3.18.14* Thalassemias and Hemoglobinopathies Flashcards
Slides* Lecture Notes* Reading (p.88-108)* Picture Powerpoint
the causes of iron overload
hemochromatosis
siderblastic anemia
thalassemia intermedia
chronic liver disease
hemoglobin types and structures
Hb A- a2B2
Hb A2- a1d2
Hb F- a2y2
(a genes are on chromosome 16 and others are on chromosome 11)
alpha thalassemia
(caused by loss of any of the four alpha genes)
alpha thalassemia trait (1 or 2): results in low MCV and MCH with high RBC. Not usually associated with anemia
Hb H (3): moderately severe (hb 7-11) microcytic, hypochromic anemia with splenomegaly. Called Hb H disease because hemoglobin H (B4) can be detected by electrophoresis.
Hb H disease
Hb H (3): moderately severe (hb 7-11) microcytic, hypochromic anemia with splenomegaly. Called Hb H disease because hemoglobin H (B4) can be detected by electrophoresis. PBS will also show target cells and poikilocytosis. Special stain can reveal “golf ball” cells cause by precipitations of B chains.
Beta thalassemia major
little or no B chain produced due to point mutations. Excess a chains precipitate in erythroblasts and mature RBCs causing severe ineffective erythropoesis and hemolysis.
Hb F 98%, Hb A2 2%
Clinical features of beta thalassemia major?
severe anemia is apparent at 3-6 months with liver and spleen enlargement due to excessive red cell destruction. Expansion of bones due to intense marrow hyperplasia leads to thalassaemic facies and thinning of cortex of many bones with tendency to fractures and bossing of the skull.
What disease is the major cause of transfusional iron overload?
thalassemia major. This is because regular transfusion when infants have low hepcidin levels.
PBS of thalassemia major
microcytic, hypochromic cells, target cells, nucleated RBCs (normoblasts), Howell-Jolly bodies are seen,.
Howell-Jolly bodies
cluster of DNA seen in RBC
beta thalassemia trait (minor)
hypochromic microcytic (low MCV and NCH) but high RBC and mild anemia (10-12). A raised Hb A2 (> 3.5%) confirms diagnosis.
thalasemia intermedia
moderate thalassemia (hb 7-10)
alpha and beta trait thalassemia
beneficial because there is not as much alpha to precipitate in the RBC.
Sickle cell disease
due to inheritance of sickle B-globin gene making Hb S (a2Bs2) which forms crystals when exposed to low oxygen tension. The red cells sickle and may block different areas of microcirculation. The sickle B-globin gene has a substitution of valine for flutamic acid in position 6 of the beta chain (Go Vols).
Hb S
gives up oxygen easily compared to Hb A (curve shifted to the right)
Sickle cell trait
benign with only hematuria cause by minor infarcgts of renal paillae. Hb S 25-45%.
Patient with thalassemia is SOB with swollen neck veins. What are you concerned with?
heart failure due to iron overload from transfusions. Thrombosis is increased
when does fetal hb switch to adult hb?
3-6 weeks after birth
how many beta chains are there?
1 per chromosome 11 (two total)
Hgb Bart’s
gamma 4
Q. Genetic cause of alpha thalassemia
a. Deletion of alpha genes
b. Point mutation in alpha gene that decreases alpha chains
c. Point mutation in alpha gene that increases alpha chains
d. Increased methylation of alpha gene promoter
A
Patient with anemia and expanded bony structure of face. How do you diagnose beta thalassemia?
a. Decreased Hgb A seen by electrophoresis
b. increased beta chains on hb electrophoresis
c. genetic analysis of chromosome 16
d. Increased hb A2 or fetal hb
D
What is the cause of hemolysis in beta thalassemia
too many alpha chains leads to aggregation and alpha hemochromes that develop under the RBC membrane leading to autoimmune hemolysis, activation of thrombosis and RBC degredation. Beta thalassemia has a lot of RBC destruction in the marrow.
clinical features of beta thalassemia
a. expanded mandible/maxilla
b. expanded bone marrow (due to hyper-erythropoiesis)
c. severe osteoporosis
d. hepatosplenomegaly
d. ischemia ulcerations
PBS of beta thal
hyperchromatic, microcytic normoblasts target cells fragments basophilic stipling howell-jolly bodies
PBS of thal trait
microcytosis
target cells
(looks a lot like iron deficiency anemia, distinguishable with some basophilic stipplling**)
What is characteristic of a thalassemia CBC?
slightly decreased Hgb
Low MCV/MCH
increased RBC
How does beta thal lead to iron overload?
many people get transfusions which increases iron. Also because ineffective erythropoiesis, their hepcidin is always low because they need a lot of iron, iron absorption is very increased
how much iron is in 1 cc prbc?
1 mg
where does iron accumulate in iron overload/ beta thalassemia?
a. liver- can lead to hemochromatosis, cirrhosis and hepatocarcinoma.
b. heart
c. endocrine cells- hypogonadism and pituitary insufficiency, pancreas leading to diabetes
How does iron overload lead to osteopenia?
a. bone marrow expansion due to hyper-erythropoiesis
b. endocrine disfunction
How do you prevent iron overload
give iron chelators
How do you diagnose beta thalassemia?
electrophoresis showing increased A2 and hb F
How do you diagnose alpha thalasemia?
Lab:
low MCV/MCH
elevated RBC
normal ferritin
(this is presumptive, actual diagnosis needs DNA screening)
PBS finding in alpha thal
microcytosis
target cells
HbH inclusion bodies look like “golf balls”
polychromasia
high RBC count
Hgb E disorder
Point mutation beta globin gene leading to unstable mRNA. Beta chain is transcribed but decreased production.
Hgb Lepore
Delta/beta fusion with marked decrease non-alpha chains
Hereditary persistence of fetal hemoglobin
Marked decrease in beta chain formation compensated by marked increase fetal hgb
Hgb Constant Spring
Base substitution terminal codon alpha gene with marked reduction in alpha genes
