Sickle Cell Disease and Trait: What Every Primary Care Physician Needs to Know

Objectives• Pathophysiology of sickle cell disease

• Inheritance of sickle cell disease

• Health maintenance for sickle cell disease

• Management of acute illness

The Management of a child with sickle cell disease is best when overseen by a multidisciplinary sickle cell clinic.

If unavailable, care should be provided in consultation with a pediatric hematologist.

Sickle Cell Disease

Pathophysiology

What Is Sickle Cell Disease?

• An inherited disease of red blood cells

• Affects hemoglobin

• Polymerization of hemoglobin leads to a cascade of effects decreasing blood flow

• Tissue hypoxia causes acute and chronic damage

Why Do Cells Sickle?

• Glutamic acid is switched to valine

• Allows the polymerization of sickle hemoglobin when deoxygenated

Normal Vs. Sickle Red Cells

Normal• Disc-Shaped• Deformable• Life span of 120 days

Sickle• Sickle-Shaped• Rigid • Lives for 20 days or

less

Hemolysis and Vaso-occlusion

Vaso-occlusion:Occurs when the rigid sickle shaped cells fail to move through the small blood vessels, blocking local blood flow to a microscopic region of tissue. Amplified many times, these episodes produce tissue hypoxia. The result is pain, and often damage to organs.

Hemolysis:The anemia in SCD is caused by red cell destruction, or hemolysis, and the degree of anemia varies widely between patients. The production of red cells by the bone marrow increases dramatically, but is unable to keep pace with the destruction.

Chronic Manifestations:• Anemia• Jaundice• Splenomegaly• Functional asplenia• Cardiomegaly and functional murmurs• Hyposthenuria and enuresis• Proteinemia• Cholelithiasis• Delayed growth and sexual maturation• Restrictive lung disease*• Pulmonary Hypertension*• Avascular necrosis• Proliferative retinopathy• Leg ulcers• Transfusional hemosiderosis*

Acute Manifestations:• Bacterial Sepsis or meningitis*

• Recurrent vaso-occlusive pain (dactylitis, muscoskeletal or abdominal pain)

• Splenic Sequestration*

• Aplastic Crisis*

• Acute Chest Syndrome*

• Stroke*

• Priapism

• Hematuria, including papillary necrosis

Hemolysis and Vaso-occlusion(continued)

*Potential cause of mortality

Sickle Cell Disease Common Genotypes

• Sickle cell anemia (SS)• Sickle Hb C disease (SC)• Sickle Beta plus

thalassemia (Sβ+

thalassemia )• Sickle Beta zero thalassemia

(Sβ° thalassemia)

• 65%• 25%• 8%

• 2%

Genotype Approximate % of US Patients

Historical Distribution of Hemoglobin Variants

Hemoglobin SHemoglobin S

Hemoglobin CHemoglobin C

Hemoglobin EHemoglobin E

Hemoglobin DHemoglobin DMalarial Regions of Africa and AsiaAlpha thalassemia occurs in all these

regions as well

Prevalence/Incidence of SCD

• Overall, SCD occurs in 1:2,000-2,500 US Newborns.• The prevalence of SCD is 1:346 African-American

infants. In addition, 1:12 African-Americans are carriers for the disorder.

• The prevalence of SCD is 1:1,100 Hispanics (eastern states); 1:32,000 Hispanics (western states).

• SCD occurs in many other ethnic groups including Northern Europeans.

Example of Sickle Cell Pedigree

• Parents with sickle cell trait: hemoglobin AS• Probability of child with hemoglobin AA: 25%• Probability of child with sickle cell trait AS: 50%• Probability of child with sickle cell disease SS: 25%

Note: Parents with Hb C and Beta thalassemia may also be at risk for child with SCD

Sickle Cell Disease

Newborn Screening

Newborn Screening for Sickle Cell Disease

• 47 states, Washington DC, Puerto Rico, and the Virgin Islands provide mandatory universal newborn screening

• Specimen must be drawn prior to transfusion• Prevention of pneumococcal septicemia• Early Detection and treatment of splenic

sequestration

Linkage to timely diagnostic, parental education, and comprehensive care markedly reduces morbidity and mortality in infancy and childhood.

Interpreting Newborn Screening ResultsSickle Hemoglobinopathies

Screening Results* Associated Disorder

FS SS or Sβ°thalassemia

FSC SC

FSA S ß+ thalassemia

FSE S Hemoglobin E

FS Variant S Variant

*Confirmatory testing requires hemoglobin separation by electrophoresis (cellulose acetate and citrate agar), isoelectric focusing, and/or high performance lipid chromatography. Solubility testing should never be used for confirmation.

Newborn Screening Result Associated Carrier State

FAS Sickle Cell Trait

FAC Hb C Carrier

FAE Hb E Carrier

FA Variant Hb Variant Carrier

Interpreting Newborn Screening Results Hemoglobinopathy Carriers

Sickle Cell Disease

Health Maintenance

And

Management

Management

• Health maintenance

• Infection prevention

• Pain management

• Sickle emergencies

• Chronic disease management

Health Maintenance• Frequent visits: every 3 to 6 months• Immunizations

– Routine immunizations (especially HiB and 7 valent pneumococcal conjugate vaccine)

– 23 valent pneumococcal polysaccharide vaccine at 2 and 5 years

• Penicillin prophylaxis beginning no later than two months

• Nutrition and fluids– Folate supplementation is controversial

Health Maintenance

• Physical exam with attention to:– Growth and development, jaundice, liver/spleen

size, heart murmur of anemia, malocclusion from increased bone marrow activity, delayed puberty

• Lab evaluations: – CBC with differential and reticulocyte count,

urinalysis, renal & liver function

Health Maintenance

Special studies• Brain- Transcranial doppler ultrasonography,

MRI/MRA• Lungs- Pulmonary function tests, Echo

cardiogram for pulmonary hypertension• Neurologic- neuropsychological testing

Current Recommendations

• Penicillin Prophylaxis: SS, SºThalassemia- 2 months to 3 years: 125 mg PO BID- 3-5 years: 250 mg PO BID- >5 years for selected patients, including those

with a history of pneumococcal infection or surgical splenectomy

• Penicillin Prophylaxis: SC and S+ - Routine use in infants and children is controversial

Eye Examination

• Retinal vessel disease– Incidence 33% in

hemoglobin SC

– Incidence 3% in SS

• Annual evaluation after age 10 years by ophthalmologist– Laser photocoagulation

for vessel disease

Sea Fan

Salmon Patch: SC

Emergencies

• Fever/infection• Acute chest syndrome• Eye trauma (hyphema) • Priapism• Stroke• Splenic sequestration• Severe pain

Fever and Infection• Fever > 38.5° C (101°F)

is an EMERGENCY• Basic laboratory evaluation:

– CBC with differential and reticulocyte count, blood, urine, and throat cultures, urinalysis, chest x-ray

• Parenteral broad-spectrum antibiotic (e.g. ceftriaxone) IMMEDIATELY after blood draw and before other procedures such as chest x-ray

• Observe after antibiotics with repeat vital signs

Indications for hospitalization & continued IV antibiotics:

• Child appears ill• Age < 1 year• Any temperature > 40°C• Laboratory values:

WBC >30,000/μL or < 5,000/μLPlatelet <100,000/μL Hb < 5g/dL

• Other complications such as splenic sequestration or acute chest syndrome

Acute Chest Syndrome

Clinically:Acute onset of fever, respiratory symptoms, new infiltrate on chest x-ray

Causes- Infection- Fat emboli- Lung infarct

Treatment- Hospitalize

- Antibiotics (broad spectrum plus macrolide)- Oxygen- Analgesics- Bronchodilators- Simple or exchange transfusion

A leading cause of death in sickle cell disease

Eye Trauma

Get sickle prep -rapid test- if sickle status unknown

Complications if untreated:-glaucoma, -optic nerve atrophy, -retinal artery blockage

Eye trauma is an emergency in ALL sickle conditions(including sickle trait)

Priapism

Treatment is difficult– Opioid pain medication– Intravenous fluids– Aspiration and irrigation of the

corpus cavernosum– Surgery– Blood Transfusions

• Impotence with severe disease or recurrent episodes

Urethra Corpus cavernosum

Commonly occurs in children and adolescents with SS or SC

Stroke

• Historically 8 to 10% of children with SS

• “Silent Stroke” in 22% of children with hemoglobin SS

Any acute neurologic symptom other than mild headache, even if transient, requires urgent evaluation.

Treatment: Chronic transfusion therapy to maintain sickle hemoglobin at or below 30%

Splenic Sequestration• Sudden trapping of blood

within the spleen• Usually occurs in infants under

2 years of age with SS• Spleen enlarged on physical

exam, may not be associated with fever, pain, or other symptoms

• Hemoglobin more than 2 g/dL below baseline, often with relative thrombocytopenia

• Severe sequestration crisis can be fatal within a few hours.

•Recurrence very common (50%)•Associated with high mortality (20%)

Splenic Sequestration

• Hemoglobin SS– Incidence increased: 6 and 36 months

• Overall incidence about 15%

• Hemoglobin SC– Incidence increased: 2 and 17 years

• Mean age 8.9 years

• Can occur in adolescence and adulthood

• Incidence about 5%

Treatments For Splenic Sequestion

• Intravenous fluids– Maintain vascular volume

• Cautious blood transfusion– Treat anemia, sequestered

blood can be released from spleen

• Spleen removal or splenectomy– If indicated

Pain Management

Acute pain• Hand-foot syndrome (dactylitis)• Painful episodes: vasoocculsion• Splenic sequestration• Acute chest syndrome• Cholelithiasis• Priapism• Avascular necrosis• Right upper quadrant syndrome

Pain ManagementPain is an emergencyPain is an emergencyHospital evaluation:• Hydration: 1.5 times maintenance unless

acute chest syndrome suspected• Assess pain level and treat

– Do not withhold opioids– Frequently reassess pain control

• Assess for cause of pain/complications

Pain Management

Mild-moderate pain• Acetaminophen

– May be hepatotoxic if liver disease is present.

• Non-steroidal anti-inflammatory agents (NSAIDs)

-Contraindicated in patients with gastritis/ulcers and renal failure

-Monitor renal function if used chronically

Pain Management

• Moderate-severe pain– Opioids are first-line treatment

– Morphine sulfate or hydromorphone

– Meperidine NOT recommended • (Metabolite causes seizures & renal toxicity)

– Acetaminophen or NSAID's in combination with opioids

– Other adjuvant medications (sedatives, anxiolytics) • May increase efficacy of analgesics

Hand Foot Syndrome - Dactylitis

• Early complication of sickle cell disease

• Highest incidence 6 months to 2 years

• Painful swelling of hands and feet

• Treatment involves fluids and pain medication

• Fevers treated as medical emergency

Renal Disease

• Renal findings– Decreased ability to concentrate urine– Decreased ability to excrete potassium– Inability to lower urine pH normally– Hematuria / papillary necrosis

• Risk factors for progressive renal failure– Anemia, proteinuria, hematuria

Gall Bladder and Liver

• Gall stones and biliary sludge– Monitor by ultrasound every 1-2 years

• Cholestasis– May progress, leading to bleeding disorders or

liver failure

• Iron overload– Due to chronic transfusions

• Chronic hepatitis

Bone Disease Diagnosis and Treatment

• Avascular necrosis of hips and shoulders– Index of suspicion

• Persistent hip or shoulder pain

• Plain film or MRI

• Treatment– Conservative

• NSAID’s and 6 weeks of rest off affected limb

• Physical therapy

Screening AVN

• Avascular Necrosis – Hip Films

– Hip MRI

– Grading of AVN• Grade I: MRI

• Grade II: Film/MRI

• Grade III: Film

• Grade IV: Film

• Grade V: Film

– No grade for AVN of the shoulder

Chronic Complications

• Anemia/Jaundice

• Brain Damage/Stroke

• Kidney failure

• Decreased lung function

• Eye disease (bleeding, retinal detachment)

• Leg ulcers

• Chronic pain management

Anemia – Jaundice

• Common and starting in the first year of life

• Decreased lifespan of sickle red cells– Hemolysis

– Anemia

– Hyperbilirubinemia

– Reticulocytosis

Stroke

• Intracranial hemorrhage– More common in adults

• Sequela overt and “silent strokes” – Paralysis: overt stroke– Neuropsychologic changes: both overt and

silent strokes • Visual-spatial impairment• Impaired memory• Poor impulse control

Renal Disease

• Proteinuria/Nephrotic syndrome• 40% of SCD patients with nephrotic syndrome

develop end-stage renal disease • Occurs in ~ 20% of all patients • Occurs in 4.5% of all pediatric patients- increased

in hemoglobin SS to 6.5%– Increased incidence with age– Increased with anemia, increased MCV, and increased

leukocyte count

• Renal failure common in adults

Leg Ulcers

• Occurs in about 25% of all hemoglobin SS patients

• Predominantly males– Incidence increased with

• Age

• Decreased hemoglobin

– Incidence decreased with alpha thalassemia

• Recurrence rate is ~ 75%

Chronic Pain

• Pain lasting >3 to 6 months

• Patients should receive comprehensive psychologic and clinical assessment

• Treatment– Analgesics– Hydroxyurea– TENS units– Relaxation techniques– Physical and occupational therapy

Adolescents and Transition of Care

• Young adults (>20 years) with frequent pain crises at greatest risk for early death

• Barriers to care for young adults– Lack of adult SCD providers

– Loss of medical coverage

– Developmental (level of independence, denial of chronic illness)

– Ineffective coping skills (passive versus active)

Adolescents and Transition of Care

• Develop explicit plan for transition

• Team approach- pediatric and adult providers, social work, school/vocational staff, support groups

• Plan gradual transition (start 1 year before)

• Continue communication between pediatric & adult providers after transition

Genetic Counseling• Who should be offered counseling?

– Parents of newborns with sickle disorders or traits– Pregnant women/prenatal counseling

• Parental testing for risk assessment– CBC with MVC– Hemoglobin electrophoresis– Quantitation of Hb A2 and F if MCV is decreased

• What is the purpose of counseling? – Education– Informed decision-making

• Content should include: – Genetic basis, risk of disease or trait (potential pregnancy outcome),

disease-related health problems, variability/unpredictability of disease, family planning

Information about sickle cell disease can be found through the American Academy of Pediatrics or from the National Institute of

Health on line at:http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf