Thalassemias and Hemoglobinopathies Flashcards
HbC is common where?
Sickle cell?
HbE?
west africa
central africa
east Asia
What globin chains are common in the fetus?
alpha and gamma (HbF) with very little beta. At birth this changes where gamma globin levels are replaced with beta globin (HbA)
What is the composition of hemoglobin A2?
2 alpha and 2 delta
HbF and HbA2 are increased in what disease?
b-thalassemia
What is common in a-thalassemia?
Hgb H (small amounts of alpha chain remaining- most hemoglobin is only beta) or Hgb Bart’s (total absence of alpha chains)
Symptoms of B-thalassemia?
expanded facial bony structure due to hematopoietic expansion in the bone marrow in those bones due to ineffective erythropoiesis
- hypercoagulability
- anemia
- hepatosplenomegaly
- ischemic ulcers
- splaying of teeth
- heart failure (from being chronically anemic)
What is ineffective erythropoiesis?
as red cells are produced they are destroyed before they can leave marrow causing accumulation and expansion of bone marrow
What is a common complication due to treatment of b-thalassemia with prbcs?
red blood cell products contain iron, so continuous transfusions (as is necessary in young patients to enhance growth) can lead to iron overload
causes endocrine dysfunction, heart failure, hemochromatosis, sex hormone maturation is delayed, hypothyroidism, diabetes, etc.
How else besides too much iron via infusion can cause iron overload?
increased iron absorption- ineffective erythropoiesis causes decreased levels of hepcidin
When transferrin saturated, NTBI circulates and may be taken up by liver, heart and endocrine cells
What happens to a-globin chains in b-thalassemia?
4 things:
1) excess a-globin form inclusion bodies leading to cell apoptosis and ineffective erythropoiesis
2) inclusion body formation stimulates immune removal via IgG and complement binding
3) Membrane damage increases rigidity leading to mechanical removal in the spleen
4) Membrane damage causes phosphatidylserine exposure leading to activation of prothrombinase complex leading to hyper coagulability
How are thalassemia diagnosed?
family history, CBC, blood smear (shows stippling and target cells), physical exam, HPLC
What will HPLC show in b-thalassemia?
elevated A2 or F hgb
What will HPLC show in a-thalassemia?
Normal HPLC and iron levels.
Disproportionately elevated RBC as compared to Hgb, very low mcv with normal ferritin.
Must use other tests:
PCR (known mutation)
Restriction Fragment Length Polymorphism Analysis (unknown mutation)
Treatment of b-thalassemia?
supportive therapy- transfusion to keep hemoglobin above 9 during development, (iron chelated therapy to relieve excess iron)
vitamin D to keep bones strong and hormone replacement for endocrinopathies
allogeneic bone marrow transplant can cure disease but not common
Where are a-globin genes found?
chromosome 16 (beta on 11)
Zero a-globin genes leads to what?
hydrops fetalis- death at birth usually. Have four gamma chains
One a-globin gene leads to what?
HbH disease with precipitated beta globin tetramers as red cells age.
Why is HbH more consistent with hemolytic anemia than an ineffective erythropoiesis?
many cells make it out of bone marrow
Symptoms of HbH?
hypersplenism in 10%, leg ulcers, and gallstones
rarely need transfusions or splenectomy or iron overload
What is Hgb E?
type of b-thalassemia caused by a point mutation in the beta globin gene leading to unstable messenger RNA
What is Hgb Lepore?
type of b-thalassemia where delta/beta fusion occurs with marked decreased non-alpha chains
What is hereditary persistence of fetal hemoglobin?
type of b-thalassemia with marked decrease in beta chain formation compensated by marked increased F hub
What is Hgb constant spring?
type of a-thalassemia caused by a base substitution of terminal codon in the alpha gene causing reduced alpha gene levels
What causes sickle cell anemia?
substitution of valine for glutamine in b-globin gene
common in 8% of AA (1 in 625 are homozygous)
What happens in sickle cell anemia?
In decreased oxygen situations, hemoglobin chains aggregate
Symptoms of sickle cell anemia?
Vascular occlusion resulting in:
- Pain crises
- Strokes
- Bone infarction
- Ischemic ulcers (decreased blood flow to skin)
- Acute chest syndrome
- Hepatopathy
- Priapism
Anemia resulting in:
- Heart failure
- Generalized weakness
- Iron overload
How else does sickle cell disease cause tissue damage besides damage?
1) increased levels of white cells that increase inflammation
2) reduction of NO via free hemoglobin interaction
What is common in small children with sickle cell?
dactylitis leading to shortening of digits
How do you diagnose sickle cell?
HPLC/electrophoresis
How is sickle cell treated?
hydroxyurea to remove methyl groups to increase HgF
prevent things that lead to sickling- infection, fever, dehydration, hypoxemia, acidosis
aggressively hydrate
transfusion in certain life threatening situations
pain control
oxygen if hypoxic
