Chapter 36 - Sickle Cell Disease

Question 1

RBCs have a lifespan of:

Answer 1

90 - 120 days

Question 2

RBCs have adult hemoglobin (…) that are shaped like …

Answer 2

• HbgA
• Donut

Question 3

What is Sickle cell disease (SCD)

Is it a dominant or recessive gene?

Answer 3

A group of inherited RBC disorders resulting from a genetic mutation in the genes that encode hemoglobin

Recessive
Patients with homozygous inheritance of the sickle cell gene (i.e., they have two copies of the mutated gene) have RBCs that contain abnormal hemoglobin, called hemoglobin S (HgbS or sickle hemoglobin).

Question 4

• After how long do sickled RBCs burst?
• What population does SCD most commonly affects?

Answer 4

Sickled RBCs burst (hemolyze) after 10 - 20 days, which causes anemia and fatigue.

SCD most commonly affects the African American population.

Question 5

• What other complications do sickled cells do?
• After how long do sx of SCD develop?

Answer 5

The irregularly shaped RBCs are unable to transport oxygen effectively, and they stick together, blocking smaller blood vessels (vascular occlusion)

Symptoms of SCD develop approximately 2 - 3 months after birth.
This is because a fetus and young infants have RBCs with fetal hemoglobin (HgbF), which blocks the sickling of RBCs.

Question 6

What can you use to measure the amount of each Hgb (A, F and S) in the blood?

Answer 6

• Hemoglobin electrophoresis test
• High-performance liquid chromatography (HPLC)

Question 7

What does vascular occlusion lead to?

What is vaso-occlusive crisis (VOC)?

Where does VOC most commonly occur?

Answer 7

Vascular occlusion prevents oxygen from reaching the tissues, causing them to become ischemic.

This can lead to different types of sickle cell crises, the most common of which is vaso-occlusive crisis (VOC), or acute pain crisis.

VOC most commonly occurs in
- lower back
- legs
- hips
- abdomen
- chest
can last for days or weeks

Question 8

What is acute chest syndrome?
How severe is it?

Answer 8

If the pain is in the chest and there is evidence of a pulmonary infection, it is called acute chest syndrome.

Acute chest syndrome is life-threatening and is the leading cause of death in SCD

Question 9

What should females with SCD use as a method of contraception? Why?

Answer 9

Due to the risk of acute stroke, females with SCD should NOT use estrogen;

The preferred methods of contraception are:
- Progestin-only contraceptives
- Levonorgestrel intrauterine devices (IUDs)
- Barrier methods

Question 10

What are the most common chronic complications of SCD?

Answer 10

• Chronic pain
• Avascular necrosis (bone death)
• Pulmonary hypertension
• Renal impairment

Question 11

What are the acute SCD complications?

Answer 11

1) Acute chest syndrome (#1 leading cause of death from SCD)
2) Anemia
3) Cholecystitis (gallbladder infection)
4) Infection
5) Multiorgan failure (kidneys, liver, lung)
6) Priapism (painful and prolonged erection)
7) Spleen sequestration
8) Stroke
9) Vaso-occlusive crisis (acute pain crisis) (Vascular occlusion most commonly causes VOC)

Question 12

What are the chronic SCD complications?

Answer 12

1) Avascular necrosis (bone death)
2) Leg ulcers
3) Gallstones
4) Pain
5) Pregnancy complications (including fetal death)
6) Pulmonary hypertension
7) Renal impairment
8) Retinopathy
9) Recurrent priapism

Question 13

What is the function of a healthy spleen?

Answer 13

A healthy spleen has several physiologic roles, including the removal of old or damaged RBCs

It aids in immune function, making and storing white blood cells and clearing some types of bacterial pathogens from the body, particularly the encapsulated organisms Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis

Question 14

What happens to the spleen in SCD pts?

Complications? Counseling for those pts?

Answer 14

• In SCD, the spleen becomes fibrotic and shrinks in size due to repetitive sickling and infarctions.
• This causes functional asplenia (decreased or absent spleen function), typically within the first year of life.
• Patients with functional asplenia are at an increased risk for serious infections;
• They require immunizations
• Prophylactic antibiotics
• Should seek medical attention when temperature is > 101.3°F.

Question 15

1- What is a Non-drug treatment for SCD

2- What are some acute complications that warrant treatment with blood transfusions?

3- When administering chronic (monthly) blood transfusions, the goal Hgb level should be:

4- What is one of the risks of blood transfusions? How do you manage it?

Answer 15

1- Blood transfusions protect against many of the life- threatening complications of SCD by providing RBCs with HgbA.

2- Stroke, acute chest syndrome and severe anemia

3- No higher than 10 g/dL post-infusion

4- Iron overload, which can lead to hemosiderosis (excess iron that impairs organ function). Chelation therapy to remove excess iron

Question 16

1- What is the only cure of SCD?

2- Is it a widely used approach? Why?

3- What population is more likely to tolerate it?

Answer 16

1- Bone marrow transplantation.

2- No, Due to the high risks; invasive treatment & substantial cost

3- Children are more likely to tolerate bone marrow transplantation than adults, who have accumulated organ damage.

Question 17

1- What is the only cure of SCD?

2- Is it a widely used approach? Why?

3- What population is more likely to tolerate it?

Answer 17

1- Bone marrow transplantation.

2- No, Due to the high risks; invasive treatment & substantial cost

3- Children are more likely to tolerate bone marrow transplantation than adults, who have accumulated organ damage.

Question 18

What are the primary drug classes used in SCD?

What are the 2 medications with FDA approval for SCD?

Answer 18

The primary drug classes used in SCD are:
1- Immunizations and antibiotics:
To reduce infection risk

2- Analgesics:
To control pain

3- Hydroxyurea or L-glutamine
To prevent or reduce the frequency of acute and chronic complications

4- Chelation therapy
To manage iron overload from blood transfusions.

• FDA approval for SCD: voxelotor and crizanlizumab.

Question 19

What organisms will most likely cause sepsis and meningitis?

What are some atypical organisms that could also cause infections?

Answer 19

• S. pneumoniae
• H. influenzae
• N. meningitidis
• Salmonella
• Atypical: Chlamydophila and Mycoplasma pneumonia

Question 20

What should you do to prevent infections?

Answer 20

1) Vaccination
2) Prophylactic Antibiotics

Question 21

Vaccination:

Routine Childhood Series

Additional Vaccines For Functional Asplenia

Answer 21

Routine Childhood Series
■ Haemophilus influenzae type B (Hib)
■ Pneumococcal conjugate (PCV13, Prevnar)

Additional Vaccines For Functional Asplenia
■ Meningococcal conjugate series plus routine boosters
■ Meningococcal serogroup B (Bexsero,Trumenba)*
■ Pneumococcal polysaccharide (PPSV23, Pneumovax23)**
■ Pneumococcal conjugate (PCV13, Prevnar) x1 in any patient;, 6 years of age, if never received as a part of routine childhood series

• At age >= 10years
  ** At age >= 2 years, booster5 years later and at age >= 65 years

Question 22

Antibiotic prophylaxis?

Answer 22

• Prophylactic penicillin, given orally,reduces the risk of death from invasive pneumococcal infections in young children.
• Infants who screen positive for SCD at birth should be initiated on twice daily penicillin and treated until age five years.
• If a patient undergoes surgical removal of the spleen, or if invasive pneumococcal infection develops despite penicillin prophylaxis, it should be continued indefinitely.

Question 23

1- How should you manage mild to moderate pain?
2- severe pain?

Answer 23

1- Mild to moderate pain can often be managed at home with rest, fluids, application of warm compresses to affected areas and the use of NSAIDs or acetaminophen.

2- For severe pain and VOC, management must be guided by the patient’s self-reported pain severity.

Outpatient analgesic use should be reviewed and a treatment plan initiated within 30 minutes of triage.

Patients with severe pain and VOC will require IV administration of opioids or patient-controlled analgesia (PCA).

Question 24

What does hydroxyurea do?
What does the long term of hydroxyurea lead to?
To whom is it indicated for?

Answer 24

• Hydroxyurea is a disease-modifying drug that stimulates production of HgbF.

Long-term use of hydroxyurea reduces:
- The frequency of acute pain crises
- Episodes of acute chest syndrome
- The need for blood transfusions.

It is indicated for:
- Adults with > 3 moderate-to-severe pain crises in one year
- Patients with severe or recurrent acute chest syndrome
- Chronic symptomatic anemia or disability
- All children > 9 months of age regardless of disease severity

Question 25

Hydroxyurea Brand

Answer 25

• Droxia
• Hydrea
• Siklos

Question 26

BBW with Hydroxyurea

Answer 26

• Myelosuppression (Dec WBCs and platelets)
• Malignancy (leukemia, skin cancer)

Question 27

Warnings with hydroxyurea

Answer 27

• Fetal toxicity
• Avoid live vaccinations
• Skin ulcers
• Macrocytosis
• Pulmonary toxicity
• Increased risk of pancreatitis, hepatotoxicity and peripheral neuropathy when used with antiretroviral drugs

Question 28

SE with hydroxyurea

Answer 28

• Inc LFTs, uric acid, BUN and SCr
• Mouth ulcers
• N/V/D
• Alopecia
• Hyperpigmentation or atrophy of skin and nails,
• Low sperm counts

Question 29

Monitoring with hydroxyurea

Answer 29

• CBC with differential every 2-4 weeks during treatment initiation and titration, then every 2-3 months once a stable dose is achieved;
• if toxicity occurs (ANC < 2,000/mm 3, platelets< 80,000/mm 3), hold hydroxyurea until the bone marrow recovers, then restart at a dose 5 mg/kg/day lower
  HgbF, uric acid, renal function, LFTs, baseline pregnancy test

Question 30

Can you get pregnant while on hydroxyurea?

Answer 30

Contraception required during treatment and after discontinuation (6 months for females, 12 months for males)

Question 31

Is hydroxyurea considered hazardous?

Answer 31

Hazardous drug - wear gloves when dispensing and wash hands before and after contact

Question 32

What should you supplement with when on hydroxyurea?

Answer 32

Folic acid supplementation is recommended to prevent macrocytosis

Question 33

How long does clinical response take when on hydroxyurea?

Answer 33

Clinical response can take 3-6 months

Question 34

Hydroxyurea Drug Interactions

Answer 34

■ There is a higher risk for potentially fatal pancreatitis,
hepatotoxicity, hepatic failure and severe peripheral neuropathy when used in combination with antiretrovirals (especially didanosine and stavudine).

■ Do not use hydroxyurea with pimecrolimus, tacrolimus (topical) and other drugs that cause myelosuppression (e.g., clozapine, deferiprone, leflunomide, natalizumab, tofacitinib).

Question 35

L-GLUTAMINE

Answer 35

Endari

• L-glutamine oral powder (Endari) is FDA-approved for adults and children age 2 5 years with SCD.
• L-glutamine is an amino acid shown to reduce acute complications of SCD (e.g., number of pain crises requiring parenteral analgesics, number and duration of hospitalizations and occurrence of acute chest syndrome).
• The mechanism of action is not fully known, but it is thought to decrease oxidative stress, which can damage sickled RBCs.

Question 36

Voxelotor

Answer 36

• Voxelotor (Oxbryta) is the first FDA-approved drug that works by inhibiting hemoglobin S (HgbS) polymerization, which is the cause of SCD.
• It is approved for patients age 2 12 years with SCD and can be given with or without hydroxyurea.

Question 37

Crizanlizumab

Answer 37

• Crizanlizumab is a monoclonal antibody that is FDA-approved to reduce the frequency of VOC in SCD.
• It works by binding to and inhibiting P-selectin, which is involved in adhesion of sickled erythrocytes to vessels (causing vaso-occlusion).
• injection

Question 38

IRON CHELATION TREATMENT

Answer 38

• Chronic blood transfusions cause iron overload, which damages the liver, heart and other organs.
• Chelation therapy is used to remove excess iron stores from the body.
• Historically, deferoxamine (the antidote for iron toxicity) was used, but it has significant toxicities, is not available in oral formulation and requires slow, prolonged infusions over 8 - 12 hours when administered by IV or SC routes.
• Oral chelating drugs, such as deferasirox (Exjade, Jadenu) and deferiprone (Ferriprox) are now more commonly used.
• Due to the side effect profile of both drugs, treatment is typically prescribed, dispensed and monitored by specialty clinics and pharmacies.

Question 39

HYDROXYUREA counseling

Answer 39

■ Anyone handling the capsules (patient or caregiver) should wear disposable gloves to reduce the risk of exposure. Wash hands before and after handling. The capsules should not be opened.

■ Can cause infections.

■ Avoid in pregnancy (teratogenic). Effective contraception required for sexually active men and women of reproductive potential, both during and after treatment.

■ Live vaccines must be avoided. Check with your physician before getting any vaccines.