Approach to Patient with

Anemia
Three Lectures
Anemia 1
Husain Alkhaldy ,MD
17/01/2021
Suggested reference👉
➢Lecture
➢Reading materials
➢Case studies
Objectives
• Definitions.
• Microcytic anemia
• Macrocytic anemia
• Normocytic anemia
• Acquired Hemolytic anemias
• Hereditary hemolytic anemia
• Approach to diagnosis of anemia.
Complete Blood Count
• Differential leucocytic counts
• Neutrophils / bands.
• Eosinophils / Basophils Medicine 2 course
• Lymphocytes./ Monocytes
• Abnormal cells .
• RBCs
• Hb / Hct. Medicine 1 :
• Indices ( MCV / MCH / MCHC) - Anemia +
• Reticulocytes - Bleeding disorders
- Thrombotic disorders
• Platelets
1/17/2021 4
🆒

Units used
count :
• RBCs (millions/ L, WBCs (thousands / L ) / Plat
thousands / L
• I drop of blood has 50 L (microns)
• 1 mm3 ( cubic millimeter) = 0.001 milliliter = 1 / L
• 109/L = 103/ L = n,000 / L = n,000 / mm3
some people use count directly on L or mm3
For example
WBC 4-11 *109/L = 4-11 *103/ L
WBC = 4,000- 11,000 / / L or
WBC = 4,000- 11,000/ mm3

concentration ; g/dL or g/L ( 13 g/dL = 130 g/L)

or percentage (%)
Volume : MCV , MPV : fl (femtolitre)
Content : like Mean Cell Hemoglobin (MCH): pg ( picogram)
Definition of Anemia

What level of Hemoglobin define

anemia ?
Decrease in the red blood cells
mass •🤚
• ⇩ Hb
• Adult male : < 13 g/dL
• ⇩ hematocrit
• Adult female : < 12 g /dL
• Normal level of hemoglobin is a
range • Pregnant female : <11 g /dL
• Normal range is slightly different
among different population
 Hemoglobin (g/dL) trend with aging
🆒 Abha:2,270 m vs. Jeddah sea level
( age / gender / altitude )

High Latitude females High Latitude males Sea level females Sea level males

16.2
16.0

15.6

15.1
Hemoglobin conc.

14.9
14.8

14.4
14.3
14.1

13.7 13.8
13.6

13.1 13.2 13.1

13.0

(18-40) (41-60) (61-80) (81-100)

Age group
Suggested Definition of anemia

Anemia Sea level Anemia High altitude – 2,500 m

• Adult male : < 13 g/dL • Adult male : < 14 g /dl

• Adult female : < 12 g /dL • Adult female : < 13 g /dl
• Pregnant female : <11 g /dL • Pregnant female : 12 g /dl

• Abha : 2,270 m
• Alsouda : 3,000 m 👍
What causes Anemia ?
• So many causes
• Frequently secondary, but can be primary
• Most of the time approach is simple and diagnosis is straightforward.
• Will go through some revision and ( home reading ) and then will
have some case studies .
Work up of Anemia
• Clinical assessment :
• Accurate history
• Physical examination
• CBC: is the physical assessment of
the hematopoietic system
• The most useful two CBC
parameters :
• MCV: mean cell Volume a
• reticulocytes
• Factory : BM
• Ingredients: iron , folate , B12 ,
and a good health
• Main regulator : EPO , TPO ,
GCSF
• Modulators : androgens ,
thyroxine, cortisol,inflammation,
genetic makeup,,,,etc.
 Why assessment of reticulocyte
response is important in the
evaluation of anemia ?

1/17/2021 12
Anemia + Reticulocytopenia =
• Primary Bone marrow disorders ( hereditary or acquired )
• Bone marrow suppression ( drugs , viral , fungal , TB , chemo)
• Hematinics deficiency
• IRON
• B12
• FOLATE
• Anemia of chronic disease .
• Erythropoietin Deficiency ( Chronic Kidney Disease)
• Hypo ( Androgen , cortisol , thyroxine )
1/17/2021 13
Healthy bone marrow can respond to the
following condition with Reticulocytosis
➢Bleeding ….
➢Hemolytic anemia…

1/17/2021 14
Recovering bone marrow can respond to the
following condition with Reticulocytosis

✓Erythropoietin supplementation .
✓Nutrient repletion ( B12, iron , folate )
✓Recovering BM ( post infection , drugs , chemotherapy )

1/17/2021 15
Please read the supplement material in how to obtain and interpret the
reticulocyte count?
Reticulocyte count
• Commenly expressed as percentage of RBC
• Daily 1-2% of RBCs die, and 1-2% new RBCs produced
• 1%-2% of RBCs
• 1% * 5,000,000 (/uL) = 50 ,000 reticulocyte (/uL)
• Roughly 50,000-100,000
• At normal conditions with normal hemoglobin , the Normal
Reticulocyte count (%) = 1-2%
• Normal absolute reticuolcyte count = 50,000-100,000 ( of the total
RBCs)
Reticulocyte count
• Any patients with hemolytic anemia should have a higher baseline
retic count ( more than 2%) because their RBCs don’t live for 100
days.
• How to utilize the retic count with all this confusion?
• Calculate the absolute count from the percentage?
• 2% * RBCs = ARC ( absolute retic count )
• Compare with normal range
• If bleeding or hemolysis, it should be higher than normal range
Classification ( why?)
The size of the RBC The activity of the BM
Mean Corpuscular volume (MCV) reticulocyte count

• Hyperproliferative
• Microcytic = MCV < 75 femtoliters (fL) • High retic index
• Normocytic = MCV 75-94 fL • bleeding / hemolysis
• Macrocytic = MCV > 94 fL • Hypo-proliferative
• <80 , ( 80-100) , > 100
• Low retic count , index
• hematinic deficiency (iron , B12 ,
folate)
• Hormone / inflammation
• Marrow disorders
Less (Hem –o- globin ) small RBC Microcytic anemia

Globin ( Alpha , Beta , gamma , delta

Heme ( iron + protoprphyrin) chains )
Microcytic Anemia

Less hemoglobin → Microcytic anemia

1. NO iron → • Iron deficiency anemia (the

commonest )
2. Iron present but not available → • anemia of inflammation , Anemia of
chronic diseases ( common )

3. iron present , available but cells can • Sideroblastic anemia ( very Rare )
not use →

4. Hereditary Less globin production → • Hemoglobinopathy : Thalassemia (a

,b) Hb E ,Hb C ( rare)

1/17/2021 21
Case study
• 14yo female presents to primary
care with a complaint of fatigue. Labs
are ordered and hemoglobin is 9.7 . She
describes periods as "fine”

• Physical examination :
• pallor
• Otherwise unremarkable
Clinical assessment
Presentation Physical examination
1. Symptoms of anemia 1. Signs related to the anemia
2. Range from asymptomatic to
severely symptomatic depending
on
• Level of anemia
• Acute or chronic
3. Presentation related to the 1. Signed related to the underlying
underlying etiology etiology
• Decreased dietary intake,
• Reduced absorption,
• blood / iron loss.
Causes of Iron
Deficiency Anemia
Clinical assessment – IDA

History gathering Physical exam

• HPI : • Pallor
• Frequently asymptomatic • Angular stomatitis
• anemia symptoms
• Advanced cases Pica ,
• Atrophic glossitis
• Medical conditions associated
with IDA
Pallor
• Palmer creases
• Nail beds
• Conjunctivae

• Patient is pale ( not pallor ) !!

Angular stomatitis Atrophic glossitis
Very rare
• Koilonychia
• The upward curving of the distal
nail plate resulting in a spoon-
shaped nail. Associated with iron
deficiency anemia and other
systemic conditions and may be
idiopathic.
Plummer Vinson Syndrome
🤚
• The most common anemia world wide is : IDA
• The second most common and first most common anemia in the
hospital setting is : anemia of inflammation ( anemia of chronic
disease )
Iron
hemostasis
How to confirm the diagnosis of IDA
• Very simple ( if u know basics of iron hemostasis )
• Iron is taking in from food
• Iron is transported in plasma by protein called Transferrin
• Iron is stored in liver , spleen , BM macrophages as ferritin ( protein
that bind multiple iron atoms )
• Iron hemostasis is regulated by hormone ( Hepcidin ) and its binding
to the iron exporter ( ferroportin).
How does
hepcidin mediate
its action
• Through binding to the iron
exporter ( ferroportin)

If the body does not need iron

• Hepcidin will increase
• will bind to ferroportin
• Ferroportin will be degraded
• No iron absorption
• No iron release from store
 What does the hormone hepcidin do ?
(Protect us from excess iron)
• Negative regulator ( like insulin) : hepcidin prevent iron absorption
and release from store
• If the body does not need iron , hepcidin ↑
• Hepcidin inhibit iron absorption ( also inhibit iron release from stores)

• If the body needs iron ( like in IDA )

• Hepcidin ⇣⇣ → iron absorption increase ( iron release from store
increase )
• hepcidin regulators ( iron status , inflammation , and erythroid activity
)
Stage 1 : normal state

• Serum iron = N
• Serum Transferrin (TIBC) = N
• Transferrin saturation = serum
iron / Serum Transferrin (TIBC)
• Serum ferritin =N
• Hb = N
Stage 2 : latent iron deficiency

• Serum ferritin = ↘
• Serum iron = ↔, ↘
• Serum Transferrin (TIBC) = N, ↗
↘
• Transferrin saturation = serum
iron / Serum Transferrin (TIBC)
• Hb = ↔ , MCV=↔
• Simply said : stores of iron are
depleted first, thus CBC will
remain normal
Stage 3 : iron deficiency anemia

• Serum ferritin =↓
• Hb = ↓, MCV =↓
• Serum iron = ↓
• Serum Transferrin (TIBC) = ↑
• Transferrin saturation = ↓
• (serum iron / TIBC)
• Serum ferritin is the single most important biochemical parameter to
confirm iron deficiency .
• However, serum ferritin is acute phase reactant , can increase with
inflammation

• Other indices are helpful when serum ferritin is normal despite iron
deficiency
🤚

Ning and Zeller , ASH-education 2019

• Iron deficiency anemia
• The peripheral blood smear is
remarkable for microcytic,
hypochromic erythrocytes, with
significant anisopoikilocytosis
(abnormalities in erythrocyte size
and shape) characteristic of iron
deficiency anemia.
Differential diagnoses of microcytic
anemia
• Iron deficiency anemia
• Anemia of inflammation ( the commonest inpatient )
• Thalassemia minor ( not common ), some other hemoglobinopathies
• Sideroblastic anemia ( very rare )
Thalassemia minor ( V. Common
scenario )
• Microcytosis : because of decreased Hb content (less globin)
• Iron stores are normal or increased
• Hb electrophoresis can detect B thalassemia , Hb E , Hb C .
• Hb electrophoresis is usually normal in A thalassemia.
• Molecular diagnosis is needed to diagnose A thalassemia
Lab findings in thalassemia minor

• Mild anemia
• Microcytosis , target cells
• MCV is usually smaller to the
degree of anemia
• RBCs usually higher to the degree
of anemia
• RDW near normal
• Ferritin is normal unless coexisting
iron deficiency anemia
Anemia of
inflammation (
ACD)
• Initially mild normocytic .
• Progress to microcytic anemia
• Iron profile overlap with that of iron
deficiency
• The most common anemia in inpatient
and second only to IDA in prevalence .
Anemia of inflammation
• inflammatory cytokines blunt ( counteract) the two hormones (
erythropoietin and hepcidin
• Initially erythropoietin inhibition will lead to mild normocytic
anemia .
• With time , hepcidin ( inhibit both iron absorption and iron release
from macrophages ) result into microcytic anemia
•
Lab findings in inflammatory anemia 🤚
• Serum ferritin in the normal range , even increased
• Inflammatory markers ↑ ( ESR , CRP )
• Hepcidin level increase↑
• Serum iron ⇩
• Transferrin (TIBC ) ⇩ (not increased like IDA)
• So transferrin saturation (s. iron / TIBC ) can be normal ( low in IDA)
⬆︎
Sideroblastic anemia
• Hereditary or acquired block in
heme synthesis
• Some drugs and lead poisoning
• Iron is available but can not be
incorporated into heme
• Iron overload can happen
• Some sideroblastic anemia is
pyridoxine responsive
Treatment of iron
deficiency anemia
👍 : good to know
• Iron deficiency anemia is not a diagnosis per se
• You must look for the underlying cause
• Common scenarios
• 1)
• 2)
• 3)
• 4)
• 5)
 ‫عالج أنيميا نقص الحديد‬
‫تعويض نقص الحديد‬ ‫•‬ ‫• معرفة السبب‬
‫األكل الصحي‬ ‫•‬ ‫• عالج السبب‬
‫حبوب الحديد والمدعمات الغذائية‬ ‫•‬ ‫• بدون معرفة السبب وعالجه ‪ ,‬تعويض‬
‫إبر الحديد‬ ‫•‬ ‫نقص الحديد ليس كافيا وستعود أعراض‬
‫األنيميا مرة أخرى‬
 ‫األكل الصحي‬
‫أكل متوازن يحتوي على جميع المجموعات الغذائية ال سيما اللحوم ‪.‬‬ ‫•‬
‫فيتامين ج يساعد على امتصاص الحديد‬ ‫•‬
‫الفواكه الحمضية تحتوي على الحديد ولكن تحتوي أيضا على مادة البولي فينول‬ ‫•‬
‫الشاي القهوة والحليب ‪ /‬الكالسيوم يقلل بنسبة كبيرة من امتصاص الحديد‬ ‫•‬
 ‫حبوب الحديد‬
‫• يوجد أنواع كثيرة في الصيدليات ‪ .‬جميعها لها تقريبا نفس المفعول وقد يزيد االمتصاص اذا‬
‫أضيف فيتامين ‪. c‬‬
‫• هناك أنواع مستخلصة من مصادر حيوانية امتصاصها أفضل ولكنها غالبا غير متوفرة‬
‫وتطلب وسعرها مرتفع قليال‬
‫• نظرا لمحدودية امتصاص الحديد فقد يحتاج المريض لفترة ال تقل عن ‪ ٦‬أشهر ‪.‬‬
‫• أعراض شائعة لكن بسيطة ولكن قد ال يتحملها البعض لحبوب الحديد ‪ ,‬كتغير الطعم ‪,‬‬
‫مغص في البطن ‪ ,‬إمساك ‪ ,‬تغير في لون البراز إلى األسود‬
‫• تعتبر الحبوب هي الخيار األول لرخص السعر خصوصا عندما تكون االنيميا بسيطة (‬
‫مستوى الهيموجلوبين فوق ‪ )١٠‬سبب االنيميا معروف وعندما تكون األعراض الجانبية‬
‫محتملة‬
• Iron should be taken between meals, and inhibitors of iron absorption
(calcium-containing foods such as dairy products, tea, and coffee)
should be avoided when the iron supplement is taken.
Medications that reduce gastric acidity such as antacids may also
impair oral iron absorption and should be similarly avoided.

Oral iron taken with vitamin C (orange juice or ascorbic acid) can
enhance iron absorption
 ‫الحديد الوريدي‬
‫• عملية تعويض نقص الحديد أصبحت أمنة بشكل كبير وسريعة وسعرها معقول‬
‫• يوجد اآلن أنواع من الحديد قد تعوض النقص في جرعة واحدة‬
‫=) ‪I.V iron ( ferrinject‬‬
‫فيرينجيكت‬
‫‪ferric carboxymaltose‬‬
‫االمبولة تحتوي على ‪ ٥٠٠‬مج‬
‫باإلمكان اخذ جرعة حتى ‪ ١٠٠٠‬مج وقد تكون كافية تماما‬
‫في بعض األحيان‬
‫)فيروساك ( ‪i.V Iron‬‬
‫االمبولة من ‪ ٥٠‬الى ‪ ١٠٠‬مج من الحديد‪.‬‬
‫اقصى كمية في الجلسة الواحدة ‪ ٢٠٠‬مج‬
‫قد تحتاج الى ‪ ١٠-٧‬جلسات حسب نقص الحديد‬
‫العالج أمن ولكن نسبة التحسس نوعا ما أكثر من األنواع‬
‫األخرى المتوفرة‪.‬‬
Case study-4
• Old gentleman with Anemia
•
• 70 year old female. Symptoms of dyspnea on
exertion, easy fatigability, and lassitude for past 2 to
3 months. Denied hemoptysis, GI, or vaginal
bleeding. Claimed diet was good, but appetite varied
• Other than pallor, no significant physical findings
were noted. Occult blood was negative.
• CBC and PBS will be provided
Normocytic anemia
MCV (80-100)
 Normocytic Anemias

• Factory : BM
• Ingredients: iron , folate , B12 ,
and a good health.
• Main regulator : EPO , TPO ,
GCSF
• Modulators : androgens ,
thyroxine, cortisol,inflammation,
genetic makeup,,,,et
• Blood loss : bleeding /hemolysis
 Normocytic anemia
• Decreased Production rate not due to hematinics deficiencies
• Primary BM diseases
• Hormone deficiencies ( cortisol , thyroxine , testosterone are important
modulators of erythropiosis)
• Erythropiotin
• Increased destruction rate
• Hemolysis
• Bleeding
macroocytic anemia MCV (>100 fl)
Case study- 5
• 37 year old male.
• Lifelong history of a seizure disorder, treated since
age two.
• At a routine check with his neurologist, he
complained of fatigue, exertional dyspnea, and
lightheadedness over the past 2-3 months.
• He appeared pale, but otherwise his physical exam
was within normal limits. He was found to have a
decreased hemoglobin, and was referred to
Hematology Clinic
 Macrocytic anemia – causes
Round macrocyte Oval macrocyte
( abnormal lipid composition of the
erythrocyte membrane ) (Abnormality of DNA maturation)
Non-megaloblastic Megaloblastic
• Liver disease • B12 deficiency
• Folate deficiency
• Alcoholism
• Renal disease / hypothyroidism
• Aplastic anemia
• Myelodysplastic syndrome
• Reticulocytosis
Pathophysiology
of megaloblastosis
• Delay in the DNA maturation
Signs and Symptoms
• Hematologic:
• common
• Anemia > ↓ white blood cells, ↓
platelets
• Increased hemolysis due to
ineffective hematopoiesis
• Gastrointestinal:
• rare
• Glossitis, malabsorption
• Neurologic:
• common with B12 . Does not
happen with folate
• NTD with folate /B12 deficiency
• Clinical picture is usually
dominated by the underlying
condition .
B12
• Peripheral nerves :Paresthesia -most often in fingers and toes. The
most common symptom of vitamin B12 Deficiency.
• Subacute combined degeneration of the cord
• Diminished vibratory sense
• Gait ataxia
• Increases deep tendon reflexes
• Memory loss
• Personality change
• Orthostatic hypotension
• Subacute combined degeneration of the spinal cord
• Any patient who presents with neurologic manifestations of
peripheral neuropathy, ataxia, or dementia should be evaluated for
cobalamin deficiency, even in the absence of concurrent anemia or
macrocytosis.
Blood film
Hypersegmented polymorphonuclear (PMN).
The presence of hypersegmented PMNs
becomes significant when they constitute
greater than 5% of PMNs with five or more
lobes or 1% with six or more lobes.

PMN = neutrophils
USEFUL TIPS
• Serum B12 and folate essay
lacks sensitivity and specificity
• B12 deficiency is associated
with
• ↑ homocysteinemia
• ￪ methylmalonic acid
• Whereas folate deficiency is
associated with
• ↑ homocysteine
• N methylmalonic acid
 How to confirm the B12 and folate deficiency?

More sensitive Less sensitive

• Measuring serum B12 and folate

DEFICIENCY HOMOCYSTEINE METHYLMALONIC ACID

FOLATE ELEVATED NORMAL

levels .
B12 ELEVATED ELEVATED

Sometimes , especially when we lack the resources to confirm the diagnosis , we

give a theraputic trail of BOTH B12 and Folate
 Iron Folate Vitamin B12
deficiency Deficiency Deficiency

Store 1000-2000 mg 10-15 mg 3-4 mg

Daily requirements 1-2 mg 0.4 mg 2.4 ug
Source Only animal
products
Most common cause Bleeding Hemolysis / Malabsorption
antifolate /
malnutrition
Time to development months Months Years
Neurologic abnormalities No No Yes

Response to treatment -- No Yes

with vitamin B12
Response to treatment -- Yes Hematologic - Yes
with folate Neurologic - no
Advanced tips in evaluation of anemia
• Real life is more complicated than in classrooms .
• Latent deficiency versus advanced deficiency
• Early anemia versus late / chronic anemia
• Coexistent two or more types of anemia make work up trickier .
• Coexistent iron and ( folate or B12 ) deficiencies can result into normocytic
anemia
• One disease can be associated with more than one mechanism of anemia ( celiac
/ CKD / hypothyroidism )
• Reticulocytosis ( large RBCs ) can cause spurious macrocytic anemia
• Anti-reticulocyte antibodies in AIHA can result into low retic hemolytic anemia
• And many others
To continue ….
Anemia _2
Acquired hemolytic anemia
Hereditary hemolytic anemia