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