Haemoglobinopathies

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					Haemoglobinopathy
             By
 Prof. Dr. Asmaa AbdulAziz
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 world’s
population and inter-ethnic mixing lead to prevailing of
these conditions within any region of the world.
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 .
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.
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
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
The diagram below shows the chances (for each pregnancy) of two carrier
parents having a child with a sickle cell or thalassaemia disorder.
If the mother is anemic & the father is healthy carrier
50% of the off springs are carriers and 50% is anaemic
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.
The term sickle-cell disease is preferred because it is more
comprehensive than sickle-cell anaemia.
2-The clinically significant haemoglobinopathies
are listed in following Table
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.
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
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
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
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.
Prevalence of Sickle cell disorders
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
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
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
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
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%)
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.
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.
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)
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 women’s
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
                                                        ANTENATAL SCREENING
                 Pregnancy
                 Offer screening                                  Negative Result
Blood sent to laboratory for haemoglobinopathy Screen       Information: No further action

                 Positive results
Information & counseling-Offer partner screening


               Partner screening                                  Negative Result
Blood sent to laboratory for haemoglobinopathy Screen
                                                            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


      Parents Make- Informed Choice                           Continue with Pregnancy

         Termination of Pregnancy
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.
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
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.
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
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.
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%
Age distribution of pneumococcal bacteremia in children with
sickle cell disease or HIV and healthy children at Boston
9.Medical Center, 1981–1998
Pneumococcal diseases in sickle cell children
include
• Pneumonia & bronchitis
• Pneumococcal meningitis
• Septicemias
• Ear infections
• Peritonitis
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
•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.
Pneumococcal vaccine can help prevent serious
Pneumococcal disease, such as pneumonia, bronchitis
meningitis and septicemia & ear infections.
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.
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 < 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
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)
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:
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 < 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 .
Don’t 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
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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