thrombocytopenia).
• Majority of patients have autoimmune mechanisms but
inherited or acquired abnormalities of hematopoietic stem cells
seem to contribute.
Table 6: Major Causes of Aplastic Anemia
• Specific abnormalities underlying some cases of aplastic
aplasia are as follows.
1. Fanconi anemia
- rare autosomal recessive disorder caused by
defects in a multiprotein complex that is required
for DNA repair.
- Marrow hypofunction becomes evident early in
life and is often accompanied by multiple
congenital anomalies, such as hypoplasia of the
kidney and spleen, and bone anomalies,
commonly involving the thumbs or radii.
2. Inherited defects in telomerase are found in 5% to
10% of adult-onset aplastic anemia. Telomerase is
required for cellular immortality and limitless
replication. It might be anticipated, therefore, that
deficits in telomerase activity could result in
premature hematopoietic stem cell exhaustion and
marrow aplasia.
3. Abnormally short telomeres, which are found in the
marrow cells of as many as one-half of those affected
with aplastic anemia. about 65% of cases fall into this
idiopathic category.
CLINICAL FEATURES
• Occurs at any age or sex, insidious onset.
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• Initial manifestation depends on cell line affected.
• Anemia - progressive weakness, pallor, dyspnea.
• Thrombocytopenia - petechial, ecchymoses, bruises.
• Neutropenia - minor infections, fever, chills.
g. PURE RED CELL APLASIA
• Primary marrow disorder in which only erythroid progenitors
are suppressed.
• Severe cases: Completely absent.
• May occur in association with neoplasms (Thymoma, large
granular lymphocytic leukemia), drug exposures, autoimmune
disorders, Parvovirus infection.
Parvovirus B19 Infection:
• Normal individuals - Transient Aplasia
• Moderate to severe - Hemolytic anemias (Aplastic Crises)
• Immunosuppressed (HIV) - Chronic red cell aplasia,
moderate to severe anemia.
h. MYELOPHTHISIC ANEMIA
• A form of bone marrow failure in which space-occupying
lesions replace normal marrow element.
• Common cause is metastatic cancer most often carcinomas
from breast, lungs, and prostate.
• Infiltrative process can also occur
• Chronic renal failure, whatever its cause, is almost invariably
associated with an anemia that tends to be
• roughly proportional to the severity of the uremia.
II. POLYCYTHEMIA
• Increase in RBCs
• Denotes an abnormally high red cell count, usually with
corresponding increase in hemoglobin levels.
• Relative: when there is hemoconcentration due to decreased
plasma volume.
• Absolute: increase in total red cell mass
• It also is associated with a condition of unknown etiology
called stress polycythemia, or Gaisböck syndrome.
• Affected individuals are usually males who are hypertensive,
obese, and anxious (“stressed”).
• Absolute polycythemia is primary when it results from an
intrinsic abnormality of hematopoietic precursors and
secondary when it stems from the response of red cell
progenitors to elevated levels of erythropoietin.
• The most common cause of primary polycythemia is
polycythemia vera, a myeloproliferative neoplasm
associated with mutations that lead to erythropoietin-
independent growth of red cell progenitors
Table 7: Pathophysiologic Classification of Polycythemia
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III. BLEEDING DISORDERS (HEMORRHAGIC
DIATHESIS
• Excess bleeding results from:
o Increased fragility of vessels
o Platelet deficiency or dysfunction
o Derangement of coagulation
• Normal hemostatic responses involve blood vessel walls,
platelets and clotting cascade.
TEST FOR HEMOSTASIS EVALUATION
1. Prothrombin time (PT) - assess extrinsic and common
coagulation pathway.
⁃ Measure the clotting of plasma after addition of exogenous
tissue thromboplastin and calcium ions.
⁃ Prolonged PT result from deficiency or dysfunction of
factor V, VII, X, prothrombin or fibrinogen.
2. Partial thromboplastin time (PTT) - assess intrinsic and
common coagulation pathways.
⁃ Clotting of plasma after the addition of kaolin, cephalin and
calcium ions
⁃ Prolongation is due to deficiency or dysfunction of factors
V, VIII, IX, X, XI, XII, prothrombin, fibrinogen or interfering
antibodies to phospholipids.
3. Platelet counts - electronic particle counter
⁃ Reference range: 150-400 x 103/uL I Abnormal counts are
best confirmed through peripheral blood smear.
⁃ Platelet clumping can cause spurious thrombocytopenia.
⁃ High counts may be indicative of a myeloproliferative
disorder.
4. Tests of platelet function include tests for platelet aggregation,
quantitative tests of von Willebrand factor, bleeding time.
Bleeding time now is replaced by aPTT and PT.
5. Specialized tests measure levels of specific clotting factors,
fibrinogen, fibrin split products and presence of circulating
anticoagulants.
A. BLEEDING DISORDERS CAUSED BY VESSEL WALL
ABNORMALITIES
• Relatively common disorders that doesn't cause serious
bleeding problems.
• Present with small hemorrhages (petechia or purpura) in
skin or membranes, particularly gingivae.
• Hemorrhages may occur in joints, muscles, subperiosteal
locations and takes the form of menorrhagia, nosebleeds,
bleeding or hematuria.
• PT and PTT are usually normal
CLINICAL CONDITIONS WITH BLEEDING DUE TO VESSEL
WALL ABNORMALITIES
a. Infections
⁃ Induce petechial and purpuric hemorrhages
⁃ Meningococcemia, septicemia, infective endocarditis,
rickettsioses
⁃ Mechanisms include vasculitis and DIC.
b. Drug reactions
⁃ Mediated by deposition of drug induced immune
complexes in vessel walls leading to hypersensitivity
vasculitis.
c. Scurvy and Ehler Danlos Syndrome
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⁃ Associated with microvascular bleeding resulting from
collagen defects that weaken walls
d. Henoch-Schonlein purpura
⁃ Systemic immune disorder characterized by a purpuric
rash, colicky abdominal pain, polyarthralgia, acute
glomerulonephritis.
e. Hereditary hemorrhagic telangiectasia (Weber-Osler-
Rendu syndrome)
⁃ Characterized by dilated, tortuous blood vessels within
thin walls that bleed readily.
f. Perivascular amyloidosis
⁃ Weaken blood vessel walls and cause bleeding.
B. THROMBOCYTOPENIA
• Reduction in platelet number constitutes an important cause
of generalized bleeding.
• Count <100,000 platelets/L is considered thrombocytopenia.
• 20,000 to 50,000 platelets/uL aggravate posttraumatic
bleeding. Platelet transfusion is required. In patients with
cardiac problems and have <70,000 platelets/uL, blood
transfusion is often done during surgery.
• <20,000 platelets/uL may be associated with spontaneous
(nontraumatic) bleeding.
• Bleeding from thrombocytopenia is associated with normal PT
and PTT. PT and PTT are for the coagulation pathway.
• Spontaneous bleeding associated with thrombocytopenia
most often involves small vessels.
• Common sites are the skin and mucous membranes of the GI
and GUT.
• Intracranial bleeding is the most feared type, it is a threat to
many patients with a markedly depressed platelet count.
CAUSES OF THROMOCYTOPENIA
• Decreased Platelet Production
• Decreased Platelet Survival
• Sequestration
• Dilution
1. CHRONIC IMMUNE THROMBOCYTOPENIC PURPURA
• Caused by auto-antibody mediated destruction of platelets.
• Occur in a variety of predisposing conditions and exposures
(secondary) or in the absence of risk factors (primary or
idiopathic).
• Secondary Chronic ITP occurs in SLE, HIV infection and B-cell
neoplasms (CLL).
• Diagnosis of primary is made after exclusion of secondary
chronic ITP.
PATHOGENESIS
• Autoantibodies are most often directed against platelet
membrane glycoproteins lIb-Illa or Ib-IX and demonstrate the
plasma and bound to platelet surface in 80% of patient.
• Antiplatelet antibodies of IgG class are found in majority the
cases.
MORPHOLOGY
• The principal changes of thrombocytopenic purpura are found
in the spleen, bone marrow, and blood, but they are not
specific.
• Secondary changes related to the bleeding diathesis may be
found anywhere in the body.
• The spleen is of normal size. Typically, there is congestion of
the sinusoids and enlargement of the splenic follicles, often
associated with prominent reactive germinal centers.
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• scattered megakaryocytes are found within the sinuses,
possibly representing a mild form of extramedullary
hematopoiesis driven by elevated levels of thrombopoietin.
• The marrow reveals a modestly increased number of
megakaryocytes. Some are apparently immature, with large,
nonlobulated, single nuclei. These findings are not specific but
merely reflect accelerated thrombopoiesis, being found in most
forms of thrombocytopenia resulting from increased platelet
destruction.
• bone marrow examination- rule out thrombocytopenias
resulting from marrow failure or other primary marrow
disorders.
• The secondary changes relate to hemorrhage, often in the form
of petechial bleeds into the skin and mucous membranes.
• The peripheral blood often reveals abnormally large
platelets (megathrombocytes), which are a sign of accelerated
thrombopoiesis.
CLINICAL FEATURES
• Commonly in adult women <40years old, female to male ratio
3:1
• Insidious in onset and characterized by bleeding into the skin
and mucosal surfaces.
• Cutaneous bleeding is in the form of pinpoint hemorrhages
(petechia) which can give rise to ecchymoses.
• History of easy bruising, nosebleeds, bleeding from the gums,
hemorrhages into soft tissues from minor trauma.
• Initially manifest with melena, hematuria or excessive
menstrual flow.
• Subarachnoid hemorrhage and intracerebral hemorrhage are
serious and fatal complications, but rarely occur.
2. ACUTE IMMUNE THROMBOCYTOPENIC PURPURA
• Caused by autoantibodies to platelet but with distinct and
course clinical features.
• A disease of childhood with equal frequency in both sexes.
• Symptoms appear 1-2 weeks after self-limited viral illness
that triggers development of autoantibodies.
• Usually self-limited and resolves spontaneously within 6
months.
• Glucocorticoids are given if thrombocytopenia is severe in
children with viral prodrome, thrombocytopenia persists.
3. DRUG INDUCED THROMBOCYTOPENIA
• Drug can induce thrombocytopenia through direct effects
on platelets and secondary to immunologically mediated
platelet destruction.
• Quinine, Quinidine and Vancomycin binds to platelet
glycoproteins and create antigenic determinants
recognized by antibodies.
• Thrombocytopenia is also a common consequence of
platelet inhibitory drugs that bind glycoprotein Ilb/Illa.
4. HEPARIN INDUCED THROMBOCYTOPENIA (HIT)
TWO TYPES OF HIT:
a. Type I - occurs rapidly after the onset of therapy, resolves
despite continuation of therapy. Results from a direct
platelet-aggregating effect of heparin.
b. Type II - less common but of greater importance, occurring
5-14 days after therapy begins and leads to life threatening
venous and arterial thrombosis.
5. HIV-ASSOCIATED THROMBOCYTOPENIA
• Thrombocytopenia is one of the most common
hematologic manifestations of HIV infections due to
impaired production and increased destruction of platelets.
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• CD4 and CXCR4, the receptor and co-receptor for HIV are
found on megakaryocytes.
• HIV infected megakaryocytes are prone to apoptosis and
impaired ability to produce platelets.
6. THROMBOTIC MICROANGIOPATHIES [THROMBOTIC
THROMBOCYTOPENIC PURPURA (TTP) & HEMOLYTIC-
UREMIC SYNDROME (HUS)]
• Thrombotic microangiopathy encompasses a spectrum of
syndromes including TP and HUS.
• Caused by insults that lead to excessive activation of
platelets depositing as thrombi in small blood vessels.
• In time, the distinguishing features of both have blurred out
as TP patients lack one feature and US patients have fever
or neurologic dysfunction.
a. Thrombotic Thrombocytopenic Purpura (TTP)
⁃ defined as the pentad of fever, thrombocytopenia,
microangiopathic haemolytic anemia, transient
neurologic deficits and renal failure.
b. Hemolytic Uremic Syndrome (HUS)
⁃ associated with microangiopathic haemolytic anemia
and thrombocytopenia, prominent of acute renal
failure and absence of neurologic symptoms, most
commonly occurring in children.
Table 8: Thrombotic Microangiopathiies
C. BLEEDING DISORDERS WITH DEFECTIVE
PLATELET FUNCTION
• Several inherited disorders: abnormal platelet function and
normal platelet count.
THREE PATHOGENICALLY DISTINCT GROUPS:
1. Defects of Adhesion - Bernard-Soulier Syndrome
2. Defects of aggregation - Glanzmann Thrombasthenia
3. Disorders of platelet secretion (release reaction) -
Storage Pool Disorders.
Bernard-Soulier syndrome
- consequences of defective adhesion of platelets to
subendothelial matrix.
- It is an autosomal recessive disorder caused by an
inherited deficiency of the platelet membrane glycoprotein
complex Ib–IX. This glycoprotein is a receptor for vWF and
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is essential for normal platelet adhesion to the
subendothelial extracellular matrix.
- Affected patients have a variable, often severe, bleeding
tendency.
Glanzmann thrombasthenia
- bleeding due to defective platelet aggregation.
- It is transmitted as an autosomal recessive trait.
- Thrombasthenic platelets fail to aggregate in response to
adenosine diphosphate (ADP), collagen, epinephrine, or
thrombin because of deficiency or dysfunction of
glycoprotein IIb–IIIa,
- an integrin that participates in “bridge formation” between
platelets by binding fibrinogen.
- The associated bleeding tendency is often severe.
Storage pool disorders
- defective release of certain mediators of platelet activation,
such as thromboxanes and granule-bound ADP.
Acquired defects of platelet function
a. Ingestion of Aspirin & other NSAID's
⁃ Aspirin-potent irreversible inhibitor of the enzyme
cyclooxygenase-required for the synthesis of
thromboxane A2 & prostaglandins.
⁃ Play an important role in platelet aggregation &
release
b. Uremia
⁃ Complex pathogenesis of platelet dysfunction
⁃ Involves defects in adhesion, granule secretion, &
aggregation.
D. HEMORRHAGIC DIATHESIS RELATED TO
ABNORMALITIES IN CLOTTING FACTORS
HEREDITARY DEFICIENCIES
• Typically affect a single clotting factor
• Most common & important inherited deficiency of coagulation
factors: factor VIll (haemophilia A) and factor IX (haemophilia
B)
• Von Willebrand disease - influence both coagulation & platelet
function
• All clotting factor deficiency cause bleeding EXCEPT factor XII
deficiency
ACQUIRED DEFICIENCIES
• Usually involves multiple coagulation factors simultaneously
• Decreased protein synthesis or shortened haft life
• Vitamin K deficiency: impaired synthesis of factors, II, VII, IX, X
& protein C - Severe parenchymal liver disease and DI
a. THE FACTOR VIII-vWF COMPLEX
• Two most common inherited disorders of bleeding: hemophilia
A & von Willebrand Disease
• Qualitative or quantitative defects
• Factor VIll-essential cofactor of factor IX, made by sinusoidal
endothelial cells and Kupffer cells (liver) tubular epithelial cells
(kidney)
b. VON-WILLEBRAND DISEASE
• Most common inherited bleeding disorders in humans, AD rare
AR
• Bleeding tendency is mild
• Most common symptoms: spontaneous bleeding from mucous
membranes (epistaxis), excessive bleeding from wounds,
menorrhagia,
• Prolonged BT in the presence of normal platelet count
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• More than 20 variants
1. Reduced quantity of circulating VWF
a. Type 1-AD
⁃ mild to moderate vWF deficiency, 70% cases
⁃ Incomplete penetrance & variable expressivity -
Mild disease with some missense mutations
b. Type 3 Autosomal Recessive
⁃ Extremely low levels of functional WF with
severe clinical manifestations
2. Qualitative defects in VWF
a. type 2 von Willebrand Disease, with several subtypes
⁃ Type 2A is the most common, 25% of cases
⁃ Autosomal dominant disorder
⁃ vWF in normal amounts
⁃ Missense mutation with defective multimer
assembly
c. HEMOPHILIA A (FACTOR VIII DEFICIENCY)
• Most common hereditary disease associated with life-
threatening bleeding
• Mutations in factor VIll, cofactor for factor IX
• X-linked recessive trait-affects mainly males &
homozygous females-inactivation of x chromosome
bearing normal factor VIl
• 30% have no family history, caused by new mutations
• Clinical severity correlates with level of factor VIll activity:
o severe disease: <1% normal levels
o moderately severe: 2-5% normal levels
o mild disease: 6-50% normal levels
• All symptomatic cases: tendency of easy bruising &
massive hemorrhage after trauma or operative procedure
• Spontaneous hemorrhages frequently occur -
hemarthroses (recurrent-progressive deformity-crippling)
• Treatment: Recombinant factor VIII
• 15% with severe hemophilia A develops antibodies-binds
and inhibits factor VIll (perceived as foreign)
d. HEMOPHILIA B (CHRISTMAS DISEASE, FACTOR IX
DEFICIENCY)
• X-linked recessive trait
• Variable clinical severity
• 15% cases -factor IX is present but nonfunctional
• PTT prolonged
• Specific factor IX assay for diagnosis
• Treatment: Recombinant Factor IX
E. DISSEMINATED INTRAVASCULAR
COAGULATION (DIC)
• Acute, subacute or chronic thromboembolic disorder
• Excessive activation of coagulation formation of thrombi in
the microvasculature in the body
• Secondary complication of many different disorders like
infections, surgery…
• Sometimes localized to specific organ or tissue
• Consumption of platelets, fibrin & coagulation factors
• Secondary activation of fibrinolysis
• Can present with signs & symptoms relating to tissue
hypoxia & infarction - Myriad Microthrombi
• Depletion of factors for hemostasis, activation of
fibrinolysis or both results to haemorrhage
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ETIOLOGY AND PATHOGENESIS
• Not a primary disease
• Clotting can be initiated by either 2 pathways:
a. Extrinsic pathway: triggered by release of tissue
factor (thromboplastin)
b. Intrinsic pathway: activation of factor XII by surface
contact with collagen or other negatively charged
substances
• Both results in the generation of thrombin-converts
fibrinogen to fibrin
• Clotting in vivo is initiated by exposure of tissue factor,
which activates factor VII.
• The most important effect of tissue factor/factor VII
complexes is activation of factor IX, which in turn activates
factor X.
• Activation of factor X leads to the generation of thrombin,
the central player in clotting.
• At sites where the endothelium is disrupted, thrombin
converts fibrinogen to fibrin; feeds back to activate factors
IX, VIII, and V; stimulates fibrin crosslinking; inhibits
fibrinolysis; and activates platelets, all of which augment
the formation of a stable clot.
• To prevent runaway clotting, this process must be sharply
limited to the site of tissue injury.
Two major mechanisms trigger DIC
a. Release of tissue factor or thromboplastic substances into
the circulation
b. Widespread injury to the endothelial cells
• Endothelial injury initiates DIC in several ways.
• Injuries that cause endothelial cell necrosis expose the
subendothelial matrix, leading to the activation of platelets
and the coagulation pathway.
• DIC is most commonly associated with obstetric
complications, malignant neoplasms, sepsis, and major
trauma.
• The triggers in these conditions are often multiple and
interrelated.
Possible consequences of DIC:
1. Widespread deposition of fibrin within the microcirculation
ischemia of more severely affected or more vulnerable
organs
⁃ Microangiopathic hemolytic anemia-fragmentation of
red cells
2. Consumption of platelets & clotting factors & activation of
plasminogen-hemorrhagic diathesis
MORPHOLOGY
• Thrombi most often found in: brain, heart, k idneys,
adrenals, spleen & liver
• Kidneys: small thrombi in glomeruli-reactive swelling of
endothelial cells, severe cases-microinfarcts, bilateral
cortical necrosis
• Lungs: numerous fibrin thrombi in alveolar capillaries-
pulmonary edema & fibrin exudation-"hyaline membranes"
- reminiscent of ARDS
• Sheehan postpartum pituitary necrosis - DIC complicating
labor & delivery
• Toxemia of pregnancy - placenta exhibits widespread
microthrombi and premature atrophy of cytotrophoblast&
syncytiotrophoblast.
• Giant hemangiomas are thrombi due to stasis & recurrent
trauma to fragile blood vessels
• In meningococcemia, fibrin thrombi within the
microcirculation of the adrenal cortex are the probable
basis for the massive adrenal hemorrhages seen in
Waterhouse-Friderichsen syndrome.
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• An unusual form of DIC occurs in association with giant
hemangiomas (Kasabach-Merritt syndrome) in which
thrombi form within the neoplasm because of stasis and
recurrent trauma to fragile blood vessels.
CLINICAL FEATURES
• Onset can be fuminant due to endotoxic shock or amniotic
fluid embolism
• Insidious & chronic in carcinomatosis, retention of dead
fetus
• 50% affected are obstetric patients having complications
of pregnancy - disorder is reversible with delivery of fetus
• 33% have carcinomatosis
• Few common patterns: hemolytic pnemia, dyspnea,
cyanosis and respiratory failure, convulsions, coma,
oliguria and acute renal failure, sudden or progressive
circulatory failure & shock
• Acute DIC, associated with obstetric complications or
major trauma, is dominated by bleeding diathesis
• Chronic DIC - cancer patients present with thrombotic
complications
DIAGNOSIS
⁃ Diagnosis is based on clinical observation & laboratory
studies: Fibrinogen levels, platelets, PT, PTT, & FDP
PROGNOSIS
⁃ Prognosis is highly variable, depends on the underlying
disorder
TREATMENT
⁃ Definitive treatment: remove or treat the inciting cause
F. COMPLICATIONS OF TRANSFUSION
1. Febrile non-hemolytic reaction
o takes the form of fever and chills, sometimes with mild
dyspnea and occurs within 6 hours of a transfusion of
red cells or platelets, the most commonly
encountered
2. Allergic Reactions
o Severe, potentially fatal allergic reactions may occur
when blood products containing certain antigens are
given to sensitized recipients
o IgA deficiency, triggered by IgG antibodies
o Urticarcial allergic reactions - triggered by presence
of an allergen in donated blood that is recognized by
IgE antibodies
3. Hemolytic Reactions
o Caused by preexisting formed IgM antibodies against
donor red cells that fix complement
o Delayed hemolytic reactions are caused by
antibodies that recognized red cell antigens that the
recipient was sensitized to previously, through prior
blood transfusion
4. Transfusion Related Acute Lung Injury (TRALI)
o Severe, frequently fatal complication in which factors
in a transfused blood product trigger the activation of
neutrophils in the lung vasculature
5. Infectious Complications
o Bacterial infections are caused by skin flora,
indicating that the contamination occurred at the time
that the product is taken from the donor
o Advances in donor screening, selection and
infectious disease testing have dramatically
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decreased the incidence of viral transmission by 9. Pica, a clinical presentation for Fe deficiency
blood products anemia, is
a. Itchiness
b. ED
IV. Reference c. Desire to eat weird things
d. A small woodland creature
Dr Refuerzo PowerPoint Presentation. RBC and Bleeding
Disorders. January 4, 2022
10. Which lab investigations would you order if you
suspect Fe deficiency anemia? (check all that apply)
Kumar, V., Abas, A., Aster, J. Robbins & Cotran Pathologic Basis of
a. CBC
Disease (10th ed). Philadelphia, USA. Elsevier. (2019).
b. Blood smear
c. Serum iron
V. Test Yourself d. Serum ferritin
e. TIBC
f. All of the above
1. Which of the following is NOT a cause of microcytic
anemia? 11. Where is beta-thalassemia most common? (check
a. Thalassemia all that apply)
b. Anemia of chronic disease a. West Africa
c. Iron deficiency anemia b. Mediterranean
d. Pancytopenia c. Arabian Peninsula
e. Lead poisoning d. South East Asia
e. Canada
2. The lab reports for a patient with low mean cell volume
show high serum ferritin and low total iron binding 12. What is the difference between beta-thalassemia
capacity. What is the most likely cause for major and beta-thalassemia minor?
this patient’s anemia? a. Homozygous vs heterozygous
a. Fe deficiency b. Acute vs chronic
b. Anemia secondary to inflammation c. Legal drinking age
c. Thalassemia
d. Hemoglobinopathy 13. Heinz bodies are made of:
a. Excess gamma chains
3. Fe is absorbed in the b. Excess alpha chains
a. Stomach c. Excess beta chains
b. Duodenum d. Excess ketchup
c. Jejunum
d. Ileum 14. Beta-thalassemia, unlike alpha-thalassemia, presents at
approximately 6 months of age.
4. Where is most nonheme iron found in the body? a. True
a. Bound to IF b. False
b. Bound to transferrin
c. Free in plasma 15. Which would you expect to see on a blood smear
d. Stored in liver for beta-thalassemia? (select all that apply)
a. Heinz bodies
5. Select the following that enhance Fe absorption b. Multinucleated neutrophils
(select all that apply) c. Target cells
a. Citric acid d. Hypochromic microcytic cells
b. Polyphenols (tea) e. Hyperchromic microcytic cells
c. Phytate (bran)
d. Calcium 16. What is the treatment for beta-thalassemia minor?
e. Ascorbic acid a. Blood transfusions
b. Iron chelation
6. What is the most important test for Fe stores? c. Bone marrow transplant
a. Serum iron d. None of the above
b. TIBC
c. Serum ferritin 17. Decreased or stopped production of alpha-globin chains
results in HbH (4 gamma chains together) and Hb Barts
7. Which of the following is not an etiology of Fe (4 beta chains together)
deficiency anemia? a. True
a. Chronic blood loss b. False
b. Increased requirement
c. Infection 18. On a CBC for alpha-thalassemia, you would see anemia
d. Malabsorption and reticulocytosis. On the blood smear, you would see
e. Decreased intake Heinz bodies, hypochromic microcytic cells, and
occasional target cells. Select the others that you would
8. TIBC increases in iron deficiency anemia because see increase:
a. Inflammatory response to deficiency a. LDH
b. Compensation by other factors b. Unconjugated bilirubin
c. Ability to absorb increases c. Conjugated bilirubin

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d. Urine urobilinogen b. No neurological symptoms in folic acid

e. Urine hemosiderin c. Muscle wasting
d. Dizziness
19. Aplastic anemia can be acquired (more common)
and inherited. What are some of the ways it can be 29. Folic acid therapy can cause sickle cell anemia
acquired? a. True
a. Postviral infection b. False
b. Pregnancy
30. Hydroxyurea increases hemoglobin production and
c. Ionizing radiation
decreases reticuolocyte cells.
d. Drugs and chemicals
e. Idiopathic a. True
f. All of above b. False

20. Aside from the gradual onset signs of anemia, what other 31. Which test can be used to detect hemolytic anemia?
clinical presentations would you see with aplastic a. Coombs test
anemia? b. Genetic testing
a. Koilonychias, “spoon nails” c. Peripheral blood smear
b. Associated thrombocytopenia, e.g., history of d. Schilling Test
bleeding from the gums
c. Neutropenia, e.g., repeated bacterial infections 32. Which anemia is classified as not being able to use iron
d. Purpura properly to synthesize hemoglobin because of an
e. Pica inherited cause.
a. Iron deficiency anemia
21. How would you diagnose aplastic anemia?
b. Hypochromic anemia
a. Blood smear
b. Bone marrow biopsy c. Aplastic anemia
c. Spleen biopsy
d. CBC 33. What is the lifespan of RBC?
e. Liver biopsy a. 120 days
b. 100 days
22. Select treatment options for aplastic anemia c. 200 days
a. IV equine ATG d. 80 days
b. Bone marrow transplant
c. Splenectomy 34. The hexose monophosphate pathway activity increases
d. Immune suppression the RBC source of
a. Glucose and lactic acid
b. 2,3-BPG and methemoglobin
23. Causes spurious decrease in MCV c. NADPH and reduced gluthathione
a. Cryofibrinogen
d. ATP and other purine metabolites
b. hyperglycemia
c. autoagglutination
d. high WBC ct 35. Which single feature of normal RBC’s is most responsible
e. reduced red cell deformability for limiting their lifespan?
a. Loss of mitochondria
24. When the entire CBC is suppressed due to either b. Increased flexibility of the cell membrane
anemia, infection or hemorrhage is called? c. Reduction of Hb iron
a. Erythroplasia d. Loss of nucleus
b. Thrombocytopenia
c. Pancytopenia
d. Leukopenia Answer Key

25. Red Cell indices: Determination of relative size of RBC –

82-98fL
a. MCH 1. D 11. B,C,D 21. B 31. A
b. MCV
c. MCHC 2. B 12. A 22. A,B,D 32. B
3. B 13. B 23. A 33. A
26. Measurement of average weight of Hgb/RBC 4. B 14. A 24. C 34. C
a. MCH 5. A 15. A, C, D 25. B 35. D
b. MCV 6. C 16. D 26. B
c. MCHC 7. C 17. B 27. C
8. C 18. A,B,D,E 28. B
27. Evaluation of RBC saturation with Hgb 9. C 19. F 29. B
a. MCV
b. MCH
10. D 20. BCD 30. A
c. MCHC

28. Vitamin b 12 and folic have the similar adverse effects

but what separates one from the other?
a. Glossitis
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VI. Appendix

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