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 comprehensive sickle cell disease center. 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 substituted for valine Allowing 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 SCD Genotype Sickle cell anemia (SS) Sickle Hb C disease (SC) Sickle S beta plus (Sβ + thalassemia ) Sickle Beta zero (Sβ° thalassemia) 65% 25% 8% 2% GenotypeGenotype prevalence

Historical Distribution of Hemoglobin Variants Hemoglobin S Hemoglobin C Hemoglobin E Hemoglobin D Malarial Regions of Africa and Asia Alpha thalassemia occurs in all these regions as well

Prevalence/Incidence of SCD In African-Americans the incidence of SCD is 1 in 375 for HbSS, 1 in 835 for HbSC and 1 in 1,667 for Sickle beta-thalassemia. In addition, 1 in 12 African-Americans are carriers for the disorder In other U.S. populations, the prevalence of sickle cell disease is 1 in 58,000 Caucasians; 1 in 1,100 Hispanics (eastern states); 1 in 32,000 Hispanics (western states); 1 in 11,500 Asians; and 1 in 2,700 Native Americans

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%

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 Results Sickle Hemoglobinopathies Screening Results*Associated Disorder FS SS or Sβ°thalassemia FSCSC FSA S ß+ thalassemia FSE S Hemoglobin E FS VariantS 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 FASSickle Cell Trait FACHb C Carrier FAEHb E Carrier FA VariantHb Variant Carrier Interpreting Newborn Screening Results Hemoglobinopathy Carriers

Sickle Cell Disease Health Maintenance And Management

Health maintenance Infection prevention Pain management Sickle emergencies Chronic disease management

Health Maintenance Frequent visits: every 3 to 6 months Immunizations –Routine immunizations –Hib- 6 months and older –23 valent Pneumovax at five 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, S  ºThalassemia –2 months to 3 years: 125 mg PO BID –Over 3 years: 250 mg PO BID When to discontinue is controversial Penicillin Prophylaxis: SC and S  + Thalassemia –SC warrants penicillin prophylaxis similar to SS –S  + Thalassemia: penicillin prophylaxis can be safely discontinued at 5 years Routine use in infants and children is controversial Special Circumstances –History of repeated sepsis, surgical splenectomy

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 Indications for hospitalization & IV antibiotics: -Child appears ill -Any temperature > 40°C -Abnormal laboratory values Start IV antibiotics IMMEDIATELY if child appears ill or temperature > 40°C (DO NOT WAIT FOR LABS)

Acute Chest Syndrome Clinically: Acute onset of fever, respiratory symptoms, new infiltrate on chest x-ray Causes –Infection –Fat emboli –Lung infarct Since you cannot distinguish between acute chest syndrome and pneumonia clinically there is no change in treatment. 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, respiratory, or other symptoms Circulatory collapse and death can occur in less than thirty minutes 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 Management Pain is an emergency Hospital 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 –Hepatotoxic 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) Moderate or less severe pain –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 receive counseling? -Parents of newborns with sickle disorders or traits -Pregnant women/ prenatal counseling What is the purpose of counseling? -Education -Informed decision-making Content should include: -Genetic basis, chances of disease or trait (potential pregnancy outcome), disease-related health problems, variability/unpredictability of disease, family planning, average life span

Information about sickle cell disease can be found through the American Academy of Pediatrics or from the National Institute of Health on line at: