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 A person with sickle cell disease has one different substance in the way it makes hemoglobin. This substance is the amino acid valine which is substituted for glutamic acid in one location. This one change causes the chemical to form long strings when it releases oxygen consequently, causing the red cell to become deformed into a "sickle" shape.

Normal Vs. Sickle Red Cells Sickle-Shaped Rigid Lives for 20 days or less Normal Disc-Shaped Deformable Life span of 120 days

Hemolysis and Vaso-occlusion 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. 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 and Vaso-occlusion (continued) 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 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* *Potential cause of mortality

Sickle Cell Disease Common Genotypes Approximate % of US Patients 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% The term sickle cell disease describes a group of complex, chronic disorders, not simply Sickle Cell Anemia. The most common sickle cell syndromes are outlined here; and result when the gene for sickle hemoglobin is inherited from both parents (Sickle Cell Anemia), when a gene for sickle hemoglobin is inherited from one parent and a gene for hemoglobin C is inherited from the other (Hemoglobin SC Disease), or when a gene for sickle hemoglobin is inherited from one parent and a gene for beta thalassemia is inherited from the other (Hemoglobin S Beta Thalassemia). There are some differences between these syndromes, but all have similar clinical manifestations. Individuals who inherit a gene for sickle hemoglobin from one parent and one for hemoglobin A from the other are genetic carriers of sickle syndromes. This is often called sickle trait and is not associated with any hematological abnormalities.

Historical Distribution of Hemoglobin Variants Hemoglobin S Hemoglobin C Where did Sickle Cell Disease originate? Hb S occurs in high frequency in populations previously exposed to falciparum malaria including those from Africa, India, the Mediterranean area, and Saudi Arabia. Because of immigration and cultural blending, sickle cell disease is now seen around the world. Although sickle cell disease occurs at a higher frequency among people of African descent (incidence is approximately 1 in 400), a person of any ethno-cultural background could potentially be affected. Overall, sickle cell disease is the most common genetic disorder in the US. Hemoglobin D Malarial Regions of Africa and Asia Alpha thalassemia occurs in all these regions as well Hemoglobin E

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 There are two genes for hemoglobin, one of which is inherited from each parent. This pedigree maps the type of hemoglobin in a family tree; helping to identify those with trait and those with disease. In this pedigree, both parents have sickle trait, 1 in 4 children will have Sickle cell disease, one half will have trait and 1 in 4 will have normal hemoglobin

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. Currently, 47 US states, Washington DC, Puerto Rico, and the US Virgin Islands mandate universal newborn screening for sickle cell disease. The remaining states (ID, NH, SD) offer SCD screening upon request. Given the benefits of early diagnosis, particularly with the high risk of life-threatening septic events in early childhood, it is critical that primary care physicians act on abnormal hemoglobinopathy results quickly to ensure that children with sickle cell disease are begun on prophylactic penicillin therapy beginning at 2 months of age.

Interpreting Newborn Screening Results Sickle Hemoglobinopathies Screening Results* Associated Disorder FS SS or Sβ°thalassemia FSC SC FSA S ß+ thalassemia FSE S Hemoglobin E FS Variant S Variant Hemoglobins identified by newborn screening are generally reported in order of quantity. Because more fetal hemoglobin ( HbF) than normal adult hemoglobin (HbA) is present at birth, most normal infants show Hb FA. Infants with hemoglobinopathies also show a predominance of Hb F at birth. Those with sickle cell disease typically show a higher level of sickle or other abnormal hemoglobin compared to normal adult hemoglobin. *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.

Interpreting Newborn Screening Results Hemoglobinopathy Carriers Newborn Screening Result Associated Carrier State FAS Sickle Cell Trait FAC Hb C Carrier FAE Hb E Carrier FA Variant Hb Variant Carrier

Health Maintenance And Management 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: Lab evaluations: 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, SbºThalassemia - 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 Sb+ - Routine use in infants and children is controversial

Eye Examination Retinal vessel disease Sea Fan Salmon Patch: SC 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 Sickle cells can cause damage to the blood vessels in the eye, especially in SC disease. New weaker blood vessels may form and break open and bleed. Early treatment with laser therapy can prevent such bleeds

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/μL Platelet <100,000/μL Hb < 5g/dL Other complications such as splenic sequestration or acute chest syndrome

A leading cause of death in sickle cell disease Acute Chest Syndrome A leading cause of death in sickle cell disease 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 Pneumonias or infections in the lung, and acute chest syndrome, caused by sickling red cells blocking blood vessels in the lung, are the most common complications. Infections are treated with antibiotics and acute chest is treated with blood transfusions. Because it is difficult to tell the two apart, both treatments are used.

Eye Trauma Eye trauma is an emergency in ALL sickle conditions (including sickle trait) Get sickle prep -rapid test- if sickle status unknown Complications if untreated: -glaucoma, -optic nerve atrophy, -retinal artery blockage Sickle cells can cause damage to the blood vessels in the eye, especially in SC disease. New weaker blood vessels may form and break open and bleed. Early treatment with laser therapy can prevent such bleeds.

Priapism Commonly occurs in children and adolescents with SS or SC Urethra Corpus cavernosum 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 Priapism is the painful erection of the penis caused by sickling red cells. This complication usually has an onset at age 5 to 35. It often occurs as a severe episode requiring hospitalization following multiple episodes of short duration, termed stuttering. Onset in the early morning, waking the patient is common. Treatment includes pain relief, hydration, exchange transfusion, and surgical shunt procedures .

Stroke Any acute neurologic symptom other than mild headache, even if transient, requires urgent evaluation. Historically 8 to 10% of children with SS “Silent Stroke” in 22% of children with hemoglobin SS 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 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 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 Sickle dactylitis is one of the first complications in sickle cell syndromes with the highest incidence between ages six months and two years. The sickle red cells cause painful swelling of the hands and feet. This is treated with fluids and pain medication. It usually will go away in a few days without any problems.

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 Cholestasis 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 Kidney damage starts very early and progresses throughout life causing complications in many individuals with sickle syndromes. The kidneys may not filter normally, passing protein and/or excessive amounts of water.

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 Anemia or a low red blood cell count, is lifelong, starting in the first year of life. The average red cell life is reduced from a normal of 120 days down to an average of 10 to 20 days in sickle cell anemia. This produces anemia, a high reticulocyte count, and a bone marrow factory that is producing 3 to 4 times more red cells than normal. Other problems related to the anemia are yellow eyes or jaundice (elevated indirect bilirubin), which later in childhood and early adult life can cause gallstones

Stroke Intracranial hemorrhage Sequela overt and “silent strokes” 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 Kidney damage starts very early and progresses throughout life causing complications in many individuals with sickle syndromes. The kidneys may not filter normally, passing protein and/or excessive amounts of water.

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% Leg ulcers are seen in 10 to 15% of older children and adults with sickle cell anemia. They may start as a simple insect bite or cut that will not heal. They are likely caused by poor circulation to the skin. Treatment includes saline wet-to-dry dressings, Unna boots, and special wound dressings. Leg elevation and use of elastic stockings are very important to speed healing.

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 More prolonged and constant pain can be seen with bone infarction, sickle arthritis, and aseptic necrosis of the femur or humerus. With chronic pain, non-steroidal anti-inflammatory medications should be used. TENS units, relaxation techniques, occupational and physical therapy approaches may be useful in reducing pain and maintaining a good lifestyle.

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