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Introduction
Def. of anemia:
Reduction below what is expected in one of these parameters:
1. Haemoglobin percentage
a) In intrauterine life the fetus lives in a relatively hypoxic environment thus the
Hb % is very high at birth about 18 gm. It falls to half this value at 10 years old
then reaches the ideal figure of 15 gm at puberty.
b) are 1-1 gm less than at any age and can be explained
Before puberty by the effect of androgen on the bone marrow
After puberty by the effect of androgen on the bone marrow + menstruation
2. Haematocrite
Haematocrite is the packed cell volume. Normally RBCs occupy about 45% of
the bloods volume & plasma represents 55% of the same volume.
3. Red cell count
RBCs count varies from 4-6 millions/cm2. are < by 1 million/cm2 than .
- The term "below what is expected" is better than "below normal" because of
the wide range of the normal figure in every parameter regarding age & gender
Pathologic physiology
Four changes occur in the body to symptoms & bad effects of anaemia:
1) Shift of O2 dissociation curve to the right makes O2 delivery easier to tissues.
This is activated by excess production of 2,3 DPG "2, 3 diphosphoglycerate" which
makes the binding bet. O2 & Hb to be loose
2) Excess production of erythropoietin & erthyropoietic factor by the kidney.
Erthyropoietic factor secreted by the kidney change erythropoietenogen
formed by the liver into erythropoietin
Erythropoietin has a stimulant effect on the bone marrow:
a) It differentiates the stem cell into the red series.
b) It early denucleates the late normoblast by activating alkaline phosphatase
enzyme inside the red cell.
c) It early releases the reticulocyte
NB.: Hypoxia of the kidney as a sequence of anaemia is the main stimulus of this
excess erythropoietin and the amount of erythropoietin is related to the amount of
kidney tissue.
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Classification of anaemia
1. Classification based on red cell size:
Microcytic, normocytic & macrocytic
2. Classification based on the value of mean corpuscular Hb concentration:
Normochromic & hypochromic
3. Classification based on the value of the color index:
Anemia with >1, =1 & with <1
4. Aetiological classification: based on the cause of anemia
NB.: It may be used in one term more than one classification as hypochromic microcytic
Physical signs:
1) Pallor
2) Hyperdynamic circulatory state Big pulse volume, tachycardia, accentuation of
Ht sounds, murmurs over the Ht mostly systolic basal, systolic apical, diastolic
apical & rarely diastolic basal, 3rd Ht sound
3) Splenomegaly especially in chronic haemolysis, but not in bone narrow failure
4) Hepatomegaly in chronic haemolysis & anaemia of chronic illness
NB.: Hepatosplenomegaly may have nothing to do with anaemia & may be just an
association
5) Peripheral neuritis in various chronic types of anaemia
6) Leg ulcer in haemolytic types specially sickle cell anaemia
Treatment:
1) Essentially is the trt of the cause
2) Blood transfusion is indicated in acute blood loss & some hematologic disorders
A) Megaloblastic Anaemia
Def.: It is a hematological disorder characterized by:
1) Pancytopenia with evidence of macrocytosis & anisocytosis
2) Megaloblastic changes of the bone marrow
3) GI &/or neurological complications
4) Good response to B12 &/or folic acid
Pathophysiology:
- Before cell division, it must reduplicate its amount of DNA.
- DNA formation needs B12 & folic acid while Hb & cytoplasm dont need DNA.
- So in B12 &/or folic acid deficiency DNA formation is arrested & consequently
the cell isnt able to divide. At the same time, the growth of the cell runs normally
resulting in big cells.
- The only dividing somatic cells are those in the bone marrow, so B12 & folic acid
deficiency show their effect mainly in the bone marrow by forming megaloblasts
instead of normoblasts.
- Most of the megaloblasts undergo intramedullary haemolysis called ineffective
erythropoiesis.
- Some of these megaloblasts can escape from the bone marrow & appear in the
peripheral bl. as macrocytes which are rapidly sequestrated by the spleen.
- Leucopenia & thrombocytopenia are caused by the same mechanism.
- The cause of the neurological complications in megaloblastic anaemia is not
known.
- Injury of any cell in the body as in buccal mucosa, vagina or gastric wall is
replaced by giant cells in cases of B12 or folic acid deficiency.
Causes of megaloblastic anaemia:
1) B12 deficiency.
2) Folic acid deficiency.
The hematological picture of megaloblastic anaemia with the presence of
macrocytes in the peripheral blood must be differentiated from normoblastic
macrocytosis as in:
1) Myxedema.
2) Aplasia of the bone marrow.
3) Liver cirrhosis.
4) Chronic alcoholism.
5) Pregnancy.
Causes of B12 deficiency:
1) Diminished intake of B12 which present in animal & bacterial products.
2) Gastric causes:
- B12 has no receptors in the intestine to carry out the absorption
- So when B12 is found in the stomach the stomach secretes the intrinsic
factor which combines with B12 and its receptors are present in the terminal
ileum.
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- We absorb B12 by the amount secreted from intrinsic factor & not by the
amount ingested from B12 so any cause which affects intrinsic factor
secretion will in turn affect B12 absorption as:
a) Gastrectomy
b) Chronic gastritis
c) Idiopathic "pernicious anaemia"
d) Congenital
3) Intestinal causes:
- Malabsorption syndrome
- Chronic diarrhea
- Diphyllobothrium latum
4) Deficiency of the substance responsible for the transformation of B12 to the
bone marrow "transcobalamin II" which is usually congenital
Causes of folic acid deficiency
1) Diminished intake as in old age (most important & most common cause)
2) Diminished absorption occurs with malabsorption syndrome & chronic diarrhea
3) Increased demands as in:
- Pregnancy
- Malignancy
- Haemolysis
- Dialysis
4) Drugs interfering with folate metabolism as:
1) Antiepileptic drugs
2) Trimethoprim
3) Methotrexate
The following are examples for megaloblastic anemia
1) Pernicious Anemia
Aetiology: 2 theories
1) Genetically determined weakness of the mucosa of the stomach at middle age
2) Autoimmune disease in which antibodies are secreted against parietal cells
"anti-parietal cell antibodies"
The net result of the two theories is defective production of the intrinsic factor which
affects the absorption of B12.
Clinical manifestations: 2 groups of symptoms are present
- Group 1 of anaemia: fatigue, palpitation, dyspnea, headache & general ill health
- Group 2 of neurological manifestations: paraesthesia, numbness of limbs,
weakness of both lower limbs, unsteadiness
Physical Signs:
1) Those of anaemia as pallor
2) Purpura due to thrombocytopenia
3) Hepatosplenomegaly
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B) Haemolytic Anaemia
Def. of haemolysis:
Diminished life span of RBCs. Normally, their life span is about 120 days.
Pathophysiology of haemolysis:
1) Anaemia:
The BM can its activity regarding the formation of the RBCs into 8 folds thus
anaemia doesn't occur in haemolysis except when life span of the RBCs is < 15
days, except in hyporegenerative crisis in which haemolysis occurs with
simultaneous depression of the bone marrow.
2) Haemoglobinuria:
- There are 2 types of Hemolysis
a. Intra-vascular: occurs inside the bl. vessels.
b. Extra-vascular: at the level of reticuloendothelial system.
- When Hb escapes from the RBCs during haemolysis it rapidly binds to various
proteins aiming to prevent its filteration in the glomerulus. These proteins are
haptoglobin, haemopexin & albumin.
- So conditions for haemoglobinuria to occur:
Haemolysis must be intravascular.
The binding capacity of Hb to the proteins is lost.
- Effect of haemoglobinuria:
It may cause tubular damage
It may result in dark urine which may mislead for the diagnosis of another
type of jaundice as the haemolytic jaundice is associated with normal
colour of urine "acholuric"
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3) Hyperbilirubinaemia:
- When the life of RBCs comes to its end:
a) Most of them show extravascular haemolysis at the level of the
reticuloendothelial cells
b) 1 % of the RBCs show intravascular haemolysis which is the cause of the 1
mg% bilirubin in bl.
- Bilirubin coming out of the destroyed RBCs is called unconjugated "indirect or
haemobilirubin " and can't pass the glomerulus with glumerular filtrate.
- This type of bilirubin goes to the liver where 3 steps occur:
1) Uptake
2) Conjugation
3) Excretion
- The excreted bilirubin is called conjugated "direct or cholebilirubin" and If it is
present in the bl. it can pass the glomerulus with glomerular filtrate.
- The conjugated bilirubin passes with bile to the intestine where it is changed
to stercobilinogen and
1) Part of it comes out with the stool to be changed into stercobilin by the
process of oxidation and this is responsible for the normal colour of the
stool.
2) The other part is absorbed and
a) Part of it passes through the portal circulation causing enterohepatic
circulation which is essential for the process of uptake.
b) The other part escapes to be filtered in the kidneys to appear as
stercobilinogen in urine "urobilinogen" which changes to urobilin in air
In severe haemolysis:
1. Bilirubin
- Present in the bl. as unconjugated type
- Doesn't appear in urine
- Its level is not high bec. the liver can its capacity regarding excretion
of bilirubin 4 folds
2. Stool is rich in stercobilinogen & stercobilin
3. Urine is rich in urobilinogen & urobilin but free from bilirubin
4) Hepatosplenomegaly:
- Hepatosplenomegaly is due to activation of the reticuloendothelial system to
make all haemolysis to be extravascular
- Also as a result of haemolysis serum iron and is precipitated in liver cells
causing Hepatomegaly
C/P of haemolysis in general:
a) Acute haemolysis: presented by
Fever, rigor, loin pain, palpitation, dark urine & jaundice
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b) Chronic haemolysis:
1) May be asymptomatic
2) Symptoms: Fatigue, headache, palpitation, faintness, dyspnea, angina &
intermittent claudications.
3) Signs:
- Pallor, tachycardia, high pulse volume
- Murmurs over the heart, mainly systolic, commonly over the base
The commonest is systolic pulmonary murmur then systolic apical murmur
Diastolic mitral murmur is rare & diastolic aortic murmur is very rare
- Jaundice & lemon colour of the skin, which is a mixture of pallor &
yellowish discoloration of jaundice
- Splenomegaly, bone deformities & leg ulcers
Investigations of haemolysis in general:
1) Blood picture:
- Anaemia is not a rule in mild haemolysis & appears when the lifespan of the
RBCs < 15 days
- In acute haemolysis
a) Anaemia is normochromic & normocytic with normal mean corpuscular
haemoglobin concentration
b) WBC count is normal
c) The platelet count is normal
- DD: Haemolysis may occur in systemic disorders as SLE where the bl. picture
follows the primary disease with more reduction in the haemoglobin
2) Bone marrow picture: 3 possibilities
a) The most common picture is hypercellular bone marrow with normoblastic
hyperplasia to compensate for the red cell destruction
b) Hypocellular bone marrow occurs in simultaneous depression of the bone
marrow & haemolysis "hyporegenerative crisis"
c) Megaloblastoid changes due to secondary B12 & folic acid deficiency
3) Serum haptoglobin: is low as it is combined with Hb to prevent its passage
through the glomerulus.
NB: Haptoglobin is a protein formed by liver & is low in haemolysis & liver cirrhosis
4) Serum iron: is high as a result of destruction of RBCs & the release of their iron
into the circulation.
5) Liver function tests:
a) Serum bilirubin is mildly & of the unconjugated type
b) Stercobilinogen is excess in stool
c) Urobilinogen is excess in urine while Bilirubin is absent
d) Other liver functions are normal
6) Determination of the RBCs lifespan by isotopic methods
7) Special investigations to reach the cause of the haemolysis:
- Type of Hb
- Osmotic fragility test.
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- Under certain conditions, this mechanism doesnt act keeping the Na in RBCs
with consequent withdrawal of excess H2O causing RBCs to take the sphere
shape & early destruction occurs.
C/P:
Haemolysis is usually chronic resulting in anaemia & jaundice with:
1) Splenomegaly
2) Leg ulcers
3) Skull deformity due to hypertrophy of their bones
4) Stunted growth
Investigations:
a) To prove the presence of haemolysis:
1) CBC
2) Serum haptoglobin
3) Bone marrow picture
b) To prove the cause of haemolysis:
1) Spherocytes in the peripheral bl. film
2) ed osmotic fragility:
Normally, RBCs stand diluted saline without haemolysis up to 0.4-0.3 %. But in
hereditary spherocytosis, haemolysis occurs earlier
TTT:
1) Bl. transfusion if Hb is markedly or in crisis.
2) Splenectomy which is better postponed after childhood.
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C/P:
- C/P of severe anaemia due to haemolysis of the sickle cells +
- C/P of arteriolar obstruction as sickle cells may form clumps obstructing the small
vessels resulting in:
1) Spleen: auto-splenectomy
2) Heart: myocardial damage
3) Kidneys: papillary necrosis
4) Brain: cerebral damage
5) Eye: retinal detachment
6) Penis: priapism
Types of crisis: 4 types
1) Painful crisis due to infarction in various organs
2) Aplastic crisis following infection & resulting in severe depression of BM
3) Haemolytic crisis which is differentiated from aplastic crisis by high
reticulocytic count while it is zero in aplastic crisis
4) Sequestration crisis which simulates haemolytic crisis but is due to trapping
of RBCs in liver & spleen
Investigations:
1) As ordinary case of haemolytic anaemia + demonstration of sickle cells in bl. film,
either spontaneously or artificially by adding sodium metabisulphite
2) Hb electrophoresis to demonstrate its abnormality
TTT:
1) Correction of the cause of disease by gene therapy (ideal ttt)
2) Avoid all precipitating factors.
3) Bl. transfusion aiming to:
- Correction of anaemia.
- of % of Hb S before elective surgery
- Exchange transfusion in emergency surgery
4) Pain is treated by analgesics.
NB.: No role for anticoagulants as occlusion of vessels occurs as a result of clumps of
RBC & not thrombosis
Glucose 6 Phosphate Dehydrogenase Deficiency "G6PD"
Sources of energy inside RBCs: 2 sources
1) Glycolytic pathway which utilizes about 90% of glucose
2) Hexose monophosphate shunt pathway which utilizes about 10% of glucose
- Glucose 6 phosphate dehydrogenose is essential for the hexose monophosphate
shunt pathway which doesnt act in absence of this enzyme
Deficiency of the enzyme glucose 6 phosphate dehydrogenose makes RBCs
vulnerable to death when exposed to severe oxidizing stress, which may be:
1) Infections
2) Fava Beans
3) Drugs as aspirin, anti-malarial, Vit K, quinidine, chloramphenicol, sulphonnamide
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Types:
a) Negro or African type:
The recently-formed RBCs show normal enzymatic levels while deficiency is
present in aged RBCs only, so C/P is not marked
b) Mediterranean type:
The enzymatic deficiency affects all RBCs, so C/P is severe
C/P:
Haemolysis occurs when the patient is exposed to severe oxidizing stress
Investigations:
1) Estimation of the activity of glucose 6 phosphate enzyme will show its deficiency
2) Blood picture shows some characteristic phenomena:
a) Blister cells: Hb appears separated from the cell membrane
b) Bite cells: the cell membrane is bit "indented"
c) Heinz bodies: denaturated Hb
3) All tests for haemolysis are +ve during an attack
TTT:
- Prevention of any of precipitating causes
- The gene of G6PD is sex-linked carried on the x-chromosome so it affects & is
carried by apparently healthy so it is wise to estimate the enzymes in all boys in
a suspicious family
Types:
1) Warm type "Coomb's test is +ve"
2) Cold type "Coomb's test is -ve"
Causes: No definite cause could be known in both types in many cases
1) Cause of warm type:
2) Cause of cold type:
- SLE
- Infectious mononucleosis
- Lymphoma
- Lymphoma
- Chronic lymphatic leukemia
- Paroxysmal cold haemoglobinuria
- Carcinomas
- Drugs as methyldopa
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c) Miscellaneous causes:
1. Insecticides
2. Viral infections
3. Tuberculosis
4. Pregnancy
5. Thymoma
6. Paroxysmal nocturnal haemoglobinuria
Clinical Picture:
- The usual form of BM depression is that resulting in pancytopenia
Anaemia
Agranulocytosis
Thrombocytopenia
- The onset may be acute after drug intake or gradual in other cases
- Throat infection is the usual presentation
Differential Diagnosis:
1. Acute leukemia
2. Agranulocytosis
3. Haemolytic anaemia
4. Thrombocytopenia
Investigations:
1) Blood picture shows pancytopenia. The presence of reticulocytes is against the
diagnosis of bone marrow failure as it indicates hyperactive marrow
- D.D. of the blood picture: other conditions that cause pancytopenia
1. Megaloblastic anaemia
2. Myelofibrosis
3. Myeloscelrosis
4. SLE
5. Paroxysmal nocturnal haemoglobinuria
6. Hypersplenism
7. Subleukemic leukemia
2) The bone marrow is hypocellular
Treatment:
1) Removal of the offending agent
2) Blood or platelet transfusion
3) Antibiotics for infection which must be safe to the bone marrow
4) Steroids especially in the congenital pure red cell aplasia
5) Thymectomy for adults in cases of pure red cell aplasia
6) Androgens may stimulate the bone marrow in some cases
7) Immunosuppression may help in some cases
8) Bone marrow transplantation is trt of choice in young patients below 20 years
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