Topic 4: Thalassemias Flashcards
what are thalassemias?
a group of inherited blood disorders in which the body makes abnormal forms of hemoglobin
patients with thalassemia produce an inadequate amount of either alpha or beta globin chains
as a result, hemoglobin synthesis is insufficient and the oxygen-carrying capacity of RBCs is reduced
both forms cause the destruction of red blood cells (RBCs), leading to anemia
what is heme made out of?
iron and porphyrin
what are the components of Hb?
heme and globin
4 heme and 4 globin chains
what is HbA2 and in which thalassemia is it seen?
two alpha and two delta chains
it is seen in higher concentrations in beta thalassemia
what is alpha thalassemia?
decrease in alpha chain production resulting in anemia of varying degrees
what causes alpha thalassemia?
deletion of one or more alleles
alpha globin gene actually has four alleles – two on each chromosome 16
alleles are co-dominantly expressed so you use all four genes to make alpha chains
the severity of the disease depends on the number of deleted alleles
what chromosome is alpha globin gene on?
16
4 alpha globin chains; 4x4=16
what happens if you don’t have enough alpha chains around?
- can’t make enough Hb
- unpaired beta (if you’re an adult) or gamma (if you are a fetus) chains clump together in little tetramers
harder to deal with alpha thalassemia because you can’t replace alpha chains; with beta thalassemia you can replace B chains with gamma or delta chains
what happens to the B or gamma tetramers formed in alpha thalassemia?
the spleen removes cells with these clumps from circulation which only worsens the anemia
beta chain tetramers in adults = HbH or H bodies
gamma chain tetramers in babies = Hb Barts
what is B thalassemia?
disease caused by a defect in the production of beta globin
what chromosome is the B globin gene encoded on?
11
there’s only 2 B alleles, not 4 like alpha globin
what are the types of mutations that can happen in B thalassemia?
B0 = beta globin production is completely gone
B+ = decrease in the production in beta globin
B+ is less severe
what happens to the alpha chains in B thalassemia?
free excess alpha globin cannot be integrated into hemoglobin and will either remain soluble or aggregate with other alpha globin molecules in the blood
soluble alpha globins are a big problem because they stick to the RBC membrane and cause membrane damage, leading to apoptosis in the marrow or phagocytosis and destruction in the spleen
What determines the severity of beta thalassemia?
Both the severity of the mutation (complete or partial) and the zygosity (homozygous vs heterozygous) determine the severity of beta thalassemia
what are the clinical manifestations of thalassemias?
- decreased Hb production
- extra medullary hematopoiesis
- hemolysis
why do thalassemia patients have decreased Hb production?
a patient with thalassemia is not producing sufficient alpha or beta globin chains
so hemoglobin synthesis will be inadequate and oxygen-carrying capacity will be affected
why do thalassemia patients have extra medullary hematopoiesis?
in severe cases of thalassemia, the body tries its best to make red blood cells anywhere it can, including places that are not typically sites of bone marrow production, such as the calvarium of the skull
why does thalassemia cause hemolysis?
Hemolysis primarily occurs in the spleen
Abnormal RBCs are phagocytosed and removed from circulation
This, along with extramedullary hematopoeisis, leads to hepatosplenomegaly
what are the clinical symptoms of thalassemia?
- pallor
- jaundice
- dyspnea
- tachycardia
- bilirubin stones in gallbladder = hemolysis
What are the three mechanisms by which patients with thalassemia can be anemic?
- poor production of hemoglobin
- ineffective hematopoiesis
- hemolysis
can all contribute to anemia in thalassemia
what is needed for a definitive diagnosis of thalassemia?
hemoglobin electrophoresis
hemoglobin electrophoresis is necessary for definitive diagnosis because it reveals the presence and amount of alpha and beta globin chains (as well as gamma and delta chains)
what does the CBC of a patients with alpha or beta thalassemia show?
low Hb
low mean cell hemoglobin concentration (MCHC) = hypo chromic
low MCV = microcytic
how is the RBC count in MILD thalassemia effected?
usually increased
big difference between thalassemia and IDA where RBC count is low
how is the RDW effected in MILD thalassemia?
low end of normal with means RBCs are microcytic BUT uniform in size
how is the hemoglobin in severe thalassemia effected?
drastically decreased
how is the RDW in severe thalassemia effected?
elevated which means there’s a big range of cells sized present
some RBCs are slightly microcytic, and some RBCs are severely microcytic
what does the blood smear of mild thalassemia look like?
RBCs are hypochromic
target cells are frequently seen
what does the blood smear of severe thalassemia look like?
you can see variations in RBC size if thalassemia is severe
nucleated blood cells
hypochromic RBCs
do mild cases of alpha and beta thalassemia require treatment?
no
patients are asymptomatic and can survive with a very mild anemia
when is a transfusion required for thalassemia?
HbH disease and thalassemia major
what is the complication with transfusions for thalassemia?
may cause iron overload unless iron chelation is used
a unit of packed RBCs has way more iron than the normal daily requirement
when can a transplant be used to treat thalassemia?
thalssemia major may be treated definitively with stem cell transplant
what’s the complication associated with a stem cell transplant for thalassemia?
graft vs. host disease
a condition in which the immune cells within the donated tissue (graft) attacks the tissue of the host
What is the main treatment of thalassemia major?
blood transfusions
What bone marrow abnormality can be seen in thalassemia major?
Hyperplastic bone marrow
Which lab values can differentiate thalassemia from iron-deficiency anemia?
Red Blood Cell Distribution Width (RDW)
RDW is elevated in iron-deficiency anemia but is normal in thalssemia
In thalassemia, the RDW is normal, most likely because the synthesis of RBCs is chronically deficient
in IDA, RDW is high because as the disease progresses, RBCs become more microcytic, so older RBCs will still be normocytic, thus the variation in size
