8/10- Sickle Cell Anemia Flashcards
What is this?
Peripheral smear of pt with sickle cell anemia
What are the underlying genetics of sickle cell anemia?
- Base substitution: GAG -> GTG
- Val instead of Glu at B6 position
- Results in HbS hemoglobin (sickle-shaped when deoxygenated)
Why are sickle-shaped RBCs a problem?
Get caught in small capillaries and cause vaso-occlusion
What are some early clinical problems in sickle cell anemia?
- Splenic sequestration
- Splenic infarction (functional asplenia by 3-6 years of age; vulnerable to infection from encapsulated organisms, e.g. pneumococcal sepsis)
- Dactylitis
- Pain episodes
- Stroke
What can be seen on PBS to indicate absence of splenic function?
- Irreversibly sickled cells
- Targets
- Spherocytes
- Howell Jolly bodies (not seen here)
Also
- Normal MCV
- Many reticulocytes
- Sometimes young WBCs
- Nucleated RBCs
What are some physical exam findings indicative of splenic sequestration?
- Irritability
- Unusual sleepiness
- Looks pale
- Weakness
- Fast heart beat
- Big spleen
- Pain on left side of abdomen
What is seen here?
Splenic infarction (also polycystic kidney disease)
What is seen here?
Dactylitis
What is the sequence of events during the evolution of the prodromal phase of the pain crisis?
Tissue necrosis consequent to ischemia elicits an inflammatory response that is associated with an increase in the serum level of acute phase reactants
What is acute chest syndrome?
How may it be prevented? Treated?
- Vaso-occlusive crisis of the pulmonary vasculature commonly seen in patients with sickle cell anemia
- Common cause of death in sickle cell
- May develop on day 3-4 on a pain crisis
Prevention: incentive spirometry
Treatment:
- Antibiotics
- Oxygen
- Blood transfusion (simple in peds vs. exchange)
What is seen here?
CXR before and after transfusion in acute chest syndrome
Flowchart for diagnosis of acute chest syndrome?
What serious complication may occur in SCD?
Epidemiology?
Prevention?
Stroke!
- 24% have stroke by age 45
- Chronic transfusion therapy for primary and secondary stroke prevention
- Can also do transcranial Doppler ultrasound to see speed of blood indicating stenosis (vel > 200 cm/s = 40% risk of stroke in 3 yrs)
Why is RBC lysis bad in the bloostream in regard to released heme?
Released heme scavenges NO in the blood
How do the types of stroke vary by age in pts with SCD?
Young: hemorrhagic
Older: infarctive
Complications of SCD?
- Acute Chest
- Stroke
- Pulmonary HTN
- Bony deformities
- Avascular necrosis
- Ankle ulcers
- Sickle cell retinopathy
What is pulmonary HTN? Diagnosis?
- Tricuspid regurgitant velocity (TRV) > 2.5 m/s (significance uncertain in pediatric pts)
- Increased TRV is a risk factor for early mortality
- Diagnosis: right heart catheterization
What skeletal issue may be observed with SCD? Describe?
Bony deformities
- Increased width between vertebrae???
What does avascular necrosis result from?
Consequence of microvascular disease
- More common in SCD
What is this?
Sickle cell retinopathy
What is the life expectancy of adults with SCD?
HbSS;
- Males; 42 yrs
- Females: 48 yrs
HbSC:
- Males: 60 yrs
- Females: 68 yrs
What are the causes of death in sickle cell disease?
Organ failure:
- Renal
- Hepatic
- Pulmonary HTN
Acute events:
- Acute chest syndrome
- Stroke
- Sepsis
On what does the variable clinical severity of SCD depend?
- Beta globin haplotypes
- HbF levels (repressors: BCL11A, HBSIL-MYB; mutations in these may increase HbF levels)
- a-Thalassemia co-inheritance
How many independent mutations of SCD are there?
4 independent mutations
Effect of fetal hemoglobin in SCD?
- HbF inhibits HbS polymerization (gamma87 glutamine of HbF prevents lateral HbS contact)
- First evidence of SCD occurs 6-12 mo after birth
- HbF levels are the best predictor of disease severity
- HbS-HPFH pts are similar to sickle cell trait
Benefits of HbF cells:
- Long lived
- Don’t require same increment of HbS induced damage as non-F cells
- Less likely to initiate adhesive events
- Associated with protection from sickle vaso-occlusion … more
How does alpha-thalassemia co-inheritance interact with SCD?
- Microcytosis
- Less Hb in the cell -> lower Hb concentration
- Less sickling -> less hemolysis
- Higher hemoglobin levels: higher viscosity
Preventive care of SCD?
Newborn Screening
Prenatal Counseling Preventative Care
- Vaccines for pneumococcus, HIB, meningococcus, Hep B
- Prophylactic penicillin until 5 years of age
Periodic checks
- UA:proteinuria
- Opthalmology exams: proliferative retinopathy
- Echocardiogram?
Transfusion therapy for SCD (when useful)?
- Primary and secondary stroke prevention
- Aplastic crises
- Acute chest syndrome
- Prior to general anesthesia
- Complicated pregnancies
- NOT used for pain crisis treatment or prevention
Complications of transfusions?
- Iron overload (Ex-Jade)
- Alloimmunization (problem matching typically African SCD pts with predominantly white blood donors)
- Hyperhemolysis syndrome (break down donated blood as well as your own)
How is Hydroxyurea (drug) used to treat SCD?
- Hydroxyurea increases HbF, which suppresses sickling
May also:
- Decrease endothelial adhesion
- Decrease WBC (pic 14)
What is seen here in regard to treatment?
Effect of hydroxyurea on PBS (untreated on left, maximal dose of hydroxyurea on right)
- Increases in hemoglobin (Hb), mean corpuscular volume (MCV), and percentage fetal hemoglobin (HbF) occur simultaneously with decreases in white blood cell count (WBC), absolute neutrophil count (ANC), ARC, and lactate dehydrogenase (LDH)
- Morphologic changes to the erythrocytes include nonreticulocyte macrocytosis, increased numbers of target cells, fewer sickled forms, and relative “blunting” of the sickled cells that remain in circulation.
How is maximum tolerated dose determined for hydroxyurea?
- ANC: 2000-2000E6/dL
- ARC > 70E6 (absolute reticulocyte count)
What is the effect of HU on lab values?
- MCV increases
- HbS decreases
- HbF increases
- Typ 1-2 g/dL rise in Hb
What are some side effects/warnings of hydroxyurea?
- Causes birth defects in animals exposed to high doses in utero
- Theoretical increased risk for hematologic maligancies
- GI symptoms
- Skin hyperpigmentation (rare)
- Excessive myelosuppression
Clinical(!) benefits of Hydroxyurea
- 50% reduction in pain crises
- 50% reduction in ACS
- Reduction in hospitalizations, transfusions
- Mortality benefit
Not Known:
- Stroke reduction
- Effect on PH
- Effect on CRI
Hydroxyurea vs. Stem Cell Transplant
How is sickle cell disease inherited?
Autosomal recessive
What are some sickle cell disease genotypes?
(genotype, name, severity, % Hb types)
Note: B+ makes some amount of normal B Hb
Describe sickle trait
- Epidemiology
- Phenotype
- Protective benefits
- 8% of African Americans
- 20% of West Africans
- 70% malarial protection
- Normal CBC
- Normal peripheral blood morphology; no sickling on the smear (even when pt is hypoxic)!
- Not a disease
What are some clinical manifestations of sickle TRAIT?
- Splenic infarction at high altitude
- Asymptomatic bacteriuria in pregnancy
- Hyposthenuria
- Hematuria
- Sudden death during exercise
- Renal medullary carcinoma
What is Hemoglobin SC disease?
- Compound heterozygote
- 50% HbS, 50% HbC
- HbC doesn’t sickle, but dehydrates cell (fewer sickled, lots of targeting, very dense spherocytes)
- Moderate to variable severity
- 25% of SCD
Hemoglobin C vs. Hemoglobin S
- Genetic mutations
- AA substitution
- Effect of mutation on Hb (structure and effect on RBC)
- Malarial protection
Pathophysiology of HbSC vs. HbSS
HbSC:
- Concentration of HbS in cell is more important than the overall % of HbS
- Hb levels range from 11-13 g/dL compared to 7-9 g/dL
- Viscosity related complications, not hemolysis related
How does the clinical course of HbSC differ from HbSS?
HbSC:
- Generally milder course
- Spleen may be functional into early adulthood (hypofunctional, splenic infarcts sequestration in adults)
- Retinopathy and AVN are more common
What is seen on the PBS of HbS-B thalassemia?
- Microcytosis
- Target cells (more)
- Increased A2
How does the clinical course of Hbs- B thalassemia compare to HbSS?
- HbS-B0 is clinically similar to HbSS
- HbS-B+ is variable
Treatment for SCD subtypes?
- HbSC and HbS-Bthal+ were not included in hydroxyurea clinical trials
- Some centers report benefit from phlebotomy in HbSC
