1. 1. Anemia Dlm Tinjauan Pk Kuliah Ums

Anemia dalam tinjauan patologi klinik

Dr Niniek Yusida SpPK MSc

Partners in Global Health Education

| the erythrocyte: an overview Contents page

2.1

*L.O. Link the components of red cell structure to red cell development and function

Image: scanning electron microscope of red blood cell

To achieve these functions the red cell has several unique properties….

Strength: it has a strong but flexible membrane able to withstand the recurrent shear forces involved in the circulation of blood.

Flexibility: the red cell is 7.8 m across and 1.7 m thick and yet it is able to fit through capillaries of only 5 m diameter. This is in-part due to the flexible membrane and shedding of the nucleus.

Biconcave shape: increases surface area available for gaseous exchange.

Haemoglobin content: unique to the red cell, it is this metaloprotein molecule which is pivotal in red cell development and Oxygen transport due to its affinity for O2.

Function The primary function of the erythrocyte is the carriage of oxygen from the lungs to the tissues and CO2 from the tissues to the lungs. The red cell also plays an important role in pH buffering of the blood.

Lifespan: Because the fully developed red blood cell has no nucleus the cell cannot divide or repair itself. The lifespan is therefore relatively short (120 days).

START HERE

FINISH HERE

http://www.medicine.swan.ac.uk/inthealth.html



Kidney

Bone marrow

Red blood cells in circulationerythropoietin

Stem cells

Erythroid precursors

An erythrocyte is a fully developed, mature red blood cell. The adult human makes approximately 1012 new erythrocytes every day by the process of erythropoiesis. This is a complex process that occurs within the bone marrow. Before an erythrocyte arrives fully functioning into the blood stream it must develop from a stem cell through an important number of stages. This module has simplified this process and highlights the key stages. Follow the numbered red boxes through to the end before continuing to the next slide.

As with much human physiology, this system works via a feedback mechanism.

4. There is no store of EPO. The production of erythropoietin is triggered by tissue hypoxia (oxygen tension sensed within the tubules of the kidney) and stops when oxygen levels are normal.

| Erythropoiesis Contents page

2.1. The erythrocyte: an overview.2.2. Erythropoiesis

2.2

2. EPO stimulates stem cells within the bone marrow which differentiate into erythroid precursors.

3. EPO continues to stimulate primitive erythroid cells (red blood cells) in the bone marrow and induce maturation.

1: Erythropoietin (EPO), a growth factor, is synthesized primarily (90%) from peritubular cells of the kidneys (renal cortex).

Macrophages surround and supply iron to these erythroprogenitor cells that become erythroblastic islands.

START HERE FINISH HERE

• List the key components of erythropoiesis (red cell production)LO




|Red cell precursors and the sequence of erythropoiesis Contents page

2.1. The erythrocyte: an overview.2.2. Erythropoiesis

2.2

Anaemia of chronic disease.

In individuals living with a chronic disease (e.g. rheumatoid arthritis),a complex interaction of inflammatory cytokines interferes with the red cell lifecycle by impairing iron metabolism and inhibiting red cell precursors. The end result is a normocytic anaemia.

Reticulocytes are an important cell in haematology as they increase in number following a haemorrhage, haemolytic anaemia or from treatment of a haematinic deficiency. They provide an excellent measure of red cell production and the age of the red cell population. In normal blood there is usually about 1 reticulocyte : 100 erythrocytes.

Key point!

Key

poin

t!

marrow

3.5 Erythrocyte: after 1 week the mature erythrocyte emerges with no organelles and high haemoglobin content. Sequence: amplification and

maturation of the erythrocyte

Pronormoblast: This is the earliest and largest cell with a large nucleus and no haemoglobin.

3.4. Reticulocytes: Considered the “teenagers” of the the life cycle! This is the FINAL stage of development before full maturation. These cells are now anucleate and contain roughly 25% of the final haemoglobin total. They reside mostly in the marrow but in healthy individuals a small number can be found in the peripheral blood. They contain some cell organelles.

Normoblasts: these cells go through a large number of progressive changes. Fundamentally they reduce in cell size but increase the haemoglobin concentration in the cytoplasm. The nucleus proportionally decreases until it is extruded before the cell is released in to the blood.

blood




|haematinics

Vitamin B12 (cobalamin) and folate (pteroylglutamic acid):

These are key building blocks for DNA synthesis and essential for cell mitosis. DNA synthesis is reduced in all cells that are deficient in either folate or vitamin B12. The bone marrow is the factory for blood cell production. In haematinic deficiency, DNA replication is limited and hence the number of possible cell divisions is reduced leading to larger red cells being discharged into the blood i.e. less DNA, less divisions and larger cells. This leads to enlarged, misshapen cells or megaloblasts in the marrow and macrocytic red cells in the blood.

• So what exactly are the haematinics? These are the key micronutrients that must be present if a red blood cell and its haemogoblin are to develop in a normal fashion.

• These major micronutrients, provided in a balanced diet, are iron, vitamin B12 and folate

• A deficiency in any one of these micronutrients can result in anaemia through impaired red cell production within the bone marrow

• Assessing haematinic status is key to the investigation of the cause of anaemiahaemoglobin deficiency;Click here see all key causes.

iron life cycle;Click here to see the key stages

Iron:

At the centre of the haem molecule is an atom of iron which binds oxygen in a reversible manner. Haemoglobin concentration in the developing red cell is a rate limiting step for erythropoiesis. In iron deficiency, red cells undergo more divisions than normal and, as a result, are smaller (microcytic) and have a reduced haemoglobin content (hypochromic). Iron deficiency is the leading cause of anaemia worldwide.

Click here to see a schematic diagram of vitamin B12 absorption

2.4

Contents page

2.1. The erythrocyte: an overview.2.2. Erythropoiesis2.3. The red cell membrane2.4 Haematinics

Erthropoiesis is also regulated by the availability of haematinics

“Check the haematinics” this is a phrase used frequently on the hospital ward!




|haematinics in haemoglobin

Iron Protoporphyrin

GlobinHaem

Haemoglobin

Thalassaemia

• Iron deficiency• Chronic

inflammation• Malignancy

Click here to return

Chronic infections and inflammatory disorders cause chronic anaemia as a result of;1. slightly shortened red blood cell life span 2. sequestration of iron in inflammatory cells called macrophages

Both procedures result in a decrease in the amount of iron available to make red blood cells.

2.4




|haematinics: the normal iron cycle


2.4

Iron deficiency can be identified best by assessing the appearances of the red cells on a blood film. Iron indices in a blood sample are helpful to confirm a lack of iron. In order to interpret these indices, it is vital to understand how the body handles iron …..

Erythroid bone marrow (normoblasts) Reticuloendothelial system;

Spleen & macrophages

Duodenum

Serum transferrin

Fe

Red blood cells

Liver

Iron is a key constituent of haemoglobin (60-70% of total body iron is stored here) and it’s availability is essential for erythropoiesis. In iron deficiency, there are more divisions of red cells during erythropoiesis than normal. As a result the red cells are smaller (microcytic) and have a reduced haemoglobin content (hypochromic).

2. Iron is then attached to a protein, transferrin in the serum (plasma), where it is transported to the bone marrow for haemoglobin synthesis.

1. Iron is absorbed from the small intestine in the ferrous state (Fe2+; approx. 1mg/day).

3. Dying red cells are recycled by macrophages in the spleen and iron is recycled into the plasma for further use.

Soluble transferrin receptors, sTfR are on the red cell surface. These can be measured and are increased in iron deficiency.

An iron deficiency profile.

Serum Iron: Reduced

Serum total iron-binding capacity (TIBC): Increased- the body works hard to bind free iron.

Serum ferritin:Reduced-since iron stores are low

Serum soluble transferrin receptors:Increased-since red cells attempt to absorb more iron.

In iron deficient states, bone marrow iron is reduced.

START

Some iron binds to apoferritin to form ferritin, a storage compound.




There are a number of key steps in the absorption of Vitamin B12. The two key locations are the stomach and the terminal ilium. Dietary vitamin B12 binds with intrinsic factor (IF) in the stomach, a transport protein produced by gastric parietal cells. The B12-IF complex then travels through the small intestine and is absorbed by special receptors in the distal ileum. This pathway is important when considering possible causes of Vitamin B12 deficiency.

Vitamin B12 deficiency can take up to two years to develop as the body has sufficient stores for this period.

Distal ileum

Site of B12 absorption

Oesophagus

StomachIF Intrinsic factor

Vitamin B12 ingested

|haematinics: vitamin B12

Pernicious anaemia: the leading cause of B12 deficiency. IgG autoantibodies target gastric parietal cells and its product IF causing an atrophic gastritis. This results in reduced secretion of intrinsic factor and therefore reduced B12-IF complex for absorption in the distal ileum.

2.4


Causes of vitamin B12 deficiency

1. Pernicious anaemia

2. Inadequate intake

3. Poor absorption




What exactly is anaemia?

Anaemia is defined as haemoglobin concentration less than the normal reference range. Reference ranges differ according to age, sex and altitude. However, in general, anaemia is defined as Hb concentration

For adult males < 13.5 g/dl For adult women < 11.5 g/dl

As well as reduced [Hb], anaemia is usually accompanied by a reduction in the number of red cells (red cell count) and packed cell volume (PCV). However this is not always the case. Red cell count and PCV may be normal in some patients with lower than normal haemoglobin levels (and hence anaemic). The total circulating haemoglobin concentration is therefore determined by….

• the circulating plasma volume • the total circulating haemoglobin mass.

The following circumstances should therefore be taken in to consideration……

Welcome to section 2! | defining anaemia

| Dehydration |

Reduced plasma volume may mask anaemia.

| Pregnancy or splenomegaly |

These can produce an increase in plasma volume reducing the apparent haemoglobin concentration even though circulating haemoglobin levels are normal.

| Acute significant blood loss |

Following acute blood loss it may take up to a day for the plasma volume to be replaced and anaemia to present. Therefore, clinical features of shock and reduced blood volume may occur before a fall in haemoglobin concentration.

Contents1. 1Introduction 1.2 use this module1.3 Learning outcomes 2.1. The erythrocyte2.2. Erythropoiesis2.3. Red cell membrane2.4. Haematinics2.5. Red cell metabolism2.6. Haemoglobin2.7. Ageing and death

Quiz 1 3.0. Defining anaemia.3.1. Prevalence3.1. Clinical features

Quiz 2 4.0. Classifying anaemia 4.1. red cell indices.4.2. Morphological

classification4.3. Aetiological

classification

5.0. Blood film: a basic

interpretation.

Quiz 3.

6.0. Glossary

7.0. References

please click on contents to repeat a section.





classification


interpretation.5.1. Anaemia cardsQuiz 3.

6.0. Glossary

7.0. References





|clinical features of anaemia

1. The cardiovascular system

Cardiac compensation is the major adaptation. Both stroke volume and heart rate increase mobilizing greater volumes of oxygenated blood to the tissues. This can present with palpitations, tachycardia and heart murmurs. Dyspnoea which occurs in severely anaemic patients may be a sign of cardio-respiratory failure.





classification


interpretation.

Quiz 3.

6.0. Glossary

7.0. References


Tissue hypoxia is the end result of the blood’s reduced oxygen carrying capacity. The compensatory mechanisms in response to hypoxia cause the clinical manifestations to develop.

An anaemic individual will have the following two key compensatory mechanisms;

2. The skin

A common sign is generalised pallor due primarily to vasoconstriction with redistribution of blood to key areas (brain, myocardium).




| clinical features of anaemiaGeneral symptoms and signs





classification


interpretation.

Quiz 3.

6.0. Glossary

7.0. References


General Symptoms

Weakness and lethargy

Shortness of breath: particularly on exercise.

Headaches

Palpitations

Confusion and symptoms of cardiac failure in elderly

Some specific signs

Click images for explanation of signs!

General Signs




| clinical features of anaemiaThis is a list of general symptoms and signs; we will cover more specific clinical features as we progress through the module.

Signs:

Pallor of mucous membranes (most common sign). This is a general sign.

Beware: pallor is quite subjective and NOT a reliable clinical sign. Be careful not to exclude anaemia on the basis of absence of pallor alone

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Signs:

Nail bed; demonstrating koilonychia (spoon-shaped nails). This is specific to iron deficiency.

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Signs

Atrophic glossitis; red large swollen tongue. This is seen in both vitamin B12 and folate deficiency.

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Signs

Angular stomitis; fissuring at corners of mouth. This is seen in both vitamin B12 and folate deficiency.

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Signs

Dysphagia: pharyngeal web (Paterson-Kelly syndrome). This occurs in iron deficiency.

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Signs

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Peripheral oedema. A general sign.





Signs

High flow murmur, bounding pulse and/or tachycardia: All features of a compensatory hyperdynamic circulation. These are general signs!

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Welcome to section 3!|classification of anaemia

Essentially there are two ways to classify anaemia, by red cell size (morphological classification) or by cause (aetiological classification). Both have their purpose and both need to be fully understood to gain a rounded understanding of anaemia.

Morphological classification

This is a practical and clinically useful classification for establishing a differential diagnosis of anaemia.

It is done by examining red cells in a blood stained smear and by automated measurements of red cell indices

Aetiological classification

This classification is based on cause and illuminates the pathological process underlying anaemia.

*Key point: In order to understand this classification it is essential to understand red cell indices reported in the full blood count (FBC). There is great reward in understanding these indices as they enable one to identify some of the underlying processes leading to anaemia and, importantly, help to formulate a differential diagnoses.





classification


interpretation.

Quiz 3.

6.0. Glossary

7.0. References





MCV: Mean cell volume; the average volume of the red cells. MCV does not provide an indicator of either haemoglobin concentration within the cells, or the number of red cells. It enables us to categorize red cells into the following;

Microcytic (MCV <80fL) a small red blood cell. Normocytic(MCV of 80-99fL) a normal size red blood cell. Macrocytic (MCV > 99fL) a large red blood cell.

This is a key index that is used daily in medical settings across the world to categorize the type of anaemia present.

It is reliable in most cases; one exception is when two pathologies occur at the same time such as vitamin B12 and Iron deficiency. MCV reports average cell volume; further assessment of cell size and how this varies within an individual can be ascertained from the red cell distribution width (RDW; see below).

MCH: Mean corpuscular haemoglobin ( normal range 26.7-32.5pg/cell): the average haemoglobin content of red blood cells. Cells with a reduced haemoglobin content are termed hypochromic and those with a normal level are termed normochromic (see below).

|red cell indices

RDW: Red cell distribution width; an index of the variation in sizes of the red cell population within an indiviual. This will be raised if two red cell populations are present. Occasionally useful if there is doubt about multiple causes of anaemia. A common cause for an increased RDW is the presence of reticulocytes.

Normochromic implies normal staining of the cells in a thin blood film. The central area of pallor is normally about 1/3 of the cell diameter

Hypochromic indicates reduced staining with increase in the central area of pallor

These are the key measures of red cell indices. They relate to the haemoglobin content and size of the red blood cells.




|interpretation of red cell indices

Microcytosis & hypochromia Normocytosis & normochromia

Microcyticabnormally small red blood cells. Microcytic anemia is not caused by reduced DNA synthesis. It is not fully understood but is believed to be due reduced erythroid regeneration.

Hypochromichypochromic cells due to a failure of haemoglobin synthesis.

Pathologies;• Iron deficiency; iron is an

essential building block of haem.

• Failure of globin synthesis; this occurs in the thalassemia's.

• Crystallization of haemoglobin: sickle cell disease and haemoglobin C.

NormocyticMany processes causing anaemia do not effect the cell size or haemoglobin concentration within cells.

Normocytic normochromic anaemia develops when there is a decrease in the production of normal red blood cells.

Pathologies;• anemia of chronic disease (some)• aplastic anemia• Haemolysis: a increased destruction

(some)• Hemolysis ;or loss of red blood • pregnancy/fluid overload: an inbalance or

an increase in plasma volume compared to red cell production

Macrocytosis & megaloblastosis

Macrocytic megaloblastic red blood cells have an unusual misshapen appearance, which is due to defective synthesis of DNA. This in turn leads to delayed maturation of the nucleus compared to that of the cytoplasm and the cells have a reduced survival time.

Macrocytosis: The exact cause of the pathological mechanisms behind these large cells is not fully understood.. It is thought to be linked to lipid deposition on the red cell membrane. Alcohol is the most frequent cause of a raised MCV!

Alcohol | Liver disease | hypothyroidism | Hypoxia | cytotoxic drugs | pregnancy |

In clinical practice megaloblastic anaemia is almost always caused by a deficiency of vitamin B12 or folate which are key building blocks in DNA synthesis.

http://en.wikipedia.org/wiki/Blood_plasma




| morphological classification of anaemia

Anaemia type

Red cell indices

Common examples

Microcytichypochromic

MCV < 80 flMCH < 27 pg/L

Iron deficiency

Thalassaemia

Sideroblastic

Normocyticnormochromic

Macrocytic

MCV > 98 fl

Folate deficiency

B12deficiency

normal

Haemolysis

Chronic disease

Marrow infiltration

Megaloblastic



Quiz 2 4.0. Classifying anaemia 4.1. red cell indices.4.2. Morphological classification4.3. Aetiological

classification


interpretation.

Quiz 3.

6.0. Glossary

7.0. References





|aetiological classification of anaemia

This classification is based on cause and illuminates the pathogenic process leading to anaemia.

You can look at anaemia from a production, destruction or pooling point of view.

Reduced Production

Insufficient production: If you consider the bone marrow to be the factory it must have enough raw material (Iron, vitamin B12 and folate) to make new blood cells. These raw material are called haematinics. If there is not enough of the raw material (a deficiency of one or more of the haematinics), then there is insufficient production.

Inefficient production (erythropoiesis): some problem with maturation of the erythroid in the marrow. Occurs in bone marrow infiltration (malignancy/leukaemia), aplastic anaemia or in the macrocytic megaloblastic anaemia.

Destruction

Reduced Cell lifespanThis is either due to loss of red blood cells in a haemorrhage (a bleed) or the excessive destruction of red blood cells in haemolysis. Haemolysis is an important cause of red cell destruction and anaemia.

Pooling: Hypersplenism.





classification


interpretation.

Quiz 3.

6.0. Glossary

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Reduced bone marrow erythroid cells • aplastic anaemia• Leukaemia or

malignancy

|classification of anaemia based on pathology

Loss of red cells due to

bleeding

Increased destruction of

red cells (haemolytic

anaemia

Failure of production of

red cells by the bone marrow

Dilution of red cells by increased

plasma volume (e.g.

hypersplenism)

Nutritional (haematinic) deficiency• Iron• vitamin B12

• folate

Ineffective red cell formation • Chronic inflam.• Thalassaemia• renal disease

immuneNon-immune

• Autoimmune warm

• Autoimmune cold

• Adverse drug reaction

• Haemolytic disease of the newborn

• Malaria• Burns• Mechanical

heart valve• Hypersplenism• PNH

Abnormal red cell membrane

Abnormal haemoglobin

Abnormal red cell metabolism

• Sperocytes

• Elliptocytes

Thalassaemia

• Sickle cell anaemia

• Pyruvate kinase deficiency

• G6PD deficiency

Inherited /inside the cell

Acquired /outside cell

anaemia

|classification of anaemia based on pathology





classification


interpretation.

Quiz 3.

6.0. Glossary

7.0. References





|blood film: a basic interpretationA blood film is an essential investigation in classifying and diagnosing the cause of anaemia. A blood sample (anticoagulated venous sample) is smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells and platelets.

Red blood cells appear paler in the centre of the cell due to their biconcave shape. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe.

Normal red cell Microcytic hypochromic

Macrocyte Target cell Basket case

Elliptocyte Fragments Tear drop poikilocyte Pencil cell

Stomatocyte Sickle cell Spherocyte Acanthocyte

Malarial parasite

Please click on each cell to see the blood film and it’s causes.

Please click here to compare blood films





classification

5.0. Blood film: a basic interpretation.

Quiz 3.

6.0. Glossary

7.0. References




Normal red blood film Microcytic hypochromic Macrocytic megaloblastic Target cells Bite cells

Elliptocyte Fragments Fragments ‘Pencil’ cells Malaria



|anaemia essential bites

R.C.I: a microcytic hypochromic anaemia

Epi: this is the most common cause of anaemia worldwide affecting around 500million daily.

Aet: 1. The most common cause of iron deficient anaemia is BLOOD loss

2. reduced intake (diet)3. Increased demand

(pregnancy)4. Malabsorption (coeliac,

gastrectomy)

IX. FBC, ferritin, serum iron,

TIBC, serum transferrin saturation.

Endoscopy/colonoscopy if suspected blood loss.

Si/Sy. Koilonychia, sore tongue, angular stomatitis, Plummer-Vinson syndrome (dysphagia due to oesophageal web), painless gastritis. Tx. Treat underlying cause, give ferrous sulphate until Hb and MCV

normal (4-6months).

iron deficieny

R.C.I.: a microcytic hypochromic anaemia

Epi: One of the most common autosomal inherited disorders. Common in Mediterranean, Africa and middle east. Gene carriers are protected from p.falciprum malaria.

Path: Reduced beta globin (of haemoglobin) production. Ineffective erythropoiesis and haemolysis

IX. blood film, Hb electropheresis

Si/Sy. Heterozygotes: often asymptomatic, mild anaemia, low MCV.

Homozygote: severe anaemia, failure to thrive in first 6 months of life, splenomegaly, bone hypertrophy (secondary to extramedullary haemopoisis). Tx. For major Thalassaemia treat with repeated blood transfusion and iron chelation.

Β-Thalassaemia


Aet: A group of autosomal recessive genetic disorders due to a haemoglobin chain mutation. Part of the haemoglobinopathies that primarily affect those of African origin (sickel cell trait can afford some protection against malaria.

Path: Abnormal haemoglobin (HbS) undergo a sickling transformation in a deoxygenated state and a permenant conformational change of shape. The red cell looses its ability to deform becoming rigid. This can cause occlusion of small vessels. These crises are precipitated by hypoxia, dehydration, infection and the cold.

IX. Electropherisis, haemoglobin solubility test.

Si/Sy: Bone pain, if chronic haemolysis- jaundice and pigment gallstones. Txt Supportive; analgesia, fluids and antibiotics if required.

Sickle cell disease

Epi:

the most common cause of a

naemia worldwide affecting around

500million daily.

Aet:

pernicious anaemia, malabsorpion,

post total gastrectomy

Ix.

B12MCV platelets. IF

antibodies, folate levels

Si/Sy:

Gradual deterioration, Irritability,

Loss of memory, Painless jaundice,

Loss of sensation , Feeling of pins

and needles in extremities. ataxic Txt

Intramuscular (IM) of 1mg of

hydroxycobalamin (Vitamin B12). There is

no oral form.

Vitamin B12 & Folate deficiencyEpi:

Aet:

increased consumption

(pregnancy), dietary

deficiency, folate antagonist

(drugs eg; methotrexate).

Ix.

folateMCV transferrin

saturation. Endoscopy/

colonoscopy if suspected blood

loss.

Si/Sy:

Gradual deterioration,

Irritability, Loss of memory,

Painless jaundice, Loss of

sensation , Feeling of pins and

needles in extremities. ataxic Txt

Intramuscular (IM) of 1mg of

hydroxycobalamin (Vitamin B12).

There is

no oral form.

Path G6PD is a key enzyme in the hexose monophosphate shunt. An important

funtion of the shunt is maintain a health haemoglobin by removing oxidant

stresses. Wihtout the enzyme, Hb breakdown resulting in haemolytic aneamia.

Aet: X-linked

Ix. Direct assay during haemolysis

Si/Sy: Koilonychia, sore tongue, angular stomatitis, Plummer-

Vinson syndrome (dysphagia due to oesophageal web),

painless gastritis. Rx Avoid precipitants of oxidative stress; drugs (anti-malarials, analgesics), fava beans.

Tx. Blood transfusion if required.

G6PD deficieny

Epi: the most common cause of anaemia worldwide affecting around

500million daily.

Aet: The most common cause of iron deficient anaemia is BLOOD loss

reduced intake (diet)Increased demand (pregnancy)Malabsorption (coeliac, gastrectomy)

Ix. FBC, ferritin, serum iron, TIBC, transferrin

saturation. Endoscopy/colonoscopy if suspected blood

loss.



painless gastritis. Txt Treat underlying cause, give ferrous sulphate until Hb and MCV

normal.

Hereditary spherocytosis;

Microcytic anaemia Macrocytic anaemia Haemolytic anaemias

Epi: the most common cause of anaemia worldwide affecting around

500million daily.

Aet: The most common cause of iron deficient anaemia is BLOOD loss

reduced intake (diet)Increased demand (pregnancy)Malabsorption (coeliac, gastrectomy)

Ix. FBC, ferritin, serum iron, TIBC, transferrin

saturation. Endoscopy/colonoscopy if suspected blood

loss.



painless gastritis. Txt Treat underlying cause, give ferrous sulphate until Hb and MCV

normal.

Aquired Haemolytic anaemias;

KEYR.C.I. Red Cell IndicesEpi. Epidemiology

Aet. Aetiology

Ix. Investigations

Si/Sy. Signs and Symptoms Path. Pathology

Tx. Treatment





classification



6.0. Glossary

7.0. References





|blood film: a basic interpretation

Contents1. 1Introduction 1.2 use this module1.3 Learning outcomes 2.1. The erythrocyte2.2. Erythropoiesis2.3. Red cell structure2.3.1. Cell membrane2.3.2 DNA synthesis2.4. Red cell metabolism2.5.Haemoglobin2.6 O2 dissociation curve 3.0. Defining anaemia.3.1. Prevalence3.2 Clinical features 4.0. Classifying anaemia 4.1. red cell indices4.2. Morphological 4.3 Aetiological classification

5.0 Blood film: a basic interpretation.


6.0. Glossary

7.0. Quiz

A blood film can provide key evidence in diagnosing anaemia. It is therefore is an essential part of all investigations into anaemia. A blood sample (anticoagulated venous sample) will be smeared onto a glass slide, fixed and stained. Red cells are examined along with white cells, granulocyte precursors, blast cells.

Red cells appear paler in their centre of the cell due to their biconcave. The pinkish colour one observes in a normal blood film is a result of the cells unique haemoglobin content. Shape, size and colour are the key variables to observe.

Please click on each cell to see the blood film, causes and explanation.





Malarial parasite

Blood film

RBC morphology: normocytic,normochromic.

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Definitions

Normocytic: A cell with an MCV within the normal rangeNormochromic: concentration of anaemia is within

the normal range

The biconcave red cell when stained shows a classical central area of pallor on a blood film.








6.0. Glossary

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Malarial parasite

Blood film

RBC morphology: Microcytic hypochromic.

ExplanationRed cells are smaller and lighter than normal and displaying a typical ‘area of central pallor’.

CauseIron deficient anaemia

Thalassaemia

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6.0. Glossary

7.0. Quiz








Malarial parasite

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Blood film

RBC morphology: macrocytic ,megaloblastic (More oval)

Cause

Macrocytic: Macrocytic megaloblastic:Liver disease Vitamin B12

Alcoholism Folate








6.0. Glossary

7.0. Quiz








Malarial parasite

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Blood film

RBC morphology: target cell

Extra: it is also possible to see one neutrophil and two platelets.

Cause

Target cells are found in peripheral blood films in a number of conditions.

1. Liver disease (obstructive jaundice).2. Thalassaemia major.3. Sickle cell anaemia.








6.0. Glossary

7.0. Quiz








Malarial parasite

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Blood film

RBC morphology: basket/blister cell.

Explanation:

Oxidant damage

Cause:

G6PD deficiency








6.0. Glossary

7.0. Quiz








Malarial parasite

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Blood film

RBC morphology: basket cell.

Explanation

Oxidant damage

G6PD deficiency

Blood film

RBC morphology: Elliptocyte. Blood film shows characteristic elliptical (elongated) red cells.

Causes

• Hereditary elliptocytosis: due to a defective cell membrane protein (Spectrin, band 4.1).








6.0. Glossary

7.0. Quiz








Malarial parasite

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Blood film


Explanation

Oxidant damage

G6PD deficiency

Blood film

RBC morphology: Elliptocyte.

Causes

• Hereditary elliptocytosis

Blood film

RBC morphology: Fragments

Cause

• Disseminated Intravascular Coagulation (DIC)• Microangiopathy• TTP• Burns• Cardiac valves








6.0. Glossary

7.0. Quiz








Malarial parasite

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Blood film


Explanation

Oxidant damage

G6PD deficiency

Blood film

RBC morphology: Tear drop poikilocyte

Definition: Poikilocyte; an individual cell of abnormal shape

Cause

• Myelofibrosis• Extramedullary haemopoiesis








6.0. Glossary

7.0. Quiz








Malarial parasite

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Blood film


Explanation

Oxidant damage

G6PD deficiency

Blood film

RBC morphology: “Pencil” cell. These are thin elongated cells. Often occur alongside microcytic

hypochromic cells, poikilocyte and

occasional target cells.

Explanation

Iron deficiency








6.0. Glossary

7.0. Quiz








Malarial parasite

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Blood film


Explanation

Oxidant damage

G6PD deficiency

Blood film

RBC morphology: Ring-forms in P.falciprum

Intracellular malarial parasite

Explanation

A certain amount of haemolysis occurs with all types of malarial infection. It can lead to DIC and intravascular haemolysis.

Malaria: Transmitted by the mosquito this disease causes up to 3 million deaths a year and is a major cause of anaemia within the tropics! See malaria module for more information.








6.0. Glossary

7.0. Quiz








Malarial parasite

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Blood film


Explanation

Oxidant damage

G6PD deficiency

Blood film

RBC morphology: Stomatocyte

Explanation

Liver diseaseAlcoholism








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Malarial parasite

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Blood film


Explanation

Oxidant damage

G6PD deficiency

Blood film

RBC morphology: Sickle cell

Explanation

In sickle cell anaemia the red blood cell undergoes a “sickling” process due the cell containing haemoglobin S. In a deoxygenated state this haemoglobin undertakes a permanent conformational change creating large polymers. As a result these cells become rigid and unable to deform. The red cell eventually looses its cell membrane and becomes damaged as it travels through the circulation changing into the sickled shape we see. This eventually leads to an early cell death (hemolysis).








6.0. Glossary

7.0. Quiz








Malarial parasite

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Blood film


Explanation

Oxidant damage

G6PD deficiency

Blood film

RBC morphology: Micro-Spherocyte. This slide shows spherocytes caused by hereditary spherocytosis. They sit amongst

larger polychromatic red cells.

Cause | Explanation

Abnormality of cytoskeleton proteins. These cells are excessively permeable to sodium influx. Cell looses membrane on passage through reticuloendothelial system. Red cell osmotic fragility is characteristically increased.








6.0. Glossary

7.0. Quiz








Malarial parasite

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Blood film


Explanation

Oxidant damage

G6PD deficiency

Blood film

RBC morphology: “Prickle” cell or small echinocytes. Especially prominent in postsplenectomy patients.

Definition: Echinocyte: cell with abnormal blunt or sharp projections on surface. Can be up to 30 projections per cell.

Explanation

• Pyruvate kinase deficiency




|glossary

Anaemia: a haemoglobin concentration in peripheral blood below normal range for sex

and age

Haemoglobin: a metalloprotien inside a red blood cell that is responsible for oxygen delivery. It is composed of four globulin chains each containing an iron containing haem group.

Macrocytic: Red cells of average volume (MCV) above normal.

Mean cell volume: the average volume of circulating red cells

Mean Corpuscular Haemoglobin (MCH): The average haemoglobin content of red blood cells.

Microcytic: red cells of average volume (MCV) below normal

Normoblast: nucleated red cell precursor normallyy found in the bone marrow

Poikilocytosis: variation in shape of peripheral blood red cells

Reticulocyte: a non-nucleated young red blood cell still containing RNA. Can be found in the peripheral blood and bone marrow.

Stem cell: resides in the bone marrow and by division and differentiation gives rise to all the blood cells

Sickle cell disease: an inherited disorder of haemoglobin of varying severity. The name arises from the deformed shape of the red blood cell takes when the abnormal haemoglobin inside them polymerizes at low oxygen concentrations.

Thalassaemias: a spectrum of inherited disorders of haemoglobin where there is an inbalance in globin chain production.





classification



6.0. Glossary

7.0. References





R.C.I: a microcytic hypochromic anaemia

Epi: this is the most common cause of anaemia worldwide affecting around 500million people.

Aet: 1. The most common cause of iron deficient anaemia is blood oss

2. reduced intake (diet)3. Increased demand (pregnancy)4. Malabsorption (coeliac, gastrectomy)

Ix. FBC, ferritin, serum iron, TIBC, serum transferrin saturation. Endoscopy/colonoscopy if suspected blood loss.

Si/Sy. Koilonychia, sore tongue, angular stomatitis, Plummer-Vinson syndrome (dysphagia due to oesophageal web), painless gastritis. Tx. Treat underlying cause, give ferrous sulphate until Hb and MCV normal (4-6months).

iron deficient anaemia; an overview

Colon cancer

microcytic hypochromic blood film.

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Epi: One of the most common inherited disorders. Common in Mediterranean, Africa and Middle East.

Path: Reduced beta globin (of haemoglobin) production. Ineffective erythropoiesis and haemolysis

Ix. blood film, Hb electrophoresis

Si/Sy. Heterozygotes: often asymptomatic, mild anaemia, low MCV.Homozygote: severe anaemia, failure to thrive in first 6 months of life,

splenomegaly, bone hypertrophy (secondary to extramedullary haemopoiesis). Tx. β-thalassaemia major requires repeated blood transfusion and iron chelation.

Β-Thalassaemia

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Aet: Autosomal recessive genetic disorders due to mutation of the gene for HbA. Affect primarily people of African origin. Sickle cell trait (HbAS) affords strong protection against malaria.

Path: Abnormal haemoglobin (HbS) undergoes a sickling transformation when in a deoxygenated state resulting in a permanent conformational change of shape. The red cell looses its ability to deform becoming rigid. This can cause occlusion of small vessels and result in sickle cell crises precipitated by hypoxia, dehydration, infection and the cold.

IX. Electrophoresis, haemoglobin solubility test.

Si/Sy: Bone pain, jaundice, pigment gallstones, leg ulcers, dactylitis in infants. Txt Supportive; analgesia, fluids and antibiotics during crises.

Sickle cell disease (HbSS); an overview

Dactylitis in a child

Blood film: sickle cells

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path: Vitamin B12 binds to IF intrinsic factor in the stomach and is absorbed in the terminal ileum

Aet: Pernicious anaemia, malabsorpion, post

total gastrectomy

Ix. B12MCV platelets. IF antibodies. Check folate levels.

Si./Sy: Gradual deterioration, Irritability, Loss of memory, Painless jaundice, Loss of sensation , Feeling of pins and needles in extremities, ataxic. Txt. Intramuscular (IM) of 1mg of hydroxycobalamin (Vitamin B12). There is no oral form.

Vitamin B12 deficiency

Aet: increased consumption (pregnancy), dietary

deficiency, folate antagonist (drugs eg; methotrexate, alcohol).

Ix. serum folate, red cell folate. MCV

Si/Sy: Jaundice. Weight loss. GI disturbances. Glossitis.

Txt. Folic acid supplementation. Exclude Vitamin B12

deficiency first.

Folate deficiency

Glossitis.

Blood film; Microcytic hypochromic

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Path G6PD is a key enzyme in the hexose monophosphate shunt. An important function of the shunt is maintain healthy haemoglobin by protection from oxidant stress. In G6PD deficiency, haemolytic anaemia occurs.

Aet: X-linked

Ix. Direct assay of G6PD activity

Si/Sy: None other than those of acute / chronic anaemia Rx Avoid precipitants of oxidative stress; drugs (anti-malarials, analgesics), fava beans.

Tx. Blood transfusion if required.

G6PD deficient anaemia; an overview

Drugs

Fava beans

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Epi: 1 in 5000 people in Northern Europe.

Aet: Autosomal dominant

Path. Defective cell membrane protein (spectrin) causes a loss of cell membrane, progressive spherocytosis and eventually premature death (haemolysis). Increased sensitivity to infections such as parvo-virus.

Ix. Blood film; spherocytesIncreased osmotic fragility.negative antiglobulin test.

Si/Sy: asymptomatic.Jaundice, splenomegalyGeneral features of anaemia

Txt Give ferrous sulphate , ferritin if deficiency

Hereditary spherocytosis; an overview

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Blood film




WARMAet: associated with the production of

autoantibodies of IgG. They attach to the red cell at body temp and are removed early by the

reticuloendothelial system.

Path: Idiopathic or precipitated by drugs or autoimmune disease, leukaemia.

IX. Bloods: unconjugated haemoglobin, LDH, Reticulocytes.Positive direct antiglobulin test.

Si/Sy: Jaundice, general features, splenomegaly

Txt Steroids, splenectomy as 2nd line. Vaccination against H. Influenza, Men C and

Pneumococcus.

Autoimmune haemolytic anaemia; an overviewThese anaemias can be split into ‘warm’ and cold’ types. This is dependent on the temperature at which the antibody reacts with the body.

COLDAet: Associated with the production of autoantibodies of IgM and are removed early by the reticuloendothelial system. Usually self-limiting.

Path: Idiopathic or secondary to infection or lymphoma.

IX. Bloods: unconjugated haemoglobin, LDH, Reticulocytes.

Positive direct antiglobulin test.

Si/Sy: Worse in cold weather, acrocyanosis (purpling of skin), Reynaud's phenomenon.

Txt Remove precipitants, keep patient warm, consider immunosuppression.

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TERIMAKASIH



1. 1. Anemia Dlm Tinjauan Pk Kuliah Ums

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