5-Sickle Cell Anemia (Lecture + Syllabus)
In SCD, priapism is thought to be caused by sickling of RBC's in _____ of penis leading to sludging and increase in intrapenile pressure
corpora cavernosa
The ________ becomes dysfunctional during infancy and the risk for serious infection by S. pneumoniae is highest in first 3 years of life
spleen
Eventually nearly half of patients will experience recurrence of splenic sequestration and ______ is performed
splenectomy
The risk for stroke in SS is highest in first 20 years of life, ______%, with a peak incidence between 4 and 8 years of age
10
_____ of SCD patients get IPD by age 5
10%
Priapism can occur as early as ______ of life and approx 30% of boys will have an episode by age 15
1 year
List 3 high risk features for bacteremia: _____appearing, WBC_____, temp_____
1) ill , 2) WBC>30,000 or <5000, 3) temp > 39.5 deg celsius
Giving SCD patients 2 vaccines against S. pneumonia and twice daily prophylactic penicillin for first 5 years of life have reduced the occurrence of invasive pneumoccoal disease by ____
10-20 fold
In sickle cell disease, RBC lifespan is ______ days, so cessation of RBC production for 10-14 days can lead to _______
10-20, profound anemia
SCD patients have _____ the risk of invasive pneumococcal disease (IPD-bacteremia or meningitis)
100-300x
_______ newborns per year with sickle cell disase
150
____ African Americans carry sickle cell trait
1:12
_______ of the general population have sickle cell disease
1:2500
____ African Americans have sickle cell disesase
1:400
Peak incidence of ACS is between ____ years
2-4
____ in Nigeria and _____ in India with SCD
4 million, 1 million
Aplastic crisis occurred in _____ of infants in a Jamaican cohort
40%
Hospitilization for stroke has decreased by ____ since TCD introduced in 1998
50%
Regular transfusions reduce risk of stroke by _____
90%
There are ______ Americans with SCD
90,000-100,000
Therapy of iron overload requires an exogenous ________ because humans lack a mechanism to increase excretion of excess iron
chelator
Common eitologies of ACS include: ______ embolism, _______, ________, viruses
chlamidya, mycoplasma
Pathogenesis of _______ varies depending on cause but commonly includes inflammation, pulmonary vascular occlusion, ventilation/perfusion mismatch, airway hyper-reactivity, and pulmonary edema
ACS (common with asthma/reactive airway disease)
______ is reaction against dissimilar antigens on the RBC membrane of the transfused cells by the recipient's immune system
Aloimmunization
Gallstones may not need intervention. Symptomatic stones or stones obstructing bile duct require _________
cholecystectomy
________ is obstruction of the biliary outflow tract by gallstone
Cholelithiasis
Sickle cell disease is a ________ anemia
chronic hemolytic
Hydroxyurea increases expression of ________
fetal hemoglobin (Hgb F)
Iron chelators include ________ (old), ______, ______
Deferroxamine (SC), Deferasirox (1x/day), Deferiprone (TID)
________ for TR jet velocity is commonly used as a screening test for PAH in adults with SCD
Electrocardiography
What factors influence polymer formation? _____, _______, & _______
low O2 tension, low pH, high intracellular [Hgb S]
Risk factors for stroke in SCD: _______, ___________
low baseline hemoglobin, recent pain crisis or chest syndrome
_______ is known to inhibit polymerization of HgbS, primary mechanism underlying SCD pathogenesis
Hgb F
________ is protective in vaso-occlusive crisis
High baseline FETAL hemoglobin
In the heterozygous state, the sickle mutation is protective from the _______ species of malaria and likely confers a survival advantage leading to continued high prevalence in sub-Saharan Africa and Middle East/India
Malaria Falciparum
_____ patients will have an ACS episode at some point
Most
_____ may occur in many locations throughout the body although lower back, legs, and arms are most common
VOCs
_______ are commonly triggered by infection, emotional stress, exposure to cold, wind, or high altitude (low O2 tension)
VOCs
Clinical outcomes of stroke include: ________ and _______
Neurocognitive deficits in all, Motor deficits in some
Symptoms of _______ may include exertion dyspnea, fatigue, and syncopal events
PAH
Less Clear indications of chronic transfusion: (tons)
Prevention of silent cerebral infarction - Severe, frequent acute chest - Severe, frequent VOC - Severe baseline hypoxia - Severe baseline anemia - Short-term following severe or life threatening event
_______ is a prolonged, painful erection in penis with typical onset in early morning
Priapism
_______ is a severe complication of SCD which typically occurs in adulthood
Pulmonary artery hypertension (PAH)
Management of an initial splenic sequestration episode typically includes cautious ______
RBC transfusion
1st event usually later (~8-10yrs) in ____
SC (sickle hemoglobin-C)
First splenic event is before age 2 in _____
SS (sickle cell anemia)
______ is the most common disease identified on newborn screening
Sickle cell disease
_________ refers to a group of heterogenous disorders which are unified by presence of at least one beta globin gene affected by sickle mutation
Sickle cell disease
A predilection to infection by encapsulated bacteria _______, has long been recognized in children with sickle cell disease, particularly those with sickle cell anemia (SS), due to functional asplenia
Streptococcus pneumoniae (also Neisseria meningiditis, Haemophilus influenzae)
Pathophysiology of stroke: ______
cerebral vasculopathy
Proliferation of intima / media of major vessels is known as _______
cerebral vasculopathy
______ predicts high risk for stroke
Transcranial doppler ultrasound (TCD)
Sickling of RBC leads to local _______ and worsening ____ which leads to further sickling in a vicious cycle toward further outflow tract obstruction and severe pain
acidosis, deoxygenation
Clinically, ___ is defined by a new pulmonary infiltrate on chest radiograph in addition to 1 or more of additional sign
acute chest syndrome
The presenting symptoms of ______ in SCD include hemiparesis, facial droop, aphasia, and more generalized symptoms including stupor and rarely seizure
acute stroke
Treatment of an acute episode of priapism may include aggressive _______ and pharmacologic efforts to decrease vascular engorgement of cavernous through agents like ________ , ______,and __________
analgesia, pseudoephedrine, etilefrine, lupron
Sickle cell anemia can affect _____ ethnicity
any
______ and _______ of cavernous by a urologist may be necessary for prolonged episodes
aspiration, irrigation
When hemoglobin is released from the red cell, _______ is produced leading to jaundice
bilirubin
Because of ongoing risk of IPD, all fevers (> 38.5 deg celsius) must be evaluated emergently with _______, ______, and ______
blood culture, blood count, empiric antibiotics
Regular _________ is required for patients on hydroxyurea
blood monitoring
List acute complication of VOC common in infants and young children that causes pain in hands and feet: ______
dactylitis
Potentially as a result of polymerization, other pathophysiologic mechanisms have been observed in SCD including: activation of vascular ____, _______, leukocyte _______, platelet _________, ______ from tissue re-perfusion
endothelium, leukocytosis, activation, activation, oxidative stress
Severe, _______ is classic hallmark of SCD
episodic pain
IF prolonged episode of priapism is untreated, fibrosis of cavernous may develop leading to permanent ________
errectile dysfunction
The physical exam for a patient with VOC may reveal ______, ______, _____, or ____, but these signs are usually absent from older children and adults and are not required for dx
erythema, edema, joint effusions, point tenderness
Treatment for acute phase stroke: _______
exchange transfusion
There is a ______ rate of recurrence of stroke in SCD without intervention
extremely high
List 7 steps in vaso-occlusion in SCD
faso-occlusive crisis1. Endothelial activation by RBC's & others 2. Recruitment of adherent leukocytes 3. Activation of recruited neutrophils & other leukocytes 4. Interaction of sickle RBC's with neutrophils 5. Vascular clogging by heterotypic cellular aggregates (± platelets) 6. Increased transit time of RBC's 7. Local ischemia creates feedback loop - worsens much of the above
SCD patients without high risk features may be discharged from ED provided _______ is available
follow up
SCD patients are at risk of IPD due to ________
functional asplenia
Iron loading occurs primarily in ______, _______, and _____ glands in patients with SCD and severe overload can result in morbidity and mortality
heart, liver, endocrine
__________ is the only curative option for patients with SCD
hematopoietic stem cell transplantation (HSCT)
A minor decreases in ___ from baseline and increased ____ are common but non-specific laboratory features of VOC
hemoglobin, white blood cell
The sickle mutation leads to the replacement of a hydrophilic glutamic acid by the ________ at position 6 of B globin protein
hydrophobic valine (GAG--> GTG)
Prevention of VOCs and dactylitis can be aided by avoidance of precipitating factors, use of ________ and maintenance of intravascular volume through oral fluid intake
hydroxyurea
_______ has been shown to reduce VOCs, ACS, blood transfusions, all-cause hospitalizations, and confers a survival advantage
hydroxyurea
________ is theorized to be a teratogen and is contraindicated in pregnancy and can rarely cause alopecia, decreased sperm count, and nausea
hydroxyurea
__________ is the only medication approved by FDA for treatment of SCD
hydroxyurea
Risk factors for VOC include ______, ______, and _______
increasing age in childhood, severe genotype (SS or SB0), high baseline hemoglobin
Sickle cell mutation does not prevent ______, just decreases likelihood of death from Malaria falciparum
infection
In addition to iron overload, transfusion related _______ and ______ formation are other potential complications of chronic transfusions
infection, alloantibody
RBC deformability and injury of RBC cytoskeleton caused by presence of Hgb S polymers ultimately result in both ______ and ______ hemolysis
intravascular, extravascular
Simple transfusion is most commonly used and carries risk of ______
iron overload
In children, most strokes in SCD are _______ in nature with hemorrhagic stroke accounting for less than 10% of the total whereas _______ stroke are more common in adults
ischemic, hemorrhagic
Hydroxyurea failed to preserve ______ and ______ function and has minimal toxicities other than myelosuppression
kidney, spleen
Exchange transfusion, either by _____ exchange or ________, is an alternative to simple transfusion which appears to greatly decrease iron loading in patients on chronic transfusions
manual, erythrocytopheresis (machine directed)
Treatment for chronic stroke: _______ vs _______
monthly transfusion, bone marrow transplant/hematopoietic stem cell transplant
It has been suggested that _____ depletion secondary to intravascular hemolysis may contribute to certain complications of SCD like pulmonary artery hypertension (controversial)
nitric oxide
There is ___ prevention for splenomegaly, although maternal education can help
no
In hematological normal children, arrest in RBC production is _______ because of 120 day lifespan of normal RBCs
not problematic
To treat VOC, we give ______, _______, and ______ as palliative measures
opioids, anti-inflammatory, IV fluid
Treatment of ACS includes: supplemental_____, _____, mechanical_____,empiric _____, _____, and careful management of______
oxygen, transfusion,ventilation, antibiotics (ceftriaxone and azithromycin) including macrolide coverage for atypical pathogens, bronchodilators, analgesia and IV fluids
In children, signs and symptoms of anemia include ______, _________, _____ activity, altered_______, and poor_______ are typical of aplastic crises
pallor, fatigue, reduced, mentation, and feeding
Infection by _________ leads to maturation arrest for RBC presursors in bone marrow for approx 10-14 days
parvovirus B19
How to prevent aplastic crisis? Give _____
parvovirus vaccine
Limitations to use of HSCT include ____ of matched siblings and _______ of suitable unrelated donors due to poor representation of minorities in bone marrow donor pool
paucity, unavailability
The most important risks of HSCT include ______ mortality, _______ disease, graft ______, and conditioning-induced infertility
per-transplant (infection), graft vs host, failure
Repeated episodes of ______ and _______ can cause a RBC to be irreversibly sickled
polymerization, sickling
Presence of hydrophobic valine residues allows HgbS to ______ in the deoxygenated state
polymerize
Classic indications for chronic transfusions are for _____ and _______ stroke prevention
primary, secondary
There are two forms of priapism: 1) _________-an episode of ______ duration 2) ________-self-limited episodes that can occur in clusters
prolonged, 4, stuttering
Rapid enlargement of _____ with resultant trapping of blood elements is known as acute splenic sequestration and occurs in approx 30% of children with anemia by 5 years of age
spleen
The suppression of endogenous RBC production by _______ of donor RBCs is another means b which complications of SCD may be ameliorated
regular transfusion
In aplastic crisis, lab eval revelase severe anemia with _______ and __________
reticulocytopneia, occasional thrombocytopenia
Hydroxyurea inhibits _______ (enzyme)
ribonucleotide reductase
Presenting signs and symptoms of cholethiasis in SCD include _______ or _______ abdominal pain, vomiting, and ________
right upper quadrant, epigastric, jaundice
Co-inheritance of B thalassemia mutation with the sickle mutation leads to ______ or _______ which accounts for 5-10% of all SCD
sickle B0 thalassemia (SB0) or sickle B+ thalassemia (SB+)
Homozygotes for sickle mutation have _______ or _______ which accounts for 60-65% SD
sickle cell anemia (SS) or hemoglobin SS disease (Bs/Bs)
Hemoglobin C, when co-inherited with the sickle mutation leads to ______ accounting for 25-30% of all SCD in US
sickle hemoglobin C disease (Bs/Bc)
Hgb S polymerizaiton ultimately causes RBCs to take on characteristic ________ in a reversible fashion
sickle shape
Transplantation works by replacing _____ erythrocyte progenitors with _______ erythrocyte progenitors in bone marrow
sickle, normal
Evaluation of a child with splenic sequestration will reveal ______ , a ______ below baseline, and _______, as all blood elements will be trapped in enlarged spleen
splenomegaly, hemoglobin, thrombocytopenia (profound anemia, decreased Hgb and platelets)
Increased bilirubin is stored in gall bladder and can precipitate to form ______
stones
HSCT is typically reserved for patients affected by severe of life threatening complications of SCD including _____ and _______
stroke, ACS
acute chest syndrome= new pulmonary infiltrate on chest radiograph + 1 or more: fever, _____, _____, chest pain, ______
tachypnea, dyspnea, hypoxia
The management of aplastic crisis includes ______ as needed until reticulocyte recovery has occured
transfusion support
In circulation, stiff, non-deformable sickled cells can lead to ________ with resultant tissue ______
vaso-occlusion, ischemia
Acute painful episodes in SCD, aka _______ last hours to many days
vaso-occlusive crisis
_______ can occur from infancy until old age and pathophysiologic mechanism is _________ with resultant infarction
vaso-occlusive crisis, bone marrow ischemia