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

2. Objectives Pathophysiology of sickle cell disease
Inheritance of sickle cell disease
Health maintenance for sickle cell disease
Management of acute illness

3. 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.

4. Sickle Cell Disease
Pathophysiology

5. 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

6. 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.

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

8. 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.

9. 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

10. 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.

11. 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

12. 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.

13. 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

14. Sickle Cell Disease
Newborn Screening

15. 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.

16. 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.

17. 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

18. Health Maintenance And Management
Sickle Cell Disease
Health Maintenance
And
Management

19. Management Health maintenance Infection prevention Pain management
Sickle emergencies
Chronic disease management

20. 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

21. 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

22. Health Maintenance Special studies
Brain- Transcranial doppler ultrasonography, MRI/MRA
Lungs- Pulmonary function tests, Echo cardiogram for pulmonary hypertension
Neurologic- neuropsychological testing

23. 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

24. 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

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

26. 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

27. 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.

28. 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.

29. 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 .

30. 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%

31. 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%)

32. 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%

33. 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

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

35. 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

36. 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

37. 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

38. 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.

39. 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

40. 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.

41. 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

42. 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

43. Chronic Complications
Anemia/Jaundice
Brain Damage/Stroke
Kidney failure
Decreased lung function
Eye disease (bleeding, retinal detachment)
Leg ulcers
Chronic pain management

44. 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

45. 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

46. 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.

47. 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.

48. 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.

49. 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)

50. 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

51. 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

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