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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 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.


15 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

16 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

17 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

18 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

19 Hemoglobin Patterns

20 Laboratory Findings in Sickle Cell Disease Chronic Hemolysis with mild to moderate anemia (Hct 20-30%) Reticulocytosis of 3-15% ( % RBCs) Unconjugated hyperbilirubinemia 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

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



24 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

25 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.

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

27 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.

28 Hemoglobin Molecule

29 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.

30 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.


32 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.

33 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.

34 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

35 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.

36 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.

37 Example of an Inheritance Pattern for Sickle Cell Trait

38 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).

39 Example of an Inheritance Pattern for Sickle Cell Trait

40 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.

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

42 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.

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

44 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.

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

46 SICKLE CELL ANEMIA Most common form of sickle cell disease identified in African Americans

47 SICKLE CELL ANEMIA Clinical 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

48 SICKLE CELL ANEMIA PRECAUTIONS 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

49 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

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

51 Clinical Manifestations of Sickle Cell Disease Hemoglobin S (HbS) results results form the substitution of a valine for glutamic acid as the sixth amino acid of the beta globin chain, that produces a hemoglobin tetramer (alpha 2/beta S2) that is poorly soluble when deoxygenated.

52 Clinical Manifestations of Sickle Cell Disease Sickle Cell Disease is used to describe those conditions associated with “ Sickling” Patients who are homozygous for HbS have the most severe form of the disease

53 Pathophysiology of Vasoocclusion Sickle cells (Hb SS) lose deformability when deoxygenated Causes vascular obstruction and ischemia Critical factor underlying painful crises, acute chest syndrome, functional asplenia, and stroke

54 Pathophysiology of Vasoocclusion Membrane damage shortens the lifespan of RBCs Causing chronic intravascular and extravascular hemolysis Intravascular hemolysis causes: Decreased nitric oxide, Increased vascular tone, and pulmonary artery hypertension

55 Pathophysiology of Vasoocclusion Damaged RBCs have irregular surfaces that cause them to adhere to the vascular endothelium promotes acute vascular occlusion leading to a proliferative “lesion” made up of WBCs, platelets, smooth muscle cells and coagulation proteins Leading to strokes and possibly Pulm HTN

56 Gladwin and Vichinsky n engl j med November 20, (21): 2254

57 Acute Painful Crisis (Sickle Cell Crisis) Acute pain (previously know as “sickle cell crisis”) Most common type of vasoocclusive events First symptom noted in over 25% of patients Most frequent symptom after the age of two

58 Clinical Manifestations of Sickle Cell Disease Dactylitis (acute pain in the hands and feet) most common symptom before the age of two Pain was the most common symptom after the age of two Splenic sequestration is the third major symptom

59 Clinical Manifestations of Sickle Cell Disease Significant predictors of adverse outcome Dactylitis before the age of 1 Hemoglobin level <7 g/dl Leukocytosis in the absence of infection

60 Pulmonary Complications Acute Chest Syndrome Bronchoconstriction/Asthma Pneumonia Pulmonary hypertension Chronic lung disease

61 Acute Chest Syndrome Presentation: Chest pain, pulmonary infiltrate and fever Most common form of acute pulmonary disease in Sickle Cell Disease Most common cause of death in SCD Etiology: pneumonia, infarction/thrombosis, fat embolus

62 Acute Chest Syndrome Presentation: Chest pain, pulmonary infiltrate and fever Most common form of acute pulmonary disease in Sickle Cell Disease Most common cause of death in SCD Etiology: pneumonia, infarction/thrombosis, fat embolus

63 Gladwin and Vichinsky n engl j med November 20, (21): 2254

64 Acute Chest Syndrome The Acute Chest Syndrome occurs in the majority of patients with sickle cell disease at least once during their lives Second most common cause of hospital admission after “painful vaso-occlusive crises”

65 Acute Chest Syndrome The Acute Chest Syndrome is a life- threatening disorder Leading cause of death in people with sickle cell anemia. Defined as the presence of a new pulmonary infiltrate on Chest Xray, with chest pain, fever, cough, dyspnea, or an elevated WBC count in a patient with sickle cell anemia.

66 Acute Chest Syndrome Caused by occlusion of the pulmonary vessels by sickled red cells. Since hypoxia is the chief stimulus for polymerization of hemoglobin S, lung disease of any type poses a particular threat to the patient with sickle cell anemia.

67 Four Major Precipitants of Acute Chest Syndrome Infection Bone Marrow Emboli Thromboembolism Atelectasis

68 Acute Severe Anemia Splenic Sequestration Crisis Aplastic Crisis Hyperhemoytic Crisis

69 Splenic Sequestration Crisis Vaso-occlusion within the spleen and pooling of RBCs leads to a marked fall in Hg and an increase in reticulocytes

70 Aplastic Crisis Transient cessation of erythropoiesis secondary to infection with parvovirus Can also occur after infection with Strep pneumoniae, salmonella, and EBV

71 Hyperhemolytic Crisis Associated with multiple transfusions Also associated with certain drugs, infections and glucose-six-phostate dehydrogenase deficiency

72 Growth and Development Growth retardation and delayed puberty are common in children with SCD

73 Infection Impairment of the spleen Patients are susecptable to encapsulated organisms such as Strep pneumo, and H flu Bacteremia Meningitis Pneumonia Osteomyelitis

74 Fever Medical emergency requiring immediate attention and treatment with antibiotics

75 Cerbrovascular/ Neurologic Disease Stroke/ TIA Intracranial Bleed Spinal Cord Infarction/ Compression Vestibular dysfunction Sensory hearing loss

76 Bone Complications Bone infarction and necrosis Osteomyelitis Osteoporosis Osteonecrosis (avascular or ischemic necrosis) Bone marrow infarction Pulmonary fat embolism (secondary to bone marrow infarction)

77 Cardiac Complications Increased Cardiac Output (secondary to chronic anemia) Myocardial Infarction (caused by increased oxygen demand that cannot be met due to the anemia and decreased oxygen carrying capacity of the RBCs)

78 Dermatolgic Complications Leg Ulcers (secondary to vasoocclusion in the skin

79 Hepatobiliary Complications Acute Hepatic Ischemia Cholestasis Hepatic sequestration crisis Iron overload secondary to multiple transfusions Acute and chronic cholelithiasis secondary to pigmented gallstones Hepatitis C secondary to blood transfusion

80 Obstetrical Complications Fetal complications: Spontaneous abortion, intrauterine growth retardation, fetal demise, low birth weight secondary to compromised placental blood flow Maternal complications: acute chest syndrome, UTI, pyelonephritis, endometritis, preeclampsia, thromboembolic events, which occur in up to 50% of pregnancies

81 Renal Complications Hematuria Proteinuria Hypertension Renal Infarction, Papillary necrosis Nephrogenic DI Focal Glomerulosclerosis Renal Medullary carcinoma, seen in black patients with sickle cell trait

82 Retinopathy Proliferative retinopathy Retinal artery occlusion Retinal detachment and hemorrhage

83 TREATMENT COMPREHENSIVE CARE — Upon diagnosis of SCD implement a Comprehensive Care program for the affected child and his\her family Because of the many manifestations of the acute and chronic complications of SCD Critical to involve specialists with expertise Multidisciplinary teams: social workers, psychologists, nurses, genetic counselors, and nutritionists.

84 TREATMENT Universal screening of newborns Prophylactic Penicillin Improved medical care Have reduced the mortality of Sickle Cell Disease from 25% to less than 3%

85 TREATMENT Begin prophylactic penicillin 125mg BID by 2-3 months of age and continue until two to three years of age. At this time increase dose to 250mg BID until the age of 5. After age 5 some clinicians elect to stop the penicillin prophylaxis Immunize against, Streptococcus pneumoniae, Haemophilus influenza,Hepatitis B and influenza

86 TREATMENT Folic Acid 1mg daily Children 16 or younger should be evaluated with transcranial doppler (TCD) to identify those children at risk for cerebrovascular accidents. Begin TCDs at age two and continue every 12 to 24 months. The risk of stroke can be reduced

87 TREATMENT Hydroxyurea Hematopoietic Stem-cell Transplantation Long Term Transfusion Therapy

88 Treatment Hydroxyurea: Only FDA approved therapy to prevent episodes of pain in SCD. Interferes with the sickle hemoglobin polymerization process by increasing the production of fetal hemoglobin

89 Cure Hematopoietic stem cell transplant. Limited to individuals less than 16 years of age

90 Hydroxyurea Cytotoxic drug that can bind metals. Used in polyc ythemia vera to decreas the elevated Hct and platelet count Inhibits ribonucleotide reductase by bindings its 2 main iron molecules and inactivating a critical tyrosyl radical that reduces the production of RBCs with a high level of HbSS Favors production of fetal Hb which arises from precursor cells that divide at a slower rate

91 Hydroxyurea A major breakthrough that shifts hemoglobin production from sickle hemoglobin to fetal hemoglobin by altering the bone marrow to favor fetal hemoglobin production

92 Hydroxyurea

93 Dose: Single daily oral dose 15 mg/kg (adjust for decreased creatinine clearance) Monitor CBC every 2 weeks Contraindicated in: pregnancy, breast feeding, severe anemia, leukopenia and thrombocytopenia Discontinue if CBC counts drop below the acceptable range

94 Hydroxyurea

95 Hematopoietic Stem-cell Transplantation Still under careful investigation in the US Currently the only potential cure for SCD




99 References American Academy of Pediatrics. (2002). Health supervision for children with sickle cell disease. Pediatrics, 109(3), Dew, A., & van Besien, K. (2010). Stem-cell transplantation for sickle cell disease. The New England Journal of Medicine, 362(10), Feld, J. J., DeBaun, M. R., & Vichinsky, E. P. (2009). Overview of the management of sickle cell disease. UpToDate. Retrieved from Firth, P. G. (2009). Pulmonary complications of sickle cell disease. The New England Journal of Medicine, 360(10), Gladwin, M. T., Sachdev, V., Jison, M. L., Shizukuda, Y., Plehn, J. F., Minter, K., … Ognibene, F. P. (2004). Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. The New England Journal of Medicine, 350(9), Gladwin, M. T., & Vichinsky, E. (2010). Pulmonary complications of sickle-cell disease. The New England Journal of Medicine, 359(21), Khan, S., & Rodgers, G. P. (2010). Hematopoietic cell transplantation in sickle cell disease.UpToDate. Retrieved from Lee, M. T., Piomelli, S., Granger, S., Miller, S. T., Harkness, S., Brambilla, D. J., & Adams, R. J.(2006). Stroke prevention trial in sickle cell anemia (STOP): Extended follow- up and final results. Blood, 108, doi: /blood Lunzer, M. M., Yekkirala, A., Hebbel, R. P., & Portoghese, P. S. (2007). Naloxone acts as a potent analgesic in transgenic mouse models of sickle cell anemia. Proceedings of the National Academy of Sciences, 104(14), doi: /pnas

100 References Medoff, B. D., Shepard, J. O., Smith, R. N., & Kratz, A. (2005). Case : A 22-year-old woman with back and leg pain and respiratory failure. The New England Journal of Medicine, 352(23), National Guideline Clearinghouse. (2007). Hemoglobinopathies in pregnancy. Retrieved from National Guideline Clearinghouse. (2007). Screening for sickle cell disease in newborns: U.S. Preventive Services Task Force recommendation. Retrieved from Platt, O. S. (2008). Hydroxyurea for the treatment of sickle cell anemia. The New England Journal of Medicine, 358(13), Rodgers, G. P. (2010). Specific therapies for sickle cell disease. UpToDate. Retrieved from Strouse, J. J., Takemoto, C. M., Keefer, J. R., Kato, G. J., & Casella, J. F. (2008). Corticosteroids and increased risk of readmission after acute chest syndrome in children with sickle cell disease. Pediatric Blood Cancer, 50(5), doi: /pbc Vinchinsky, E. (2009). Overview of the clinical manifestations of sickle cell disease. UpToDate. Retrieved from Virginia Department of Health. (2005). Sickle cell anemia (Hb SS Disease). Retrieved from Virginia Department of Health Division of Women’s and Infant Health. (n.d.). A counseling guide for sickle cell and other hemoglobin variants. The Virginia Sickle Cell Awareness Program. Retrieved from

101 References Yanni, E., Grosse, S. D., Yang, Q., & Olney, R. S. (2009). Trends in pediatric sickle cell disease-Related mortality in the United States, The Journal of Pediatrics, doi: /j.peds Ye, L., Chang, J. C., Lin, C., Sun, X., Yu, J., & Wai Kan, Y. (2009). Induced pluripotent stem cells offer new approach to therapy in thalassemia and sickle cell anemia and option in Prenatal diagnosis in genetic diseases. Proceedings of the National Academy of Sciences, 106(24), doi: /pnas West, MS, Wethers, D, Smith, J, et al. The Cooperative Study of Sickle Cell Disease: Laboratory profile of sickle cell disease: A cross-sectional analysis. J Clin Epidemiol 1992; 45:893.


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