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SICKLE CELL DISEASE. JOHN M KAUFFMAN JR DO ASSOCIATE DEAN FOR POSTGRADUATE AFFAIRS VIA COLLEGE OF OSTEOPATHIC MEDICINE. Goals and Objectives. At the conclusion of this program, the attendee will have a better understanding of: The genetics and transmission of Sickle Cell Disease

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    2. Goals and Objectives • At the conclusion of this program, the attendee will have a better understanding of: • The genetics and transmission of Sickle Cell Disease • The Diagnosis and pathophysiology of Sickle Cell Disease • The management of the complications of Sickle Cell Disease • The current treatment of Sickle Cell Disease

    3. Sickle Cell Disease: A Case • A 22yo AA woman is transferred to your hospital with respiratory failure. You are asked to see her in the emergency department. In the ED the patient is in obvious distress with a RR of 45 and an O2sat of 72%. Her ABG revealed 7.34/44/59/23/76% on 3 liters O2 by nasal canula.

    4. Sickle Cell Disease: A Case • The patient had been diagnosed with Sickle Cell Anemia at age 6 and was hospitalized for a sickle cell crisis at age 12. 24 hours prior to admission in your hospital she was seen in another ED with severe pain (10/10) in her back thighs and knees. She was nauseated and had vomited once. She denied chest pain, SOB, fever, chills, abdominal pain, dysuria, constipation or diarrhea.

    5. Sickle Cell Disease: A Case • Within 10 hours of admission to your hospital, the patients O2 sat dropped to 40% and she was intubated. Her ABG revealed: 7.35/44/80/22/94% on the vent with 100% O2 TV=350, and 22cm of peep. • What is your diagnosis?

    6. Definitions • Sickle-Cell Disease: A group of blood disorders caused by a mutation in the hemoglobin gene. • Common Sickle Cell Diseases Include: • Sickle Cell Anemia • Hemoglobin SC Disease • Sickle Beta Thalasemia • Sickling and sickle cell disease also confer some resistance to malaria

    7. Definitions • Sickle-Cell Anemia : Sickle-cell anemia is the name of a specific form of sickle-cell disease in which the individual is homozygous for the mutation that causes HbS. Normal hemoglobin is called hemoglobin A, but people with sickle cell anemia have only hemoglobin S, which in the homozygous form, turns normal, round red blood cells into abnormally curved (sickle) shapes. Sickling decreases the cells' flexibility and predisposes the carrier to potentially serious complications. Sickle-cell anemia is also referred to as "HbSS", "SS disease", "hemoglobin S" etc.

    8. Sickle Cell Anemia

    9. Definitions • Sickle Cell Trait: condition in which a person has one abnormal allele of the hemoglobin beta gene ( heterozygous), but does not display the severe symptoms of sickle cell disease that occur in individuals who have two copies of the abnormal Hb S allele ( homozygous) • About 2 million Americans have sickle cell trait. The condition occurs in about 1 in 12 African Americans.

    10. Sickle Cell Disease • Sickle cell disease (SCD) is the most common genetic disorder identified in African Americans, • Also found in people from South and Central America, the Mediterranean and the Middle East.

    11. Sickle Cell Disease • In the United States, it’s estimated that sickle cell anemia affects around 50,000 people, mainly African Americans. The disease occurs in about 1 out of every 700 African American births. • Before the era of Hydroxyurea, the average life expectancy was in the 40’s

    12. Clinical Hallmarks of Sickle Cell Disease (SCD) • Vaso-occlusion • Hemolysis

    13. Diagnostic Testing: • Cellulose acetate electrophoresis is a standard method of separating Hb S from other hemoglobin variants. However Hb S, G, and D have the same electrophoretic mobility with this method.

    14. Diagnostic Testing: • Citrate agar electrophoresis seperates Hb S from Hb D and G • Thin-layer isoelectric focusing and high performance liquid chomatography (HPLC) are highly accurate tools for the diagnosis of sickle or other hemoglobin variants

    15. Diagnostic Testing • In Summary: Cellulose acetate electrophoresis with either citrate agar electrophoresis or a solubility test allows a definitive diagnosis of sickle cell syndrome • Alternatively, thin layer isoelectric focusing will separate Hb S, D, and G and can replace the two electrophoretic methods. • However, thin-layer isoelectric focusing still requires a confirmatory solubility test for Hb S

    16. Newborn Screening • Mandated in all 50 states and the District of Columbia. • Most states use either thin-layer isoelectric focusing (IEF) or high performance liquid chromatography (HPLC) as the initial screening test. • Both methods have extremely high sensitivity and specificity for sickle cell anemia. Specimens must be drawn prior to any blood transfusion (false negative) • Extremely premature infants may have false positive results when adult hemoglobin is undetectable

    17. Screening Programs • Selective screening of infants of high-risk parents • Universal testing of newborns • Selective screening misses up to 20% of AA newborns with SCD • sickle cell diagnoses doubled when screening was changed from targeted to universal

    18. Hemoglobin Patterns

    19. Laboratory Findings in Sickle Cell Disease • Chronic Hemolysis with mild to moderate anemia (Hct 20-30%) • Reticulocytosis of 3-15% (.5-1.85% RBCs) • Unconjugatedhyperbilirubinemia • Sickled RBCs on peripheral smear • Low serum erythropoietin secondary to progressive renal disease • Folate and Iron deficiency secondary to increased utilizaton of folate and urinary excretion of iron

    20. Peripheral Blood Smear • Sickled red cells • Polychromasia indicative of reticulocytosis • Howell-Jolly bodies secondary to splenic infarcts • Normochromic, normocytic RBCs

    21. Findings in Sickle Cell Disease • The Cooperative Study of Sickle Cell Disease looked at Lab Data in 2600 people with SCD • Mean WBC counts elevated especially in children < age 10 • Thrombocytosis seen individuals < age 18 • Serum Alk Phos elevated until puberty

    22. TIMING OF SCREENING • Test all newborns at the time of birth • Verify screening results at first office visit • Perform confirmatory tests no later than 2 months of age.

    23. Most common types of sickle cell disease • Hemoglobin SS disease (also called Sickle Cell Anemia) • Hemoglobin Sickle-C disease • Sickle Beta-Thalassemia.

    24. Hemoglobin • Hemoglobin: Definition and Structure • Hemoglobin carries oxygen from the lungs to tissues and CO2 from the tissues to the lungs for excretion. • Hemoglobin molecule consists of two parts: • Porphyrin group or heme • Protein or globin portion. • Globin is made up of four polypeptide chains attached to the porphyrin ring • Four types: alpha, beta, delta and gamma.

    25. Hemoglobin Molecule

    26. Sickle Cell Hemoglobin • In normal Hemoglobin A, glutamic acid is on the 6th position of the beta chain, while in sickle-cell disease, this glutamic acid is replaced by valine (point mutation) leading to the formation of sickle cells. • Polymerization: the two beta chains fit into each other forming a longitudinal polymer (or lock and key) causing the cell to become deformed and very rigid leading to vessel occlusion. • Polymerization: activated by infections, hypoxia, acidosis, physical exercise, vasoocclusion due to cold as well as dehydration.

    27. Sickle Cell Hemoglobin In sickle cell hemoglobin (HbS) glutamic acid in position 6 (in beta chain) is mutated to valine. This change allows the deoxygenated form of the hemoglobin to stick to each other.

    28. Normal Adult Hemoglobin • Primarily Hemoglobin A • 2 alpha chains and 2 beta chains • Beta chain synthesis begins early in fetal development • Sixth week of gestation, hemoglobin A composes about 7% of the total hemoglobin; the percentages slowly increase throughout the pregnancy • Thirtieth week there is a switch from gamma chain to beta chain production.

    29. Fetal Hemoglobin • At birth babies have mostly fetal or F hemoglobin • falls to the normal level of less than 3 to 5% by the time the infant is 5-6 months of age • Adults have less than 2% fetal hemoglobin. • Fetal hemoglobin is made up of two alpha and two gamma chains.

    30. STRUCTURAL FORMULA FOR NORMAL HEMOGLOBIN • A Major Adult Hemoglobin 2 Alpha Chains + 2 Beta Chains • F Fetal Hemoglobin 2 Alpha Chains + 2 Gamma Chains • A2 Minor Adult Hemoglobin 2 Alpha Chains + 2 Delta Chain

    31. HEMOGLOBINOPATHIES • Hemoglobinopathy: disease or trait caused by a defect in the genetic code for hemoglobin synthesis • Over 600 known hemoglobin variants reported • Vast majority of abnormal hemoglobin result from the mutation of a single polypeptide chain.

    32. Genetics of Sickle Cell Trait • Heterozygous subject (sickle cell trait (A/S), an abnormal gene is inherited from one parent and it directs the formation of abnormal hemoglobin. • A normal gene is inherited from the other parent and it directs the formation of normal hemoglobin.

    33. Example of an Inheritance Pattern for Sickle Cell Trait

    34. Genetics of Sickle Cell Disease • Homozygous subject, identical abnormal genes are inherited; one from each parent, and the majority of the hemoglobin is abnormal, such as in sickle cell anemia (S/S).

    35. Example of an Inheritance Pattern for Sickle Cell Trait

    36. HEMOGLOBIN A/S SICKLE CELL TRAIT • GENOTYPE: AS • Beta chain variant • Each red cell contains a mixture of A (60%) and S (40%). • Amount of A in each cell is enough to prevent sickling under most physiological conditions.

    37. POPULATIONS AFFECTED • African Americans: 8-10% • Hispanic Americans: 2% • Occurs frequently in Greeks, Italians, Saudi Arabians, East indians and Middle Easterners

    38. CLINICAL SYMPTOMS of Sickle Cell Trait • NOT associated with anemia. • Offers some protection against malaria. • Occasional hematuria and hyposthenia (impaired renal concentrating ability) • Splenic infarction reported to occur at altitudes greater than 7,000 feet • Greater risk for sudden death under extreme conditions such as those that might occur during basic training in the military. • severe dehydration, malnutrition, physical overexertion and exhaustion. This risk though increased, is small.

    39. PRECAUTIONS • Avoid hypoxic situations: deep sea diving, flying in unpressurized aircraft, strenuous physical activity over a prolonged period of time.

    40. COUNSELING POINTS TO BE MADE • Person is a healthy carrier • Person is not sick. • Sickle cell trait is not a disease. • Sickle cell trait will not cause you to be anemic. • There is a small amount of hemoglobin S, but not enough to change the shape of the red blood cell. • The red blood cells of a person with sickle cell trait remain round and flexible.

    41. SICKLE CELL ANEMIA • GENOTYPE: S/S • Hemoglobin S (90-100%) • Hemoglobin F may be slightly elevated

    42. SICKLE CELL ANEMIA • Most common form of sickle cell disease identified in African Americans

    43. SICKLE CELL ANEMIAClinical Symptoms • Most severe form of sickle cell disease • Clinical course variable • Severe anemia • Vaso-occlusion, pain episodes, organ damage • Aplastic episode, splenic sequestration, increased risk for infection • If HbF is greater than 10% there is a decreased risk of stroke

    44. SICKLE CELL ANEMIAPRECAUTIONS • Genetic counseling and screening to clarify risk for child born with sickle cell disease • Referral to High Risk OB Clinic for pregnancy. • Avoid Hypoxia, dehydration

    45. Clinical Manifestations of Sickle Cell Disease • Vasoocclusion and hemolysis are the hallmarks of sickle cell disease • Vasoocclusion results in recurrent painful episodes (sickle cell crisis) • Dactylitis (acute pain in the hands and feet) is the most common initial symptom

    46. Most Common Complications of Sickle Cell Disease • Acute Painful Crisis (Sickle Cell Crisis) • Acute Chest Syndrome • Stroke • Chronic Lung Disease • Avascular Necrosis • Leg Ulcers