CLINICAL APPROACH

OF ANEMIA
Dr. dr. Ikhwan Rinaldi, SpPD - KHOM
 Overview

Decrease of red A public health Anemia is found in

blood cells, seen in problem, especially 1.62 billion of
the low quantity of in developing population
Hemoglobin1 countries worldwide

In Indonesia, Iron deficiency is

anemia is mostly the 1st cause of
found in children & anemia, among
pregnant women2 other ethiologies2

1. Price S. A., Wilson L. M. Patofisiologi Konsep Klinis Proses-Proses Penyakit. Vol 1. Ed 6. Jakarta: Penerbit Buku Kedokteran EGC: 2006. P 255-256.
2. Benoist B., McLean E., Egli I., Cogswell M. Worldwide prevalence of anaemia 1993-2005; WHO Global Database on Anaemia. WHO Press: Geneva: 2008. P
1-8.
Prevalence of Anemia
Worldwide Anemia Prevalence (De Maeyer EM, et al, 1989)
Location Children Children Men Women Pregnant
0-4yo 5-12 yo 15-49 yo Women
Developed 12% 7% 3% 14% 11%
countries
Developing 51% 46% 26% 59% 47%
countries
Worldwide 43% 37% 18% 51% 35%

Indonesia Anemia Prevalence (Husaini, et al, 1989)

Preschool School age Women Pregnant Men
children children Women
Indonesia
30-40% 25-35% 30-40% 50-70% 20-30%
 Hematopoiesis

Started from a stem

Hematopoiesis  Formation or
cell  by regulation
“hemo” (blood) & development of
mechanism, forming
“poiesis” (forming)1 blood cells
progenitor cells

Erythropoiesis: Erythropoiesis Other factors

progenitor cells occurs within the affecting
differentiated into bone marrow, erythropoiesis:
erythroblast differentiating into EPO, B12, folic
precursors erythrocytes2 acid, and Fe3

1. Longo. D. L. Harrison’s Hematology and Oncology. New York: Mc-Graw Hill: 2010. P 2-7, 81-82.
2. Theml H., Diem H., Haferlach T. Color Atlas of Hematology Practical Microscopic and Clinical Diagnosis. Thieme Verlag: Stuttgart: 2004. P 2 – 7.
3. Saladin K. S. Anatomy and Physiology: The Unity of Form and Function. 5th ed. McGraw-Hill: New York: 2010. P 683-693
 Formed elements
Plasm (water
Hematopoiesis
(erythrocyte,
leucocyte, & molecules,
protein, fat, etc)
thrombocyte)

Slight amount of cells

with huge capability of
proliferation

Cells differentiating into

lineage-committed
precursors, stimulated
by growth factors

Inherit derivative of
blood cells
(Colony Forming Unit/
CFU)

Precursor cells

Mature cells

Fernandez K. S., Alarcon P. A. Development of the Hematopoietic System and Disorders of Hematopoiesis that Present During Infancy and
Early Childhood. Pediatric Clinics of North America; 2013; 60(6):1273-89
Erythropoiesis

EPO – EPO Receptor

Folic acid & B12 Hb + Fe 

Affecting DNA synthesis  circulating
blood cells maturation oxygen
 Iron is a vital trace Form of iron in body Men:
element which is essential tissues: functional 50 mg/kgbw
in hemoglobin, myoglobin, iron substance, Women:
Luminal phase and various enzymes storage iron & 35 mg/kgbw
(iron from food is formation transport iron
digested in
stomach)
Mucosal phase
(occurs in duodenum (Feri)
& proximal jejunum
mucosal. Absorption Ferric reductase
is set by “set-point”
in Kripta Lieberkuhn) (Fero)
Corporeal phase Hephaestin
(iron is absorbed in (ferrooxydase)
enterocyte 
intestine capillary -
apotransferin)
Degradation of Hemoglobin

Globin
Diagnostic Approach of Anemia

Physiological Probability
Anamnesis
Findings Approach

Physical Morphological
examination Findings

Laboratory Reticulocyte
examination Index
 Diagnostic Approach of Anemia
Physical Examination

• Anamnesis of main complaint (fatigue & weakness),

probable etiologies, past illness history, family history
• Physical Examination (anemic conjunctiva, icteric sclera,
organomegaly, etc)1
• Laboratory Examination (erythrocyte counts, hemoglobin
level, hemathocryte, retyculocyte counts, MCV, MCH,
MCHC, leucocyte and platelet counts, Fe serum, TIBC,
serum ferritin, biopsy)2

Reticulocyte Index

• < 2  marrow hypoproliferation, maturation defect

• > 2  hemolytic anemia3
1. Conrad M. E. Anemia. In: Walker H. K., Hall W. D., Hurst J. W. Clinical Methods; The History, Physical, and Laboratory Examinations. 3 rd ed. Boston: Butterworths: 1990. P 703-708.
2. Bakta. I. M. Pendekatan Terhadap Pasien Anemia. Dalam: Setiati S., et all. Buku Ajar Ilmu Penyakit Dalam. Jilid II. Ed 6. Jakarta: Interna Publishing: 2014. P 2575-2579.
3. Bain B. J. Blood Cells. 5 th ed. West Sussex: John Willey & Sons Ltd.: 2015. P 28-29.
 Reticulocyte Index

Patient Hematocryte= Absolute reticulocyte percentage

% Reticulocytes x
45

% Reticulocyte x Red Blood Cell Count = Absolute Reticulocyte Count

Bain B. J. Blood Cells. 5th ed. West Sussex: John Willey & Sons Ltd.: 2015. P 28-29.
 Diagnostic Approach of Anemia
Morphological Approach

• Microcytic Hypochromic Anemia (Thallasemia, chronic disease, iron deficiency, lead

poisoning, congenital sideroblastic anemia)
• Normocytic Normochromic Anemia (acute blood loss, hemolysis, erythrocyte
production suppression)
• Macrocytic Normochromic Anemia (Megaloblastic (B12, folic acid def, infection,
MDS) and non-megaloblastic (liver dysfunction, aplastic anemia, retyculocytosis) 1

Physiological Approach

• Decrease of erythrocyte production

• Increase of erythrocyte destruction
• Blood loss2

Probability Approach

• This approach is done after the type and etiology of anemia is known, and relate it
to the etiology pattern that is mostly found within the area 3

1. Ford J. Red blood cell morphology. Int. Jnl. Lab. Hem. 2013, 35, 351–357
2. Conrad M. E. Anemia. In: Walker H. K., Hall W. D., Hurst J. W. Clinical Methods; The History, Physical, and Laboratory Examinations. 3 rd ed. Boston: Butterworths: 1990. P 703-708
3. Bakta. I. M. Pendekatan Terhadap Pasien Anemia. Dalam: Setiati S., et all. Buku Ajar Ilmu Penyakit Dalam. Jilid II. Ed 6. Jakarta: Interna Publishing: 2014. P 2575-2579.
 Physical Examination

Reticulocyte Index

<2 >2

Morphological Approach
Hemolytic and blood
loss:
Normocytic Microcytic/ Blood loss
Normochrom Macrocytic
Intravascular hemolytic

Hipoprolipheration: Maturation defect: Metabolic defect

Marrow damage Cytoplasm defect (iron Abnormality of

(aplasia, fibrosis) deficiency, thalassemia, membrane

Iron deficiency sideroblastic anemia) Hemoglobinopathy

Stimulation decrease Nucleus defect (B12, Autoimmune defect

(renal or metabolic folic acid deficiency,
refracter anemia, drug  
defect)
toxicity)
 Peripheral Blood Smears (Morphological Approach)

Iron Deficiency Anemia Sickle Cell Anemia

1. Iron Deficiency Anemia. WebPath. Available at: http://library.med.utah.edu/WebPath/TUTORIAL/IRON/IRON.html#1

2. Bain BJ. Diagnosis from the blood smear. N Engl J Med 2005; 353:498-507.
 Peripheral Blood Smears (Morphological Approach)

Pernicious Anemia Myelodysplastic Syndrome

Bain BJ. Diagnosis from the blood smear. N Engl J Med 2005; 353:498-507
 Peripheral Blood Smears (Morphological Approach)

Acute hemolysis in G6PD deficiency

Microangiopatic hemolytic anemia

Bain BJ. Diagnosis from the blood smear. N Engl J Med 2005; 353:498-507
 Peripheral Blood Smears (Morphological Approach)

Hereditary poikylocytosis Hereditary spherocytosis

Bain BJ. Diagnosis from the blood smear. N Engl J Med 2005; 353:498-507
 Peripheral Blood Smears (Morphological Approach)

Paroxysmal cold hemoglobinuria Beta Thalassemia

Peripheral smear in beta-zero thalassemia
minor showing microcytes (M), target cells
(T), and poikilocytes.

1. Bain BJ. Diagnosis from the blood smear. N Engl J Med 2005; 353:498-507
2. Advani P. Beta Thalassemia Workup. Medscape. Available at: http://emedicine.medscape.com/article/206490-workup#c7. Updated on Nov 08, 2016.
Patophysiology
Nutrition
Deficiency

Anemia Chronic disease

Hemolytic
anemia
Production of
erythrocyte

Blood loss
 Iron Deficiency Anemia
Definition & Reduction in total body iron to an extent that iron stores are
Causes
fully exhausted and some degree of tissue iron deficiency is present

Increase of iron demand, increase of iron loss, decrease of iron

absorption

Pathophysiology Negative iron balance (demand of iron or iron loss increases) over the
ability to absorb iron
Blood loss over 10 – 20 mL of erythrocyte

Depleted iron store (normal iron store in adults: 3-5g)

Depleted iron store (low ferritin serum <30 mg/dL), low Fe serum,
increase of TIBC and protoporphyrin1

1. Longo. D. L. Harrison’s Hematology and Oncology. New York: Mc-Graw Hill: 2010. P 70-73.
Diagnostic Approach of Iron Deficiency Anemia
Serum ferritin <
15μg/L; Serum
transferrin receptor
varies; Bone-
Anamnesis (Chronic Definitive marrow iron – iron
fatigue) measurements stain <; Storage
iron <; TIBC >

Hb measurement <
Physical examination 12 g/dL; Peripheral
(anemic conjunctiva, smear (MCV & MCH
Screening
koilonychia, glossitis <); Transferrin
measurements
or dysphagia) – saturation <16%;
rarely seen Zinc protoporphyrin >
80 μmol/mol ;
Reticulocyte Hb
(CHr) ≤ 28 pg

Cook J. D. Diagnosis and management of iron-deficiency anaemia. BMJ 2005. 18 (2). P 319-322.
Zimmermann MB., Hurrell RF. Nutritional iron deficiency. Lancet 2007: 370: p 511-20.
 B12 & Folic Acid Deficiency
Daily B12 1 mcg
needs
Folic acid 100 – 200 mcg

Cause Inadequate diet, malabsorption (anemia pernisiosa),

increase of cell proliferation, loss of folic acid through
kidney, medicines (anticonvulsant)

Laboratory Megaloblastic anemia1,2

findings

Other Nutrition Deficiency: vitamin

A, vitamin B6, vitamin C, and zinc.
1. Longo. D. L. Harrison’s Hematology and Oncology. New York: Mc-Graw Hill: 2010. P 70-73.
2. Provan D. ABC of Clinical Hematology. 2nd ed. London: BMJ Publishing Group: 2003. P 5 -8.
 Diagnostic Approach of Megaloblastic Anemia
B12 or Folic acid
deficiency anemia
in therapy

Increased
Laboratory
Anamnesis &
examination (Hb<,
Physical Reticulocyte index
macrocytic
Examination
erythrocyte)
Normal or
decreased

B12 deficiency Serum B12

anemia decreased Bone marrow
Megaloblastic
examination

Folic acid deficiency Serum folic acid

anemia decreased Non-
megaloblastic

1. Longo. D. L. Harrison’s Hematology and Oncology. New York: Mc-Graw Hill: 2010. P 70-73.
2. Provan D. ABC of Clinical Hematology. 2nd ed. London: BMJ Publishing Group: 2003. P 5 -8.
 Chronic Diseases
Chronic Failure of EPO production
Kidney
Disease

Decrease of erythrocyte lifespan (Hemolytic Uremic

Syndrome)

Malignancy Malignancy (Hematological & other site

and other malignancies)
diseases
Infection  HIV/AIDS, tuberculosis, malaria,
osteomyelitis, chronic abcess, dan sepsis
Cytokine dysregulation (in elderly)1,2,3

1. Longo. D. L. Harrison’s Hematology and Oncology. New York: Mc-Graw Hill: 2010. P 70-73.
2. Provan D. ABC of Clinical Hematology. 2nd ed. London: BMJ Publishing Group: 2003. P 5 -8.
3. Lichtman M. A., Beutler E., Shigsohn U., et al. Williams Hematology. 7 th ed. New York: Mc-Graw Hill Medical: 2007.
Diagnostic Approach of Chronic Disease

Laboratory findings
(Hematological: Hb,
Anamnesis & Physical MCV, MCH <, leucocyte,
Iron serum <
examination thrombocyte & Non-
hematological: ureum,
creatinine)

Chronic Disease Anemia

TIBC < & Ferritin serum
Bone marrow iron (+) (CKD/ malignancy/
N/ >
infection)

EPO
Bone marrow biopsy
Infection markers
 Hemolytic Anemia
Autoimmune AHA warm type (hemolysis is mediated by IgG molecules at the
temperature 370C)& cold type (hemolysis is mediated by C3 at the
temperature <370C)  Direct Antiglobulin Test

Medicine Induced Hemolytic

Icteric sclera; organomegaly; increased in indirect & total bilirubin, LDH;

normocytic normochromic anemia

Non- Thallasemia (defect of globin synthesis)  Thallasemia α & β  Hb

analysis
autoimmune
Sickle cell anemia  defect of hemoglobin structure (HbS)

Shear stress on erythrocyte

Infection (Clostridium Welchii  hemolisin; Mycoplasma pneumonia)1,2,3

1. Kasper D. L., Fauci A. S., Longo D., et al. Harrison’s Principles of Internal Medicine. 16 th ed. New York: Mc-Graw Hill: 2005. P 365-366
2. DeLoughery T. G. Hematology: Autoimmune Hemolytic Anemia. Vol 8. Wayne: Turner White Communications: 2013. P 1 – 11.
3. Ghosh A. K. Mayo Clinic Internal Medicine Review. 8 th ed. Kanada: Mayo Foundation for Medical Education and Research: 2008. P 411-412.
 Anamnesis (fatigue)
Physical examination (icteric
sclera, organomegali) Warm antibodies
Laboratory (Hb <, indirect
bilirubin >, total bilirubin >, LDH >)
Autoimmune HA Cold antibodies

Mixed

Immune
DAT + Alloimmunization ABO compatibility
mediated

By haptens

Drug-induced HA By autoantibodies

By immune
complexes

Ruiz EF, Cervantes MA. Diagnostic approach to hemolytic anemias in the adult. Rev Bras Hematol Hemoter. 2015:37 (6): 423-425.
 DAT

Enzymopathies
-

+ Congenital HA Hemoglobinopathies
Nonimmune
mediated

Membranopathies
Peripheral
blood smear
Big vessels

- + Traumatic

Small vessels

PNH, - Infectious
Family history
hypersplenism
Exogenous

Toxic

+
Endogenous

Ruiz EF, Cervantes MA. Diagnostic approach to hemolytiv anemias in the adult. Rev Bras Hematol Hemoter. 2015:37 (6): 423-425.
 Diagnostic Approach of Hemoglobinopathies

Laboratory findings
Anamnesis (Family Physical examination
(Hb <, MCV-MCH < or
history, development (icteric, anemic,
N, reticulocyte >,
& growth history) splenomegaly)
inclusion body)

Hemoglobin
Globin chain
electrophoresis (HbF ,
synthesis, Varian
HbA2, HbH > in
structural Hb analysis,
Thalassemia; and
intracellular HbF
HbS in Sickle Cell
distribution)
Anemia)

Bakta. I. M. Pendekatan Terhadap Pasien Anemia. Dalam: Setiati S., et all. Buku Ajar Ilmu Penyakit Dalam. Jilid II. Ed 6. Jakarta: Interna Publishing: 2014. P 2575-2579
 Thallasemia

Chaudry S., Herman W. Thallasemia. McMaster Patophysiology Review. Available at: http://www.pathophys.org/thalassemia/
 Production of Erythrocyte
Anamnesis &
Physical
Aplastic
examination
Leukemia Anamnesis &
Anemia Physical
examination
Laboratory
findings: Hb may
be normal or <, Clinical syndrome Laboratory
with increased AML, CML caused by decrease of findings: Hb < with
blood cells production
leucocyte and normal or low
normal or low leucocyte and
thrombocyte thrombocyte +

Myelodisplasia
< CGU-GM and BFU-E
Low reticulocyte Syndrome Low reticulocyte
index + normocytic index + normocytic
normocrom normochrom
Direct toxicity to
hematopoietic stem
BMP: Varies, cells, marrow defect,
depends on the
ALL, CLL defect of production, BMP: Hypocellularity
and cellular and
types of leukemia humoral immune
suppression
Lichtman M. A., Beutler E., Shigsohn U., et al. Williams Hematology. 7th ed. New York: Mc-Graw Hill Medical: 2007.
 Blood Loss
Blood loss >
20-30% of
blood volume

Anemia clinical Increase of

manifestation mortality

Cardiovascular Blood loss >

collapse 50%

Lichtman M. A., Beutler E., Shigsohn U., et al. Williams Hematology. 7th ed. New York: Mc-Graw Hill Medical: 2007.
 Treatment of Anemia Given based on definitive
diagnosis

Transfusion Supplementation

B12 1000-2000 mcg oral daily or

Hb < 8 g/dL injection 1000 mcg within 3-7 days
interval
Blood type, ABO group and RhD
Folic acid 5 – 15 mg/ day
(incompatibility tests)

Whole blood, PRC, leuco depleted red Iron supplement 150-200 mg daily orally,
cells, washed RBC1,2,3 200 mg iron within 10 mins (IV)1,4

1. Longo. D. L. Harrison’s Hematology and Oncology. New York: Mc-Graw Hill: 2010. P 76-81.
2. Weinstein R. 2012 Clinical Practice Guide on Red Blood Cell Tranfusion. Massachusetts: 2012. P 1-4.
3. WHO. The Clinical Use of Blood Handbook. Geneva: World Health Organization Blood Transfusion Safety: 2001. P 23-77.
4. Lichtman M. A., Beutler E., Shigsohn U., et al. Williams Hematology. 7th ed. New York: Mc-Graw Hill Medical: 2007.
 Treatment of Anemia
EPO Immunosuppressant

Darbapoietein alfa 0, 45 ug/ kg IV weekly Corticosteroid (glucocorticoid) in AIHA warm

(CKD) type: Prednisone 1-1.5 mg/kg daily

Epoietin alfa 50 – 150 unit/ kg weekly (CKD) Rituximab (cold type AIHA)

Epoietin alfa 20000-40000 u weekly SC Antilymphocyte Globulin (ATG) 15-40 mg/kg

(MDS)1 daily in 4-10 days (aplastic anemia)3,4,5

Epoietin alfa 150 u/kg 3 times weekly SC in

4 weeks (Hematology or non hematology
malignancy)2
1. Kasper D. L., Fauci A. S., Longo D., et al. Harrison’s Principles of Internal Medicine. 16 th ed. New York: Mc-Graw Hill: 2005. P 1658-1659
2. National Comprehensive Cancer Network. Myelodysplastic Syndromes. NCCN: 2016. P 23-24.
3. Zanella A., Barecellini W. Treatment of autoimmune hemolytic anemias. Hematologica. 2014: 99(10): 1547-54.
4. Lichtman M. A., Beutler E., Shigsohn U., et al. Williams Hematology. 7 th ed. New York: Mc-Graw Hill Medical: 2007.
5. DeLoughery T. G. Autoimmune Hemolytic Anemia. Hematology. Vol 8. Wayne: Turner White Communications: 2013. P 1 – 11.
Conclusion
Approach: physical
exam, reticulocyte
Anemia is decrease of index, morphologic
red blood cells approach,
physiological,
probability approach

Etiology: Nutrition
Deficiency, Chronic Treatment: Transfusion,
disease, Hemolytic supplementation, EPO,
anemia, Production of immunosuppressant
erythrocyte, Blood loss