hemoglobinopathies Flashcards
2 hemoglobinopathies
- sickle cell
- thalassemia
predominant adult hemoglobin
Hemoglobin A
* 2 alpha globin and 2 beta globin chains
- Stiff, sickle-shaped red blood cells
- Hemolytic anemia w/ significant clinical manifestations
Hemoglobin S: beta chain abnormalities
- A lab test that separates
DNA, RNA, or protein
molecules based on their
size and electrical charge - An electric current is used
to move molecules
through a gel with smaller
particles moving faster
than larger ones
Electrophoresis
caused by gene that results in HbS instead of HbA
* Abnormal beta-globin
* Autosomal recessive
* Causes shape distortion of deoxygenated Hgb
Common Chronic hemolytic anemia
sickle cell disease
how does sickle cell cause chronic organ damage
little ischemic events that cause lots of mini strokes and pain.
spleen usually first affected. cellular debris is cleaned out by spleen. it is working overtime and the gunk gets backed up in the spleen and it gets bigger and bigger. they’re spleen is not working.
how do sickled cells cause occlusive vascular crises
- These cells are also more fragile—chronic hemolysis
- Increased cell adhesion and platelet activation
- Release of inflammatory molecules
- Decreased nitric oxide availability
- Viscous blood
Most common in individuals from or descended from Africa (90% in the US), India, the Middle East, the
Mediterranean, the Caribbean, and Central and South America
- from malaria
sickle cell anemia
The betaS (sickle cell anemia) gene is seen frequently in
American Black children
when is sickle cell usually identified and symptomatic
identified on prenatal or newborn screening (everyone is screened)
Not symptomatic until 5-6 months of age.
how to confirm sickle cell after electrophoresis
- Confirm the diagnosis with HbS electrophoresis or genetic testing to
identify variant hemoglobins - May coexist with beta or alpha thalassemia, HbC
why is there a wide variation in clinical manifestations for sickle cell
hemoglobin F levels varies in people
What causes blood cells to sickle?
low oxygen problem
What is the role of hemoglobin F?
Transporting oxygen from mothers bloodstream to the developing fetus during pregnancy
Why are these patients immunocompromised? (Sickle cell)
Damaged spleen which works to filter out bacteria and other pathogens
signs and symptoms of sickle cell disease
- Chronic hemolytic anemia
- Jaundice
- Calcium bilirubinate gallstones
- Splenomegaly in childhood
- Poorly healing skin ulcers over the lower tibia
- Bone necrosis
- Can lead to osteomyelitis** (SICKLE CELL VIGNETTE)
- Salmonella, Staph
- Risk for life threatening anemia
- Hemolytic or aplastic crises (usu after infection)
sickle cell lab findings
- Chronic hemolytic anemia
- Hct is usually 20–30%.
- Peripheral smear: 5-50% of RBCs are sickled
- Reticulocytosis: 10–25%
- Nucleated RBCs
- Hallmarks of hyposplenism: Howell-Jolly bodies and target cells
- asplenia
- WBC count is often elevated to 12,000–15,000/mcL (12–15 × 109/L)
- Reactive thrombocytosis may occur
- Elevated indirect bilirubin
- Confirm diagnosis with electrophoresis: HbS
- Subset of Pts have persistent HgbF
abnormal red blood cells with nuclear remnants/clusters of DNA
- spleen is not working because these are usually removed from the body
Howell Jolly bodies
RBCs w/central round Hgb and pale rim
target cells
hallmark of sickle cell lab findings
Howell jolly bodies
- Moderately severe hemolytic anemia
- Reticulocytosis, hyperbilirubinemia
- Permanently sickled cells
- Chronic sickle cell
- Tissue hypoxia with damage
- Spleen, heart, kidneys, lungs
- Renal damage
- Growth impairment
- Risk for infection d/t spleen impairment (by adulthood asplenia)-
encapsulated organisms - Pneumococcus pneumoniae, Haemophilus influenza
- Septicemia, meningitis
CHRONIC sickle cell disease
- Vaso-occlusive crises, also called pain crises ***
- Vicious cycle of sickling, obstruction, hypoxia –> sickling….
- Hgb release from sickled cells binds and inactivates NO
- Episode of hypoxic injury and infarction
- Most patients with SCA experience pain by the age of 6
years. - Can be triggered by infection, dehydration, hypoxemia, cold
temperature, low humidity, stress, acidosis - Most of the time no specific trigger is known
- Bones, lungs, liver, brain, spleen, penis
- Bones are most common site in children—distinguish from osteomyelitis
- Hand-foot syndrome, ie dactylitis**
Perform a thorough evaluation for other life-threatening causes that can be misattributed to sickle cell pain
ACUTE CRISIS sickle sell disease
complications of sickle cell disease: acute crisis
- Vaso-occlusive crises
- Not associated with acute hemolysis
- Acute chest syndrome-can be fatal
- Crisis of the lungs
- Fever, cough, chest pain, pulmonary infiltrates
- Pulmonary inflammation can cause sluggish blood flow
- What then?
- Priapism
- 45% of males after puberty, can lead to ED
- Stroke, retinopathy
Sequestration crises-can be fatal
- In children with intact spleens
- Entrapment of RBCs leads to rapid spleen enlargement
- Hypovolemia –> shock
Aplastic crises (bone marrow stops working)
- Infection of red cell progenitors with parvovirus B19
- EPO cessation and sudden worsening of anemia
SCD treatment
allogeneic hematopoietic stem cell transplantation
(if performed before the onset of significant end-organ damage (for kids))
Hydroxyurea
(reduces complications, can be started at 9 months, increases Hgb F
* Used for more than 3 or more pain crises a year)
- Abx (helps in infection)
prophylactic Abx for kids with sickle cell
- Prophylactic PCN 125 mg orally twice daily until age 3 years
- Then 250 mg orally twice daily until age 5 years
- longer if pneumococcal vaccination series has not been completed or if there
is history of invasive pneumococcal infection or splenectomy - Routine vaccinations plus the following:
- 23-valent pneumococcal polysaccharide vaccine (in addition to 13-valent
conjugate pneumococcal vaccine) by age 5 years - Haemophilus influenzae type b for unvaccinated children > 5 years old
- Meningococcal vaccines: quadrivalent in infancy and Meningococcal B vaccine
at age 10 years - Additional screenings (Proteinuria, HTN, retinopathy and others)
SCD Crisis management
- Oxygen for sats <95%
- Fluids
- Pain control
- Fever control if needed
- Transfusion if needed
- Incentive spirometry
- Abx-for acute chest syndrome
- Monitor for and treat renal failure
- LMWH tinzaparin-shortens course
- Adjuvant therapy includes hydroxyurea, antihistamines, anxiolytics, and antiemetics
- Splenic crisis-monitor for hypovolemic shock
- Aplastic crises-supportive care and transfusions as needed
- Adaptive mutation
- Pts many not know they have it
- Amount of hemoglobin S varies
sickle cell trait
How does sickle cell trait manifest?
we don’t really know
- Pulmonary embolism?
- The renal medulla is acidotic
- Causes sickling
- Microscopic or gross hematuria
- Hyposthenuria
- Possible CKD-this relationship is not clear
- 2010 NCAA mandated screening for all Division 1 Athletes
- More likely to die from sudden death from high exertion
- Often on the first day of training
sickle cell trait
what to recommend to athletes with SCT
- stay hydrated
- set your own pace
- avoid altitude
- don’t exercise if you don’t feel well
- Reduced synthesis of alpha or beta globin chains
- Hereditary—autosomal recessive
- RBCs don’t get sufficient hemoglobin—>anemia
- Small, pale RBCs
- Normal or elevated RBC count
- Usu w/ elevated Retic count
- Significant variability in clinical presentation
thalassemias
Two alpha-globin gene copies on each chromosome 16
* i.e. four genes
* usually d/t gene deletion**
* More affected alleles = more severe
* 5% of world’s population
alpha thalassemia
- One beta-globin gene copy on each chromosome 11
- usually a point mutation***
- 1.5% of world’s population
beta thalassemia
Hemolytic anemia of variable severity: Worse with infections or other stressors
- Fatigue, dyspnea
- Possible pallor, splenomegaly, hepatomegaly, jaundice
- Frequent infections
- Cholelithiasis
Mild-to-moderate thalassemia-like skeletal changes such as:
* maxillary hypertrophy
* skull “bossing”
* prominent malar eminences (bony abnormalities)
- Leg ulcers (rare)
- Delayed growth in children
- Some level of iron overload–especially in older patients
alpha thalassemia signs and symptoms
CBC:
- Microcytic, hypochromic anemia
- RBC count normal or increased
- Serum Fe an Fe stores normal or increased
Peripheral smear:
- Target cells: central round Hgb and pale rim
- Teardrop cells: formed by abnormal/fibrotic bone marrow
- basophilic stippling: basophilic granules that are dispersed through
the cytoplasm of RBCs
- Heinz bodies in Hgb H – insoluble beta chain tetramers
- Howell-Jolly bodies - remnants of RBC nuclei that are normally removed by the spleen
- Hemoglobin electrophoresis
- Genetic testing
alpha thalassemia labs
hallmark of alpha thalassemia on labs
teardrop cells
Carrier treatment
none
trait treatment
none
⍺-Thal. Minor treatment
folate, avoid oxidative stress (sulfa drugs), avoid supplemental iron
Severe disease (Hb H) treatment
- Blood transfusions weekly
- Iron chelation therapy
- Splenectomy (stops RBC destruction)
- Bone marrow transplant (Hgb H)
Hb bart’s treatment
incompatible with life
Reduced or absent beta chain synthesis
* Increase in ratio of HgbA2 (delta) and Hgb F (gamma) relative to HgbA
* A variety of molecular defects
* Beta0=absent
* Beta+=reduced
* Variable degree
beta thalassemia
Minor beta thalassmia clinical presentation
asymptomatic. May have mild anemia
Intermedia beta thalassemia clinical presentation
Anemia, hepatosplenomegaly, bony disease
Major (Cooley’s Anemia) beta thalassemia clinical presentation:
- Asymptomatic at birth due to fetal Hgb
- Symptomatic at 6 months as fetal Hgb declines
- Frontal bossing and maxillary hyperplasia due to extramedullary hematopoiesis
- Hepatosplenomegaly
- Severe anemia with jaundice, dyspnea, and pallor
- Osteopenia (pathologic fractures)
- Iron overload
- Pigmented gallstones
CBC:
* MCV low
* RBC count may be increased
* Serum iron may be increased
- Peripheral smear:
- Target cells
- Teardrop cells
- Basophilic stippling
- Nucleated RBC’s
beta thalassemia labs
what does electrophoresis for beta thalassemia trait show
Increase in Hgb A2 –> alpha chains
couple with delta chains
what does electrophoresis for beta thalassemia major show
- Little to no normal Hgb A
- Increase in Hgb F –> Alpha chains
couple with gamma chains
Beta Thalassemia Diagnosis: X-rays
Bossing of the skull with “hair on
end” appearance (HALLMARK)
Result of extramedullary
hematopoiesis that results in new
bone formation in the skull producing perpendicular radiations
beta thalassemia treatment
No care necessary. Genetic counseling may benefit
beta thalassemia Major/severe anemia treatment
- Periodic blood transfusions
- Vitamin C and folate supplementation
- Avoid excess iron
- May require iron chelation w/ Deferoxamine
- Splenectomy if refractory
- Bone marrow transplant
