PENDAHULUAN ANAEMIA

Prof. dr. C Suharti PhD SpPD-KHOM, FINASIM

INTRODUCTION
Definition of anemia:
Anaemia is defined as a reduced haemoglobin level in the
peripheral blood.
The principal effect is decreased oxygen-carrying capacity of the
blood.
Mild Hb 10-12 g/dl (M)
Hb 9-11 g/dl (F)
Moderate Hb 8-10 g/dl (M)
Hb 7-9g/dl (F)
Severe Hb concentrations are below this level
Normal Hb: 13.5-17.5 g/dl (M)
11.5-15.5 g/dl (F)
Normal Blood Count: adult values
Hb 13.5-17.5 g/dl (M); 11.5-15.5 g/dl (F)
RBC 4.5-6.5 x 1012/l (M); 3.9-5.6 x 1012/l (F)
PCV (haematocrit) 40-52% (M); 36-48% (F)
MCV 80-95 fl
MCH 27-34 pg
MCHC 30-35g/dl
Reticulocytes 0.5-2.0%
Platelets 150-400x109/l
WBC (total) 4.0-11.0 x109/l
Neutrophils 2.5-7.5 x109/l
Lymphocytes 1.5-3.5 x109/l
Monocytes 0.2-0.8 x109/l
Eosinophils 0.04-0.44 x109/l
Basophils 0.01-0.1 x109/l
• Hct, Hb, RBC: determine degree of anemia
• Red cell indices (MCV, MCH, MCHC): determine normocytic,
macrocytic, microcytic, normochromic, hypochromic.
• RDW: measure aniscytosis.
• Reticulocyte count or index: estimate marrow response
• Blood film: determine red cell shape, Hb content, red cell inclusion,
abnormalities white cells and platelet.

Hct, hematocrit; Hb, hemoglobin, RBC, red blood cell; RDW, red cell distribution width
Classification of Anemia

MCV: mean corpuscular volume (fl) – equal 10-15L

▪ Microcytic anemia: MCV <80fl

▪ Normocytic anemia: MCV 80-95fl
▪ Macrocytic anemia: MCV >95-100fl
 Normal hematopoiesis
Production Erythrocytes
(Erythropoiesis)
▪ Life span: 100-120 d
▪ Occurs in the bone marrow
▪ Stimulated by hormone EPO
(erythropoietin) released by the
kidney, in response to reduced
oxygen level
▪ Daily replacement 0.8-1% of
circulating RBCs
▪ Erythrpoiesis can increase 4-5 fold
when necessary, if iron level or
nutrition are adequate.
Factors affect RBC size

▪ Immature RBC (Reticulocyte): larger

▪ Microcytic anemia:
o red cell size decreased due to reduced Hb
o less haem (I.e.iron) or imbalance in globin chain synthesis (Thalassaemia)

▪ Maturation disorder during erythropoiesis result in microcytosis if the

cytoplasma is affected, or macrocytosis if defects of nuclear maturation occur.
Microcytic Anemia
MICROCYTIC ANAEMIA
▪ MCV <80fl in person confirmed anemia.
▪ The main causes:
1. Iron deficiency (blood loss, dietary deficiency, malabsorbtion)
2. Hemoglobinopathies (e.g. Thalassaemia)
3. Sideroblastic anaemia (rare genetic or acquired disorders)
4. Anaemia of chronic disease (also associated with normocytc)
Hemoglobin
The causes of a hypochromic, microcytic anaemia. These include lack of iron (iron
deficiency) or of iron release from macrophages to serum (anemia of chronic
inflammation or malignancy), failure of protoporphyrin synthesis (sideroblastic
anaemia) or of globin synthesis (α- or β- thalassemia)
Investigating of the cause of microcytic anemia

• Menorrhagia
• GI bleeding: oesophagitis, oesophageal varices, ulcerated hernia,
peptic ulcer, IBD (inflammatory bowel disease), malignancy,
angiodysplasia
• Malabsorbtion: coeliac disease, atrophic, Helicobacter pylory
infection
• Pharmacological: NSAID/non-steroid anti-inflammatory drugs,
corticosteroids (cause gastritis erosions/ulceration), anticoagulants,
antiplatelets.
• Pregnancy (increase demand)

Coeliac disease: autoimmune disorders –small intestine –genetically predisposed (gluten

Patients with chronic disease

Many long-term conditions associated with inflammation can cause

normocytic anemia, which progress to microcytic anemia:
▪ Chronic inflammation: chronic infections, autoimmune conditions (e.g.
rheumatoid arthritis, SLE, inflammatory bowel disease, malignancy
▪ Chronic heart failure
▪ Chronic kidney disease

In chronic inflammation, inflammatory cytokines inhibit iron transport by blocking

iron from leaving macrophages and other cells for iron trafficking→ fungctional
iron deficiency. Inflammatory cytokines also suppress EPO secretion.
Iron Defficiency Anemia
Symptoms of Anemia

• Symptoms of anemia depend on how rapidly the condition has

developed.

• Patients who have had an acute bleed are more likely to be

symptomatic (have not time to compensate for the reduce Hb levels)
Signs and Symptoms of Anemia

▪ Cardiovascular Exertional dyspnea, tachycardia, palpitations,

and Respiratory orthopnea, angina.
cardiomegaly, murmurs, vascular bruits,
↑respiratory rate.
▪ Neurologic Headaches, tinnitus, dizziness, faintness, loss of
concentration, fatigue, cold sensitivity.
▪ Skin Pallor of skin, mucous membranes, nailbeds, and
palms.
▪ Gastrointestina Anorexia, nausea, constipation, diarrhea.
l
▪ Genitourinary Menstrual irregularity, amenorrhea,
menorrhagia, loss of libido or potency.
Physical Examination

• Pallor
• Smooth red tongue, stomatitis
• Angular cheilitis
Rare findings limited to severe chronic deficiency:
• Koilonichia
Laboratory Changes

Red blood cells:

• Anisocytosis, ↑ RDW (red cell distribution width)
• Mild ovalocytosis, target cells
• Hypochromia (low MCHC), microcytosis (low MCV)
• Reticulocyte N or ↓
Platelets:
• Thrombocytosis or thrombocytopenia

RDW, measures variation in RBC size (anisocytosis) or RBC volume

The Differentiation

Iron Deficiency Anemia of Chronic Haemoglobinopathies

Disease (thalasaemia,
sideroblastic anemia)
Serum ferritin Decreased Increased Increased
Serum iron Decreased Normal or decreased Normal or increased
TIBC Normal or increased Normal or decreased Normal
Transferrin saturation Decreased Normal or decreased Normal or increased
Serum soluble Increased Normal or decreased Increased
transferrin receptor
Serum Ferritin
• Serum ferritin: iron storage protein that keeps iron in soluble and
non-toxic form.
• sFerritin reflects true iron stores (uncomplicated iron deficiency)
• Ferritin is an acute phase protein, can be raised by inflammation,
infection, chronic disease and malignancy
• Ferritin is stored in the liver: liver disease or inflammation may result
in elevated levels.
The differentiation anemia in people with normal and raised
ferritin
Serum iron levels (SI) Decreased: in IDA and in Inflammation
acute/chronic
Elevated: in thalassaemia and sideroblastic
anemia
SI may be affected by recent diet
→ SI levels give an idea the dynamic iron
transport rather than iron stores
Total iron binding capacity A measure of the maximum amount of iron the
(TIBC) blood can carry. In IDA: TIBC normal or
increased. Because transferrin is a negative
acute phase protein, generally decreased with
chronic inflammation. TIBC unchanged in
thalassaemia and sideroblastic anemia

IDA, iron deficiency anemia; Transferrin, transport iron in blood

 The differentiation anemia in people with normal and raised
ferritin
Transferrin Calculated from SI/TIBC give a measure of iron trafficking
saturation and availability for erythropoiesis. It is not a measure of iron
stores. In IDA and chronic inflammation: normal or reduced
Serum soluble A measure of erythropoietic activity, related to the number
transferrin receptor of erythroblast in BM. Less affected by inflammation than
serum ferritin.
Elevated: chronic hemolysis, IDA, ineffective erythropoiesis
(thalassaemia, myelodysplastic syndrome)
Other indices of FBC Reduced MCH (mean cell Hb), hypochromia (decreased Hb
and blood film concentration in RBC, increased RDW (variation in cell size),
irregularity shaped cells (poikilocytosis), and reduced MCHC
(mean cell Hb concentration)

IDA, iron deficiency anemia; BM, bone marrow; FBC; RBC red blood cell;
Developmental Stages of Iron Deficiency

Iron depletion ▪ storage iron decreased or absent

Iron deficiency ▪ storage iron decreased or absent

▪ low serum iron
▪ low transferrin saturation

Iron-deficiency anemia ▪ storage iron decreased or absent

▪ low serum iron
▪ low transferrin saturation
▪ low hemoglobin level
The development of iron deficiency anaemia. Reticuloendothelial
(macrophage) stores are lost completely before anaemia develops. MCH,
mean corpuscular haemoglobin; MCV, mean corpuscular volume
Laboratory Changes

Serum Ferritin:
• Levels < 10 μg/L, characteristic of IDA
• Levels 10 to 20 μg/L: presumptive (not diagnostic)
• May be ↑with concomitant inflammatory disease (e.g., rheumatoid
arthritis), chronic renal disease, malignancy, hepatitis, or iron
administration.
• IDA can be suspected in RA or other severe inflammatory states if the
ferritin < 60 μg/L.

IDA, iron deficiency anemia; RA, rheumatoid arthritis

Blood Count in Iron Deficiency: example

Hb 7.5 g/dl
RBC 4.05 x 1012/l
PCV 26%
MCV 64 fl
MCH 18.5 pg
Reticulocytes 2.6%
WBC 7.5x109/l
differential Normal
Platelets 530x109/l
Red cells (iron deficiency anaemia)
hypochromic, microcytic
Poikilocytes : pencil cells (A)

A
A
Red cells (Iron deficiency anaemia):
hypochromic, microcytic
target cells (A), pencil cells (B)

A
Diagnosis

• Diagnosis: Hb, MCV, MCH, Blood film (cell pencil), Ferritin, sTfR
• If the diagnosis is established, search for a source of blood loss if
unapparent
• GI loss is the most prevalent of blood loss in men, uterine/menstrual
loss in women.

GI, gastrointestinal
Differential Diagnosis

• Iron Defisiency vs
• Thalassaemia vs
• Anemia of Chronic Disease
Management Microcytic Anemia

• Review and correct any dietary factorst

• Oral iron supplementation:
o Failure to respond to treatment: ongoing iron loss? (GI tract investigation)
o Taken on empty stomach
o GI irritation can occur: nausea, epigastric pain, constipation or diarroea
o Hb should be checked periodically
• Parenteral iron supplementation: patients who are unable to tolerate
oral iron supplementation and patients with malabsorption
• 150-200 mg elemental iron in 3 to 4 doses, 1 hour before meals (65
mg of elemental iron is contained in 325mg of ferrous sulfate)
• Do not give with meals or antacids or with inhibitors of acid
production.
• A few patients may complain of GI intolerance to pills, pyrosis,
constipation, diarrhea, and/or metalic taste and require ↓ daily dose,
change of oral iron preparation.
Elemental Iron Content of Different Oral Iron
Formulation
Iron salt Dose Elemental iron content
Ferrous Fumarate 200mg 65mg
Ferrous sulfate (tablet) 325mg 105mg
Ferrous sulfate (liquid) 150mg (in 5ml) 30mg (in 5ml)
Length of Treatment

• To replenish iron stores, continue oral therapy for 12 months after Hb

levels is normal
• Therapy may be needed indefinitely if bleeding continues.
Parenteral Iron Therapy

Indications:
• Malabsorbtion
• Intolerance to oral preparations (colitis, gastritis)
Iron dextran, Iron sucrose
 Thalassaemia
Hemoglobin
▪ A group of genetic disorders,
characterized by
hypochromic microcytic red
cells and ineffective
erythropoiesis.

▪ Caused by imbalance in the

synthesis of alpha and beta
globin chain.
Thalassaemia
Alpha Thalassaemia
• Deletion of alpha globin genes (4 genes)
• Deletion single gene (silent alpha
thalassaemia): mild decrease MCV (still
be in reference range), usually not
anemia
• Deletion 2 genes (alpha thalassaemia
trait): microcytosis (MCV 65-78),
hypochromia, mild anemia.
• Deletion 3 genes (HbH disease): anemia,
severe microcytosis, require intermittent
blood transfusion
• Deletion 4 genes (all): fetal hydrops
• Alpha thalassaemia: Indian, SEA, North
Africa , Middle East and Pacific people.
Beta Thalassaemia
• Mutation in the beta genes (2 genes)
• The severity of disease depends on
number and nature of the mutations
• Single mutated gene (Beta thal. Minor or
trait); mild anemia, marked hypochromic
microcytic (MCV 60-75fl)
• Mutation 2 genes (Beta thal. major):
severe transfusion dependent anemia.
• Beta globin synthesis starts around the
time of birth → become apparent during
the first year of life
• Beta thal: Mediterranean ethnicities,
lesser: Chinese, Asians and African
Americans
Sideroblastic Anemia
• Mixed group: inherited and acquired disorders
• Cause: poor iron incorporation into haem
• Dimorphic blood film: normochromic normocytic and hypochromic
microcytic
• Sideroblastic anemia: relatively rare, most commonly due to
myelodysplasia
• Other causes: excessive alcohol consumption, heavy metal poisoning (lead,
zinc), medicine (isoniazid, chloramphenicol) and cooper deficiency.
• Congenital form: rare
• Definitive diagnosis: bone marrow aspirate (BMA)→ ring sideroblast
Normocytic Anemia
Normocytic Anemia

• Normal MCV (80-95fl) in person with anemia

• The primary causes:
o Acute blood loss
o Hemolysis
o Early stage nutrient deficiency before micro or macrocytic anemia develops (e.g.
iron, folate, vitamin B12)
o Kidney disease
o Chronic disease
o Bone marrow disorders
 Investigating the cause

• Acute blood loss: obvious

• Significant hemolysis: jaundice and/or discoloration of the urine
→ Both conditions require emergency referral (rarely present
asymptomatic)
• Reticulocyte count: lowered in marrow disorders (decrease RBC
production), and increased (blood loss or hemolysis/destroyed
(normal level: 1-2%)
• Liver function tests, serum creatinine and CRP: provide information
to identify underlying conditions

CRP, C reactive
Macrocytic Anemia
Macrocytic Anemia

• Macrocytic anemia: MCV >95-100fl in a person with anemia.

• Macrocytic occur due to abnormalities in erythropoiesis, defect in DNA synthesis,
change in the structure of cell membrane, alterations in cell fluid volume
• Macrocytic anemia:
1. Anemia megaloblastic
2. Anemia non-megaloblastic
Megaloblastic Anemia

Megaloblastic anemia is characterized:

o RBC larger than normal, with nuclei less mature than their surrounding cytoplasm
→ due to DNA synthesis is defective and slower than the rate of development of
the rest of the cell.
o Hypersegmented nuclei (≥6 lobes)
Causes: vitamin B12 or folate deficiency
Non-Megaloblastic anemia:
DNA synthesis is not affected. Causes: alcohol, liver disease,
myelodysplasia.
Vitamin B12 (Cobalamin)

• Found in food of animal origin: liver, meat, fish

• Absorbtion: distal ileum
• Vit B12 – glycoprotein IF (synthesized by gastric parietal cells) →
bind to cubilin (receptor for IF) → direct endocytosis the cubilin IF-
B12 complex in the distal ileum, where B12 is absorbed and IF
destroyed.
• Transport: transcobalamins, which delivers B12 to BM

BM, bone marrow, IF, intrinsic

factor
 Causes of severe vitamin B12 deficiency

Nutritional
▪ Vegan
▪ Malabsorption
▪ Congenital lack or abnormality of intrinsic factor (IF)
▪ Total or partial gastrectomy
Intestinal causes
▪ Ileal resection
▪ Crohn’s disease
Crohn’s disease: chronic inflammatory of GI tract
Causes of Folate Deficiency

• Nutritional • Inflammatory disease:

• Old age o Crohn’s disease
• Proverty o TBC
• Malabsorbtion o Rheumatoid arthritis
• Pregnancy, lactation, o Psoriasis
• Hemolytic anemias o Exfoliative dermatitis
• Myelofibrosis • Malignant disease:
• Liver disease o Carcinoma
o Myeloma
o Lymphoma
The absorption of dietary vitamin B12
after combination with intrinsic factor
(IF), through the ileum.

Folate absorption occurs through the

duodenum and jejunum after
conversion of all dietary forms to
methyltethrahydrofolate (methyl THF).
TC, transcobalamin.
Clinical Features of Megaloblastic Anemia

• Signs of anemia
• Jaundice (mild) → the excess breakdown Hb (ineffective
erythropoiesis in BM)
• Glossitis, angular stomatitis
• Mild symptoms of malabsorbtion (loss of weight)
• Purpura (thrombocytopenia)
• Many asymptomatic patients are diagnosed when a blood count
has been perormed for another reason (reveal macrocytosis).
Vitamin B12 neuropathy

• Severe B12 deficiency cause a progressive neuropathy

• Neuropathy is symetrical (lower limbs more than upper limbs)
• Symptoms: tingling, difficulty in walking and may fall over in the
dark.
Neural Tube Deffect

Folate or B12 deficiency in the mother predisposes to neural tube

defect (NTD):
oAnencephaly
oSpina bifida
oEncephalocele (in the fetus)
Treatment
Vit. B12 deficiency Folate deficiency
Compound Hydroxycobalamin Folic acid
Route Intramuscular Oral
Dose 1.000 ug 5mg
Initial 6x 1.000ug over 2-3 weeks Daily for 4 month
Maintenance 1.000 ug every 3 months Life long therapy in: chronic
inherited hemolytic
anemias, myelofibrosis,
renal dialysis
Prophylactic Total gastrectomy Pregnancy, severe hemolytic
Ileal resection anemias, dialysis,
prematurity.
THANK YOU
Some of the more frequent variations in size (anisocytosis) and shape (poikilocytosis) that may be
found in different anaemias. DIC, disseminated intravascular coagulopathy; G6PD, glucose-6-phosphate
dehydrogenase; HUS, haemolytic uraemic syndrome; TTP, thrombotic thrombocytopenic purpura.
Tatap Muka Modul 3.2
Sistem Hematologi
Semester Gasal Tahun 2017/2018
Pokok Bahasan
▪ Pengantar Modul (PK)
▪ Defisiensi vitamin dan mineral (Gizi)
▪ Pendahuluan Anemia (IPD)
▪ Anemia Defisiensi (PK)
▪ Anemia Aplastik (PK)
▪ Anemia akibat infeksi Parasit
(Parasit)
▪ Imunopatologi bacterial
(Mikrobiologi)
▪ Anemia pada anak (IKA)
▪ Aspek klinik perdarahan (IPD)
▪ Anemia Hemolitik (PK)
▪ Hematinik/Koagulan (Farmasi)
▪ Lekemia (PK)
▪ Hemostasis dan Fibrinolisis (PK)
▪ Aspek laboratorium transfuse darah
(PK)
▪ Imunopatologi viral
▪ Aspek klinik Transfusi darah
▪ Filariasis
▪ Bakteremia dan sepsis pada anak
▪ Infeksi viral (Demam dengue, DHF,
DSS)