Haemoglobinopathy

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Haemoglobinopathy

• By
• Prof. Dr. Asmaa AbdulAziz

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Definition The haemoglobinopathies are
inherited disorders of haemoglobin synthesis
(thalassaemias) or structure (sickle cell
disorders) that are responsible for significant
morbidity and mortality allover the world. They
are seen mainly in individuals who originate from
Africa, the Middle East,, the Mediterranean, Asia
and the Far East. However, the increased mobility
of the worlds population and inter-ethnic mixing
lead to prevailing of these conditions within any
region of the world.
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These disorders result in errors in
oxygen-carrying capacity of haemoglobin .
Diseases linked to genetic predisposition are not
only kill prematurely, but result in long years
of ill health and disability, loss of work and
income, possible poverty, loneliness and
depression.
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Sickle cell and thalassaemia are inherited
disorders that are passed on from parents to
children through unusual haemoglobin genes.
People only have these disorders if they inherit
two unusual haemoglobin genes one from their
mother, and one from their father. People who
inherit just one unusual gene are known as
carriers. (Some people call this having a
trait.) Carriers are healthy and do not have
the disorders.
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• Individuals with Haemoglobinopathy are
• either healthy carriers (trait ) i.e. unaware of
  their carrier status unless specifically
  screened. If a couple both carry a
  haemoglobinopathy trait there is a 1 in 4 chance
  with each pregnancy that their child will inherit
  a clinically manifested haemoglobinopathy.
• or having clinically manifested
  haemoglobinopathy

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Who can be a carrier? Anyone can be a healthy
carrier. This means you are more likely to be a
carrier if your ancestors came from the
Mediterranean (for example Cyprus, Italy,
Portugal, Spain), Africa, the Middle East, India,
Pakistan, South America or south and south-east
Asia. Is it important to know if you are a
carrier? 1- Healthy sickle cell carry may have
some problems in rare situations (Lack of oxygen
,for example), when having an anesthetic or
during deep-sea diving. Knowing that you carry
sickle cell can help you manage these situations.
However, people who carry thalassaemia or other
unusual haemoglobin genes do not experience these
problems. 2-If a carrier gets married from
another carrier (Consanguinity) they will have
one in four baby with clinically manifested
disorders
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The diagram below shows the chances (for each
pregnancy) of two carrier parents having a child
with a sickle cell or thalassaemia disorder.
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If the mother is anemic the father is healthy
carrier 50 of the off springs are carriers and
50 is anaemic
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Sickle Cell is a condition that affects the
normal oxygen carrying capacity of red blood
cells. When the cells are de-oxygenated and under
stress in sickle cell conditions, they can change
from round flexible disc-like cells to elongated
sickle or crescent moon shape. The effect of
these changes is that the cells do not pass
freely through small capillaries and form
clusters, which block the blood vessels. This
blockage prevents oxygenation of the tissues in
the affected areas resulting in tissue hypoxia
and consequent pain (known as sickle cell crisis
pain) other symptoms of sickle cell disorders
include severe anaemia, susceptibility to
infections and damage to major organs.
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The term sickle-cell disease is preferred because
it is more comprehensive than sickle-cell
anaemia.
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2-The clinically significant haemoglobinopathies
are listed in following Table
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• In children, sickle-shaped red blood cells often
  become trapped in the spleen, leading to a
  serious risk of death before the age of seven
  years from a sudden profound anaemia associated
  with rapid splenic enlargement or because lack of
  splenic function permits an infection.
• Affected children may present with painful
  swelling of the hands and/or feet (hand-foot
  syndrome).
• Survivors may suffer recurrent severe painful
  crises, as well as acute chest syndrome
  (pneumonia or pulmonary infarction), bone or
  joint necrosis, or renal failure.

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Thalassaemia Major It is the most severe form
of thalassaemia, results in the inability of the
body to produce haemoglobin, resulting in life
threatening anaemia. Those with the condition
require regular therapeutic treatment and blood
transfusion . Bone marrow transplantation is a
treatment option
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The impacts of genetic disorders on infectious
diseases (Malaria Sickle cell disorders) Many
studies showed reduced morbidity and mortality
from malaria ( Falciparum) patients with
thalassemia major and minor (the carriers) (up to
50), and decreased numbers of circulating
parasites (by 80) The mechanism of resistance
may consist of decreased parasite replication
within the erythrocyte or enhanced splenic
clearance of parasitized erythrocytes. A person
who carries the sickle cell gene has a survival
advantage against malaria
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The sickle cell trait confers a selective
advantage resistance to severe malaria. The
mechanism of this protection however, remains
incompletely understood. Proposed mechanisms
include decreased parasite growth in the red
cells and enhanced removal of parasitized cells
by the spleen. In patients with sickle cell
trait, although some protection against malaria
and its complications is present, severe or
complicated malaria can occur. However , severe
hemolytic infarctive crises are anticipated if
patients with sickle cell diseases get Malaria
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Prevalence of haemoglobinopathies   The World
Health Organization (WHO) estimates that globally
at least approximately 5 of adults are
carriers for a haemoglobin condition 2.9 for
thalassaemia and 2.3 for sickle cell
diseases Carriers are found allover the word
because as a result of migration the populations
of different ethnic groups to different regions
of the world.
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Prevalence of Sickle cell disorders
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SITUATION in Africa The highest prevalence of
sickle-cell trait is in parts of Africa among
people with origins in equatorial Africa, the
Mediterranean basin and Saudi Arabia. In Africa,
the highest prevalence of sickle-cell trait
occurs between latitudes 15 North and 20 South
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Over 300 000 children are born each year with a
severe haemoglobinopathy. 30 are born with
thalassaemia syndromes while 70 have sickle-cell
anaemia With worldwide migration, these
diseases are as much a feature of Europe, the
United States and Australia as of the countries
where they originated. Prevalence varies from
under 0.1 births per 1,000 in some parts of the
world to more than 20 per 1,000 in parts of
Africa. In America, approximately 70,000- 80,000
people suffer from sickle cell disease . They
are mainly of African Origin       
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The situation in KSA In a study carried in KSA
,the incidence of hemoglobulin S for the studied
neonates was 14.4 and ranged from 0.8 in Najran
to 26.4 in Al-Qurayyat, KSA. In the eastern
provinces the disease is generally milder whereas
in the western provinces the disease is severe
and similar to that reported in African
populations
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• In Bahrain Genetic disorders of haemoglobin are
  prevalent. In a study of the hospital population
  covering
• 56 ,198 Bahrainis, it was found that
• Sickle-cell disease was 2 of newborns
• Sickle-cell trait was 18 of newborns
• Carriers of the thalassaemia gene was 24 of
  newborns .
• From this study it was concluded that
• The mild form of SCD predominates.
• Hematological values are similar to those of
  patients from Eastern Province, Saudi Arabia,
  where the mild form of the disease predominates

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• Sickle-cell disease in Bahrain and Saudi Arabia
  presents special features. SCD in this area is
  clinically mild, and mortality is low in both
  children and adults .
• However, some cases died from septicemias
  Pneumococcal diseases.
• In this study the most precipitating factors
  for crisis were
• Exposure to cold (45 of cases).
• Fever or elevated body temperature (35),
• Exhaustion severe physical activity (35),
• Hot humid weather (10)
• Crowded places (10)

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National Control program for haemoglobinopathies
The development of appropriate national control
programme is now accepted and introduced in many
parts of Asia such as in Bahrain, the Islamic
Republic of Iran and Saudi Arabia. China, India,
Indonesia, Malaysia, Maldives, Singapore and
Thailand.
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The control program depends on the
characteristics the requirements of individuals
with haemoglobinopathies. Sickle cell disorders
People with sickle cell disorders can have
attacks of very severe pain can get serious,
life-threatening infections are usually
anaemic need medicines (antibiotics
Pneumococcal vaccine) throughout their lives to
prevent infections. Thalassaemia major People
with thalassaemia major are very anaemic
need blood transfusions every four to six weeks,
need injections and medicines throughout their
lives. There are also other, less common,
haemoglobin disorders. Many of these are not
serious.
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National Control program for sickle cell
diseases 1- setting up sickle-cell screening and
genetic counseling programmes in high prevalence
countries. The disease should be identified
during the prenatal period or at birth as part of
a routine screening programme. Genetic counseling
and screening can lead to reduction in the number
of children born with the trait. The programme
should be developed at the primary care level
with appropriate referral system. 3-Parents must
be counseled to seek medical care for all febrile
events in children with sickle cell diseases.
2-Supplementation of antibiotics, rest, good
nutrition, folic acid 3-Training of health
personnel in prevention, diagnosis and case
management should be an integral part of the
national programme. 4-Integration of national
control program for sickle-cell disease within
the national programmes for prevention control
of non-communicable diseases (Cancer , Diabetes)

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• The antenatal screening programme
• Parent screening for sickle cell and thalassaemia
  aims to
• identify women/couples at risk of a pregnancy
  with sickle cell or thalassaemia disorders and
• provide appropriate referral care for prenatal
  diagnosis with continuation or termination of
  pregnancy according to womens choices.
• In most of the countries where sickle-cell
  disease is a major public health concern
• National programmes for its control do not exist.
  
• Basic facilities to manage patients are absent,
• Screening for sickle-cell disease is not common
  practice The diagnosis of the disease is made
  when severe complication occurs.
• As a result, more than 50 of the children with
  the severe form of the disease die before the age
  of five from infection or severe anaemia

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ANTENATAL SCREENING
Pregnancy
Offer screening Blood sent to laboratory for
haemoglobinopathy Screen
Negative Result Information No further action
Positive results Information counseling-Offer
partner screening
Partner screening Blood sent to laboratory for
haemoglobinopathy Screen
Negative Result Information No further action
Positive results At risk couple Information
counseling-Offer prenatal diagnosis
Prenatal
diagnosis Fetal blood Sampling/ Chorionic Villus
sampling

Unaffected Fetus Information- No further action
Affected fetus- Information counseling
Continue with Pregnancy
Parents Make- Informed Choice
Termination of Pregnancy
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Premarital diagnosis In the Saudi society,
consanguineous marriages are high (60).
Recently, the Saudi government introduced a new
legislation regarding premarital testing for the
2 common genetic disorders namely, sickle cell
trait and thalassemia. The advantage of
premarital diagnosis is that affected births
could be prevented if couples at risk were
identified.
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• NEONATAL SCREENING
• The newborn sickle cell screening is part of the
  existing bloodspot programme for Phenylketonurea
  (PKU) and congenital hypothyroidism (CHT).
• Neonatal haemoglobinopathy screening primarily
  aims to
• identify infants with SCDs , in order to start
  prophylactic antibiotic therapy and vaccination (
  Pneumococcal vaccine) as early as possible.
• detects carriers. For each baby detected with
  SCDs, neonatal screening detects between 17 and
  100 sickle cell carrier babies. Parents of a
  carrier child should be informed about the
  carrier result

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• In UAE, a standard form for neonatal screening is
  issued to every baby born hospital, where 99 of
  deliveries occur, and mothers are informed about
  the procedures importance of neonatal screening.
• in January 1995 by screening for Phenylketonurea.
  
• in January 1998. Screening for congenital
  hypothyroidism
• In January 2002, the Ministry of Health decided
  to launch a pilot study for neonatal screening of
  sickle cell disease before expanding it at the
  national level.
• Newborn infants are brought to MCH centre on the
  fifth day for collection of blood samples by heel
  prick onto filter paper
• The aim of the Screening program for
  haemoglobinopathy is to
• To detect infants with haemoglobin traits,
• To identify children with clinical disease and
• To counsel couples at risk for having future baby
  with sickle cell disorders.
• All infants confirmed with sickle cell disease
  started prophylactic penicillin by the age of 2
  months and follow-up was arranged with the
  cooperation of haematologist.

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• Genetic counseling
• It is the process through which knowledge about
  the genetic aspects of illnesses is shared by
  trained professionals with those who are at an
  increased risk or either having a genetic
  disorders or having them to be passed to their
  unborn offspring.
• Genetic counseling is aiming to
• replace misunderstandings of the causes of
  genetic disease with correct information
• informing parents about the resources available
  for diagnosis, treatment and prevention.
• helping the families in decision making, which
  have life long consequences
• The family physician usually handles most of the
  genetic counseling during routine clinical visits

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A survey of 500 parents, with children who have a
genetic diseases was carried, to find their
knowledge about genetic diseases indicated that
the majorities were unaware of etiologies,
symptoms, inheritance and therapies. This was
particularly true for parents with lower
education. Until recently a genetic counselor
only advised of possibilities of recurrence of
such a disease in the family. The new policy of
genetic counseling is to help the family in
making the correct decision for preventing the
disease in the extended family and the prevention
of a similar condition in future pregnancies.
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• Pneumococcal diseases in children with Sickle
  cell disorders
• Children with sickle cell anaemia have an
  increased susceptibility to severe bacteria
  infection, particularly from Streptococcus
  pneumoniae. The risk of infection is greater in
  the first 3 years of life specially at4 months.
• The incidence of Pneumococcal diseases for
  children with sickle cell disease is 18.4cases
  per 100 patients/year compared with 0.02 to 0.06
  patientss per 100 healthy children /year
• This infection may be the first clinical
  manifestation of disease and carries .
• The case fatality rate of Pneumococcal diseases
  in these children is 30

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Age distribution of pneumococcal bacteremia in
children with sickle cell disease or HIV and
healthy children at Boston Medical Center,
19811998.9
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• Pneumococcal diseases in sickle cell children
  include
• Pneumonia bronchitis
• Pneumococcal meningitis
• Septicemias
• Ear infections
• Peritonitis

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• The Risk Factors for Recurrent Pneumonia in
  Children which include
• Sickle-cell diseases
• Impaired immune system) HIV, cancer, leukemia (
• Viral respiratory Infections
• Gastroesophageal reflux disorder
• Inborn lung or heart defects
• Asthma

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• The causative agents Streptococcus pneumonia
• Children under 2 years old are at highest risk
  for serious disease.
• The organisms spread from person to person
  through close contact.
• Pneumococcal infections can be hard to treat
  because the bacteria have become resistant to
  some of the drugs that have been used to treat
  them. This makes prevention of Pneumococcal
  infections is more important.

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Pneumococcal vaccine can help prevent
serious Pneumococcal disease, such as pneumonia,
bronchitis meningitis and septicemia ear
infections.
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There are two types of Pneumococcal vaccine 1-
Pneumococcal polysaccharide vaccine (PPV)
contains purified capsular polysaccharide from
each of 23 serotypes of Pneumococcal
bacteria 2-Pneumococcal conjugate vaccine (PCV)
contains capsular polysaccharide from seven
serotypes of Pneumococcal bacteria conjugated to
protein The vaccines are inactivated, do not
contain live organisms and cannot cause the
diseases against which they protect.
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• Pneumococcal polysaccharide vaccine (PPV)
• Adults develop a good antibody response to a
  single dose of PPV by the third week following
  immunization.
• Not used in children lt two years of age because
  of poor antibody responses .
• The overall efficacy in preventing Pneumococcal
  bacteraemia is 50 to 70
• Post-immunization antibody levels begin to wane
  after five years

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Pneumococcal conjugate vaccine (PCV) The antibody
response in young children can be improved by
conjugating the polysaccharide to proteins. The
conjugated vaccine is immunogenic in children
. The efficacy is 97 after giving the fourth
dose The vaccine protects against Pneumococcal
meningitis, bacteraemia, pneumonia and otitis
media. For children under one year of age)
First dose of 0.5ml of PCV at 2nd month Second
dose of 0.5ml, at 4th month A third dose of
0.5ml at 6th month The fourth dose of 0.5ml at
13th month Subcutaneous at anterolateral thigh
Children over one year of age and under five
years of age A single dose of 0.5ml of PCV
(subcutaneous upper arm)
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• In general the Pneumococcal vaccine should be
  given to Children having
• heart condition
• chronic lung ,liver disease
• diabetes mellitus
• weakened immune system
• Children with damaged spleen or no spleen Or
  Sickle cell anaemia thalassaemias .
• These children should be managed as follow

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Infants under one year of age Give PCV
vaccine as routinely recommended at two and
four months of age with a booster dose at around
13 months of age. Children aged 12 months to lt
five years If they have a single dose of PCV
before ,they should receive a second dose of PCV
( Separated by two months) because they may have
a reduced immune response for the first dose of
the vaccine. At-risk children aged five years
and over PCV is not recommended .
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Dont give the PCV vaccine to Children had a
serious (life-threatening) allergic reaction to a
previous dose of this vaccine ( as it contains
protein) Give the PCV vaccine to Children even
with minor illnesses, such as mild fever or
diarrhea Postponed the PCV vaccine for children
who are moderately or severely ill .Wait until
they recover before getting the vaccine
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• Adverse effects following PCV
• 25 had local redness, tenderness, or swelling
• Up to about 1 out of 3 had a fever
• Some children become drowsy, or had anorexia
• So far, no serious reactions have been associated
  with this vaccine.

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Best Wishes