Hemaglobinopathies Flashcards
Where are the genes for globin located?
alpha globin clusters- 16p13.3 (zeta, pseudozeta, alpha1, alpha2)
beta gene cluster- 11.p15.5 (epsilon, two gammas, delta, beta)
List the structure of each kind of human hemaglobin.
HbA- alpha2; beta2 HbA2- alpha2;delta2 HbF- alpha2;gamma2 HbH- beta4 (abnormal) HbBart- gamma4 (abnormal)
What labs are used to evaluate hemoglobinopathies?
- CBC (shows amount of Hb in blood and gives MCV showing microcytosis and macrocytosis)
- sequencing of alpha and beta globin genes
- Hb electrophoresis
- Isoelectric focusing
- HPLC (NBS)
What are the possible results on HPLC and what do they indicate?
F>A: normal
F>A>S: sickle cell trait
F>S>A: sickle cell disease
What are the divisions of hemaglobinopathies?
quantitative (thalassemias)
qualitative (abnormal hemoglobins- HbS, Hbe, HbC, etc)
What are the possible thalassemia genotypes?
alpha thalassemia- deficiency in alpha globin production
beta thalassemia- deficiency in beta globin production
delta beta thalassemia- deficiency in delta and beta globin production
What are the possible thalassemia phenotypes?
minor/trait- asymptomatic
intermedia- moderate symptoms; some need transfusion
major- severe; transfusion dependent
Describe the general disease pathology of thalassemias.
decreased globin production imbalance in globin production excessive globin precipitates hemolysis ineffective erythropoiesis anemia, bone marrow expansion, extramedullary hematopoiesis (spleen and liver), increased iron absorption
Describe alpha thalassemia in general.
don’t make enough alpha globin –> too much beta, gamma, and delta globin so they pair with each other to produce excessive HbH and HbBart which are abnormal and disruptive
normally caused by deletions
What are the genotypes and phenotypes of alpha thalassemias?
normal= 4 functional genes
silent carrier= 3 functional genes
alpha thalassemia trait= 2 functional genes (cis or trans)
HbH disease= 1 functional gene
Barts/Hydrops Fetalis= no functional gene (not compatible with life)
Describe Alpha Thal Silent Carrier.
small DNA deletions removing 1 alpha gene (R or L cross-over results in one copy with one alpha gene and the other with three copies of the alpha gene)
completely asymptomatic
Describe Alpha Thalassemia Trait.
loss of 2 alpha globin genes
Asia: equal cis and trans
Africa: most all trans
in neonatal period can be diagnosed by excess HbBarts
once older HbH in small quantities (though may not be detected because it is too unstable)
presents with mild anemia, hypochromia, microcytosis
often mistaken for iron deficiency anemia (but will not respond to iron replacement)
otherwise asymptomatic
need counseling about inheritance risks (depending on whether cis or trans)
Describe HbH disease.
loss of 3 alpha genes –> thalasemia intermedia
excessive HbBart (neonatal) and HbH (older)
unstable hemaglobin –> hemolytic picture
moderate anemia and microcytosis
variable clinical presentation and therapeutic needs
Describe Hb Constant Spring.
HbH variant genotype --/alphaCS,alpha phenotype intermedia mutation in stop codon --> 31 aa longer --> unstable alpha globin chain prevalent in SE Asia present with a more severe phenotype
Describe HbBarts/Hyrdops Fetalis.
complete absence of alpha globin
incompatible with life
high levels of HbH and HbBarts
intrauterine transfusions with postnatal chronic transfusions and SCT are being utilized but not common practice
How are thalassemias related to intellectual disability?
ATR16: large deletions in 16p13.3
ATRX syndrome: point mutation in ATRX gene at Xq13.3
classic facial features include hypertelorism and broad nasal bridge
Describe beta thalassemias in general.
beta globin production decreased/variable percent (beta+) or absent (beta0) but alpha can still bind to delta or gamma globin which increases HbF and/or HbA2
problems begin around 6 months of age (transition from HbF to HbA dependent)
mostly point mutations (not deletions)
What are the phenotype/genotypes of beta thalassemias?
normal= beta beta
beta thalassemia trait= beta/beta0 or beta/beta+
beta thalassemia intermedia= beta+/beta+ or beta+/beta0 or betaE/beta+ or betaE/beta0
beta thalassemia major (Cooley’s anemia)= beta0/beta0
Describe beta thalassemia trait.
beta/beta0 or beta/beta+
asymptomatic
mild anemia, mild hypochromia, mild microcytosis
increased HbF and HbA2
often misdiagnosed as iron deficiency because it can mimic or mask it on hemoglobin electrophoresis (both will show falsely normal or low HbA2)
treat iron deficiency first to rule out
Describe beta thalassemia intermedia.
beta+/beta0 or beta+/beta+ or betaE/beta+ or betaE/beta0 mild to moderately severe anemia microcytosis and hyperchromia elevated HbF and HbA2 hepatosplenomegally possible wide clinical spectrum affected by alpha globin gene mutations as well (eg. triplications in alpha globin causing further imbalances) ALWAYS sequence both genes will see target cells on microscopy
Describe beta thalassemia major.
beta0/beta0
severe anemia develops in 1st year
severe microcytosis and hypochromia
organomegally and growth failure
transfusion dependent
hemochromotosis due to excess iron absorption and transfusion
clinical features: bony expansion, central bossing, hypertelorism, “hair on end” XR appearance
lifespan without bone marrow transplant is ~40-50 years but improved with chelation
What therapies/management strategies are available for beta thalassemia major?
BMT needed for cure
pharmaceutical induction of gamma globin (hydroxyuria only one approved right now- response is variable with large side effect profile)
gene/cell therapy
chronic “hypertransfusion” therapy
What are the tradeoffs of chronic hypertransfusion therapy?
Performed every 2-4 weeks aim for Nadir 10gm/dL suppress ineffective erythropoiesis improve growth and development decreases bony changes and organomegally Need: iron chelation, regular screening for iron overload, desferrioxamine/deferiprone/deterasirox, endocrine monitoring, growth/bone age checks, cardiac function tests, HIV/hepatitis serology
What do qualitative hemaglobinopathies affect?
decreased solubility (HbS and HbC) decreased O2 affinities (Hb Kansas) increased O2 affinity (Hb Syracuse) abnormal heme iron oxidation (HbM, methemoglobinemia) Instability (Hb Koln, Hb Hasharon)
What is Sickle Cell Disease?
point mutation in the beta globin chain (6 Glu –> Val)
AR
polymerize when deoxygenated–> give O2 –> de-polymerize (process damages membrane)
high frequency in Africa but found in some rates in North America, South America, South Asia, and the Mediterranean
most common inherited blood disorder in the US
diagnosed on NBS with confirmatory hemoglobin characterization needed
Describe the pathophysiology of Sickle Cell Disease.
erythrocyte adhesion to endothelium (VLA4-VCAM interaction)
scavenging and depletion of nitric oxide
increased adhesion and recruitment of neutrophils
activation of coagulation system
Name the types of Sickle Cell Disease.
HbSS (sickle cell anemia)
HbS/beta0 thalassemia
HbS/beta+ thalassemia
HbS/HbE syndrome
SbSC disease
HbS/hereditary presence of fetal Hb (S/HPHP)
rare combo of HbS with other abnormal hemoglobins such as HbD, G, HbO, and others
Describe HbSS.
sickle cell anemia
most common
homozygotes for S globin
usually severe or moderately severe phenotype with shortest survival
Describe HbS/beta0 thalassemia.
doubel heterozygotes for HbS and beta) thalassemia
clinically indistinguishable from sickle cell anemia
Describe HbS/beta+ thalassemia.
mild to moderate severity with variability in different ethnicities
Describe HbS/HbE syndrome.
very rare
phenotype similar to HbS/beta+ thalassemia
Describe SbSC disease.
double heterozygotes fro HbS and HbC
moderate clinical severity
Describe Hb (S/HPHP).
HbS/hereditary presence of fetal Hb
very mild/ asymptomatic
What lab findings are consistent with the sickle cell genotype SS?
Hb+: 6-9 HbS: >90% HbA: 0% HbA2: <3.5% HbF: <10% HbC: 0%
What lab findings are consistent with sickle cell genotype Sbeta0 thal?
Hb+: 7-9 HbS: >80% HbA: 0% HbA2: >3.5% HbF: <20% HbC: 0%
What lab findings are consistent with sickle cell genotype Sbeta+ thal?
Hb+: 9-12 HbS: >60% HbA: 10-30% HbA2: >3.5% HbF: <20% HbC: 0
What lab findings are consistent with sickle cell genotype SC?
Hb+: 9-14 HbS: 50% HbA: 0 HbA2: <3.5% HbF: <1% HbC: 45%
What lab findings are consistent with sickle cell genotype AS?
Hb+: normal HbS: <40% HbA: >60% HbA2: <3.5% HbF: <1% HbC: 0
What are some clinical findings of sickle cell anemia?
asymptomatic until about 6 months old
dactylitis (inflammation of fingers)
List the acute complications of sickle cell disease.
Vaso-occlusive pain crisis (VOC) Infection and fever CNS complications (eg. stroke) pulmonary complications (eg. asthma, restrictive lung disease, pulmonary HTN, acute chest syndrome) opthalmological cardiac acute anemias renal orthopedic
What is a vaso-occlusive pain crisis?
most common complication of SCD
bone pain due to necrosis after clotting
if pain is atypical, evaluate for other causes
What are other causes of pain in SCD?
chronic pain syndromes
neuropathic pain
How are vaso-occlusive pain crises managed?
analgesia within 30 minutes of triage NSAIDS/opioids antihistamines (PRN with opioids for ithcing) fluids O2
Why is it important to have infection prevention and fever management in SCD patients and how are they managed?
immune compromised at baseline
splenic dysfunction
increased susceptibility to encapsulated bacteria
use prophylactic penicilin at diagnosis (discontinue at age of 5 years if UTD on vaccinations)
if ANY fever is present –> immediate and emergent evaluation and management with blood culture and IV antibiotics
What is acute chest syndrome?
second most cause of hospitalizations for SCD patients
most common cause of death in SCD patients
respiratory symptoms plus “new infiltrate” on chest XR
generally treated with IV antibiotics and transfusion if that is not effective
What therapeutic options are available for SCD?
hydroxyuria (acts on S phase of cell cycle, ribonucleotide reductase inhibitor)
novel agents (anti-inflammatory such as Crizanlizumab or hemoglobin mods such as Voxelator)
allogenic HSCT (can use reduced intensity conditioning)
gene therapy
What is Hemoglobin C disease?
less soluble –> crystallization (intra and extracellular)
mild chronic hemolytic anemia
intermittent jaundice and splenomegally
target cells, microcytosis
What is Hemoglobin E disease?
both qualitative and quantitative
beta 26 Glu–> Lys mutation
most common in SE Asia
