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Roland B. Scott Memorial Symposium Pharmacologic Treatment of Sickle Cell Disease

Roland B. Scott Memorial Symposium Pharmacologic Treatment of Sickle Cell Disease. Kwaku Ohene-Frempong, MD Professor of Pediatrics, University of Pennsylvania Director Emeritus, Sickle Cell Center The Children’s Hospital of Philadelphia. Disclosure Nothing to disclose.

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Roland B. Scott Memorial Symposium Pharmacologic Treatment of Sickle Cell Disease

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  1. Roland B. Scott Memorial SymposiumPharmacologic Treatment of Sickle Cell Disease Kwaku Ohene-Frempong, MD Professor of Pediatrics, University of Pennsylvania Director Emeritus, Sickle Cell Center The Children’s Hospital of Philadelphia

  2. DisclosureNothing to disclose Kwaku Ohene-Frempong, MD Professor of Pediatrics, University of Pennsylvania Director Emeritus, Sickle Cell Center The Children’s Hospital of Philadelphia

  3. Sickle Cell Disease: Pharmacologic Treatment Sickle cells - first observationWalter Noel’s blood smear - Dec 31, 1904

  4. Sickle Cell Disease: Pharmacologic Treatment When deoxygenated When oxygenated… - O2 + O2 …Hb S molecules polymerize into long fibers; mishapen, dehydrated and adherent sickle cells. …single Hb S molecules in free in solution; allows red cell to be soft, round, and deformable Pathophysiology of SCD In a red blood cell containing mostly Hb S… - O2 + O2

  5. Sickle Cell Disease: Pharmacologic Treatment Pathophysiology of SCD 1. Molecular pathology 2. Biochemical pathology • Cellular pathology • Vascular pathology • Clinical pathology

  6. Sickle Cell Disease: Pharmacologic Treatment Pathophysiology of SCDConsequences of Hb S polymerization and RBC sickling • Red cell injury • Hemolysis • RBC dehydration and dense cell formation • Adhesion of RBC to venule endothelium • Formation of heterocellular aggregates (WBC, ISC) • Vasooclusion • Local hypoxia, increased Hb S polymer formation • Propagation of vasooclusion in adjacent vasculature • Dysregulation of vasomotor tone by vasodilator mediators (NO)

  7. Sickle Cell Disease: Pharmacologic Treatment Molecular pathology of SCD It all started in the genes!

  8. Sickle Cell Disease: Pharmacologic Treatment Gower 1: z2 e2 Gower 2: a2 e2 Portland: x2 g2 ------------------ F: a2 g2 A2: a2 d2 A: a2 b2 < 2% < 3% 96% Hemoglobins by age > 1 yr Molecular pathology of SCDRegular Hemoglobin Genes and Products

  9. Sickle Cell Disease: Pharmacologic Treatment Gower 1: z2 e2 Gower 2: a2 e2 Portland: x2 g2 ------------------ F: a2 g2 A2: a2 d2 S:a2 bs2 2-20% 3% 80-95% Hemoglobins in SS by age > 1 yr Molecular pathology of SCDHemoglobin Genes and Products in SCD-SS

  10. Sickle Cell Disease: Pharmacologic Treatment GAG GTG Glutamic acid Valine Molecular pathology of SCDThe sickle mutation The s Mutation 6th Codon of -Globin Gene The same mutation found in all s genes around the world

  11. Sickle Cell Disease: Pharmacologic Treatment 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 10 10 146 146 Normal glu A - - - - - - - - val Sickle S - - - - - - - - Molecular pathology of SCDNormal versus sickle beta globin

  12. - O2 + O2 deoxygenated oxygenated - O2 + O2 + O2 deoxygenated oxygenated RBC containing mostly normal Hb RBC containing mostly Hb S

  13. Sickle Cell Disease: Pharmacologic Treatment Clinical Pathology of SCD 1. Anemia 2. Vasoocclusion 3. Chronic organ damage

  14. Sickle Cell Disease: Pharmacologic Treatment Clinical Pathology of SCD 1. Anemia • Chronic intravascular hemolytic anemia • Acute episodes of severe anemia • Transient red cell aplasia (parvovirus B19) • Acute splenic sequestration • Acute hemolysis (“hyperhemolysis”)

  15. Sickle Cell Disease: Pharmacologic Treatment Clinical Pathology of SCD • Vasoocclusive complications • Microvascular occlusion • clinically silent • Macrovascular occlusion • acute ischemic/infarctive damage • pain episodes • stroke • priapism • acute chest syndrome • renal papillary necrosis • splenic infarction

  16. Sickle Cell Disease: Pharmacologic Treatment Clinical Pathology of SCD 3. Chronic organ damage • Splenic dysfunction • high risk of bacterial infection • Progressive dysfunction of: • lungs - oxyhemoglobin desaturation, pulmonary hypertension • kidneys - proteinuria, renal failure • gallbladder - gallstones • eyes - proliferative retinopathy • joints - osteonecrosis, arthritis • heart - CHF

  17. Sickle Cell Disease: Pharmacologic Treatment Pharmacological therapy in SCDPotential targets • Intracellular Hb composition • Intracellular Hb concentration • RBC Transit time • circulatory factors • local tissue factors • systemic factors • O2 extraction from oxy-Hb S • Vascularity/ vascular pathology • Nitric oxide bioavailability • Multi-genetic and environmental factors

  18. Pharmacotherapy of SCD

  19. Sickle Cell Disease: Pharmacologic Treatment Pathophysiology of SCDVasoocclusion (1) A. Prolongation of the RBC microvascular transit time caused by: • Enhanced red cell adhesion to endothelium and heterocellular aggregate formation • Abnormal cation homeostasis with cell dehydration, dense-cell formation, and • irreversibly sickled cell formation • Abnormal vasomotor tone favoring vasoconstriction (via NO, endothelin-1, and eicosanoid dysregulation)

  20. Sickle Cell Disease: Pharmacologic Treatment Pathophysiology of SCDVasoocclusion (2) B. Reduction in delay time to HbS polymer formation caused by: • Red-cell deoxygenation • Increase in intracellular HbS concentration • Low concentrations of protective Hb types (eg, HbF, HbA2) • Fall in pH C. Miscellaneous potential modulators • Free-radical release and reperfusion injury • Coagulation activation with proadhesive thrombin formation

  21. Sickle Cell Disease: Pharmacologic Treatment Pharmacotherapy of SCDHb F Induction

  22. Sickle Cell Disease: Pharmacologic Treatment Pharmacotherapy of SCDAnti-adhesion agents

  23. Sickle Cell Disease: Pharmacologic Treatment Pharmacotherapy of SCDNitric oxide donors/regulators

  24. Hydroxyurea Therapy in Sickle Cell Disease Kwaku Ohene-Frempong, M.D. The Children’s Hospital of Philadelphia

  25. Effect of Hb F on Polymerization of Deoxy-Hb S A. 100% Hb S Hb S B. 75% Hb S / 25% Hb F F/S Hybrid Hb F

  26. Hydroxyurea Therapy in Sickle Cell Disease Effect of Hb F on SCD 1. In vitro gelation studies have shown that Hb F is effective inhibitor of gelation. 2. Patients with high Hb F levels (> 20%) documented to have mild clinical course. 3. Patients with S-HPFH produce 25-35% Hb F in every RBC beyond infancy, and are clinically asymptomatic.

  27. Hydroxyurea Therapy in Sickle Cell Disease Effect of Hb F on SCD

  28. Hydroxyurea Therapy in Sickle Cell Disease Beneficial RBC Effects of HU Treatment in SCD-SS • Increase in F-cell numbers and Hb F concentration per F cell • Inhibition of cation depletion and dense-cell formation • Reduction in stress reticulocytes and hemolytic rate • Increased deformability with improved rheology • Inhibition of sickle red cell-endothelium adhesion • Inhibition of sickle erythrocyte adhesion to extracellular matrix components, including fibronectin,thrombospondin, and laminin

  29. Hydroxyurea Therapy in Sickle Cell Disease Beneficial non-RBC Effects of HU Treatment in SCD-SS • Quantitative reduction in leucocyte count • Qualitative changes in leucocytes, including reduction in leucocyte-free-radical production and activation marker L-selectin • Reduction in soluble VCAM-1 concentrations (indicative of decreased endothelial activation) • In-vivo NO release

  30. Hydroxyurea Therapy in Sickle Cell Disease Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH Study) EFFECT OF HYDROXYUREA ON THE FREQUENCY OF PAINFUL CRISES IN SICKLE CELL ANEMIA Charache, et al.. NEJM, 1995

  31. Multicenter Study of Hydroxyurea in SCA (MSH) Effect of Hydroxyurea Therapy on SCD Complications PlaceboHUp value Pain, episodes/yr. 4.5 2.5 < 0.001 Pain hospitalization 2.4 1.0 < 0.001 No. with acute chest 51 25 < 0.001 No. transfused 73 48 0.001

  32. Steinberg, et al: JAMA 2003: 280; 1645

  33. Hydroxyurea Therapy in Sickle Cell Disease Effect of HU and Hb F on Mortality Steinberg, et al: JAMA 2003: 280; 1645

  34. Hydroxyurea Therapy in Sickle Cell Disease Questions So why is every adult with SCD-SS NOT on hydroxyurea? What to do about the children?

  35. Hydroxyurea Therapy in Sickle Cell Disease Effects of Hydroxyurea on SCD

  36. Hydroxyurea Therapy in Sickle Cell Disease Effects of Hydroxyurea on SCD Zimmerman, et al. 2004

  37. Hydroxyurea Therapy in Sickle Cell Disease Effects of Hydroxyurea on SCD Zimmerman, et al. 2004

  38. Hydroxyurea Therapy in Sickle Cell Disease Effects of Hydroxyurea on SCD Hankins, et al. 2005

  39. Hydroxyurea Therapy in Sickle Cell Disease Effects of Hydroxyurea on SCD Hankins, et al. 2005

  40. Hydroxyurea Therapy in Sickle Cell Disease Effects of Hydroxyurea on SCD Hankins, et al. 2005

  41. Hydroxyurea Therapy in Sickle Cell Disease Effects of Hydroxyurea on SCD Hankins, et al. 2005

  42. Hydroxyurea Therapy in Sickle Cell Disease What are the treatment goals? • Hematologic • Hb F (> 20%) • Hb concentration (9 - 10 g/dL) • 2. Clinical • pain episodes • acute chest episodes • 3. Therapeutic dose • dose adjustments to maintain goals 4. Period of observation

  43. Hydroxyurea Therapy in Sickle Cell Disease Effects of Hydroxyurea on SCD Zimmerman, et al. 2004

  44. NIH Consensus Development Conference on Hydroxyurea Treatment for Sickle Cell Disease February 25-27, 2008

  45. Hydroxyurea Therapy in Sickle Cell Disease Short- and Long-Term Side Effects

  46. Hydroxyurea Therapy in Sickle Cell Disease Barriers to Treatment 1. Patient Level • Fears - cancer, birth defects, infertility, uncertainty of other potential long-term risks • Concern - non-FDA-approved status for children means HU an experimental drug • Lack of knowledge about HU as a therapeutic option • Lack of perception that HU is currently the only therapy that directly modifies disease process • Lack of adherence to treatment regimen • Need for frequent monitoring of hydroxyurea response

  47. Hydroxyurea Therapy in Sickle Cell Disease Barriers to Treatment 2. Parent / Family / Caregiver Level • Fears - cancer, birth defects, infertility, uncertainty of other potential long-term risks • Concern - non-FDA-approved status for children means HU an experimental drug • Lack of knowledge about HU as a therapeutic option • Lack of perception that HU is currently the only therapy that directly modifies disease process • Difficulty in communication between patients and caregivers regarding the use of HU and other therapeutic options

  48. Hydroxyurea Therapy in Sickle Cell Disease Barriers to Treatment • 3. Provider Level • • Lack of knowledge about HU as a therapeutic option • Concerns - cancer, birth defects, infertility, uncertainty of other potential long-term risks • Provider bias and negative attitudes toward SCD patients and their treatment • • Lack of clarity in HU treatment regimens and undertreatment in adults • • Limited number of physicians with expertise in use of HU for SCD • • Failure to engage patients/caregivers in treatment decision making in a developmentally appropriate manner • Lack of perception that hydroxyurea is currently the only therapy that directly modifies the disease process

  49. Hydroxyurea Therapy in Sickle Cell Disease Barriers to Treatment • 4. Systems Level (a) • Financing (lack of insurance, type of insurance, underinsurance, • scope of coverage, copays, reimbursement, payment structures) • • Geographic isolation • • Lack of coordination between academic centers and community-based • clinicians • • Limited access to comprehensive care centers and comprehensive • care models • • Problems in transitioning from pediatric to adult care

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