Hemoglobinopathies Flashcards
what variables can shift the oxygen saturation curve?
pH, CO2, 2,3-BPG, temperature
what does a left-shifted oxygen sat curve mean?
you need a lower partial pressure of oxygen to have hemoglobin 50% saturated - which means hemoglobin holds on to oxygen, less likely to deliver oxygen to tissues
what does a right-shifted oxygen saturation curve mean?
a higher partial pressure of oxygen is needed to saturate hemoglobin - hemoglobin has less affinity for oxygen and more likely to deliver o2 to tissues
Composition of HbA
two alpha
two beta
Composition of HbF
two alpha
two gamma
Composition of HbA2
two alpha
two delta
Composition of Hb Gower I
two zeta
two epsilon
Composition of Hb Portland
two zeta
two gamma
Composition of Hb Gower II
two alpha
two epsilon
Composition of Hb Barts
four gamma chains
Composition of Hb H
four beta chains
what are the embryonic hemoglobin chains?
zeta
epsilon
when might you see an elevated hemoglobin F?
- bone marrow failure syndromes
- sickle-cell
- beta-thal
- hereditary persistence of hemoglobin F
when do you see hemoglobin barts?
four alpha gene deletion, resulting in tetramers of gamma chains
when do you see hemoglobin H disease?
three alpha chain deletion, resulting in tetramers of beta chains
how does a three alpha gene deletion manifest?
hemoglobin A, hemoglobin H disease mild anemia (usually NOT transfusion dependent), neonatal jaundice can have marked clinical variability
what is hemoglobin E?
beta + mutation with decreased production of beta globin chains. if compound heterozygote with beta 0, can result in transfusion dependent phenotype
how can homozygous mutations of beta globin gene present?
as transfusion dependent or non transfusion dependent - variable!
genetics of non-transfusion dependent beta thal?
can be heterozygote for beta+ or beta-0, or can be homozygous and need transfusions during times of erythroid stress
symptoms of beta thal trait (heterozygote) / minor?
usually asymptomatic
may have microcytosis, mild anemia
pathophysiology of iron overload in thalassemia
ineffective erythropoiesis and increased iron uptake by gut
complications of thalassemia
- poor growth
- pain
- iron overload - cardiac dysfunction, endocrinopathies
- pigmented gallstones
- pain as a result of marrow expansion
- skeletal abnormalities
endocrine effects of thalassemia
hypogonadism - due to pituitary iron deposition
hypothyroidism
insulin resistance/diabetes
poor growth
causes of cardiac dysfunction in thalassemia
severe anemia iron overload endocrinopathies (diabetes) pulmonary hypertension increased cardiac output vitamin deficiencies due to hypermetabolic state
possible late effects of splenectomy
thrombosis
pulmonary hypertension
how does a baby with a three alpha gene deletion present?
hemoglobin A (reduced), hemoglobin H disease (four beta chains), neonatal jaundice, hemolytic anemia
how do babies with beta thal present?
may become symptomatic around 6 months of life
peripheral film of beta thal or hemoglobin H disease?
microcytosis, hypochromia
bizarre RBC morphology
what other changes on hemoglobin analysis might you see with beta thal?
increase hemoglobin F (2alpha+2gamma) and A2 (2alpha+2delta)
hallmark of HbH disease?
elevated hemoglobin barts (4gamma) along with hemoglobin H (4beta)
what is hemoglobin E?
a mutation of beta globin gene, heterozygotes may have microcytosis and hypochromia. homozygotes have hypo/micro/target cells. minimal anemia.
only Hemoglobin F present in newborn?
deletion of delta and beta region
hereditary persistence of fetal hemoglobin
inheritance of SCD
autosomal codominant
how much hemoglobin S does a heterozygote (AS) have?
35-45% HbS
phenotype of alpha thalassemia co-inherited with HbSS?
less anemia, less SS complications
genetic cause of HbS
point mutation (A-T) in 6th codon of beta globin gene on chromosome 11, causing a glutamic acid to valine substitution
how to differentiate osteoporosis vs VOC as cause of bony pain
ESR
hx of bony crisis
pain in multiple locations
most common cause of death in HbSS
acute chest
prevention of ACS?
increased HbF (via HU, prophylactic RBC transfusions)
complications of HbSS?
VOC ACS stroke (usually ischemic) priapism splenic sequestration aplastic crisis
stroke prevalence in homozygous HbSS
11%
highest incidence in first decade of life
factors associated with increased risk of stroke
history of TIA sibling with HbSS and stroke recent ACS / frequent ACS hypertension nocturnal hypoxemia abnormal transcranial doppler
management of stroke in HbSS
if ischemic - exchange transfusion (goal: reduce HbS to < 30%), followed by chronic transfusion
if hemorrhagic - consider chronic transfusion
risk of recurrent stroke in HbSS
70% have recurrence within 3 yrs
how common is priapism in HbSS
30-45% of males with HbSS
75% of these occur before 20 yrs of age
when to go to ED with priapism?
episode > 2 hrs
prevention of priapism?
- pseudoephedrine QHS
- can try HU (although limited evidence)
- leuprolide injections to suppress HPA access
consider vasodilating agents (ie, sildenafil) - regular transfusions
how to differentiate splenic sequestration vs aplastic crisis?
reticulocytes (elevated in sequestration, suppressed in aplastic crisis)
when to consider splenectomy in child with splenic sequestration?
if one major or two minor splenic sequestration episodes
end organ damage in HbSS
- cognitive functioning / neuropsych deficits (silent stroke)
- cardiovascular function (chronic anemia / increased cardiac output), pulmonary hypertension
- chronic lung disease, pulmonary fibrosis, asthma
- renal failure
- chronic hepatomegaly
- pigmented gallstones
- avascular necrosis
- retinopathy (in HbSC)
- adenotonsillar hypertrophy (as a result of loss of splenic tissue)
which type of sickle cell is at increased risk of retinopathy
SC
causes of death in HbSs
infection with encapsulated organism
ACS
stroke
organ failure
how to prevent alloimmunization in child with HbSS
match for Rh and Kell (at minimum)
benefit of HU in HbSS
less VOC
less ACS
reduces mortality
dosing of HU
start at 15-20 mg/kg/day, increased Q8weeks until 35 mg/kg/day or favourable response
toxicity associated with HU
neutropenia thrombocytopenia bone marrow suppression (low retics) stomach upset, headache birth defects (child bearing age women should be on OCP)
indicators of response to HU
clinical improvement
lab parameters: increase in HbF (typically to 10-20%), rise in Hb of 10-20, increased MCV
defining feature of HbC
rhomboid / hexagonal crystals of hemoglobin
three things predicting outcome after BMT in patients with thalassemia? name of criteria system?
Pesaro criteria
- hepatomegaly > 2cm
- liver fibrosis
- irregular chelation
non blood test ways to measure iron overload
MRI liver / liver biopsy
SQUID
cardiac T2 MRI
