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SGD CASE: HEMATOLOGY

Weakness:
the state or condition of lacking strength
Dizziness:
a sensation of spinning around and losing one's balance
Anorexia:
a lack or loss of appetite for food (as a medical condition)
Vomit:
eject matter from the stomach through the mouth.
Numbness:
the state of being numb. "tingling and numbness in the left arm"
tinglinging :
experience or cause to experience a slight prickling or stinging sensation.

Ecteric eyes:

Hepatosplenomegaly:
is a disorder where both the liver and spleen swell beyond their normal size, usually due
to an infection such mononucleosis or viral hepatitis
Smooth:
having an even and regular surface or consistency
Beefy red tongue:
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THE FACTS

The blood that circulates throughout the body performs a number of critical functions.
It delivers oxygen, removes carbon dioxide, and carries life-sustaining nutrients. By
transporting long-distance messengers such as hormones, blood helps the various parts of the
body communicate with each other. These important functions are performed by blood cells
working in partnership with the liquid part of the blood (plasma). Most of the cells in it are red
blood cells (erythrocytes). White blood cells (leukocytes) are also present in smaller numbers.
Their role is to defend your body against foreign material, including infections, viruses, and fungi.

Anemia is a state that occurs when hemoglobin (an iron-protein compound in red blood
cells that transports oxygen) is decreased and your body has too few red blood cells.
When there are too few red blood cells due to a lack of vitamin B12, the condition is
described as pernicious anemia. The term pernicious was adopted many years ago when there
was no effective treatment and this condition was inevitably fatal. Today, excellent therapies are
available and most people can lead a normal life with very little adverse effects.

Pernicious anemia can affect all racial groups, but the incidence is higher among fair-
haired people, especially those whose ancestors came from Scandinavia or Northern Europe. It
usually doesn't appear before the age of 30, although a juvenile form of the disease can occur in
children. About 4% of Canadians have insufficient blood levels of vitamin B12.

Alternative names for pernicious anemia are vitamin B12 deficiency (malabsorption),
Addison's anemia, and congenital pernicious anemia.

CAUSES

Pernicious anemia is caused by a deficiency of vitamin B12, which is needed for normal
production of red blood cells.
It is often hereditary. Risk factors include a history of autoimmune endocrine disorders, a
family history of pernicious anemia, and Scandinavian or Northern European descent.

The meat and dairy products we eat are our primary sources of vitamin B12. However,
except in strict vegetarians, pernicious anemia isn't simply caused by not eating enough of these
foods. Usually, it is because of a failure in the complex process the digestive tract must go
through to absorb vitamin B12.
In order for vitamin B12 to be absorbed by the small intestine, the cells that line a part of
the stomach must produce a substance called intrinsic factor (IF).
This substance attaches itself to vitamin B12, and both are absorbed in combination into
the lowest portion of the small bowel (ileum), just before the small bowel enters the colon. If the
ileum is damaged or removed in the course of surgery, the intrinsic factor/vitamin B12
combination will not be absorbed. People with conditions like Crohn's disease, who often have
surgery to remove part of their ileum (the part of the small intestine where vitamin B12 is
absorbed), should be screened for vitamin B12 deficiency and treated if needed.
Lack of intrinsic factor may also be congenital (present at birth). This form of
pernicious anemia (called juvenile or congenital) is usually seen before a child is three years old.
It is believed that only one parent needs to carry the gene for this disorder to pass it along to a
child.
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Less common causes of decreased B12 absorption include chronic pancreatitis,

malabsorption syndromes, certain medications, and, very rarely, increased metabolism of B12
through longstanding hyperthyroidism. A very common cause of B12 deficiency in the elderly is
inadequate absorption of dietary B12.

Pernicious anemia is often also seen in combination with some autoimmune endocrine
(gland) diseases such as type 1 diabetes, hypoparathyroidism, Addison's disease, and testicular
dysfunction.

MAKING THE DIAGNOSIS

If you have the basic symptoms of anemia, your doctor will probably perform various
tests. One of these tests will measure the amount of vitamin B12 in the blood. The blood will be
examined under a microscope to assess the size and shape of the red blood cells. In cases of
pernicious anemia, these cells will be larger and there will be fewer of them.

If the amount of vitamin B12 in the blood is found to be low, your doctor may perform
additional tests to confirm that your body has sufficient levels to perform regular cell processes.
Rarely, a bone marrow test is needed to confirm the diagnosis.

Historically, a test called the Schilling test was ordered, but this is no longer performed in
common practice.

People with pernicious anemia have an increased incidence of stomach cancer. The
doctor will need to follow up on any clinical findings (e.g., symptoms, positive test for traces of
blood in the stool) that suggest a problem with the digestive system, and further tests such as X-
rays or an endoscopy (inspecting the inside of the body with a small viewer on a flexible tube)
may be necessary.

DIFFERENTIAL DIAGNOSES

Pathophysiology

Classic pernicious anemia is caused by the failure of gastric parietal cells to produce
sufficient IF (a gastric protein secreted by parietal cells) to permit the absorption of adequate
quantities of dietary vitamin B-12. Other disorders that interfere with the absorption and
metabolism of vitamin B12 can produce cobalamin deficiency, with the development of a
macrocytic anemia and neurologic complications.

Cobalamin is an organometallic substance containing a corrin ring, a centrally located

cobalt atom, and various axial ligands (see the image below).
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Pernicious anemia. The structure of cyanocobalamin is depicted. The cyanide (Cn) is in

green. Other forms of cobalamin (Cbl) include hydroxocobalamin (OHCbl), methylcobalamin
(MeCbl), and deoxyadenosylcobalamin (AdoCbl). In these forms, the beta-group is substituted
for Cn. The corrin ring with a central cobalt atom is shown in red and the benzimidazole unit in
blue. The corrin ring has 4 pyrroles, which bind to the cobalt atom. The fifth substituent is a
derivative of dimethylbenzimidazole. The sixth substituent can be Cn, CC3,
hydroxycorticosteroid (OH), or deoxyadenosyl. The cobalt atom can be in a +1, +2, or +3
oxidation state. In hydroxocobalamin, it is in the +3 state. The cobalt atom is reduced in a
nicotinamide adenine dinucleotide (NADH)–dependent reaction to yield the active coenzyme. It
catalyzes 2 types of reactions, which involve either rearrangements (conversion of l
methylmalonyl coenzyme A [CoA] to succinyl CoA) or methylation (synthesis of methionine).The
basic structure known as vitamin B12 is solely synthesized by microorganisms, but most animals
are capable of converting vitamin B12 into the two coenzyme forms, adenosylcobalamin and
methylcobalamin. The former is required for conversion of L- methylmalonic acid to succinyl
coenzyme A (CoA), and the latter acts as a methyltransferase for conversion of homocysteine to
methionine.

When either cobalamin or folate is deficient, thymidine synthase function is impaired.

This leads to megaloblastic changes in all rapidly dividing cells because DNA synthesis is
diminished. In erythroid precursors, macrocytosis and ineffective erythropoiesis occur.

Severe neurological impairment, usually subacute combined system degeneration,

occurs in cobalamin deficiency. However, vitamin B12 deficiencies can also present as
peripheral neuropathy, psychosis, or leukoencephalopathy. Cobalamine neurological disorders
can occur independently of hematological manifestations of pernicious anemia. The biochemical
impairment in neurological degeneration may differ from hematological changes

Dietary cobalamin is acquired mostly from meat and milk and is absorbed in a series of
steps, which require proteolytic release from foodstuffs and binding to IF. Subsequently,
recognition of the IF-cobalamin complex by specialized ileal receptors—cubilin receptors—must
occur for transport into the portal circulation to be bound by transcobalamin II (TCII), which
serves as the plasma transporter.

The cobalamin-TCII complex binds to cell surfaces and is endocytosed. The

transcobalamin is degraded within a lysozyme, and the cobalamin is released into the
cytoplasm. An enzyme-mediated reduction of the cobalt occurs with either cytoplasmic
methylation to form methylcobalamin or mitochondrial adenosylation to form adenosylcobalamin
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Defects of these steps produce manifestations of cobalamin dysfunction. Most defects

become manifest in infancy and early childhood and result in impaired development, mental
retardation, and a macrocytic anemia. Certain defects cause methylmalonic aciduria and
homocystinuria. See the image below.

Pernicious anemia.
Inherited disorders of cobalamin (Cbl) metabolism are depicted. The numbers and letters
correspond to the sites at which abnormalities have been identified, as follows: (1) absence of
intrinsic factor (IF); (2) abnormal Cbl intestinal adsorption; and (3) abnormal transcobalamin II
(TC II), (a) mitochondrial Cbl reduction (Cbl A), (b) cobalamin adenosyl transferase (Cbl B), (c
and d) cytosolic Cbl metabolism (Cbl C and D), (e and g) methyl transferase Cbl utilization (Cbl
E and G), and (f) lysosomal Cbl efflux (Cbl F)

Pernicious anemia probably is an autoimmune disorder with a genetic predisposition.

The disease is more common than is expected in families of patients with pernicious anemia,
and it is associated with human leukocyte antigen (HLA) types A2, A3, and B7 and type A blood
group.

Antiparietal cell antibodies occur in 90% of patients with pernicious anemia but in only
5% of healthy adults. Similarly, binding and blocking antibodies to IF are found in most patients
with pernicious anemia. A greater association than anticipated exists between pernicious anemia
and other autoimmune diseases, including thyroid disorders, type 1 diabetes mellitus, ulcerative
colitis, Addison disease, infertility, and acquired agammaglobulinemia. An association between
pernicious anemia and Helicobacter pylori infections has been postulated but not clearly proven.

Cobalamin deficiency may result from dietary insufficiency of vitamin B12; disorders of
the stomach, small bowel, and pancreas; certain infections; and abnormalities of transport,
metabolism, and utilization (see Etiology). Deficiency may be observed in strict vegetarians. [3]
Breastfed infants of vegetarian mothers also are affected. Severely affected infants of vegetarian
mothers who do not have overt cobalamin deficiency have been reported.

Meat and milk are the main source of dietary cobalamin. Because body stores of
cobalamin usually exceed 1000 µg and the daily requirement is about 1 µg, strict adherence to a
vegetarian diet for more than 5 years usually is required to produce findings of cobalamin
deficiency.

Classic pernicious anemia produces cobalamin deficiency due to failure of the stomach
to secrete IF (see the image below).
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Pernicious anemia.
Cobalamin (Cbl) is freed from meat in the acidic milieu of the stomach where it binds R
factors in competition with intrinsic factor (IF). Cbl is freed from R factors in the
duodenum by proteolytic digestion of the R factors by pancreatic enzymes. The IF-Cbl complex
transits to the ileum where it is bound to ileal receptors. The IF-Cbl enters the ileal absorptive
cell, and the Cbl is released and enters the plasma. In the plasma, the Cbl is bound to
transcobalamin II (TC II), which delivers the complex to nonintestinal cells. In these cells, Cbl is
freed from the transport protein.

In adults, pernicious anemia is associated with severe gastric atrophy and achlorhydria,
which are irreversible. Coexistent iron deficiency is common because achlorhydria prevents
solubilization of dietary ferric iron from foodstuffs. Autoimmune phenomena and thyroid disease
frequently are observed. Patients with pernicious anemia have a 2- to 3-fold increased incidence
of gastric carcinoma

5. WHY RBC ARE SPECIALIZED?

Red blood cell, also called erythrocyte, cellular component of blood, millions of which
in the circulation of vertebrates give the blood its characteristic colour and carry oxygen from the
lungs to the tissues. The mature human red blood cell is small, round, and biconcave; it appears
dumbbell-shaped in profile. The cell is flexible and assumes a bell shape as it passes through
extremely small blood vessels. It is covered with a membrane composed of lipids and proteins,
lacks a nucleus, and contains hemoglobin—a red, iron-rich protein that binds oxygen.The
function of the red cell and its hemoglobin is to carry oxygen from the lungs or gills to all the
body tissues and to carry carbon dioxide, a waste product of metabolism, to the lungs, where it
is excreted. In invertebrates, oxygen-carrying pigment is carried free in the plasma; its
concentration in red cells in vertebrates, so that oxygen and carbon dioxide are exchanged as
gases, is more efficient and represents an important evolutionary development. The mammalian
red cell is further adapted by lacking a nucleus—the amount of oxygen required by the cell for its
own metabolism is thus very low, and most oxygen carried can be freed into the tissues. The
biconcave shape of the cell allows oxygen exchange at a constant rate over the largest possible
areaThe red cell develops in bone marrow in several stages: from a hemocytoblast, a
multipotential cell in the mesenchyme, it becomes an erythroblast (normoblast); during two to
five days of development, the erythroblast gradually fills with hemoglobin, and its nucleus and
mitochondria (particles in the cytoplasm that provide energy for the cell) disappear. In a late
stage the cell is called a reticulocyte, which ultimately becomes a fully mature red cell. The
average red cell in humans lives 100–120 days; there are some 5.2 million red cells per cubic
millimetre of blood in the adult human
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Though red cells are usually round, a small proportion are oval in the normal person, and
in certain hereditary states a higher proportion may be oval. Some diseases also display red
cells of abnormal shape—e.g., oval in pernicious anemia, crescent-shaped in sickle cell anemia,
and with projections giving a thorny appearance in the hereditary disorder acanthocytosis. The
number of red cells and the amount of hemoglobin vary among different individuals and under
different conditions; the number is higher, for example, in persons who live at high altitudes and
in the disease polycythemia. At birth the red cell count is high; it falls shortly after birth and
gradually rises to the adult level at puberty.

Why RBC MUST CONTIUALLY BE REPLACED? The

average adult has around 10 pints of blood (roughly 8% of your body weight).  Making a blood
donation uses about 1 pint, after which your body has an amazing capacity to replace all the
cells and fluids that have been lost.

Red blood cells

Millions of red cells are being made and dying every second. When you give blood you
lose red cells and the body needs to make more to replace them. Special cells in the kidneys,
called peritubular cells, sense that the level of oxygen in the blood has decreased (due to the
loss of red cells) and start secreting a protein called erythropoietin. This passes through the
bloodstream until it reaches the bone marrow (the soft fatty tissue inside the bone cavities).

The bone marrow produces stem cells, the building blocks that the body uses to make
the different blood cells – red cells, white cells and platelets. The erythropoietin sends a
message to the stem cells telling more of them to develop into red blood cells, rather than white
cells or platelets.

How fast does OUR body make blood?

Our body makes about 2 million new red cells every second, so it only takes a number of
weeks to build up stores of them again.
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What about white cells and platelets? A number of other messenger proteins also
stimulate the production of these cells in the bone marrow, and over the next few days levels
return to normal.

DESCRIBE PLATELETS. WHY ARE THEY UNIQUE?

Platelets are tiny blood cells that help body form clots to stop bleeding. If one of blood
vessels gets damaged, it sends out signals that are picked up by platelets. The platelets then
rush to the site of damage and form a plug, or clot, to repair the damage.

The process of spreading across the surface of a damaged blood vessel to stop bleeding
is called adhesion. This is because when platelets get to the site of the injury, they grow sticky
tentacles that help them adhere. They also send out chemical signals to attract more platelets to
pile onto the clot in a process called aggregation.

Platelets are made in bone marrow along with white and red blood cells. bone marrow is
the spongy center inside bones. Another name for platelets is thrombocytes. We can say a clot
or a thrombus. Once platelets are made and circulated into bloodstream, they live for 8 to 10
days.

Under a microscope, a platelet looks like a tiny plate.

 A normal platelet count is 150,000 to 450,000 platelets per microliter of blood.

 Risk for spontaneous bleeding develops if a platelet count falls below 10,000 to 20,000.
But when the platelet count is less than 50,000, bleeding is likely to be more serious if an
individual is cut or bruised. 

What happens if your platelet count is high or low

Medical conditions associated with abnormal platelets or abnormal platelet counts: 

 Thrombocytopenia. In this condition, your bone marrow makes too few platelets, or
your platelets are destroyed. If your platelet count gets too low, bleeding can occur under
the skin as bruising, inside the body as internal bleeding, or outside the body through a
cut that won't stop bleeding or from a nosebleed. Thrombocytopenia can be caused by
many conditions, including several medicines, cancer, kidney disease, pregnancy,
infections, and an abnormal immune system.
 Thrombocythemia. In this condition, your bone marrow makes too many platelets.
People with thrombocythemia may have platelet counts that exceed 1 million. Symptoms
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can include blood clots that form and block blood supply to the brain or the heart. The
cause of thrombocythemia is unknown.
 Thrombocytosis. This is another condition caused by too many platelets, but platelet
counts do not get as high as in thrombocythemia. Thrombocytosis is more common and
is not caused by abnormal bone marrow. Instead, the cause is another disease or
condition in the body that stimulates the bone marrow to make more platelets. Causes
include infection, inflammation, some types of cancer, and reactions to medicines.
Symptoms are usually not serious, and the platelet count goes back to normal when the
underlying condition gets better.
 Platelet dysfunction. There are many rare diseases associated with poor platelet
function, when the number of platelets is normal, but the platelets donot work normally.
Some medicines, such as aspirin, can inhibit normal platelet function. It is important to
know which medicines affect platelet function and to appreciate that while taking these
medicines there is an increased risk of bleeding. 

Platelets are tiny but important cells in blood that helps body control bleeding.

DESCRIBE HOW CARBONDIOXIDE IS BEING TRANSPORTED IN THE BLOOD.

Carbon dioxide is produced by cell metabolism in the mitochondria. The amount

produced depends on the rate of metabolism and the relative amounts of carbohydrate, fat and
protein metabolized. The amount is about 200 ml min −1 when at rest and eating a mixed diet; this
utilises 80% of the oxygen consumed, giving a respiratory quotient of 0.8 (respiratory quotient =
rate of carbon dioxide production divided by rate of oxygen consumption). A carbohydrate diet
gives a quotient of 1 and a fat diet 0.7.

Carbon dioxide is transported in the blood from the tissue to the lungs in three ways: 1 (i)
dissolved in solution; (ii) buffered with water as carbonic acid; (iii) bound to proteins, particularly
haemoglobin.

Approximately 75% of carbon dioxide is transport in the red blood cell and 25% in the
plasma. The relatively small amount in plasma is attributable to a lack of carbonic anhydrase in
plasma so association with water is slow; plasma plays little role in buffering and combination
with plasma proteins is poor.

Dissolved carbon dioxide

Carbon dioxide is 20 times more soluble than oxygen. arterial blood will contain about 2.5
ml per 100 ml of dissolved carbon dioxide and venous blood 3 ml per 100 ml. A cardiac output of
5 litre min−1 will carry 150 ml of dissolved carbon dioxide to the lung, of which 25 ml will be
exhaled

Carbonic acid
Carbon dioxide combines with water to form carbonic acid, a reaction accelerated by
carbonic anhydrase. The carbonic acid then freely dissociates
CO2 + H2Ocarbonic anhydrase⇌H2CO3⇌H+ + HCO−3

The enzyme carbonic anhydrase is present in a number of organs of the body including
the eye, kidney and brain; however, for this purpose, it is the red blood cell carbonic anhydrase
that is important
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Bound to haemoglobin and other proteins

Carbon dioxide combines rapidly to the terminal uncharged amino groups (R-NH2) to form
carbamino compounds
R−NH2 + CO2 ⇌ RNH − CO2 + H+
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