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![Therapy
Hydroxyurea
S-phase cytotoxic, myelosuppressive drug: inhibits ribonucleotide
reductase
Induces proliferation of early erythroid progenitors
Leads to ↑ Hgb F production (α2γ2)
γ subunit production α2 γS does not polymerize
Additional effects of hydroxyurea:
↓ Neutrophil numbers and neutrophil activation
↓ stress reticulocytes, ↓ reticulocyte adhesion
↓ endothelial adhesion properties (↓VCAM-1, ↓ laminin, ↓thrombospondin)
Improved RBC hydration and MCV
Increased [Hgb]](https://image.slidesharecdn.com/sicklecelldiseasesandip-130720225259-phpapp02/75/Sickle-cell-disease-sandip-35-2048.jpg)
Uploaded bySandip Gupta
Sickle cell disease sandip
1. Sickle cell disease is an inherited blood disorder that affects hemoglobin and causes red blood cells to take on a sickle, or crescent, shape. 2. The prevalence of sickle cell disease varies by ethnicity, with the highest rates seen in African Americans at about 1 in 375 individuals. 3. Complications of sickle cell disease include anemia, infections, acute pain episodes, stroke, and damage to organs like the lungs, kidneys, spleen, and liver over time if not properly managed.
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Speaker introduction for the presentation on sickle cell disease by Dr. Sandip Gupta.
Prevalence noted in various populations: 1 in 375 in African-Americans for HbSS, with other ethnicities varied.
Description of sickle cell disease as an inheritable condition affecting hemoglobin, with effects on blood flow.
Detailed process of how red blood cells sickle due to hemoglobin deoxygenation and subsequent changes.
Discussion on the impact of rigid hemoglobin S fibers on red blood cells and factors influencing polymerization.
Differences in shape, rigidity, and lifespan of normal vs. sickle red blood cells.
Severity of sickle cell disease linked to specific genotypes with varying clinical manifestations.
Interpreting newborn screening results and associations with specific sickle hemoglobinopathies.
Impact of vaso-occlusion and hemolysis resulting in pain and organ damage, along with chronic manifestations.
Emergency protocol for fever in sickle cell disease, emphasizing immediate hospital evaluation and treatment.
Recognizing symptoms of ACS and recommended treatments including oxygen and blood transfusions.
Involuntary erections lasting over 30 minutes, treatment options, and age of onset considerations.
Identification of stroke symptoms and management strategies in patients with sickle cell disease.
Risks, incidence, and effects of splenic sequestration in infants and children with sickle cell disease.
Management options for splenic sequestration including IV fluids and possible splenectomy.
Approaches to manage acute pain from various complications in sickle cell disease using medications.
Overview of hand-foot syndrome as an early complication, treatment strategies including fluids.
Renal impairment issues associated with sickle cell disease, including hematuria and proteinuria.
Potential liver issues such as gallstones and iron overload resulting from chronic transfusions.
Focus on avascular necrosis, diagnostic methods, and conservative treatment options.
Summary of chronic complications including anemia, brain damage, and the need for ongoing management.
Guidelines on who should receive genetic counseling and topics to be discussed.
Strategies for health maintenance including routine check-ups and necessary laboratory evaluations.
Guidelines for penicillin prophylaxis addressing different sickle cell genotypes.
Various therapy options, including hydroxyurea and stem cell transplantation.
Goals and challenges faced in gene therapy for sickle cell, addressing stability and safety.
Expression of gratitude to the audience for their attention.
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- 1. DR SANDIP GUPTA PGT,PEDIATRICS
- 2. 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
- 3. Sickle Cell Disordersin India
- 4. What Is SickleCell 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 β-globin gene (chromosome 11q) mutation GAGGTG at 6th codon Glutamic Acid Valine at the 6th amino acid along the β-globin chain
- 5. Why Do CellsSickle? Sickling Mechanism 1. Deoxygenation HgbS protein conformational change 2. Hydrophobic Valine exposed at molecular surface 3. Val6 of B2 chain of 1st Hgb S chain forms hydrophobic bond with Phe85 and Leu88 of a 2nd Hgb S B1 chain 4. Pairing Hgb S monomers polymerize to form Hgb S chains 5. Hgb S polymers precipitate in RBCs as long, rigid fibers.
- 6. Pathophysiology HgbS fibersare rigid Hgb S fibers deform RBC membranes Membrane disruption exposes transmembrane proteins and lipids that are pro-inflammatory Progressive sickling makes cells dense and inflexible Frenette et al., Journal of Clinical Investigation 117(4): 850-858, 2007
- 7. Pathophysiology Factors that PromoteHgb S polymerization: Low pO2 / Hypoxia Prolonged “Delay Time” – time RBC spends in microcirculation Low pH High Hgb S concentration Genotype-dependent Cellular “Dehydration” Volume depletion (total body) Sickling Activation K+ / Cl- cotransporter and Gardos Ca2+- activated K+ efflux channels ion and water efflux Low Hgb F concentration α2γS: gamma globin chains bind Hgb S chains and inhibit Hgb S polymerization, thus countering sickling process
- 8. Normal Vs. SickleRed Cells Normal Disc-Shaped Deformable Life span of 120 days Sickle Sickle-Shaped Rigid Lives for 20 days or less
- 9. Clinical Syndromes Disease Severityis Genotype –Dependent Genotype Hgb SS Hgb S / β0 thalassemia Hgb SC Hgb S / α thalassemia Hgb S / D Hgb S / A Hgb S / E Hgb S / β+ thalassemia Hgb S / HPFH WorseningDiseaseSeverity Asymptomatic + / - Mild Anemia
- 10. Interpreting Newborn ScreeningResults 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 FAS Sickle Cell Trait FAC Hb C Carrier FAE Hb E Carrier FA Variant Hb Variant Carrier onfirmation.
- 11. Hemolysis and Vaso-occlusion Vaso-occlusion: Occurswhen 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.
- 12. 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
- 13. 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)
- 14. Acute Chest Syndrome Clinically: Acuteonset of fever, respiratory distress, chest pain, 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
- 15. ACS : Treatment Oxygen ( Spo2>90%) Blood transfusion therapy Emperical antibiotics( cephalosporin+ macrolides) Cont respiratory therapy( incentive spirometry,physio) Optimum pain control Fluid management.
- 16. Priapism: INVOLUNTARY ERECTIONFOR>30 min STUTTERING&REFRACTORY Treatment is difficult Opioid pain medication Intravenous fluids Aspiration and irrigation of the corpus cavernosum(>4hr) Blood Transfusions Impotence with severe disease or recurrent episodes Prevention: Hydroxyurea,Etilefrine Surgical shunt procedures Urethr a Corpus cavernosum Commonly occurs in children and adolescents with SS or SC Age of onset is 5-35 yrs. Early morning
- 17. Stroke: Any focalneuro deficit>24hr&/or↑intT2W MRI 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%
- 18. Splenic Sequestration Suddentrapping of blood within the spleen Usually occurs in infants under 2 years of age with SS Spleen enlarged ,hypovolemia, Hb↓>2% ,reticulocytosis ,↓pl atelet count,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%)
- 19. Splenic Sequestration HemoglobinSS Incidence increased: 6 and 36 months Overall incidence about 30% Hemoglobin SC Incidence increased: 2 and 17 years Mean age 8.9 years Can occur in adolescence and adulthood Incidence about 5%
- 20. Treatments For Splenic Sequestion Intravenous fluids Maintain vascular volume Cautious blood transfusion Treat anemia with 5ml/kg of PRBC splenectomy If indicated
- 21. Pain Management Acute pain Hand-foot syndrome (dactylitis) Painful episodes: vasoocculsion Splenic sequestration Acute chest syndrome Cholelithiasis Priapism Avascular necrosis Right upper quadrant syndrome
- 22. PRECIPTATING FACTORS: physicalstress, infection , dehydration,hypoxia ,exposure to cold, acidosis 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
- 23. 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
- 24. Pain Management Moderate-severepain 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
- 25. 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
- 26. Renal Disease Renalfindings 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
- 27. Gall Bladder andLiver 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
- 28. Bone Disease Diagnosisand 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
- 29. Chronic Complications Anemia/Jaundice Brain Damage/Stroke Kidney failure Decreased lung function Eye disease (bleeding, retinal detachment) Leg ulcers Chronic pain management
- 30. GENETIC COUNSELLING Whoshould 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
- 31. Health Maintenance Frequentvisits: 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
- 32. Health Maintenance Physicalexam 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
- 33. Health Maintenance Special studies Brain- Transcranial doppler ultrasonography, MRI/MRA Lungs- Pulmonary function tests, Echo cardiogram for pulmonary hypertension Neurologic- neuropsychological testing
- 34. Current Recommendations PenicillinProphylaxis: 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
- 35. Therapy Hydroxyurea S-phase cytotoxic, myelosuppressivedrug: inhibits ribonucleotide reductase Induces proliferation of early erythroid progenitors Leads to ↑ Hgb F production (α2γ2) γ subunit production α2 γS does not polymerize Additional effects of hydroxyurea: ↓ Neutrophil numbers and neutrophil activation ↓ stress reticulocytes, ↓ reticulocyte adhesion ↓ endothelial adhesion properties (↓VCAM-1, ↓ laminin, ↓thrombospondin) Improved RBC hydration and MCV Increased [Hgb]
- 36. Therapy Hydroxyurea Dosing: Initiationof Treatment: Hydroxyurea 15-20mg/kg/day in single daily dose Check CBC Q 2wks, Hgb F Q 6-8 wks, serum chem Q 2-4 wks May require Tx Continuation: If no major toxicity, escalate dose Q 6-8wk by 2.5-5 mg/kg until desired endpoint reached may go upto 35mg/kg Reduces painful episodes, ACS by 50%. Treatment Endpoints: Decreased pain / pain crises Hgb F 15-20% Acceptable myelotoxicity: <2500 neutrophils / ul < 90,000 platelets / ul Hgb < 5.3 g/dL
- 37. Therapy Other Hgb F– inducing Agents Short-chain fatty acids (sodium butyrate) Mechanism: Histone deacetylation Baboons: ↑ Hgb F Phase II study (N=15): 11 responders, Increased Hgb F 7% 21% 5-Azacytidine and 5-Aza-2’deoxycytidine Mechanism: Demethylation of DNA 9-month Phase I/II study (N=7): Increased Hgb F 3.1% 13.9% Erythropoietin
- 38. Therapy Allogeneic Stem CellTransplantation Only Therapy Offering Curative Potential for sickle cell disease As of 2002, only ~150 patients had undergone SCT Patient recruitment hindered by: Difficult pt selection - Absence of early prognostic markers in SCD Majority of patients do not have donor High mortality risk of SCT Risk of long-term treatment-induced malignancy Risk of GVHD Pts >16 have demonstrated poor outcomes d/t comorbidities Two multicentre series of allogeneic SCTs have been undertaken, 1 in US, 1 in Europe
- 39. 2002 NIH Guidelinesfor SCT Eligibility in Sickle Cell Disease
- 40. Therapy Gene Therapy Goal:Transfer anti-sickling β-globin genes Obstacles: poor onco-retroviral vector stability low viral titres and gene transfer efficiency difficulty packaging large β-globin gene and regulatory elements safety concerns
- 41.