CMPP: Hemolytic Anemias Part 3

HBB, chromosome 11

sickle cell disorders result from mutation of the ____ gene which is located on ____________.

HBB gene

provides instructions for beta-globulin

hemoglobin S

sickle cell disorders are characterized by the presence of RBCs which contain...

autosomal recessive

the inheritance of sickle cell disorders is...

Hemoglobin S (HbS)

sickle hemoglobin that is made of alpha2/betaS2; found on chromosome 11 position 6 (beta chain issue)

chromosome 11 position 6 (beta chain issue)

sickle hemoglobin results from a mutation in what gene?

Glutamic acid --> valine

HbS results from the substitution of 1 amino acid on the beta chain. What is the original amino acid, and what does it get switched to?

Glutaminc acid is hydrophilic

Valine is hydrophobic

differences between glutamic acid and valine

beta

patients with sickle cell disorders have a genetic defect in the ____ chains

sickle cell disorders

what is the most common inherited blood disorder in the US?

sub-saharan Africa

there is a high prevalence of sickle cell disorders in what regions?

may provide protection against plasmodium falciparum -- disrupts life cycle and causes cells to lyse before protozoa can replicate

why has sickle cell prevalence increased due to natural selection?

thalassemia

G6PD

sickle cell

what are protective conditions against malaria?

DNA based tests (PCR)

--> chorionic villus sampling

--> amniocentesis

how does prenatal screening for sickle cell disorders work?

screening is MANDATORY

--> done via heel stick within 72 hours, and a second screen within 1-2 weeks

--> positive tests are then confirmed using DNA analysis

how do newborns get screened for sickle cell disorders?

National Sickle Cell Disease Control Act

focuses on providing the following for sickle cell disease -- information, education, counseling; screening, testing; research and treatment

45%

in the USAF, navy, and marine corps screen dismisses all individuals with HbS > ___

Sickledex test

is the screening for test that shows sickling of rbc's when oxygen tension is low; not a great test; done on Division I/II athletes

Sickle cell trait

heterozygous condition that occurs when one beta globin gene carries the sickle mutation and one normal allele; benign carrier condition; "usually" asymptomatic; life expectancy is not reduced

around 6 months -- prior to this, the majority of hemoglobin is HbF

around what time of life do HbS levels increase in those with sickle cell trait?

no, unless they are REALLY down bad

are sickle cells seen on peripheral smear for those with sickle cell trait?

HbA>HbS

adult electrophoresis results in one with sickle cell trait

usually asymptomatic, but there is some increased...

hematuria

renal medullary carcinoma

presentation of those with sickle cell trait

renal medullary carcinoma

what cancer is seen almost exclusively in young patients with sickle cell trait?

hematuria or flank pain

all sickle cell trait patient with what symptoms need additional workup?

splenic infarct, splenic sequestration, priapism, traumatic hyphema, DVT

--> can occur with sickle cell trait, but mostly occurs with sickle cell disease

what are some examples of vaso-occlusive phenomena?

dehydration, extreme hypoxia, low O2 concentration (altitude)

in sickle cell trait, vast-occlusive phenomena are RARE, but can occur under what conditions?

hematuria, CKD

Renal medullary CA

Rhabdo

Splenic infarct as high altitude

what are some health implications associated with sickle cell trait?

education!

treament for sickle cell trait

birth control

what medication can increase a patient with sickle cell trait's risk of DVT?

Sickle cell disease

it forms polymers and sickles

when HbS becomes deoxygenated, how does that change its shape?

repeated shape changes damage RBC membrane --> damaged cell membranes have a higher affinity for one another and start to stick

how do repeated shape changes associated with sickle cells affect RBCs long term?

right

HbS shifts the oxygen dissociation curve in what direction?

when HbS gives O2 to tissue, it sickles, which can lead to damage to RBC membranes and complications

how does the right shift associated with HbS pose problems to patients?

Right shift of HbS favors O2 release

Oxygen release results in deoxygenated HbS

Deoxygenated HbS sickles

cycle of HbS and the changing or RBC shape

Calcium enters the cell

Water and K+ exit the cells

Cells dehydrate and change shape

how does sickling occur in RBCs?

6 months -- high levels of circulating HbF is protective

patients are usually asymptomatic prior to what age?

chronic low-level vasoconstriction-occlusive pain

chronic anemia

icterus/jaundice

pigmented stones (cholelithiasis)

splenomegaly/functional asplenia

hematomegaly

skeletal changes (growth retardation and extra medullary hematopoiesis)

presentation of sickle cell disease

vasoocclusive crisis

what is the most common initial presentation of sickle cell disease?

reduced life expectancy

vaso-occlusive phenomena

chronic pain

health implications associated with sickle cell disease

Hb is very low

WBC is elevated (chronic inflammatory state)

Hemolytic picture (LDH, retic, unconjugated bili, low haptoglobin)

what are some unique lab findings associated with sickle cell disease

sickle cells, howell-jolly bodies, target cells

what cell types are present on peripheral smear for one with sickle cell anemia

HbA is SIGNIFICANTLY reduced

HbF is increased

HbS is SIGNIFICANTLY increased

what are the results seen on Hb electrophoresis for one with sickle cell disease

prevention

treatment of complications

cure

three-pronged approach to sickle cell disease treatment

stem cell transplant + gene editing drugs

what is the only available cure for sickle cell disease

infection

what is the leading cause of SS death in children?

acute chest syndrome

what is the leading cause of SS death in adults?

Penicillin V -- reduce pneumococcal infxns

prophylaxis of what drug should be administered in young children?

newborn period to age 5

when is penicillin V prophylaxis begun in children?

erythromycin

what drug for pneumococcal prophylaxis should be used if the patient has a PCN allergy?

101.5

fever > _______ is a medical emergency in those with sickle cell disease

all recommended childhood vaccines

annual influenza -- NOT live attenuated

COVID

what immunizations should a patient get if they have sickle cell disease?

PCV 20

MCV 4

Men B

what vaccines that are NOT a part of the standard childhood vaccines should be administered to those with sickle cell disease?

Strep. pneumoniae H. flu

common causes of infxn in children with sickle cell disease

S. aureus, E. coli, S. pneumoniae, Salmonella

common causes of infxn in adults with sickle cell disease

Hydroxyurea

foundation for management of sickle cell disease; prevents pain crises, reduces hospitalizations

increases production of HbF, which indirectly decreases HbS

Hydroxyurea MOA

suppresses all cell lines producing low WBC, platelets, and RBCs

side effect(s) of hydroxyurea

megaloblastic

hydroxyurea can cause what kind of anemia?

L-glutamine (antioxidant that prevents pain crisis/acute complications of SCD)

Folic acid prophylaxis (high cell turnover)

Daily multivitamin WITHOUT iron (high cell turnover)

what supplements should be given to those with sickle cell disease?

symptomatic anemia

acute stroke

multi-organ failure

acute chest syndrome

when are blood transfusions indicated in sickle cell disease?

since patients have chronic pain as well as acute pain episodes

why is pain control indicated for those with sickle cell disease

replaces the patients stem cells with donor stem cells

mechanism of action for allogenic hematopoietic stem cell transplantation

to prevent graft vs host disease

why is lifelong immunosuppression required after an allogenic hematopoietic stem cell transplant?

myeloid malignancies

an allogenic hematopoietic stem cell transplant increases the risk for...

vaso-occlusive complications not well controlled with medical therapy

--> acute chest syndrome, frequent pain episodes, stroke

indications for allogenic HSC transplantation

CRISPR/Cas9 gene-edited therapy modifies patients HSCs, which are harvested, manipulated, and then rein fused (modified autologous transplant)

mechanism of action for gene editing therapies in sickle cell disease

exagamglogene autotemcel (Casgevy)

lovotibeglogene autotemcel (Lyfgenia)

gene editing agents used in sickle cell disease

blood cultures

CBC with diff

metic count

empiric parenteral abx (preferably within 60 min)

if one with sickle cell disease has a fever > 101.5, what should be done after seeking medical attention?

HbS sickles during times of decreased O2 --> blood becomes more viscous --> microcirculation becomes obstructed --> ischemia or injury to organ occurs (painful)

why does vaso-occlusive crisis occur in those with sickle cell disease?

presence of HbA/HbF -- why we use hydroxyurea

what tends to have an inhibitory effect on the vaso-occlusive process associated with sickle cell disease?

nothing -- most often

hypoxia

dehydration

cold weather

ETOH intoxicaiton

pregnancy

emotional stress

risk factors for vaso-occlusive crisis in those with sickle cell disease

fever

swelling

HTN

N/V

acute pain

common symptoms of vaso-occlusive crisis in sickle cell disease

2-7 days, suddenly

on average, vaso-occlusive crises associated with sickle cell disease lasts ______ and terminates _____.

no

is increased frequency of sickled cells on peripheral smear diagnostic for vaso-occlusive crisis?

pain control (NSAIDs/opioids)

AGGRESSIVE rehydration

Abx

Hydroxyurea

Transfusion (IF necessary)

generic tx for vaso-occlusive crises

acute chest syndrome

what is the most common acute pulmonary disease in SS/leading cause of adult SS death

new infiltrate on CXR with fever, chest pain, hypoxia, wheezing, cough/respiratory distress

--> can look like pneumonia, so be careful to note PMH!

acute chest syndrome is associated with....

increased sickling in pulmonary microvasculature caused by infxn, hypoventilation, or bone marrow/fat emboli

MOA of acute chest syndrome

hypoxia, inflammation, acidosis

sickling in pulmonary vasculature causes...

IDENTIFY it!

Pain control (opioids)

hydrate (with caution)

supplemental O2 support

Empiric Abx

Venous thromboembolism prophylaxis

Transfusion (if necessary)

how to treat acute chest syndrome

can cause pulmonary edema

why should one hydrate patients with acute chest syndrome with caution?

Cefotaxamine AND Azithromycin OR moxifloxacin

what abx are indicated in acute chest syndrome?

Aplastic crisis

A condition characterized by pancytopenia, a rapid drop in Hb, WBC and platelets, and a retic count <1% that occurs in pts with underlying sickle cell disease; patient tends to recover within 7-10 days

within first 5 yrs of life

in those with sickle cell disease, splenic sequestration usually occurs...

Splenic sequestration

medical emergency that occurs when there is a pooling of sickled cells within the spleen

sudden onset splenomegaly, pallor, lethargy

presentation of splenic sequestration

rapid drop in Hb, hypovolemic shock, or death

the pooling/sequestering of sickled cells within the spleen can lead to...

Transfusions

IV hydration support

Elective splenectomy once stable to prevent recurrence (without this, recurrence is common)

treatment for splenic sequestration

Dactylitis

severe pain in small bones of hand and feet (hand-foot syndrome)

infants

Dactylitis is common in what population?

autoimmune hemolytic anemias

infection -- malaria, clostridium

microangiopathic anemia

extra corpuscular causes of hemolysis

no

does an XR show changes in Dactylitis?

hydration

pain control

warm compresses

initiate hydroxyurea

treatment for Dactylitis

Avascular necrosis

infarction of the bone trabeculae

femoral head, collapse of the femoral head

avascular necrosis usually occurs at the _________ can results in __________.

difficulty weight bearing

avascular necrosis presents with...

asplenia

why are osteomyelitis and septic arthritis common in SCD?

long bones

common site for osteomyelitis