HaemoglobinopathiesHaemoglobinopathies

HaemoglobinopathiesHaemoglobinopathies

Inherited disorders of Hb Inherited disorders of Hb Structure and/or functionStructure and/or function

ThalassaemiasThalassaemias Sickle cell disordersSickle cell disorders Unstable haemoglobinsUnstable haemoglobins

Worldwide occurrenceWorldwide occurrence 5% of world population harbor alleles for hemoglobinopathies5% of world population harbor alleles for hemoglobinopathies 300,000 children born each year with hemoglobinopathy300,000 children born each year with hemoglobinopathy 200,000 children born yearly in Africa with Sickle Cell Disease200,000 children born yearly in Africa with Sickle Cell Disease

Areas of PrevalenceAreas of Prevalence Sub-Saharan Africa Sub-Saharan Africa

S.C. trait frequency 10-40%S.C. trait frequency 10-40% S.C. disease freq </= 2%S.C. disease freq </= 2% Highest rates in Ghana,Highest rates in Ghana, Nigeria, UgandaNigeria, Uganda

http://www.nslc.wustl.edu/sicklecell/part3/biogeography.html

EpidemiologyEpidemiology

What is Sickle Cell Anemia?A serious condition in which red blood

cells can become sickle-shapedNormal red blood cells are smooth and

round. They move easily through blood vessels to carry oxygen to all parts of the body.

Sickle-shaped cells don’t move easily through blood vessels. They’re stiff and sticky and tend to form clumps and get stuck in blood vessels.

The clumps of sickle cell block blood flow in the blood vessels that lead to the limbs and organs. Blocked blood vessel can cause pain, serious infection, and organ damage.

Normal Haemoglobin

Normal Adult Blood

αα22ββ22 = Hgb A (97%) = Hgb A (97%)

αα22δδ22 = Hgb A2 (2%) = Hgb A2 (2%)

αα22γγ22 = Hgb F (<1%) = Hgb F (<1%)

http://sickle.bwh.harvard.edu/hbsynthesis.html

Pathophysiology• Inheritance of mutated hemoglobin β-globin

chain• Mutation of GAG GTG at 6th codon at

chromosome 11• Glutamic acid Valine at 6th AA

– α1α2, β1β2 = normal hemoglobin

– α1α2, β1βS = heterozygote = Sickle trait

– α1α2, βSβS = homozygous recessive = Sickle cell disease

PathophysiologyA. Valine give non-

polarity (hydrophobic) to haemoglobins. Val6 of B2 chain of 1st HbS chain forms hydrophobic bond with Phe85 and Leu88 of a 2nd HbS B1 chain

B. Negative charge and size of Glutamic acid prevent haemoglobin to aggregate

B) Charge and size prevent 6 Glu from binding.

A) Haemoglobin bindings

Normal and Sickled Red Blood Cells in Blood Vessels

Figure A shows normal red blood cells flowing freely in a blood vessel. The inset image shows a cross-section of a normal red blood cell with normal hemoglobin.

Figure B shows abnormal, sickled red blood cells clumping and blocking the blood flow in a blood vessel. The inset image shows a cross-section of a sickled red blood cell with abnormal strands of hemoglobin.

Inheritance of Sickle Cell Anemia

If one parent has sickle cell trait (HbAS) and the other does not carry the sickle hemoglobin at all (HbAA) then none of the children will have sickle cell anemia.

There is a one in two (50%) chance that any given child will get one copy of the HbAS gene and therefore have the sickle cell trait.

It is equally likely that any given child will get two HbAA genes and be completely unaffected.

Inheritance of Sickle Cell Anemia

If both parents have sickle cell trait (HbAS) there is a one in four (25%) chance that any given child could be born with sickle cell anemia.

There is also a one in four chance that any given child could be completely unaffected.

There is a one in two (50%) chance that any given child will get the sickle cell trait.

Inheritance of Sickle Cell Anemia

If one parent has sickle cell trait (HbAS) and the other has sickle cell anaemia (HbSS) there is a one in two (50%) chance that any given child will get sickle cell trait and a one in two (50%) chance that any given child will get sickle cell anemia. No children will be completely unaffected.

Inheritance of Sickle Cell Anemia

If one parent has sickle cell anaemia (HbSS) and the other is completely unaffected (HbAA) then all the children will have sickle cell trait.

None will have sickle cell anemia.

The parent who has sickle cell anemia (HbSS) can only pass the sickle hemoglobin gene to each of their children.

Sickle cell disease: Sickle cell disease: clinical problemsclinical problems

Anaemia (Anaemia (Hb 7-9g/dl in Hb Hb 7-9g/dl in Hb SSSS))

InfectionsInfections Painful crisesPainful crises StrokeStroke Leg ulcersLeg ulcers Visual lossVisual loss Chronic organ damageChronic organ damage

– Kidneys, lungs, joints, heartKidneys, lungs, joints, heart

Clinical problems by ageClinical problems by age

ChildrenChildren::InfectionInfection

Splenic sequestrationSplenic sequestration

PainPain

StrokeStroke

AdultsAdultsPainPain

InfectionInfection

Chest syndromeChest syndrome

Chronic organ damageChronic organ damage

Painful crisisPainful crisis Commonest problem for patientsCommonest problem for patients Pain is variable in severity and site and Pain is variable in severity and site and

may be excruciating may be excruciating Unpredictable throughout lifeUnpredictable throughout life Often precipitated by infection, physical Often precipitated by infection, physical

environment, stress, menstrual cycleenvironment, stress, menstrual cycle Associated with fear and anxietyAssociated with fear and anxiety Majority of patients manage at home Majority of patients manage at home

and only require admission for severe and only require admission for severe pain or other complicationspain or other complications

Appropriate management in the early Appropriate management in the early stages will reduce length and severity stages will reduce length and severity of crisisof crisis

Management of acute Management of acute sickle crisissickle crisis Analgesia Analgesia

– stepladder approachstepladder approach Treat associated infectionTreat associated infection FluidsFluids Monitor for acute complications Monitor for acute complications

Infections in SCDInfections in SCD Most common cause of death in Most common cause of death in

children but a major problem at all children but a major problem at all agesages

Due to splenic dysfunction from Due to splenic dysfunction from sickle damagesickle damage– occurs from a few months of ageoccurs from a few months of age– especially with certain bacteria eg especially with certain bacteria eg

pneumococcal sepsis : 400 x pneumococcal sepsis : 400 x risk risk Infection may be rapidly Infection may be rapidly

overwhelmingoverwhelming

Infection in SCD Infection in SCD

prevention:prevention:– educationeducation– Penicillin from 3/12 agePenicillin from 3/12 age– Pneumococcal, Hib, Meningococcal Pneumococcal, Hib, Meningococcal

vaccinesvaccines– travel prophylaxis : malariatravel prophylaxis : malaria

aggressive treatment of aggressive treatment of infectionsinfections

Acute sequestration Acute sequestration crisiscrisis SplenicSplenic

– mostly < 2yrsmostly < 2yrs– acute massive splenic enlargement, acute massive splenic enlargement,

Hb, shock Hb, shock– often associated with infectionoften associated with infection– significant mortalitysignificant mortality– requires emergency transfusionrequires emergency transfusion

TREATMENT FOR SCDTREATMENT FOR SCD

1 Folic acid and penicillen 1 Folic acid and penicillen administrationadministration

2 analgesics2 analgesics

3 transfusion therapy3 transfusion therapy

4 bone marrow transplant4 bone marrow transplant