Approach to

Patients with

Anemia
Prof. Dr / Nabil Lymon
Blood Cells
and
Hemoglobin
structure
 :Definitions
- Anemia :
is defined as the lowering of hemoglobin concentration
below the established normal levels:
In male < 13.5 gm/dl & In female < 11.5 gm / dl.
- Anemia is a clinical sign not a diagnostic entity.

- Hematocrit (Hct):
is the proportion, by volume, of the blood occupied by
red blood cells. The hematocrit (Hct) is expressed as a
percentage, normal levels are :
0.4 - 0.54 in Adult male & 0.37 - 0.47 in Adult female
For example, a hematocrit of 25% means that there are
25 milliliters of red blood cells in 100 milliliters of
blood.
 :Definitions
Red Cell Indices
Are measurements that indicate the size and
hemoglobin content of red cells:
M.C.V (Mean Corpuscular Volume)

M.C.H (Mean Corpuscular Hemoglobin)

M.C.H.C (Mean Corpuscular Hemoglobin Concentration)

 M.C.V (Mean Corpuscular Volume):
Referred to the average volume of red cells , normally = 76 - 96 fl
It can be calculated from an independently-measured red blood cell
count and hematocrit:

MCV  (femtoliters) = 10 x HCT(percent) ÷ RBC

(millions/µL)

MICROCYTOSIS & MACROCYTOSIS : 

By definition, microcytosis is taken to mean the presence of RBCs
with a MCV less than normal, while macrocytosis means the
presence of RBCs with an MCV greater than normal.
 M.C.H (Mean Corpuscular Hemoglobin):

or "mean cell hemoglobin" (MCH), is a measure of the mass

of hemoglobin contained by a red blood cell. It is
diminished in microcytic anemias, and increased in
macrocytic anemias. It is calculated by dividing the total
mass of hemoglobin by the RBC count :-
MCH=Hb/RBC
A normal value in humans is 27 to 32 picograms/cell
 M.C.H.C
(Mean Corpuscular Hemoglobin Concentration):

is a measure of the concentration of hemoglobin in a given volume of

packed red blood cell.
It is diminished ("hypochromic") in microcytic anemias, and
normal ("normochromic") in macrocytic anemias (due to larger
cell size, though the hemoglobin amount or MCH is high, the
concentration remains normal).
It is calculated by dividing the hemoglobin by the hematocrit:
M.C.H.C = Hb / Hct
A normal value is 30 to 36 g/dl.
 Signs &Symptoms of
Anemia
- Cardiovascular :
- Cardiovascular :
Exertional Dyspnea Palpitations Orthopnea
Tachycardia Angina Claudications
Cardiomegally Bounding peripheral Pulses
Murmurs Vascular bruits Pedal edema

- Neurological :
Headache Tinnitus Dizziness
Faintness Fatigue Cold
Sensitivity Loss of Concentration
 Signs &Symptoms of
Anemia
- Skin :
Pallor of skin , mucous membranes, nail beds and palms.
- Gastrointestinal :
Anorexia Nausea Constipation
Diarrhea
- Respiratory :
Increased Respiratory Rates
- Genitourinary :
Menstrual irregularity Amenorrhea Menorrhagia
Loss of libido or potency
- Fundus Examination :
Retinal Exudates Rarely Papilloedema
Is the patient Anemic or
not ?
Anemic means single or
total decrease in :
- Hb
- Hct
- RBCs count
in But …?
millions

What Type of Anemia..?

This depends on the RBCs
indices
 Red Cell Indices
According to MCV & MCH
Normal Decreased

Normocytic Microcytic
Normochro
mic Anemia Increased Hypochromi
c Anemia
Macrocytic

Anemia
 Anemia
It may be due to :
- Acute Blood Loss

- Aplastic Anemia
- Hemolytic Anemia ( Except
Thalasemia)
Which of Which- A.O.C.D
….? (Anemia Of Chronic
(Diseases Do Reticulocytic
Count
Normal Low or Absent
High
A.O.C.D e.g.: B.M.F
TB, SLE, Malignancy, Rh. “Aplastic Anemia” - Acute Blood
Arthritis
Loss
BM biopsy or BM
Note:
aspiration show : ( search for
- Evidence of the cause
Acellular or Hypo- evidence of
- Anemia May be Micro-
cytic Hypochromic
cellular BM the cause)

- Hemolytic
 - low Hb &/or Hct & /or RBCs count
- Normal RBCs indices
- Reticulocytosis

Do Indirect Serum Billirubin

Unconjugated Hyper-
billirubinemia
“
jaundice”

Other Evidences of Hemolysis e.g.:-

- Hemoglobinuria - Hemoglobinemia
(increased free Hb)
- Decreased Haptoglobin.

What is the Further

………..?Step Coombs Test
 Coombs Test
Positive Negative
Immune Non-immune
Hemolytic Hemolytic
Anemia: Anemia:
May be due to :
- Membrane Defect e.g.
Spherocytosis (lab
- Iso immune show increased O.F.) &
P.N.H
- Auto immune - Enzyme Defect
e.g. G6PD (lab : Enz. assay)
- Hb Defect
(Hemoglobinopathy)
Red Cell Indices
According to MCV & MCH
Decreased

Microcytic

Increased Hypochromi
c Anemia
Macrocytic

Anemia
Microcytic Hypochromic
Anemia
- The Commonest Cause is:
Iron Deficiency Anemia
-Other Causes: - Thalasemias
- Sedroplastic Anemia
- Lead Poisoning
- A.O.C.D
Which of Which ….?
: Do Iron Studies
- Serum Iron
- Serum Ferritin
- T.I.B.C (Total Iron Binding
Capacity)
- Transferrin Saturation
 According to Iron Studies
Iron Thalassem Sideroplas A.C.O.D
Deficiency ia tic
Anemia Anemia
Serum Fe

Serum Normal N or
Ferritin
T.I.B.C Normal
Transferri
n
Saturatio
n
Iron Deficiency Anemia
Iron Deficiency Anemia
Iron Notes:
Studies - Search For The
Serum Fe Cause:
Serum e.g.:
Ferritin Chronic Blood Loss
T.I.B.C Ankylostoma
Transferri Cancer Colon
n Nutritional causes
Saturation - Severe Aniso-cytosis
and Poikilo-cytosis:
Increased R.D.W(N ≤
13%)
Anisocytosis with
hypochromia and
(microcytes (IDA
Spoon Nails:
If nails look scooped out, like a
spoon, it could be a sign of iron-
.deficiency anemia
Plummer Vinson Syndrome
Left : Spoon shaped finger nails
Right : Showing angular cheilitis, and
dry skin
Plummer Vinson
Syndrome
Iron Deficiency Anemia
 Thalassemia
Iron Notes:
Studies - Hb Electrophoresis
Serum Fe will show:
Serum Persistence of
Ferritin Hb[f]
T.I.B.C - Specific Clinical
Features of
Transferri
Thalasemia:
n
Saturation Huge Spleen
Mongoloid Faces
Hemosedrosis
Thalassemia minor
is an inherited form of hemolytic anemia that
is less severe than thalassemia major. This
blood smear from an individual with
thalassemia shows small (microcytic), pale
(hypochromic), variously-shaped
(poikilocytosis) red blood cells. These small
red blood cells (RBCs) are able to carry less
oxygen than normal RBCs
Thalassemia, being a genetic disease, runs in
a family. Most are silent carriers or suffer
mild anemia. Severe cases such as the
Hemoglobin H disease with enlarged spleen,
small body and malnourished look shows
more prominent symptoms. [Pic below:
[Enlargement of spleen, small body
 Sideroplastic Anemia
Iron Notes:
Studies Sedroplastic Anemia is
Serum Fe due to:
Serum Normal - B6 Deficiency
Ferritin - Drugs e.g.: INH
- Inherited
T.I.B.C Normal
Blood film show:
RBCs contain Iron
Transferri
Granules
n
Saturation Treated by:
B6 supply
Many rounded sideroblasts are present
in this field. This is the hallmark
feature of sideroblastic anemia
 Lead Poisoning
Notes:
- History is Suggestive.
- Elevated Serum Lead level.
- Purely Motor Neuropathy (foot and
wrist drop)
- Blood Film show:
Basophilic Stippling of RBCs
Basophilic Stippling of
RBCs
Basophilic stippling appears as round, dark-
blue granules in red blood cells on smears
stained with supra vital stains such as
brilliant cresyl blue.
They may be observed in lead poisoning,
exposure to some drugs, severe burns,
anemia, or septicemia. The granules are
precipitated ribosomes and mitochondria
Red Cell Indices
According to MCV & MCH

Increased

Macrocytic

Anemia
Macrocytic Anemia
- In Which :
- low Hb &/or Hct & /or RBCs count
- Increased RBCs indices
- Causes :
# Folic Acid Deficiency # B12 Deficiency

- Search For The Cause:

# Pregnancy # Mal-absorption
Syndrome
# Chronic Gastritis # Atrophic Gastritis
# Cancer Stomach # Iliac Resection
# Drugs: Methotrexate / Metformin / Epanutin

- To be sure do the following tests:

Serum Folic Acid / Serum B12 /
Schilling test / FIGLU test
Schilling
Test
The Schilling test is
performed to evaluate
vitamin B12 absorption.
B12 helps in the
formation of red blood
cells, the maintenance of
the central nervous
system, and is important
for metabolism.
Normally, ingested
vitamin B12 combines
with intrinsic factor,
which is produced by
cells in the stomach.
Intrinsic factor is
necessary for vitamin
B12 to be absorbed in
the small intestine.
Certain diseases, such as
pernicious anemia, can
result when absorption
of vitamin B12 is
FIGLU test
a test of vitamin b12 deficiency,
folic acid deficiency, liver disease,
or genetic deficiency of glutamate
formimino-transferase, based on
urinary excretion of formimino-
glutamic acid (figlu), an
intermediate metabolite in
histidine catabolism in the
conversion of histidine to glutamic
acid, with the formimino group
being transferred to
. tetrahydrofolic acid
(commentary- )1
 A healthy 52-year-old man presents to the doctor’s
office complaining of increasing fatigue for the past 4-
5 months. He exercise every day but lately he has
noticed becoming short of breath while jogging.
 He denies orthopnea. Paroxysmal nocturnal (PND), or
swelling in his ankles. The patient reports occasional
joint pain for which he uses over the counter
ibuprofen.
 He denies bowel changes, melena or bright red blood
per rectum, but reports vague left side abdominal pain
for a few months off and on, not related to food intake.
The patient denies fever, chills, nausea or vomiting.
 He has lost a few pounds intentionally with diet and
exercise.
.Cont
 On examination, his weight is 90kg and he is
aferbrile. There is slight pallor of conjunctiva, skin
and palms.
 No lymphadenopathy is noted chest is clear to
auscultation bilaterally.
 Cardiovascular system: regular rate and rhythm,
with no rub or gallop.
 There is a II/IV systolic ejection murmur.
 His abdomen is soft, nontender and without
hepato-splenomegaly.
 Bowel sounds are present. He has no extremity
edema, cyanosis or clubbing.
 His peripheral pulses are palpable and symmetric.
A hemoglobin level is 9.2g/dl, MCV 75µ3
Discuss the most likely diagnosis
 What is the differential diagnosis
such case?
 Investigations of insulin
malabsorption
 Comprehension
Questions
1- A 25year-old man with a history of a duodenal
ulcer is noted to have a hemoglobin level of
10g/dl. Which of the following is most likely to be
seen on laboratory investigation?
a- Reticulocyte count of 4%.
b- Elevated total iron-binding capacity (TIBC).
c- Normal serum ferritin.
d- MCV of 105 fL.
2- A 22-years-old Woman is pregnant and 14 weeks gestation.
Her hemoglobin level is 9g/dl. She asks why she could have
iron deficiency when she is no longer menstruating. Which of
the following is the best explanation:

a- Occult gastrointestinal blood loss.

b- Expanded blood volume and transport to the fetus

c- Hemolysis

d- Iron losses as a result of relative alkalosis of pregnancy

3- A 35-year-old man has undertaken a self
imposed diet for 3 months previously, he
has been healthy, but now complains of
fatigue. His hemoglobin level is 10g/dL and
his MCV is 105fL. Which of the following is
the most likely etiology of his anemia?
a- Iron deficiency
b- Folate deficiency
c- Vitamin B12 deficiency
d- Thalassemia
e- Sideroblastic anemia
 Match the following laboratory
parameters (a to e ) to the clinical
(picture (4 to 6
MCV Ferritin TIBC RDW
a- Elevated Decreased Elevated Decreased
b- Decreased Decreased Elevated Increased

c- Normal Elevated Normal Normal

d- Decreased Increased Normal Normal

e- Elevated Increased Decreased Increased

4- A 20 year-old woman with heavy menses.

5- A 34 year-old man of Mediterranean descent with a
family history of anemia.
6- A 50 year-old man with severe rheumatoid arthritis.
 Conclusions
 Anemia is a clinical finding, not a diagnosis and
requires some investigation to determine the
underlying etiology.
 Iron deficiency anemia in men or
postmenopausal women is primarily a result of
gastrointestinal blood losses; therefore, finding
iron deficiency anemia in this patient
population warrants a through GI workup.
 Iron deficiency anemia in women of
reproductive age is most often caused by
menstrual blood loss.
.Cont
 The fecal occult blood testing (FOBT) is negative
in about 50% of patients with GI cancer.
Therefore, a negative FOBT in the presence of
iron deficiency anemia should not discourage you
from pursuing a through GI workup.
 The mean corpuscular volume, RDW and the
reticulocyte index are important parameters in
the evaluation of anemia.
Polycythaemia
 Polycythaemia refers to an increase in red cell
count, haematocrit and usually haemoglobin.
 There are two main types of polycythaemia, the
classification depending on the results of
measurement of red cell mass and plasma volume:
 Relative (pseudo) polycuthaemia: due to decrease in
plasma volume.
 True polycythaemia: the red cell mass in increased.
(True polycythaemia may either a primary or secondary).
 Primary true
polycythaemia
In the meloproliferative disorder polythaemia rubra vera (PRV),
there is uncontrolled production of red cells by the marrow,
even though erythropoietin is switched off.
 Clinical features: hypertension, splenomegaly, arterial and
venous thrombosis, pruitus, plethoric features, peptic
ulceration, gout.
 Laboratory features: there is high red cell count,
haemoglobin, haematovril, whole blood viscosity and uric
acid. The white cell count, platelete count and neutrophil
alkaline phosphates are also increase and the latter three
parameters help to distinguish PRV from secondary
polycythaemia.
 Secondary true
polycythaemia
 This condition is associated
with increased levels of
erythropoietin, which is
produced by other the kidney
or an ectopic tumor.
 Cause of secondary
polycythaemia
Increased renal erythrpoietin Inappropriate erythropoietin
production due to hypoxia production

• Physiological • From the kidney

Adaptation to altitude in neonates (eg pyonephrosis, renal cysts, renal
artery stenosis after renal
transplantation)
• Congential cyanotic heart • From a tumor (ectopic
disease erythropoietin secreted in an
(eg Fallot’s tertragoly, uncontrolled fashion)
Eisenmenger’s complex) (eg carcinoma of the kideny, giant
uterine fibroids, hepatoma,
cerberallar haemangioma)
• Respiratory related
Smoking
COPD
•High- affinity haemoglobins
(eg haemoglobin M)
Relative polycythaemia
 A reduction in circulating plasma volume can be to pyrexia,
diarrhoea, vomiting and diuretic therapy.
Gaisbok’s polycythaemia
 Refers to a from of stress polycythaemia; this has been
noticed in middle-aged men who have stressful occupations, a
chronically reduced plasma volume of uncertain cause.
Treatment of polycythaemia
 Treatment is indicated for polycythaemia as high blood
viscosity leads to an increased incidence of thrombosis,
hypertension, stroke and athermanous vascular disease.
 Venesction to a great haematocril: the packed cell
volume is more closely related to the blood
viscosity than is the haemoglobin (as repeated
vensection may result in iron-deficient red cells
with a low haemoglobin content). Venesection may
be traditional or isovolamic (with saline
replaement). The latter is used in patients with
cardiovascualr risk factors (eg angina or
hypertension), in those who are taking drugs that
may impair physiological response to vensection
(ACE inhibitors, beta blockers), or in patients with
relative polycythaemia.
 Cytotoxic agent (particularly
hydroxyurea): this presuppose
erythropoiesis ad cause a
macrocytosis which is not related to
vitamin B12 or folate deficiency.
Unlike other cytotoxic agents (eg
busslfan) it is unlikely to be
leukaemogenic.
 Aspirin and anticoagulants: if the
patient presents with thrombosis.
Multiple
myeloma
 Myeloma
 In myeloma there is a clonal proliferation of plasma
cells and the clinical manifestations of disease "= are
-Mated to substances secreted by the plasma cells as
much as to the effects of marrow infil­tration.
Clonality (all diseased cells originating from one
parent plasma cell) may be confirmed by: 
 the presence of a paraprotein (monoclonal) band on serum
electrophoresis, or by
 Immunopheno typing the increased numbers of plasma cells
in the bone marrow, and finding,. that they all express
either kappa or lambda light chains rather than a
mixture of the two.
 Paraprotein sub-types
 The normal immunoglobulin
concentrations in serum parallel the
relative frequency of the three main
sub-classes of myeloma paraprotein.
Hence, IgG is the most common form
of myeloma, followed by IgA, with IgM
being the least common type.
 Plasma hyperviscosity syndrome may be found This: consists of
confusion, capillary bleeding, oedema and renal impairment. The
incidence of hyperviscosity syndrome relates to the size of the
immunoglobulin molecule as well as its concentration. As IgM is
the largest molecule (750, 000 daltons) this syndrome is seen
relalatively frequently in IgM myeloma, less frequently in IgA
myeloma and rarely in IgG myeloma:. Transfusion should be
avoided in patients with plasma hyperviscosity syndrome, as it
will, cause a big increase in whole blood viscosity.
 Cryoglobulin: rarely, the paraprotein may be a
cryoglobulin, so that the protein precipitates from
plasma in the cold. This may be a cause of
vasculitis. Some myeloma paraproteins precipitate
within tissue to form amyloid.
 Bence-Jones protein
 Sometimes, the malignant plasma cells are so
defective that they cannot make a complete
immunoglobulin molecule and are only able to
make light chains. The latter are small enough to
he filtered within the glomerulus and to appear in
the urine as Bence-Jones proteinurias. They may
obstruct the renal tubules and contribute to the
renal failure which is often found in myeloma.
Role of cytokines in myeloma
 Osteoclast-activating factors stimulate
the normal osteoclasts to dissolve bone
and lead to bone pain, hypercalcaemia
and pathological fractures in myeloma.
In other myeloma cases, IL -6 may be
produced in excess by bone marrow
stromal cells infected with human
herpes virus (HHVB).
Treatment of myeloma
 Inn younger patients, most centers are moving away from single-
agent melphalan therapy towards continuous low-dose combination
chemotherapy such as VAD (Vincristine, Adriamycin and
Dexamethasone) or ZDex (oral idarubicin and dexamethasone).
Malignant cells are most sensitive to the action of chemotherapy
when they are dividing; as plasma cells divide relatively infrequently,
it is necessary to administer the chemotherapy over several days in
order to maximise the chances of treatingg dividing cells.
 Thalidomide has a proven role in myeloma treatment
although its mechanism of action remains uncertain. It is
likely to inhibit cytokine release, but an anti-
angiogenesis activity has not been ruled out.
 Bisphosphonates, such as monthly intravenous
pamidronate, have an important role in the prevention
off pathological fractures and in the treatment of
myeloma-associated hypercalcaemia.
 Monoclonal gammopathy of undetermined
significance (MGUS)
 A common clinical problem is the differentiation
between myeloma and MGUS (benign
monoclonal gammopathy) in patients found to
have a paraprotein. Ten per cent of patients
with MGUS develop myeloma at 5 years, and
50% at 15 years. It is probable that most
patients would eventually develop myeloma but
many die of other causes before this occurs.
 Differentiation of myeloma from
MGUS

MGUS Myeloma
Low level of paraprotein (< 20 High level of
g/I for an IgG paraprotein) paraprotein
Paraprotein level remains Level rises
stable over a period of Other immunoglobulin
observation depressed levels are depressed
(months or years) Clinical evidence of
Other immunoglobulin levels myeloma
are normal
No clinical evidence of myeloma
(bone disease, renal disease)
Commentary
 A healthy 52-year-old man presents to the doctor’s office
complaining of increasing fatigue for the past 4-5 months. He
exercises every day but lately he has noticed becoming short of
breath while jogging, he denies orthopnea, paroxysmal
nocturnal (PND), or swelling in his ankles. The patient reports
occasional joint pain for which he uses over the counter (OTC)
ibuprofen, he denies bowel changes, melena or bright red blood
per rectum, but reports vague left side abdominal pain for a
few months off and on, not related to food intake.
 The patient denies fever, chills, nausea or vomiting, he
has lost a few pounds intentionally with diet and exercise.
On examination, his weight is 90kg and he is aferbrile.
There is slight pallor of conjunctiva, skin and palms. No
lymphadenopathy is noted chest, is clear to auscultation
bilaterally, regular rate and rhythm of pluse with no rub or
gallop, There is a grade II/IV systolic ejection murmur, his
abdomen is soft, nontender and without hepato-
splenomegaly, bowel sounds are present. He has no
extremity edema, cyanosis or clubbing, his peripheral
pulses are palpable and symmetric. A hemoglobin level is
9.2g/dl, MCV 75µ3, MCH 25 Pgm.
 Discuss the most likely diagnosis.
 Differential diagnosis of this case.
 The typical features of acute hepatic failure
include, except:
 Onset within 8 weeks of the initial illness.
 Hepatoplenomegaly and ascitis.
 Encephalopathy and fetor hepaticus.
 Nausea, vomiting and renal failure.
 Cerebral oedema without papilloedema.

 The typical feature of primary biliary cirrhosis

include:
 Xanthomata of the palmar creases and eyelids.
 Poor prognosis even in asymptomatic patients.
 Hepatomegaly without splenomegaly.
 Dilated bile ducts on ultrasonography.
 Improved survival rate without immunosuppressant therapy.
 The clinical features of acromegaly include, except:
 Arthropathy and myopathy.

 Hypertension and impaired glucose tolerance.

 Goiter and cardiomegaly.

 Increased sweating and headache.

 Skin atrophy and decreased sebum secretion.

 Causes of short stature in childhood include, except;

 Klinefelter's syndrome.

 Turner's syndrome.

 Emotional deprivation.

 Cushing's syndrome.

 Primary hypothyroidism.
 Which of the following studies is most sensitive for
detecting diabetic nephropathy:
 Serum creatinine level
 Creatinine clearance
 Urine albumin
 Glucose tolerance test
 Ultrasonography

 Haematocrit value of 45% means that:

 45% of the Hb in the plasma.
 45% of the total blood volume is made up of plasma.
 45% of the total blood volume is made up of blood cells.
 45% of the Hb is in the red blood cell.
 An anaemic subject has R.B.Cs count
3.5millom/mm3, PCV42% & Hb 14gm%, by
using the blood indices this subject most
probably has?
 Aplastic anaemia.
 Macrocyric hyperhormic anaemia.
 Normocytic normochromic anaemia.
 Microcytic hypochromic anaemia.

 If a man's plasma agglutinates both A and B

red cells, he is group:
 B
 A
 AB
 O
 Clinical features suggesting severe aortic
stenosis include, except:
 Early systolic ejection click.
 Pulsus bisferiens.
 Heaving displaced apex beat.
 Syncope associated with angina.

 Which of these is not a peripheral sign of

infective endocarditis?
 Osler's nodes.
 Splinter haemorrhages.
 Janeway lesions.
 Clubbing.
 Palmar erythema.
 Thrombin is required for activation of all the
following except:
 Plasminogen
 Fibrinogen
 Clot retraction
 Factor III

 All the following drugs for the treatment of

peptic ulcer disease alter gastric acid pH except:
 Calcium carbonate
 Cimmetidine
 Omeprazole
 Pirenzepine
 Sucralfate
 Characteristic feature of cholestatic jaundice
include, except:
 Dark green stool.
 Dark brown urine.
 Conjugated hyperbilirubinaemia.
 Serum alkaline phosphatase concentration increased >2.5
normal.
 Increased serum bile acid concentrations.

 The typical clinical features of diabetic

ketoacidosis include, except:
 Abdominal pain and air hunger.
 Rapid weak pulse and hypotension.
 Dry skin and polyuria.
 Vomiting and constipation.
 Coma with extensor plantar response.
 Cause of polyuria include, except:
 Chronic hyperglycaemia.
 Chronic renal failure.
 Hypercalcaemia.
 Hypothyroidism.
 Lithium toxicity.

 All the following drugs are associated with an

increased risk of osteoporosis in adults except:
 Cyclosporine
 Dilantin
 Herparin
 Presnisone
 Ranitidine
Thank You