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Roland B. Scott Memorial Symposium Pharmacologic Treatment of Sickle Cell Disease Kwaku Ohene-Frempong, MD Professor of Pediatrics, University of Pennsylvania.

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Presentation on theme: "Roland B. Scott Memorial Symposium Pharmacologic Treatment of Sickle Cell Disease Kwaku Ohene-Frempong, MD Professor of Pediatrics, University of Pennsylvania."— Presentation transcript:

1 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

2 Disclosure Nothing 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 cells - first observation Walter Noel’s blood smear - Dec 31, 1904 Sickle Cell Disease: Pharmacologic Treatment

4

5 Pathophysiology of SCD In a red blood cell containing mostly Hb S… …single Hb S molecules in free in solution; allows red cell to be soft, round, and deformable When oxygenated… + O2 - O2 …Hb S molecules polymerize into long fibers; mishapen, dehydrated and adherent sickle cells. When deoxygenated + O 2 Sickle Cell Disease: Pharmacologic Treatment

6 Pathophysiology of SCD 1. Molecular pathology 2. Biochemical pathology 3.Cellular pathology 4.Vascular pathology 5.Clinical pathology Sickle Cell Disease: Pharmacologic Treatment

7 Pathophysiology of SCD Consequences 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) Sickle Cell Disease: Pharmacologic Treatment

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

9 Molecular pathology of SCD Regular Hemoglobin Genes and Products Sickle Cell Disease: Pharmacologic Treatment Gower 1:  2  2 Gower 2:  2  2 Portland:  2  F:  2  2 A 2 :  2  2 A:  2  2 < 2% < 3% 96% Hemoglobins by age > 1 yr

10 Molecular pathology of SCD Hemoglobin Genes and Products in SCD-SS Sickle Cell Disease: Pharmacologic Treatment Gower 1:  2  2 Gower 2:  2  2 Portland:  2  F:  2  2 A 2 :  2  2 S:  2  s % 3% 80-95% Hemoglobins in SS by age > 1 yr

11 Molecular pathology of SCD The sickle mutation Sickle Cell Disease: Pharmacologic Treatment GAGGAG Glutamic acid GTGGTG Valine The  s Mutation The same mutation found in all  s genes around the world 6th Codon of  -Globin Gene

12 Molecular pathology of SCD Normal versus sickle beta globin Sickle Cell Disease: Pharmacologic Treatment val glu AA Normal SS Sickle

13 RBC containing mostly Hb S - O2 + O2 RBC containing mostly normal Hb + O2 - O2 oxygenated deoxygenated oxygenated deoxygenated

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

15 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”) Sickle Cell Disease: Pharmacologic Treatment

16 Clinical Pathology of SCD 2.Vasoocclusive complications Microvascular occlusion  clinically silent Macrovascular occlusion  acute ischemic/infarctive damage  pain episodes  stroke  priapism  acute chest syndrome  renal papillary necrosis  splenic infarction Sickle Cell Disease: Pharmacologic Treatment

17 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 Sickle Cell Disease: Pharmacologic Treatment

18 Pharmacological therapy in SCD Potential targets Intracellular Hb composition Intracellular Hb concentration RBC Transit time  circulatory factors  local tissue factors  systemic factors O 2 extraction from oxy-Hb S Vascularity/ vascular pathology Nitric oxide bioavailability Multi-genetic and environmental factors Sickle Cell Disease: Pharmacologic Treatment

19 Pharmacotherapy of SCD

20 Pathophysiology of SCD Vasoocclusion (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) Sickle Cell Disease: Pharmacologic Treatment

21 Pathophysiology of SCD Vasoocclusion (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 Sickle Cell Disease: Pharmacologic Treatment

22 Pharmacotherapy of SCD Hb F Induction AgentMode of actionHuman trials HydroxyureaStress erythropoiesis; selection of F-cells Phase 3, successful Short chain fatty acids Histone deacetylase inhibitor; reactivation of  -gene expression Promising in small studies; high doses required; variable responses DecytabineCytosine analog; DNA methyltransferase inhibitor Promising in small pilots Sickle Cell Disease: Pharmacologic Treatment

23 Pharmacotherapy of SCD Anti-adhesion agents AgentMode of actionHuman trials RheothRxImprove micro- vascular blood flow Phase 3, reduced duration of pain episode, analgesic use Sickle Cell Disease: Pharmacologic Treatment

24 Pharmacotherapy of SCD Nitric oxide donors/regulators AgentMode of actionHuman trials NOImprove micro- vascular blood flow Shortens duration of pain ArginineNO synthase substrate Reduce PA systolic pressure SildenafilPhosphodiesterase-5 inhibitor May help in pulmonary hypertension and priapism Sickle Cell Disease: Pharmacologic Treatment

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

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

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

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

29 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 Hydroxyurea Therapy in Sickle Cell Disease

30 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 Hydroxyurea Therapy in Sickle Cell Disease Beneficial non-RBC Effects of HU Treatment in SCD-SS

31 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 Hydroxyurea Therapy in Sickle Cell Disease

32 Effect of Hydroxyurea Therapy on SCD Complications Multicenter Study of Hydroxyurea in SCA (MSH) Placebo HU p value Pain, episodes/yr < Pain hospitalization < No. with acute chest 5125 < No. transfused

33 Steinberg, et al: JAMA 2003: 280; 1645

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

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

36 Effects of Hydroxyurea on SCD Hydroxyurea Therapy in Sickle Cell Disease

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

38 Effects of Hydroxyurea on SCD Zimmerman, et al Hydroxyurea Therapy in Sickle Cell Disease

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

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

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

42 Effects of Hydroxyurea on SCD Hankins, et al Hydroxyurea Therapy in Sickle Cell Disease

43 What are the treatment goals? 1.Hematologic Hb F (> 20%) Hb concentration ( g/dL) 2. Clinical pain episodes acute chest episodes 3. Therapeutic dose dose adjustments to maintain goals 4. Period of observation Hydroxyurea Therapy in Sickle Cell Disease

44 Effects of Hydroxyurea on SCD Zimmerman, et al Hydroxyurea Therapy in Sickle Cell Disease

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

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

47 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 Hydroxyurea Therapy in Sickle Cell Disease

48 Barriers to Treatment Hydroxyurea Therapy in Sickle Cell Disease 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

49 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 Hydroxyurea Therapy in Sickle Cell Disease

50 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 Hydroxyurea Therapy in Sickle Cell Disease

51 Barriers to Treatment 4. Systems Level (b) Limited access (e.g., geographic distribution, recruitment, and retention of clinicians competent in provision of comprehensive care to SCD patients) Inadequate Government, industry, and philanthropic support for the care of patients who have sickle cell disease Development and promotion of hydroxyurea are hindered by lack of commercial interest in the development and promotion of hydroxyurea Lack of visibility and empowerment of SCD advocacy groups Cultural and language barriers to the provision of appropriate care Inadequate information technology systems to support the long-term care of patients who have sickle cell disease Hydroxyurea Therapy in Sickle Cell Disease

52 Final Question So why are we not using hydroxyurea for many more patients with sickle cell disease? Hydroxyurea Therapy in Sickle Cell Disease


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