Haemoglobinopathies

Haemoglobinopathies Inherited disorders of Hb Structure and/or function Thalassaemias Sickle cell disorders Unstable haemoglobins

Epidemiology Worldwide occurrence Areas of Prevalence 5% of world population harbor alleles for hemoglobinopathies 300,000 children born each year with hemoglobinopathy 200,000 children born yearly in Africa with Sickle Cell Disease Areas of Prevalence Sub-Saharan Africa S.C. trait frequency 10-40% S.C. disease freq </= 2% Highest rates in Ghana, Nigeria, Uganda http://www.nslc.wustl.edu/sicklecell/part3/biogeography.html

What is Sickle Cell Anemia? A serious condition in which red blood cells can become sickle-shaped Normal 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 α2β2 = Hgb A (97%) α2γ2 = 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

Pathophysiology A) Haemoglobin bindings 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 Negative charge and size of Glutamic acid prevent haemoglobin to aggregate B) Charge and size prevent 6b Glu from binding.

Normal and Sickled Red Blood Cells in Blood Vessels 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. 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.

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

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

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

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. Inheritance of Sickle Cell Anemia

Sickle cell disease: clinical problems Anaemia (Hb 7-9g/dl in Hb SS) Infections Painful crises Stroke Leg ulcers Visual loss Chronic organ damage Kidneys, lungs, joints, heart

Clinical problems by age Children: Infection Splenic sequestration Pain Stroke Adults Chest syndrome Chronic organ damage

Painful crisis Commonest problem for patients Pain is variable in severity and site and may be excruciating Unpredictable throughout life Often precipitated by infection, physical environment, stress, menstrual cycle Associated with fear and anxiety Majority of patients manage at home and only require admission for severe pain or other complications Appropriate management in the early stages will reduce length and severity of crisis

Management of acute sickle crisis Analgesia stepladder approach Treat associated infection Fluids Monitor for acute complications

Infections in SCD Most common cause of death in children but a major problem at all ages Due to splenic dysfunction from sickle damage occurs from a few months of age especially with certain bacteria eg pneumococcal sepsis : 400 x  risk Infection may be rapidly overwhelming

Infection in SCD prevention: aggressive treatment of infections education Penicillin from 3/12 age Pneumococcal, Hib, Meningococcal vaccines travel prophylaxis : malaria aggressive treatment of infections

Acute sequestration crisis Splenic mostly < 2yrs acute massive splenic enlargement,  Hb, shock often associated with infection significant mortality requires emergency transfusion

TREATMENT FOR SCD 1 Folic acid and penicillen administration 2 analgesics 3 transfusion therapy 4 bone marrow transplant