HEMATOLOGY

I. Anemias II. Blood loss anemia

Anemia is defined as a decrease in  Acute Blood Loss
erythrocytes and hemoglobin, resulting in  Chronic Blood Loss
decreased oxygen delivery to the tissues.
Anemia is suspected when the hemoglobin is: Acute Blood Loss

 Characterized by a sudden loss of blood

 <12 g/dL in girls
resulting from trauma or other severe
 <11 g/dL in boys
forms of injury
1. Relative (pseudo) anemia

 RBC mass is normal, but plasma

volume is increased

2. Absolute anemia

 RBC mass is decreased, but plasma

volume is normal. This is indicative
of a true decrease in erythrocytes and
hemoglobin.

Relative (pseudo) anemia

o Secondary to an unrelated condition and
can be transient in nature
o Causes include conditions that result in
hemodilution, such as pregnancy and
volume overload.
o Reticulocyte count normal;
normocytic/normochromic anemia
Absolute anemia
o Mechanism
 Decreased delivery of red cells into
circulation
 Increased loss of red blood cells
from the circulation
 Clinical symptoms: Hypovolemia, rapid
pulse, low blood pressure, pallor
 Laboratory
o Normocytic/normochromic anemia
o Initially normal reticulocyte count,
hemoglobin/hematocrit;
o In a few hours, increase in platelet
count and leukocytosis with a left
shift, drop in
hemoglobin/hematocrit and RBC;
o Reticulocytosis in 3-5 days
Chronic Blood Loss

 Characterized by a gradual, long-term

loss of blood; often caused by
gastrointestinal bleeding
 Laboratory:
o Initially normocytic/normochromic
anemia that
o Over time causes a decrease in
hemoglobin/hematocrit;
o Gradual loss of iron causes
microcytic/hypochromic anemia
 HEMATOLOGY

 Laboratory findings:
Microcytic/hypochromic anemia;

 Low:
o serum iron
o Ferritin
o hemoglobin/hematocrit,
o RBC indices, reticulocyte count
III. Impaired or Defective Production low;
Anemias  High:
 RDW and total iron-binding
 Iron-deficiency anemia capacity (TIBC)
 Anemia of chronic disease  Smear shows
 Sideroblastic anemia  Ovalocytes/pencil forms
 Lead poisoning  Hypochromic, microcytic anemia
 Porphyrias
 Megaloblastic anemia
 Non-megaloblastic macrocytic anemia
 Aplastic anemia
 Myelopthisic anemia

1. Iron-deficiency anemias

 Most common form of anemia in the

United States
 Prevalent in infants and children,
pregnancy, excessive menstrual flow,
elderly with poor diets, malabsorption
syndromes, chronic blood loss (GI blood
loss, hookworm infection)  Clinical Signs and Symptoms
o Fatigue
o Dizziness
o pica
 HEMATOLOGY
o stomatitis (cracks in the corners of
the mouth)
o glossitis (sore tongue)
o koilonychia (spooning of the nails)
2. Anemia of Chronic Disease
 Due to an inability to use available iron
for hemoglobin production
 Impaired release of storage iron
associated with increased hepcidin level
 Associated with: Persistent infections,
Chronic inflammatory disorders (SLE,
rheumatoid arthritis, Hodgkin lymphorna,
cancer)
 Laboratory findings
o Normocytic and normochromic or
slightly microcytic/hypochromic anemia
 Low:
o serum iron
o TIBC
 High/Increased:
o ESR
o Normal to Increased:
o Ferritin
3. Sideroblastic anemia
 Caused by blocks in the protoporphyrin
pathway resulting in defective
hemoglobin synthesis and iron overload
 Excess iron accumulates in the
mitochondrial region of the immature
erythrocyte in the bone marrow and
encircles the nucleus; cells are called
ringed sideroblasts.
 Excess iron accumulates in the
mitochondrial region of the mature
erythrocyte in circulation; cells are called
siderocytes; inclusions are siderotic
granules (Pappenheimer bodies on
Wright's stained smears).
 Laboratory findings
 HEMATOLOGY

o Microcytic/hypochromic anemia large amounts are excreted in urine

 Low: and/or feces.
o TIBC  Clinical symptoms: Photosensitivity,
 Normal to Increased: abdominal pain, CNS disorders
o Ferritin
o Serum iron

4. Lead Poisoning

 Multiple blocks in the protoporphyrin

pathway affect heme synthesis.
 Seen mostly in children exposed to lead-
based paint 6. Megaloblastic anemia

 Defective DNA synthesis causes

abnormal nuclear maturation; RNA
synthesis is normal, so the cytoplasm is
not affected.
 Laboratory findings
o Macrocytic/normochromic anemia
o Blood smear
 Clinical symptoms:
o Abdominal pain,
o Muscle weakness,
o Gum lead line that forms from
blue/black deposits of lead sulfate
 Laboratory findings
o Normocytic/normochromic anemia
o Blood smear
o Basophilic stippling!!!!

o Pancytopenia,
o Oval macrocytes and teardrops
o Hypersegmented neutrophils

5. Porphyrias

 These are a group of inherited disorders

characterized by a block in the
protoporphyrin pathway of heme
synthesis. Heme precursors before the
block accumulate in the tissues, and  Chemistry
o LD
 HEMATOLOGY

o Bilirubin
o Iron
 HEMATOLOGY
 Vitamin B12 deficiency
o Intrinsic factor is secreted by parietal
cells and is needed to bind vitamin
B12 for absorption into the intestine.
 Pernicious anemia
o Caused by deficiency of intrinsic
factor,
antibodies to intrinsic factor, or
antibodies to parietal cells
o THERE IS CNS/NEUROLOGIC
INVOLVEMENT !!!!!!
 Folic acid deficiency
o causes a megaloblastic anemia with
a blood picture and clinical
symptoms similar to vitamin B12
deficiency, EXCEPT:
o THERE IS NO CNS/NEUROLOGIC
INVOLVEMENT !!!!!!
7. Nonmegaloblastic anemia macrocytic
anemias
 Include alcoholism, liver disease, and
conditions that cause accelerated
erythropoiesis. The erythrocytes are
round, not oval as is seen in the
megaloblastic anemias.
8. Aplastic anemias
 Bone marrow failure causes
pancytopenia.
 Laboratory:
o Decrease in hemoglobin/hematocrit
and reticulocytes
o Normocytic/normochromic anemia
o No response to erythropoietin
Aplastic Anemia:
1. Genetic
2. Idiopathic
3. Acquired
Genetic aplastic anemia (Fanconi anemia)
 Autosomal recessive trait
 Dwarfism, renal disease, mental
retardation
 Strong association with malignancy
development, especially acute
llymphoblastic leukemia
 HEMATOLOGY

 Antibiotics: Chlorampenicol and

sulfonamides
 Chemicals: Benzene and herbicides
 About 30% of acquired aplastic anemias
are due to drug exposure
 Viruses: B19 parvovirus secondary to
hepatitis, measles, CMV, and Epstein-
Barr virus
 Radiation or chemotherapy
 Myelodyplastic syndromes, leukemia,
solid tumors, paroxysmal nocturnal
hemoglobinuria
 Idiopathic (primary): 50-70% of aplastic
anemia

Diamond-Blackfan anemia
IV. Hemolytic anemias
1)True red cell aplasia (leukocytes and platelets
 Classification
normal in number)
o Acute versus chronic
2) Autosomal inheritance o Inherited versus acquired
o Intrinsic versus extrinsic
8. Myelopthisic (marrow replacement) anemia
o Intravascular versus extravascular
 Hypoproliferative anemia caused by o Fragmentation versus macrophage-
replacement of bone marrow mediated
hematopoietic cells by malignant cells or
fibrotic tissue
 Associated with cancers (breast,
prostate, lung, melanoma) with bone
metastasis
 Laboratory findings
o Normocytic/normochromic anemia
 Blood smear
o Leukoerythroblastic blood picture
o Teardrop cells
 HEMATOLOGY

o Increased osmotic fragility

o Increased serum bilirubin

Part 1: Hemolytic anemias due to
intrinsic defects
2. Hereditary elliptocytosis
 Normocytic/Normochromic anemias
 Usually hereditary a. Autosomal dominant; most persons
 Reticulocytosis asymptomatic due to normal erythrocyte
life span; >25% ovalocytes on the
1. Hereditary spherocytosis peripheral blood smear

 Most common membrane defect; b. Membrane defect is caused by

autosomal dominant; characterized by polarization of cholesterol at the ends of
splenomegaly, variable degree of the cell rather than around pallor area.
anemia, spherocytes on the peripheral
blood smear

 LABORATORY
o Spherocytes, MCHC may be >37
3. Hereditary stomatocytosis
g/dL,
 HEMATOLOGY
a. Autosomal dominant; variable degree
of anemia; up to 50% Stomatocytes on
the blood smear
b. Membrane defect due to abnormal
permeability to both sodium and
potassium; causes erythrocyte swelling
4. Hereditary acanthocytosis
a. Autosomal recessive; mild anemia
associated with steatorrhea,
neurological and retinal abnormalities;
50-100% of erythrocytes are
acanthocytes
b. Increased cholesterol:lecithin ratio in
the membrane due to abnormal plasma
lipid concentrations; absence of serum
p-lipoprotein needed forlipid transport
5. G6PD (glucose-6-phosphate
dehydrogenase) deficiency
 Sex-linked enzyme defect; most
common enzyme deficiency in the
hexose monophosphate shunt
 Results in oxidation of hemoglobin to
methemoglobin (Fe3+); denatures to
form Heinz bodies
 Usually, not anemic until oxidatively
challenged (primaquine, sulfa
drugs); then severe hemolytic anemia
with Reticulocytosis
7. Pyruvate kinase (PK) deficiency
 Autosomal recessive; most common
enzyme deficiency in Embden
Meyerhof pathway
 Lack of ATP causes impairment of
the cation pump that controls
intracellular sodium and potassium
levels
 Decreased erythrocyte deformability
reduces their life span.
 Severe hemolytic anemia with
Reticulocytosis and echinocytes
 HEMATOLOGY

1. Warm autoimmune hemolytic anemia

(WAIHA)
8. Paroxysmal nocturnal hemoglobinuria
 RBCs are coated with IgG and/or
a) An acquired membrane defect in which
complement. Macrophages may
the red cell membrane has an increased
phagocytize these RBCs, or they may
sensitivity for complement binding as
remove the antibody or complement
compared to normal erythrocytes
from the RBC's surface, causing
b) Etiology unknown
membrane loss and spherocytes.
c) All cells are abnormally sensitive to lysis
 Laboratory result
by complement.
o Spherocytes, MCHC may be >37
 Characteristics:
g/dL, increased osmotic fragility,
o Pancytopenia;
bilirubin, reticulocyte count
o chronic intravascular hemolysis
o Occasional nRBCs present
causes hemoglobinuria and
o Positive direct antiglobulin test
hemosiderinuria at an acid pH at
(DAT) helpful in differentiating from
night;
hereditary spherocytosis.
 PNH noted for:
o Low leukocyte alkaline phosphatase 2. Cold autoimmune hemolytic anemia
(LAP) score; (CAIHA or cold hemagglutinin disease)
o Ham's and sugar water tests used in
diagnosis;  RBCs are coated with IgM and
o Increased incidence of acute complement at temperatures below
37°C.
leukemia
 Can be idiopathic, or secondary to
Part 2: Hemolytic anemias due to Mycoplasma pneumoniae, lymphoma, or
Extrinsic/Immune defects infectious mononucleosis
 Laboratory result
 Normocytic/Normochromic anemias o Seasonal symptoms; RBC clumping can
 Extrinsic to RBC be seen both macroscopically and
 All are acquired disorders that can microscopically;
cause accelerated destruction
 Reticulocytosis
 Immunologic in origin
 HEMATOLOGY
o MCHC >37 g/dL; increased bilirubin,
o reticulocyte count; positive DAT detects
complement-coated RBCs
3. Paroxysmal cold hemoglobinuria (PCH)
 An IgG biphasic Donath-Landsteiner
antibody with P specificity:
o Fixes complement to RBCs in the cold
(less than 20°C);
o The complement-coated RBCs lyse
when warmed to 37°C
 Laboratory result
o Variable anemia following hemolytic
process;
o Increased bilirubin and plasma
hemoglobin, decreased haptoglobin;
o DAT may be positive;
o Donath-Landsteiner test positive
4. Hemolytic transfusion reaction
 Recipient has antibodies to antigens on
donor RBCs; donor cells are destroyed.
 Laboratory: Positive DAT, increased
plasma hemoglobin
5. Hemolytic disease of the newborn (HDN)
 Rh negative woman is exposed to Rh
antigen from fetus and forms IgG
antibody; this antibody will cross the
placenta and destroy RBCs of the
next fetus that is Rh positive.
 May be due to Rh incompatibility
(erythroblastosis fetalis)
Part 3: Hemolytic anemias due to
Extrinsic/Nonimmune cause
 Normocytic/Normochromic anemias
 Trauma to the RBCs
 All are acquired disorders that can
cause accelerated destruction
 With schistocytes and thrombocytopenia
1. Microangiopathic hemolytic anemia
(MAHAs)
a. Disseminated intravascular coagulation
(DIC)
b. Hemolytic uremic syndrome (HUS)
c. Thrombotic thrombocytopenic purpura
(TTP)
2. Macroangiopathic hemolytic anemia
a. Traumatic cardiac hemolytic anemia
(Waring-blender syndrome)
 Red cell fragmentation due to
defective heart valve
b. Exercise-induced hemoglobinuria
(March hemoglobinuria)
o March hemoglobinuria
o Transient hemolytic anemia that occurs
after forceful contact of the body with
hard surfaces (e.g., marathon runners,
tennis players)
 HEMATOLOGY

o Other causes  No Hgb A is produced, and

 Infections approximately 80% Hgb S and 20% Hgb
 Chemicals F (the compensatory hemoglobin) are
 Drugs seen. Hgb A2 is variable.
 Snake venom  Hemoglobin insolubility results when
o Thermal burns deoxyhemoglobin is formed.
 Cause direct damage to the RBC Hemoglobin crystallizes in erythrocytes.
membrane, producing acute It is characterized by the classic sickled
hemolysis, which is characterized by shape of erythrocytes.
severe anemia with many
schistocytes and micro-spherocytes.

V. Hemoglobinopathies
 Clinical Findings
 These are a group of inherited disorders o Erythrocytes become rigid and
causing structurally abnormal globin trapped in capillaries; blood flow
chain synthesis due to amino acid restriction causes lack of
substitutions (qualitative defect) oxygen to the tissues, resulting

1. Sickle Cell Disease (Hb SS)

 Sickle cell disease is caused when

valine replaces glutamic acid at position
6 on both beta chains.
 It results in a decrease in hemoglobin
solubility and function.
 Defect is inherited from both parents.
\

in tissue necrosis

 Clinical Findings
 HEMATOLOGY
o All organs are affected, with kidney
failure being a common outcome;
hyposplenism and joint swelling also
occur.
o Vaso-occlusive crisis occurs with
increased bone marrow response to
the hemolytic anemia.
o Crisis can be initiated by many
physiological factors, including
surgery, trauma, pregnancy, high
altitudes, etc.
o Apparent immunity to Plasmodium
falciparum
o Diagnosis is made after 6 months of
age (time of beta-gamma globin
chain switch), with life expectancy of
50 years with proper treatment.
Death usually results from infection
or congestive heart failure.
 Laboratory diagnosis
o Severe normochromic/normocytic
hemolytic anemia with
polychromasia resulting from
premature release of reticulocytes;
o Bone marrow erythroid hyperplasia
(M:E ratio decreases)
o Sickle cells, target cells, nucleated
RBCs, Pappenheimer bodies, and
Howell-Jolly bodies are seen.
o Increased bilirubin and decreased
haptoglobin are characteristic due to
hemolysis
2. Sickle Cell Trait (Hb AS)
 Sickle cell trait is caused when valine
replaces glutamic acid at position 6 on
one beta chain.Defect is inherited from
one parent. One normal beta chain can
produce some Hgb A.
 Approximately 60% Hgb A and 40% Hgb
S are produced, with normal amounts of
Hgbs A2 and F.
 Sickle cell trait generally produces no
clinical symptoms. Anemia is rare but, if
present, will be
normochromic/normocytic, and sickling
can occur during rare crisis states (same
as in Hgb SS).
 Positive hemoglobin solubility screening
test
 Apparent immunity to Plasmodium
falciparum
3. Hgb C Disease/Hgb CC
 Hgb C disease is caused when lysine
replaces glutamic acid at position 6 on
both beta chains. Defect is inherited
from both parents.
 Occurs in the African-American and
African populations
 No Hgb A is produced; approximately
90% Hgb C, 2% Hgb A2, and 7% Hgb F
are produced. Mild anemia may be
present.
 Laboratory diagnosis
 Normochromic/normocytic anemia
with target cells; characterized by
intracellular rodlike C crystals
 HEMATOLOGY
3. Hgb SC disease
 Laboratory diagnosis
o Moderate to severe
normocytic/normochromic anemia
with target cells; characterized by
SC crystals; may see rare sickle
cells or C crystals; positive
hemoglobin solubility screening test
4. Hgb E disease
 Caused when lysine replaces glutamic
acid at position 26 on the beta chain
 Found more commonly in Southeast
Asian, African, and African-American
populations
 Homozygous condition results in mild
anemia with microcytes and target cells;
heterozygotes are asymptomatic.
4. Hgb D disease
 Caused when glycine replaces glutamic
acid at position 121 on the beta chain
 Found more commonly in Middle
Eastern and Indian populations
 Both homozygous and heterozygous
conditions are asymptomatic.
VI. Thalassemia
 Group of inerited disorders causing
decreased rate of synthesis of a
structurally normal globin chain
(quantitative defect); characterized by
microcytic/hypochromic RBCs and
target cells
 Classification
o According to the globin chain
involved!
 Alpha thalassemia
 Beta thalassemia
Beta thalassemia
1. Major/homozygous (Cooley anemia)
2. Minor/heterozygous
Part 1: Beta thalassemia
A. Major/homozygous (Cooley anemia)
 Markedly decreased rate of synthesis or
absence of both beta chains results in
an excess of alpha chains; no Hgb A
can be produced; compensate with up to
90% Hgb F.
 Excess alpha chains precipitate on the
RBC membrane, form Heinz bodies, and
cause rigidity; destroyed in the bone
marrow or removed by the spleen
 Symptomatic by 6 months of age;
hepatosplenomegaly, stunted growth,
jaundice; prominent facial bones,
especially the cheek and jaw; iron
overload from RBC destruction and
multiple transfusions cause organ failure
 HEMATOLOGY

a. Major (hydrops fetalis)

b. Hgb H disease
c. Minor/trait
d. Silent carrier

A. Major (hydrops fetalis)

 All four alpha genes are deleted; no

normal hemoglobins are produced.
 80% hemoglobin Bart’s (4 gamma globin
chains) produced; cannot carry oxygen
 Incompatible with life; die in utero or
shortly after birth

 Laboratory
o Severe microcytic/hypochromic
anemia,
o Target cells
B. Hb H disease
o Teardrop cells
o Many nRBCs,  Three alpha genes are deleted.
o Basophilic stippling, Decrease in alpha chains leads to
o Howell-Jolly bodies, beta chain excess.
o Pappenheimer bodies,  Hemoglobin H (4 Betta globin
o Heinz bodies; chain), an unstable hemoglobin, is
o Increased serum iron and increased produced.
bilirubin reflect the hemolysis  Heinz bodies form and rigid RBCs
are destroyed in the spleen
B. Minor/heterozygous  Distinguishing characteristics
include: moderate
 Decreased rate of synthesis of one of
microcytic/hypochromic anemia; up
the beta chains; other beta chain normal
to 30% Hgb H; the rest is Hgb A.
 Laboratory:
o Mild microcytic/hypochromic C. Minor/trait
anemia, with a normal or slightly
elevated RBC count; target cells,  Two alpha genes are deleted.
o Basophilic stippling Patients are usually asymptomatic
o Hgb A is slightly decreased and discovered accidentally. Up to
o Hgb A2 is slightly increased to 6% Hgb Bart's in newborns may be
helpful in diagnosis; absent by 3
compensate
months of age
Part 2: Alpha thalassemia
 HEMATOLOGY

 Mild microcytic/hypochromic anemia

often with a high RBC count and
target cells

D. Silent carrier

 One alpha gene is deleted. Patients

are asymptomatic and are often not
diagnosed unless gene analysis is
done.
 Borderline low MCV may be the only
sign.
 Thalassemia/Hemoglobinopathy
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