Sickle Cell Disease

Submitted by Marina E. Bitanga BSN, RN, CCRN

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Sickle Cell Disease

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Sickle cell disease (SCD) is the most common genetic blood disorder in the United States. This disease is also known as HbS disease, Hemoglobin S disease, SCD, Sickle cell disorders, and Sickling disorder due to hemoglobin S. It is a group of inherited red blood cells caused by mutations in the beta globin gene that leads to faulty hemoglobin protein called hemoglobin S. The flexible red blood cells become hard and sticky and look like a C-shaped farm tool called a sickle. There is shortage of red blood cells because the sickle cells die early. There is marked flawed hemoglobin causing interference in the delivery of oxygen to tissues. The sickle cells also get stuck when they travel through small blood vessels thereby clogging the blood flow causing pain and other serious problem such as infection, acute chest syndrome, and stroke.

Sickle cell disease (SCD) is a chronic vascular disease, with a range of acute and chronic complications driven by on-going vaso-occlusion.

There is no cure for most people with sickle cell anemia. But treatments can relieve pain and help prevent complications associated with the disease.

SCD means if someone has sickle cell disease, it was passed down through genes from their birth parents. Each birth parent provides one hemoglobin (HB) gene. Normal hemoglobin is called HbA. HbS is a change to the Hb gene. An abnormal HbS genes causes red blood cells to become sickle shaped, which can limit the amount of oxygen the red blood cells can carry through the body.

The hemoglobin gene inherited from each birth parent is very important because it can cause:

  • Sickle cell disease
  • Sickle cell trait, but not having SCD
  • Not having sickle cell disease and not carrying the sickle cell trait

The aim of treatment for patients with SCD is symptom control and the prevention or management of complications.

Data and Statistics

In the United States, it is estimated that:

  • SCD affects approximately 100,000 Americans
  • SCD occurs among about 1 out of every 365 Black or African - American births
  • SCD occurs among about 1 of every 16,300 Hispanic – American births
  • About 1 in 13 Black or African – American babies is born with sickle cell trait (SCT)

Mortality

1999 – 2002 = sickle – cell related deaths among Black or African – American children younger than 4 years of age fell by 42%. The drop coincided with the introduction in 2000 of a vaccine that protects against invasive pneumococcal disease.

Relative to the rate for the period 1983 through 1986, the SCD mortality rate for the period 1999 through 2002 decreased by:

  • 68% at age 0 through 3 years;
  • 39% at age 4 through 9 years; and
  • 24% at age 10 through 14 years.

Mortality among children with sickle cell disease identified by Newborn Screening during 1990 – 1994 – California, Illinois, and New York:

  • Among children with Hb SS disease, 1% died as a result of SCD – related causes during the first 3 years of life.
  • By the end of 1995, California and Illinois cumulative mortality rate was 1.5 per 100 Black or African – American children with SCD. The equivalent cumulative mortality rate for all Black or African – American infants born during this period in California and Illinois was 2.0 per 100 Black or African – American newborns.

The median survival for SCD patients in the United States is about 42 years with significant pre- morbid complications, although recent data suggest survival maybe better in some Western countries. About 95% of children in the United States and Europe survive until 18 years of age, but with significant vascular complications by age 20 years as well as chronic organ failure leading to premature death in their fourth and fifth decade. About 240,000 children born annually in African have SCD and only 20% survive their second birthday. All these morbidity seen in SCD is due to vascular disease and tissue necrosis that occur as a consequence of the chronic haemolytic anaemia[16].

Economic Costs

2005 = medical expenditures for children with SCD averaged $11,702 for children with Medicaid coverage and $14,772 for children with employer – sponsored insurance. About 40% of both groups had at least one hospital stay.

  • 1989 – 1993, an average of 75,000 hospitalizations due to SCD occurred in the United States, costing approximately $475 million.

SCD is also a significant public health issue globally. The international burdens have a domestic impact because many immigrants and refugees may have move to the United States from countries where the disease is most common, but potentially undiagnosed.

The estimated cost of care for SCD in the US is about$1.1 billion dollars per year, the majority of which is paid for through public insurance programs like Medicaid and Medicare.

Diagnosis

Diagnosing SCD includes complete medical history as well as physical examination.

History

  1. Nature, location, duration, and severity
  2. What are the precipitating conditions
  3. Any history of analgesic use for this pain and previous episodes
  4. What are the accompanying symptoms like fever, shortness of breath, etc.
  5. Any history of previous sickle cell complications including acute chest syndrome, stroke, etc.
  6. Allergies patient might have
  7. Does patient use cocaine

Physical examination

With special attention to areas at risk for sickle cell complications

  1. Hydration status of the patient
  2. Cardio / Pulmonary exam
  3. Any bone pain/ swelling
  4. Look for sites of infection
  5. Abdominal (Liver and Spleen) / GU Exam (Priapism)
  6. Neurologic exam
  7. Assessment of pain

Screening tests:

Blood Test:

To learn whether people carry a gene – or have the trait – for an abnormal hemoglobin that they could pass on to a child.

This information makes parents better informed about the chances of having a child with some type of sickle cell disease.

Newborn Screening:

  • Important to better prevent complications
  • Blood from a heel prick is collected in “spots” on a special paper. The hemoglobin from this blood is analyzed in special laboratory. If a baby is found to have sickle cell disease, health providers from special follow – up newborn screening group then contact the family directly to make sure they know the results. Newborn screening programs also find out whether the baby has abnormal hemoglobin trait.

Prenatal Screening:

  • Using sample amniotic fluid or tissue taken from the placenta.
  • Testing before birth can be done as early as 8 to 10 weeks into the pregnancy.
  • Looks for sickle hemoglobin gene rather than abnormal hemoglobin.

Diagnostics

  • CBC, platelet and reticulocyte count

  • Chest xray with respiratory symptoms, oxygen requirement or chest pain

  • Blood cultures if febrile; other cultures as indicated

  • Abdominal ultrasound, liver function tests, amylase, lipase for right upper quadrant, epigastric or severe abdominal pain

  • Type and crossmatch if hemoglobin is > or equal 1.5 gms below baseline; request minor– antigen matched, sickle negative, leucocyte depleted pack red blood cells

  • Blood tests

    - Blood counts can reveal an abnormal Hb level in the range of 6-8 grams per deciliter
    - Blood films may show RBCs that appear as irregularly contracted cells
    - Sickle solubility tests look for the presence of Hb S
  • Hb Electrophoresis

Always needed to confirm the diagnosis of sickle cell disease. It measures the different types of hemoglobin in the blood.

Main Types of Sickle Cell Disease

Hemoglobin SS Disease

  1. Often called Sickle Cell Anemia and the most common and severe type of SCD.
  2. Occurs when you inherit the hemoglobin S gene mutation from both parents.
  3. The body only produces hemoglobin S in this type of SCD

Hemoglobin SB0 (Beta Zero) Thalassemia

  1. Occurs when you inherit the hemoglobin beta S gene from one parent and a hemoglobin beta 0 thalassemia gene mutation from the other parent.
  2. Also called Sickle Cell Anemia because the body also produces only hemoglobin S.

Hemoglobin SC Disease

  1. The second most common type of SCD.
  2. Inherit the hemoglobin beta S gene from one parent and hemoglobin C gene from the other.

Hemoglobin SB + (Beta) Thalassemia

  1. Occurs when you inherit the hemoglobin beta S gene from one parent and hemoglobin beta plus thalassemia gene from the other parent.
  2. Less severe than hemoglobin SS disease because body produces some normal hemoglobin.

Hemoglobin SD, Hemoglobin SE, And Hemoglobin SO

  1. Less common and usually less severe types of SCD.

Sickle cell trait

  1. People who only inherit a mutated gene (hemoglobin S) from one parent. They may have no symptoms or reduced symptoms.

Early Signs and Symptoms

  • Yellowish color of the skin, known as jaundice, or whites of the eyes, known as icterus, that occurs when large number of red cells undergo hemolysis
  • Fatigue or fussiness from anemia
  • Dactylitis which is a painful swelling of the hands and feet

Treatments

SCD is a disease that worsens overtime. Pain management has traditionally been the focus of treatment for inpatients with sickle cell disease, but the assumption was that pain was infrequent in outpatients. Treatments are available that can prevent complications and lengthen the lives of people with this condition. Treatment depend on the symptoms and severity.

  1. Hydrourea = decrease several complications of SCD and treatment is very safe with proper monitoring and when given by medical specialists experienced in caring for patients with SCD, showing fewer crises and longer life. This medicine is beneficial even in children as young as 2 years of age.

    Hydroxyurea can cause the blood’s white cell count or platelet count to drop but rarely can worsen anemia. When the patient stops taking the medicine, the side effects quickly go away and the medicine can be restarted in lower dose by the doctor.

    The side effects of taking this medicine during pregnancy or for long time are not completely known.

  2. Endari (L-glutamine oral powder) = approved by Food and Drug Administration to reduce number of sickle cell crisis in adults and children older than age five.

  3. Stem Cell transplant (bone marrow transplant) = this procedure infuses healthy cells, called stem cells, into the body to replace damaged or diseased bone marrow (center of the bone where blood cells are made). Side effects of stem cell transplant include occasional life-threatening illness or death.

  4. Voxelotor = approved by Food and Drug Administration (FDA) in 2019 to treat adults and children 12 years and older with SCD. The oral medicine prevents red blood cells from forming the sickle shape and binding together thereby decreasing the destruction of some red blood cells, lowering risk for anemia and improves blood flow to the organs. Possible side effects headache, diarrhea. Abdominal pain, nausea, fatigue, and fever. Rashes, hives, or mild shortness of breath may rarely occur as allergic reactions.

  5. Crizanlizumab-tmca = approved by FDA in 2019 to reduce number of pain crises experienced by adults and children 16 years and older with SCD. This medicine is given through an IV in the vein. It helps prevent blood cells from sticking to blood vessel walls causing blood flow blockage, inflammation, and pain crises.

    Possible side effects include nausea, joint pain, back pain, and fever.

  6. Penicillin = taken two times a day by children with SCD helps reduce the chance of having a severe infection caused by the pneumococcus bacteria. Liquid form for newborns and tablets for older children.

    Usually stopped by the doctor after a child has reached age of 5 though some prefer to continue this medicine throughout life, particularly for person with hemoglobin SS or hemoglobin SB0 Thalassemia. People with splenectomy, surgical removal of spleen, or past infection with pneumococcus should keep taking this medicine throughout life.

Complications / Prevention / Treatment

1. Hand – Foot Syndrome

Swelling in the hands and feet is the first symptom of SCD associated with fever caused by sickle cells getting stuck in the blood vessels and blocking the flow of blood in and out of the hands and feet.

Treatment: Pain medicine and increase in fluids.

2. Pain

This is the most common complication and the number one reason that people with SCD go to the Emergency Room or hospital. Also caused by sickle cells getting stuck and clog the blood flow when they travel through small blood vessels. The most common locations of acute pain in SCD are the arms, thighs, shin, lower back, and knee.

Prevention of pain in SCD includes:

  • Drink plenty of water - Oral fluids Intake should be at least 1 – 1 ½ times maintenance fluids for children or 128 oz of oral fluids for adults weighing 50 Kg., if not nauseated.
  • Try not to get too hot or too cold
  • Try to avoid places or situations that cause exposure to high altitudes like flying, mountain climbing, or cities with high altitudes
  • Try to avoid places or situations with exposure to low oxygen levels like mountain climbing or exercising extremely hard such as in military boot camp or when training for an athletic competition.
  • Adults with severe SCD can take medicine called hydrourea to help reduce number of pain crises

Treatment:

Over the counter pain medications such as ibuprofen and aspirin. People with severe pain takes opioid medications such as morphine daily along with additional pain medication.

If patient is using a long – acting opioid such as MS Contin, Oxycontin, Methadone, or fentanyl patches at home, these medications should be continued as an inpatient. Patient – Controlled Analgesia (PCA) pumps should be used, per intravenous if access available, and per subcutaneous if no IV access is available. Choice of drugs are morphine, dilaudid, and fentanyl.

Use of NSAIDs maybe considered as an adjunct therapy in patients whose BUN and creatinine are within normal limits and who have no history of acute or chronic renal failure.

Alternative pain treatments include moist heat, massage, and physical therapy.

Distraction mechanisms to cope with pain include:

  • Talking on the phone
  • Walking in the hall
  • Watching television
  • Sleeping

These coping mechanisms should not be misinterpreted that painful episodes are resolved.

Bone pain crisis is the most common SCD pain which is a complication of occlusive pain, that can lead to bone or bone marrow infarction and osteonecrosis, avascular necrosis, and acute pain that cause hospital admissions.

Hydration

Free water replacement vs. volume replacements are the guiding principles and both are important. One standard intravenous fluid recommended is D5 ½ NS at 100 – 125 cc/ hour. Monitor patients with chronic cardiac or renal disease to avoid fluid overload. Ringer’s Lactate should not be used as it may produce an acidotic state that will promote crises in sickle cell patients. Oral hydration is acceptable for patients with poor venous access, using SQ opioids, and able to drink adequate amount of fluids (1-2 liters/day) as long as patient is not nauseated or vomiting.

3. Anemia

This is a very common complication of SCD where the red blood cells die early causing not enough healthy red blood cells to carry oxygen throughout the body. Anemia causes person to have:

  • Tiredness
  • Irritability
  • Dizziness and lightheadedness
  • Fast heart rate
  • Difficulty breathing
  • Pale skin color
  • Jaundice which is the yellow color to the skin and whites of the eyes
  • Slow growth
  • Delayed puberty

Treatment:

Blood transfusions are necessary to treat anemia. Sudden worsening of anemia resulting from infection or enlargement of the spleen is a common reason for a transfusion. Health problems might occur for people receiving multiple blood transfusions because of the iron content of the blood. Iron overload, called hemosiderosis, can damage liver, heart, pancreas, and other organ leading to diabetes mellitus. Iron cardiomyopathy is rare, detectable in about 2.5% of chronically transfused SCD patients and is one iron toxicity that is separate from SCD damage. Iron chelation therapy should be started on patients with SCD receiving regular blood transfusions to reduce excess iron levels.

Patients receiving blood transfusions may occasionally require diuretic such as lasix to prevent fluid overload.

Prevent complications of blood transfusion for SCD patients:

  1. Only be given when appropriate
  2. Thorough medical history should be obtained when transfusions are indicated.
  3. Extended matching of all patients with SCD on at least C, E, and Kell antigens and possibly more depending on medical history and antibody screening results.
  4. Monitor iron levels and develop plan to lower those levels when excess is detected.
  5. Donor recruitment targeted to African Americans to minimize differences between donor and recipient minor cell antigens.
  6. Educate patients and families on transfusions indications and complications.
  7. Health care providers should recognize the appropriate indications for transfusions, the times when transfusion is not indicated, and steps for reducing and managing potential transfusion complications.
  8. Reliable interinstitutional blood bank communication to reduce risk of failing to detect transient antibodies and re-exposing the patient to an evanesced antibody with future transfusions.

4. Infection

Pneumonia is a leading cause of death in infants and young children.

Prevention:

  • Vaccines can prevent against harmful infections.
  • Family and care takers must wah their hands with soap and clean water many times each day.
  • Foods should be prepared safely.
  • Children with SCD should get all regular childhood vaccines. Adults should have the flu vaccine every year and the pneumococcal vaccine, and any other recommendations by the doctor.
  • Take penicillin or any other antibiotic prescribed by a doctor every day until at least 5 years of age.

Treatment:

Treated with antibiotic medications and sometimes blood transfusions. See a doctor right away if with fever. Early treatment of infection can help prevent problems.

Management of infection includes urine and blood cultures if patient develops fever. Notify the doctor for heart rate > 100 or < 60, if systolic BP is > 150 or < 90, if diastolic BP is > 90 or < 50, respiratory rate > 24 or < 12.

5. Acute Chest Syndrome

Signs and symptoms are similar as pneumonia and include chest pain, coughing, difficulty breathing, and fever.

Prevention:

Hydrourea to help prevent acute chest syndrome. Patients must be monitored closely with regular blood testing and dose adjustments to help prevent complications.

Treatment:

Oxygen / Incentive Spirometer = check pulse oximeter and if oxygen saturation is 90% or more on room air, do not administer supplemental oxygen as it may suppress the bone marrow’s ability to manufacture new red blood cells. If O2 saturation is < 90% on room air, give humidified oxygen at 2 liters/ minute via nasal cannula, and re-check oxygenation in 15 minutes to assure adequate oxygenation.

Incentive spirometer improves both oxygenation and lung expansion thus prevent bone infarct-related acute chest syndrome. Patients with sickle cell pain are on high doses of opioids putting them at risk for respiratory suppression and for atelectasis since most of these patients will be lying in bed. Using incentive spirometer at least every 2 hours while awake decreases the patient’s with chest pain to progression to acute chest syndrome.

Medicine to treat an infection

Medicine to open airways to improve air

Blood transfusion

Exchange transfusion is the preferred therapy for acute chest syndrome in adults. In children if hemoglobin > 8 gms, simple transfusion is more common.

6. Splenic Sequestration

This happens when large number of sickle cells get trapped in the spleen and cause it to suddenly get large. Symptoms include sudden weakness, pale lips, fast breathing, extreme thirst, abdominal pain on the left side of the body, and fast heart rate. Splenic sequestration can worsen anemia.

Prevention:

Regular blood transfusions or the spleen can be removed to stop it from happening again.

Treatment:

Blood transfusion should be done in consultation with a blood specialist as patients sometimes become overload with fluid when the blood is released from the spleen.

7. Vision Loss

Blindness can occur when the blood vessels in the eye become blocked with sickle cells and the retina gets damaged.

Prevention:

Yearly eye check by specialized eye doctor to look for any damage to the retina.

Treatment:

Laser treatment often can prevent further vision loss.

8. Leg Ulcers

Occurs usually in lower part of legs. More in males than females and usually appear from 10 – 50 years of age. Causes include trauma, infection, inflammation, and interruption of the circulation in the smallest blood vessels of the leg.

Treatment:

  • Treated with medicated creams and ointments
  • Strong pain medications
  • Use of cultured skin grafts provided in specialized centers
  • Bed rest and keep the leg/ legs raised to reduce swelling

9. Stroke

This happens if sickle cells get stuck in a blood vessel and clog blood flow to the brain. About 10% of children with SCD will have symptomatic stroke.

Prevention:

Transcranial doppler ultrasound = used to identify children at risk for stroke

Frequent blood transfusions if with abnormal transcranial doppler ultrasound to prevent stroke.

Watch closely for people having frequent blood transfusions to prevent too much Iron build up in the body causing life – threatening damage to the organs.

10. Deep Vein Thrombosis (DVT) and Pulmonary Embolism

These are caused by sickle red cells increasing coagulation and induce an increased risk of blood clot in a deep vein (DVT), or in the lung (PE).

Treatment:

  1. Anticoagulants (blood thinners) = most commonly use to treat DVT or pulmonary embolism. They reduce ability of blood to clot, preventing the clot from becoming larger while the body reabsorbs it, and reducing the risk of further clots developing.

  2. Injectable anticoagulants:

    - Unfractionated heparin (injected into a vein)
    - Low molecular weight heparin (LMWH) – injected under the skin
    - Fondaparinux – injected under the skin

  3. Oral anticoagulants:

    - Warfarin
    - Dabigatran
    - Rivaroxaban
    - Apaxiban
    - Edoxaban

  4. Thrombolytics are clot busters, work by dissolving the clot.

  5. Inferior Vena Cava = used when anticoagulants cannot be used or do not work well enough. A filter can be inserted inside IVC to capture or trap an embolus before it reaches the lungs.

  6. Thrombectomy = removal of clot for patients with DVT.

  7. Embolectomy = removal of blockage in lungs caused by clot in patients with pulmonary embolism.

Signs and symptoms of a DVT:

  • Swelling of the affected limb
  • Pain or tenderness not caused by injury
  • Skin that is warm to the touch, red, or discolored

Signs and symptoms of PE:

  • Difficulty breathing
  • Chest pain that worsens with a deep breath or cough
  • Coughing up blood
  • Faster – than – normal or irregular heartbeat

Prevention:

  1. Improve blood flow in your legs when sitting for long periods of time, following bed rest or traveling more than 4 hours by moving your legs and exercise calf muscles.
  2. Walk around at least every 2-3 hours if able to.
  3. Do seated leg stretches like raise and lower your heels while keeping toes on the floor, raise and lower your toes while keeping heels on the floor, and tighten and release leg muscles.
  4. Medications or wearing graduated compression stockings.

11. Pulmonary Hypertension

Due to damage to the lungs related to decreased blood flow resulting in high blood pressure in the lungs (pulmonary hypertension) and scarring of the lungs (pulmonary fibrosis). This makes it more difficult for the lungs to transfer oxygen to the blood resulting in more frequent sickle cell crises.

Other possible complications:

  1. Damage to body organs like liver, heart or kidneys, tissues or bones because not enough blood is flowing to the affected areas.
  1. Malnutrition and growth retardation among adolescents can cause a delayed onset of puberty and, in males, infertility.
  2. Gallstones
  3. Painful erection of the penis, called priapism, can last less than 2 hours or more than 4 hours, occurs in about 35% of men
  4. Renal medullary carcinoma – very rare form of kidney cancer

Conclusions

Key Points:

  • Sickle cell disease is an inherited blood disorder marked by defective hemoglobin.
  • It inhibits the ability of hemoglobin in red blood cells to carry oxygen.
  • Sickle cells tends to stick together, blocking small blood vessels causing painful and damaging complications.
  • Sickle cell disease is treated with pain medications as needed, drinking 8 – 10 glasses of water each day, blood transfusions, and medications.

Early diagnosis and prevention of complications is critical in SCD treatment. Treatment aims to prevent organ damage including strokes, prevention of infections, and treatment options are different for each person depending on the symptoms.

High proportion of adults suffer from severe, chronic pain that significantly diminishes their quality of life. Most of patients with pain not relieved by the pain medications they are taking at home within 24 to 48 hours end up going to the Emergency Department for further pain management.

References

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