Thalassemia Flashcards
1 Hemoglobin consists of
4 Fe2+
4 Porphyrin
4 globin chains
globin chain production
Required 4 chains of AA
- 2 homologous chains
Alpha = chromosome 16
- alpha (Hgb A1,A2, F, Gower2)
- (hgb Gower 1, portland)
Beta = chromosome 11
- beta (hgb A1)
- delta = hgb A2
- gamma (hgb F, porland
- epsilon (hgb Gower 1 and 2)
-
Hemoglobin F
a2y2
60-90% in fetus
Hemoglobin A1
a2b2
95-97%
Adult
Hemoglobin A2
a2d2
2-3%
Adult
hemoglobin electrophoresis
problem: some hgb chains will migrate to the same site.
Combat this by running different types of agar held at different pHs
Cellulose acetate
pH: 8.6
Loaded at cathode
Alkaline pH gives hemoglobin a negative charge which travels from (-) cathode to (+) anode
Citrate agar
pH: 6.0
Load in center
Hgb chains will travel in either direction depending on its type
Isoelectric focusing
- uses a pH gradient across polychrylamide gel
1. seperated based on isoelectric point
2. expensive and slow
3. creates distinguishable bands
high performance liquid chromatogrpahy
pushes sample in solvent (mobile phase) at high pressure through a column of stationary phase material that allows us to seperate and identify compounds
- expansive and small sample size
- fully automated and quantitaitve
Kleihauer Betke-Stain / KB stain
fetal hgb can be quantified by an acid-elution stain.
acidic pH (3.3) is applied to an air-dried, alcohol fixed blood smear
- hgb A is eluted off
- hgb F is resistant
smear is further treated and stained with eosin or erythrosine
- normal adult red cells - ghost cells (mom)
- hgb F cells - stained baby
Fetal hgb cells can be quantitated to determine fetal trauma in pregant mom or hereditary persistance of hgb f
gower 1
gower 2
portland
embryo (z2e2)
embryo (a2e2)
embryo (z2 y2)
hemolytic anemia
resulting from the shortened survival of RBCs
RBC destruction lab findings
Decreased
- RBC count, hgb, hct
- haptoglobin
- hemopexin
increased
- total bilirubin
- methemal bumin
- hemoglobinemia
- hemoglobinuria
- LDH
RBC count
Bone marrow erythroid hyperplasia
(m:e shifting towards E)
osmotic fragility
determines RBC hemolysis resitance by placing blood in different concentrations of hypotonic saline
in hypotonic saline… RBC will take in water and swell, until
- reach equilibrium
- cell leaks/ruptures (lyses)
Thalassemia
- Hemolytic anemia
- hemoglobinopathy
- microcytic, hypochromic anemia
thalassemia definition
group of disorders that result in decreased production of globin chains in hgb resulting in microcytic, hypochromic anemia
defect in alpha or beta chain
thalassa is greek for
“sea” or “sea in the blood”
1st discovered by Thomas cooley and Pearl Lee
- first named “cooleys anemia” found in a population of mediterrabeab children
now termed Beta Thalassemia Major
haplotype
group of genes inherited together from a single parent
Chain 0
gene results in complete absence of globin chain.
ex: a0 or b0
Chain +
gene results in reduced production of globin chain
a+ or B+
type of thalassemia is going to named after the chain most affected
alpha thalassemia involved missing/mutated alpha genes
same with beta ^
Thalassemia pathophysiology
- abnormal gene causes failure to produce functional mRNA for specific globin chain
- any specific globin chain produced are structurally normal, but decreased (or absent)
- decerase amount of normal hgb(A1)
- rate of synthesis between a/b are not equal
- imbalance of 2 types of homologous chains
Alpha (a) thalassemia
excess beta and gamma globin chains build up
- Hemoglobin Bart’s = 4 gamma chains
- Hemolgobin H = 4 beta chains
tetramers are useless and precipitate in older cells
shorten life span by hemolysis
hemoglobin bart’s
4 gamma chains
hemoglobin H
4 beta chains
Beta B thalassemia
excess alpha build up
forms pairs of a2
pairs precipitate in RBC precursors
causes apoptosies in RBC precursors in BM
results in ineffective erythropoiesis
Beta thalassemia info
- high frequency in mediterranean area
- doesn’t present until switch is complete from gamma chain syntehsis -> beta chain syntehsis
1. usually after birth
2. clinically seen during 1st year of life
body compensates by increase gamma and delta chains to form hgb F and hgb 2
B thalassemia - B+
gene produces a reduced amount of beta chains
Type 1 B+
10% of normal beta production
- least amount of globin chains of the three types
Type 2 B+
50% of normal beta production
type 3 B+
have a greater amount of beta production and very mild symptoms
Normal conditions (B thalassemia)
Genetic haplotype: BB
No anemia
B Thalassemia Minor
haplotype: BB0, BB+
Also called Beta thalassemia trait
B thalassemia intermedia
B+B+
Less severe B+ types
B thalassemia Major
B0 B0
B+ B+
B0 B+
Most severe
B Thalassemia Minor
BB0 or BB+
- mild increase in Hgb F and Hgb A2
- mild microcytic, hypochromic anemia; although RBC count may be normal/increased
Usually asymptomatic, but may see symtpoms if under stress (ex: pregnancy)
B thalassemia intermedia
B+ B+, with less severe types
- not transfusion dependen t
- bridge between minor and major in terms of severity
- varible anemia symptoms
1. jaundice
2. splenomegaly
3. long surviving thalassemia symptoms - treatment: supportive therapy with occasional transfusion
B thalassemia major
B0 B0, B+B+, B+B0
(homo and heterozygous compounds)
Usually begins presentation during first year of life
- gamma chain - beta switching
symptoms: failure to thrive, pallor, anemia, enlarged spleen jaundice and irritability
B thalassemia major pathophysiology
Bone changes (skull, long bones, hand)
Liver and spleen enlarge - hepatosplenomegaly
B thalassemia major - bone changes
Hand Bone
Mongoloid faces
- overgrown “moon face” with prominent cheekbones, wide-spaced eyes, sunken nose, flot bones, face rounded.
Skull
- radiating striations giving typical “hair on end” appearance
B thalassemia major - untreated
Children will have numerous complications
- *massive hepatosplenomegaly - due to extramedullary erytropiesis *
- recurren tinfection
- spontanous fractures
- leg ulcers
- dental problems
Usually dies in early childhood or short after birth
B thalassemia major - treatment
Lifelong recurrent blood transfusion
splenectomy (after 5 yrs old)
Future options: BM/ stem cell transplant
B thalassemia major - treatment options
Mutliple transfusions + increased iron absorption (ineffective erythropoiesis) = iron overload
Transfusion treatment plans should include iron chelation therapy
B thalassemia major Lab findings
CBC
Hemoglobin electrophoresis
CBC
- low hgb (2-3 g/dl)
- low MCV, MCH, MCHC
- Increased RDW
Electrophoresis
- mostly Hgb F and Hgb A2
B thalassemia major - peripheral smear
Microcytic (4+), hypochromic (4+)
Anisocytosis and Poikilocytosis
Target cells
Schistocytes / fragments
Basophilic Stippling
Accelerated (ineffecive) erythropoiesis
- polychromasia
- lots of nRBCs
- Howell jolly bodies
Alpha thalassemia info
- asian populations
- manifest in utero or immediately at birth
- during fetal life
1. gamma chain build up
-After birth
1. beta chain buildup
Tetramers of excess chains form:
- Hgb Barts = 4gamma chains
- Hgb H = 4 beta chains
Alpha thalassemia haplotypes
2 alpha (a) genes (a1a2) are present on chromosome 16
a0 thalassemia = a thalassemia 1(–)
complete absence of any alpha chains
borth alpha genes on chromosome 16 are nonfunctioning
a+ thalassemia = alpha thalassemia 2 (-a)
- reduction in output of alpha chains
- one gene is functonal and other is nonfunctional
normal conditions
aa
(aa/aa)
silent carrier of alpha thalassemia
aa+
(aa/a-)
alpha thalassemia minor
aa0 (aa/–)
a+a+ (-a/-a)
Hemolgobin H disease
a0a+
(–/-a)
Hemoglobin Bart’s hydrops fetalis syndrome
a0a0
(–/–)
silent carrier of alpha thalassemia
aa+ (aa/a-)
small amount of hgb bart’s at birth, but disappears during development
- eventually leads to normal hgb electrophoresis
asymptomatic
most of you will see borderline low MCV (78-80 fL)
A thalassemia minor
aa0 (aa/–) or a+a+ (-a/-a)
- hgb Bart present at birth 5-15% but disappears during development and foes not go on to produce hgb H
1. eventually had normal hgb electrophoresis
Mild microcytic, hypochromic anemia
Hemoglobin H disease
a0 a+ (–/-a)
- variable degree of microcytic, hypochromic anemia and splenomegaly or bone related changes.
5-40% Hgb H (4 beta chains)
remaining is Hgb A1 and A2
Small amounts of Hgb Barts (4 gamma chains)
RBC gives “golf ball apperance” with supervital stain
Hemoglobin Bart’s Hydrops Fetalis Syndrome
a0a0 (–/–)
lethal disease - usually stillbirth or spontaneous abortion.
no alpha chains produces
only Hgb present after embryonic phase is :
Hgb Barts - 4 gamma chains
Length of gestation is dependent on Hgb Portland and Hgb Gower I production since Hgb Bart cannot deliver oxygen
Thalassemia general lab findings
CBC
- Low Hgb
- Low MCV
- Low MCH
- Low MCHC
Iron Studies
- N/ High serum iron
- high serum ferritin
- normal TIBC
- normal to high tranaferrin Sat%
Peripheral Smear:
- microcytic, hypochromia
- Reticulocytosis
- Poikilocytosis - elliptocytes, target cells, fragments.
Osmotic fragility
- decreased. due to higher surface to volume ratio
