Haemolyticanaemia
Genetic disorders of hemoglobin:
These are inherited diseases caused by reduced or abnormal synthesis of globin chains.
Hemoglobin synthesis:
The main function of hemoglobin is to carry O
2
to the tissue and to return carbon
dioxide(CO
2
) from the tissue to the lungs ,in order to achieve this gaseous exchange they
contain specialized protein hemoglobin, each molecule of normal adult hemoglobin (Hb
A) consists of four polypeptide chains α
2
β
2
each with its own haem group.Normal adult
blood also contain small quantities of two other haemoglobins: Hb F and HbA
2.
These
also contain α chains but with γ and δ chain respectively instead of β chains.
Normal hemoglobin in adult blood:
Hb A
Hb F
Hb A
2
Structure
(globin
chains)
α
2
β
2
α
2
γ
2
α
2
δ
2
Normal (%)
96-98
0.5-0.8
1.5-3.2
Haemoglobin F is the predominant Hb in fetal and neonatal life, the major switch from
fetal to adult Hb occurs 3-6 months after birth .
Hemoglobin abnormalities
These result from the following:
1-reduced rate of synthesis of normal α or β globin chains(theα and β thalasemias).
2-synthesis of an abnormal Hb(HB S).
The genetic defect of haemoglobin are the most common genetic disorder world wide,β
thalasemias is more common in the Mediterranean region ,while α thalasemias is more
common in the far east.
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Thalassaemias
These are a heterogeneous group of genetic disorders that result from a reduced rate of
synthesis of α and β chains.
α thalassemia syndromes: These usually caused by gene deletion. Normally thereare four
copies of α globin genes ,the clinical severity can be classified according to the number
of genes that are missing or inactive:
♦ Loss of all four genes completely suppressed α chains synthesis and because α chains
are essential in fetal as well as in adulthaemoglobin this is incompatible with life and lead
to death in utero(hydropsfetalis).
♦ Three α genes deletion leads to moderately sever(Hb 7-11g/dl),microcytic hypochromic
anaemia with splenomegaly,this is known as Hb H disease.
♦ The α thalassemia traits are caused by loss of one or two genes and are usually not
associated with anaemia.
β thalassemia syndromes
β thalassemia major:
Pathogenesis:
this condition occur in one in four offspring if both parents are carrier of the β
thalassemia trait. Either no β chains or small amounts are synthesized ,two important
conditions contribute to the pathogenesis of anaemia in thalassemia :
●red cells haemolysis results from unbalanced rates of β globin and α globin chain
synthesis, unpaired α chain form insoluble aggregates that precipitates within the red cells
and cause membrane damage, these cells are removed by the spleen
(extravasculerhaemolysis)
●ineffective erythropoiesis which is destruction of red cells precursor inside the bone
marrow ,result from α chain precipitation in the erythroblast.
Anaemia results from above mechanisms cause tissue hypoxia which stimulate
erythropoietin which cause erythroid hyperplasia and marrow expansion responsible for
skeletal changes. Repeated blood transfusion together with ineffective erythropoisis leads
to systemic iron over-load.
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β thalassemia unlike α thalassemia ,the majority of genetic lesions are point mutation
rather than gene deletions.
Clinical features :
1-Sever anaemia becomes apparent at 3-6 months after birth when the switch from γ to β
chains production should take place.
2-Enlargment of the liver and spleen occurs as the result of excessive red cells destruction
,extramedullaryhaemopoisis, and because of iron overload.
3-Expantion of the bones caused by intense marrow hyperplasia leads to
thalassemicfacies and to thinning of the cortex of many bones with a tendency to fracture
and bossing of the skull with a(hair-on-end )appearance on x-ray.
4-The patient can be sustained by blood transfusion but iron overload caused by repeated
transfusion is inevitable unless chelating therapy is given.
Iron damages the liver and endocrine organs with failure of the growth, delayed or absent
puberty ,diabetes mellitus, hypothyroidisms and hypoparayhyroidism.
Skin pigmentations as a result of excess melanin and haemosidrin gives a gray
appearance at an early stages of iron overload.
Most importantly iron damages the heart and in the absence of intensive iron chelating
thereby, death occurs in the second or third decade usually from congestive heart failure
or cardiac arrhythmia.
5-infection can occur in thalassemic patient for a variety of reasons:
●In infancy anemic child is prone to bacterial infection.
●If splenectomy has been carried out and prophylactic penicillin is not given
,pneumococcal ,haemophilus and meningococcal infection are likely to occur.
●Yesiniaentercolitica occur in iron-loded patient being treated with deferoxamine and it
may cause sever gastroenteritis.
●Transmissionof viruses(such HIV virus) by blood transfusion, may happened in some
patients.
6-osteoporosis may occur ,it is more common indiabetic patient withendocrine
abnormalities.
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Laboratory finding:
1-Hypochromic microcyticanaemia due to reduced the synthesis of normal Hb A with
reticulocytosis, nucleated red cells and target cells in peripheral blood film.
2-Haemoglobin electrophoresis reveals complete absence of Hb A and almost all the
circulating hemoglobin being Hb F.
3- DNA analysis to identify the genetic defects.
4- Assessment of iron status :these tests can be performed to assess iron over load and
include:
♦ serum ferritin which is the most widely used.
♦ serum iron and total iron binding capacity.
♦ bone marrow biopsy.
♦ liver biopsy.
♦ deferoxamine induced iron excretion test.
5- Assessment of tissue damage by iron over-load:
♦cardiac function assessed by :clinical examination, ECG, chest x-ray and
echocardiograghy.
♦ liver function assessed by :liver function tests, liver biopsy ,CT scan and MRI.
♦ endocrine function assessed by: clinical examination (growth and sexual
development),glucose tolerance test, thyroid and parathyroid and adrenal function,growth
hormone assay and radiology for bone age.
Treatment:
1-Reguler blood transfusions is needed to maintain Hb level above 10 g/dl at all times,
this usually require transfusion of 2-3 units every 4-6 weeks.
2-Reguler folic acid is given(5 mg /day).
3-Iron chelating thereby is used to treat the iron over-load,the most established drug is
a- Deferoxamine which is inactive orally and it is given by separate infusion bag 1-2
g with each unit of blood transfused or can be given by continuous subcutaneous
infusion 40 mg/Kg over 8-12 hour,5-7 days weekly. The drug indicated in infants
after transfusion of 10-15 units of blood.Deferoxamine may have side effects
include: high tone deafness, retinal damage, bone abnormalities and growth
retardation.
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b- Deferiprone, is an orally active iron chelator. It may be used alone or in
combination with deferoxamine and it is more effective thandeferoxamine in
removing cardiac iron. Its side effects include arthropathy, agranulocytosis,
neutropenia, and gastrointestinal disturbances.
c- Deferasirox, is the newest orally iron chelator. It is given once daily.Its side
effects include skin rash and transient changes in liver enzymes.
4- Vitamin C ( 200 mg/ day), increases excretion of iron produced by deferoxamine.
5- Splenectomy, may be needed to reduce blood requirement which should be delayed
until the patient is over 6 years old because of the high risk of dangerous infections post
splenectomy.
6- Endocrine therapy: is given either as replacement because of end organ failure or to
stimulate the pituitary if puberty is delayed. Diabetes will require insulin therapy.
7- Immunization against hepatitis B.
8- Allogeneic Bone Marrow transplantation.
β thalassemia minor:
This is a common usually a symptomatic characterized by hypochomic microcytic blood
picture and mild anemia, a raised Hb A2 ( > 3.5%) confirms the diagnosis
Thalassemia Intermedia:
Are cases of thalassemia of moderate severity who don’t need regular transfusions and
this is a clinical syndrome which may be caused by a variety of genetic defects. The
patients may show bone deformity, hepatoslenomegaly, extramedullary haemopoiesis
and features of iron over load caused by increased iron absorption.
Sickle cell anemia
Etiology and pathogenesis:
Sickle cell disease is a group of hemoglobin disorder in which the sickle β globin gene is
inherited. Sickle β globin gene result from single base substitution at position number
6,this leads to an amino acids changes from glutamic acid to valine in the β chain.
Hb S(Hb α
2
β
2
s
)is insoluble and form crystals when exposed to low oxygen tension,
deoxygenated sickle Hb polymerized into long fibers and red cells become sickle-like
which may block different areas of microcirculations or large vessels causing infarct of
various organs.
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Clinical features:
Sever hemolyticanemia associated with crises, the symptoms of anemia are usually mild
inrelation to the severity of anemia, this because HbS gives up oxygen to the tissue easily
compared with Hb A. The crises may be vaso-occlusive, visceral, a plastic or hemolytic.
1-Painfulvaso-occlusive crises: these are the most frequent and precipitated by many
factors such as infection, dehydration, acidosis and deoxygenated states likehigh altitude,
operation ,exposure to cold and obstetric delivery.
Infarct can occur in a variety of organs including the bones, the lungs and the spleen,the
most serious vaso-occlusive crises is of the brain which cause a stroke. Hand-foot
syndrome(painful dactylitis caused by infarcts in small bones) is frequently the first
presentation of the disease and may lead to digits of varying lengths.
2- Visceral sequestration crises:these are caused by sickling within organs and pooling of
the blood, often with a sever exacerbation of anaemia.The acute chest syndrome is
serious complication and the most common cause of death after puberty ,it present with
dyspnea and chest pain,treatment by analgesia, oxygen and exchange transfusion.
Splenic sequestration present with splenomegaly, falling Hemoglobin and abdominal pain
,it is typically seen in infants and treatment is with blood transfusion ,attacks may be
recurrent and splenectomy is often needed.
3-Aplastic crises: these occur as a result of infection with parvovirus or from folate
deficiency and characterized by fall in hemoglobin as well as reticulocytes.
4- Hemolytic crisis:characterized by an increased rate of haemolysis with a fall in
hemoglobin and a rise in reticulocytes.
5-Other clinical features:
Ulcer of lower legs as a result of vascular stasis and local ischemia.
Enlarged spleen in infancy and early childhood but later is often reduced in size
as a result of infarction ( Autosplenectomy).
Pulmonary hypertension.
Proliferative retinopathy.
Chronic damage to the liver due to micro infarct.
Pigment gall stones.
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Osteomylitis.
Laboratory finding:
1- The hemoglobin is usually 6-9 g/ dl, low in comparison to symptoms of anemia.
2- Sickle cells and target cells . Features of splenic atrophy ( Howell-Jolly bodies).
3- Screening tests for sickling are positive when the blood is deoxygenated.
4- Hemoglobin electrophoresis: in HbSS, no Hb A is detected,Hb F is usually 5-
15%.
Treatment:
1- Prophylactic: avoid factors known to precipitate crisis, especially dehydration,
anoxia, infections, stasis of circulation and cooling of the skin surface.
2- Folic acid, (5 mg once weekly).
3- Good general nutrition and hygiene.
4- Pneumococcal, Haemophilus and Meningococcal vaccination. Hepatitis B
vaccination is also given as transfusion may be needed.
5- Regular oral penicillin should start at diagnosis and continue at least until puberty.
6- Crisis treatment: rest, warmth, rehydration and antibiotics if infection is present.
Analgesia ( paracetamol, non-steroidal anti- inflammatory agent and opiate). Blood
transfusion if there is sever anemia with symptoms. Exchange transfusion may be
needed if there is neurological damage, visceral sequestration crisis or repeated
painful crisis. This is aimed to achieve an Hb S percentage of less than 30 in sever
cases and after a stroke is continued for at least 2 years.
7- Careful anesthetic and recovery technique to avoid hypoxemia or acidosis.
8- Routine transfusions throughout pregnancy are given to those with a poor obstetric
history or a history of frequent crises .
9- Transfusions: sometimes given repeatedly as prophylaxis to patients having
frequent crises or who have had major organ damage (e.g. of the brain). The aim is
to suppress Hb S production over a period of several months or even years. Iron
overload which may need chelation therapy is common problem.
10- Hydroxyurea( 15-20 mg/ kg) can increase Hb F and improve clinical course of
patients who are having three or painful crises each year. It should not be used
during pregnancy.
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11- Stem cell transfusion can cure the disease.
12- Researches on Butyrates which enhance Hb F synthesis and increase solubility of
Hb S.
13- Researches on Gene- therapy.
Sickle cell trait
This isabenign condition in which there is inheritance of normal hemoglobin and
sickle hemoglobin ,there is no anemia and normal appearance of red cells in blood
film. Haematuria is the common symptom and caused by minor infarcts to the
renal papillae.
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