Hemoglobinopathies Flashcards
hemoglobinopathy definition
disorder involving hemoglobin
disorder involving heme
porphyria
globins expressed embryonically
epsilon
globins expressed fetally
gamma, alpha (HbF)
globins expressed in adults
alpha, beta (HbA) & alpha, gamma (HbA2)
what types of deletions tend to affect the alpha globin?
deletional mutations leading to zero condition (no production)
what types of deletions tend to affect the beta globin?
nondeletional mutations which tend to lead to plus mutations (decreased production)
types of nondeletional mutations
transcription, mRNA processing, transport, translation, mRNA stability, protein function mutations
composition of typical adult hemoglobin
two alpha, two beta globins and heme
structural hemoglobinopathies
qualitative defects in hemoglobin function
examples of structural hemoglobinopathies
sickle hemoglobins, low/high O2 affinity, unstable hemoglobins, methermoglobins
thalassemia definition
quantitative defects in hemoglobin production (Hb made is normal, just not enough is made)
types of thalassemias
alpha, beta, hereditary persistence of fetal, fusion hemoglobins
most important thing to know about severity of thalassemia****
the degree of alpha/beta chain imbalance predicts the severity of the phenotype***
characteristics of thalasemmia anemia
microcytic, hypochromic
alpha thalassemia
deficiency in HbA (alpha/beta) with excess HbH (beta/beta)
HbH
beta homotetramer hemoglobin corresponding with alpha thalassemia. soluble and nontoxic
alpha thalassemia trait
-a/-a or –/aa. quite mild (slightly low levels of Hb, and slightly small MCV)
HbH disease
–/-a. high levels of HbH present. still quite mild symptoms
hydrops fetalis
–/–. complete alpha thalassemia. fatal before birth
most common alpha thalassemia in blacks
-a/-a. common but not an issue for offspring
most common alpha thalassemia in asians
aa/– common, which can lead to hydrous fetalis in offspring
beta thalassemia
deficiency in Hb (alpha/beta) and excess alpha homotetramers, which precipitate and are toxic!
beta thalassemia minor (trait)
B/B* (one of two genes is defective). decreased Hb & MCV. Increase HbA2 as compensation
beta thalassemia intermedia
B+/B* (two defective genes with one mutation being milder) or B+/B+ (two mild mutations). vast phenotypes, anemia, low MCV
beta thalassemia major
B/B (two defective genes). very anemic, very low MCV, 10% HbA2, 90% HbF as compensation.
characteristic most indicative of beta thalassemia?
increased HbA2 levels!
clinical presentation of severe beta thalassemia
family history, ethnic background, poor growth/development, jaundice, frontal bossing, splenomegaly, hypochromic/microcytic anemia with targeting, normal iron levels, INCREASED HBA2
consequences of alpha homotetramer precipitation
erythroid progenitor membrane damage=ineffective erythropoiesis & RBC membrane damage=accelerated removal=hemolytic anemia
—>both lead to profound anemia
consequence of ineffective erthyroid mass due to profound anemia in beta thalassemia?
compensatory erythropoiesis (marrow from atypical locations, frontal bossing) & extra medullary erythropoiesis (splenomegaly)
most common causes of microcytic anemia
iron deficiency & thalassemia
distinguish iron deficiency vs beta thalassemia
TEST IRON LEVELS
DIAGNOSE: Hb=9, MCV=74, Ferritin=2
Iron deficient anemia
DIAGNOSE: Hb=11, MCV=65, Ferritin=Nl
thalassemia
DIAGNOSE: A=94%, A2=5%, F=0%
increased A2=beta thalassemia minor (major would have higher A2, like 10% and increased F)
DIAGNOSE: Hb=3.5, MCV=57, Ferritin=1822
thalassemia
DIAGNOSE: A=0, A2=10%, F=90%
beta thalassemia major
treatment for thalassemia
PRBC transfusion or chelating agents (remove iron), bone marrow transplant
genetic basis of sickle cell disease
single missense mutation that results in Glu–>Val substitution in beta globin
cause of sickle shape?
when deoxygenated, Hb assembles into long polymer fibers that destroy RBC membrane structure.
theories on pathophysiology of sickle disease
log jam model, RBC dehydration, cellular adhesion, reduced NO bioavailability
treatment for chronic sickle cell disease
hydroxyurea=inducer of fetal gamma glob in (no hydrophobic site for polymerization). bone marrow transplant
blood characteristics of sickle cell disease
moderate anemia, normocyti/normochromic RBCs, drepanocytes (sickle)
AA Hb electrophoresis
A=97, A2=<3, F=0, S=0
AS Hb electrophoresis
A=60, A2<3, F=0, S=40 (40/60 RULE)
SS Hb electrophoresis
A=0, A2<10, S=90
DIAGNOSE: A=40, A2=5, F=0, S=60
co inherited beta thalassemia with sickle cell (B+ reducing levels of A, Bs increasing levels of S)
DIAGNOSE: A=80, A2=1.5, F=0, S=20
co inherited alpha thalassemia with sickle cell
DIAGNOSE: Hb=14, MCV=85, A=59, A2=2, F=0, S=39
sickle cell trait
DIAGNOSE: Hb=8, MCV=88, A=0, A2=2.5, F=2, S=96
sickle cell disease
DIAGNOSE: Hb=11, MCV=72, ferritin=477, A=10, A2=7, F=7, S=76
coinherited beta thalassemia and sickle cell in beta globin (Bs/B+)