Migration of Sickle Cell Disease Gene

Transcription

1 Sickle Cell Disease

2 Migration of Sickle Cell Disease Gene Distribution of malaria Sickle cell disease has three genetic origins in Africa.

3 Geographic Distribution of Hemoglobin S in the World 0-3% 3-6% 6-9% 9-12% 12-15% >15% North America South America Europe Africa Asia South East Asia Australia

4 Sickle Cell Mutation Chromosome 16 Chromosome 11

5 Hemoglobin Beta Globin Sickle Cell Mutation (ß6Glu Val) Beta Globin Sickle Cell Mutation Heme Iron Atom Alpha Globin Heme Alpha Globin Iron Atom

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9 Probability of Inheritance AA AA AS AA AA Normal AS Sickle Trait SS Sickle Cell 0% chance 0% chance

10 AS AS AS SS SS SS 25% chance 75% chance 100% chance

11 Hemoglobin Electrophoresis Normal (AA) Sickle Trait (AS) Sickle Cell (SS) CONTROL A2 S F A J Linus Pauling, 1948

12 Magnified Structure of Polymer Homogeneous nucleation Growth Heterogeneous nucleation Growth & alignment 63 Å Val Axis Leu 88

13 Flow Flow No Flow O 2 Polymer

14 Determinants of Hemoglobin S Polymerization 0% 40% 70% 100% Oxygen Concentration Intracellular hemoglobin composition Intracellular hemoglobin concentration Oxygen saturation

15 O2 +O2

16 Red Blood Cell Longevity Normal SS/HbF SS days Days days days

17 Water Balloon Analogy Balloon filled with water Balloon filled with water Balloon filled with water and ice crystals Balloon filled with water and ice crystals X X

18 Symptoms Organ Failure Intense Unpredictable Pain Tissue Swelling Chronic Anemia Chronic Stress Tissue Injury

19 Complications of Sickle Cell Disease Anemia, Leukocytosis Indirect Hyperbilirubinemia Isosthenuria, Chronic Renal Failure Retinopathy Obstructive Sleep Apnea Pulmonary Hypertension Cardiomegaly Functional Asplenia Chronic Complications Delayed Puberty Avascular Necrosis Skin Ulcers

20 Stroke, Meningitis Glaucoma, Retinal Infarction Sickle Hepatopathy Papillary Necrosis Acute Chest Syndrome Spelenic Sequestration Splenic Infarction Priapism Cholelithiasis Bone Marrow Infarction, Osteomyelitis Acute Complications

21 Markers of severe disease Early onset of clinical manifestations (dactylitis) Severe manifestations of disease (CVA, recurrent acute chest syndrome) >3 painful events/year Low Hb F levels SS + Sb 0 thal > SC or Sb + thal Leukocytes

22 Causes of Death in Adults Am J Hematol 81: 858, 2006

23 The Importance of the Genotype Disorder Clinical Severity Hb (g/dl) SS usually marked 6-10 S/b 0 thal moderate-marked 6-10 S/b + thal mild-moderate 9-12 SC mild-moderate 10-15

24 Sickle Trait (AS) Normal life expectancy Rare sickling occurrences and splenic infarction (Ryan Clark Steelers) Asymptomatic hematuria and hyposthenuria (dehydration) Increased risk of sudden death Increased risk of medullary carcinoma of the kidney

25 Survival SS v SC

26 Severity of Common SCD variants

27 Morbidity Differences SS v SC

28 Infectious complications Children with SCD have increased susceptibility to bacterial infections: S. Pneumoniae, N. Meningitidis Prophylaxis with oral penicillin in children with sickle cell anemia: A multicenter, randomized, double-blind, placebo-controlled clinical trial trial (1986) 84 percent reduction in the incidence of infection in penicillin group, as compared with the group given placebo Basis for universal screening

29 Survival by Pain Frequency

30 Survival By Fetal Hemoglobin

31 Pulmonary Hypertension

32 Therapy of Pulmonary Hypertension

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34 Transfusions and SCD <5% of the blood donated to Central Blood Bank comes from African-American donors Disparate expression of minor red cell antigens between ethnic groups 20-30% of patients develop allo-antibodies 5-10% of those with antibodies develop delayed transfusion reactions

35 Types of Transfusions Simple transfusion: leukoreduced, HbS-, antigen-matched PRBC. Keep Hct 30 Exchange transfusion Replacing the patient s PRBC with Hb S- PRBC Requires 6-8 PRBC units Requires double lumen catheter

36 Patients were randomly assigned to Aggressive transfusion regimen designed to maintain a preoperative hemoglobin level of 10 g per deciliter (range, 9 to 11) and a hemoglobin S level of 30 percent or less (group 1) conservative transfusion regimen designed to maintain the hemoglobin level at 10 g per deciliter (range, 9 to 11), regardless of the percentage of hemoglobin S (group 2) Both regimens prevented perioperative complications and conservative equally effective as aggressive regimen

37 Indications for Transfusion Simple Transfusions Symptomatic anemia (high output cardiac failure, dyspnea, angina, CNS dysfunction) Sudden decrease in Hb (acute spleen or hepatic sequestration) Low Hb (~5g/dL) with fatigue/dyspnea Preparation for surgery w general anesthesia

38 Indications for Transfusion Acute CVA Exchange Transfusion Multiple organ system failure Acute chest syndrome Priapism unresponsive to other treatments Retinal surgery

39 Unclear Indications Intractable or frequent painful episodes Leg ulcers Prior to IV contrast dye Complicated pregnancy Adults with CVA Chronic organ failure

40 No Indication Chronic steady state anemia Uncomplicated painful crisis Infections Minor surgery without general anesthesia Aseptic necrosis of hip/shoulder Uncomplicated pregnancy

41 Allo-sensitization in SCD

42 Alloantibodies in SCD Antigen Frequency Antibody Frequency non-aa AA in SCD Rh D 85% 92% 13% C 70% 30% 30% E 30% 19% 42% Kell 9% 2% 28%

43 Iron Overload Iron overload after >20 PRBC Invasive vs. non invasive diagnostic methods Controversy on ferritin threshold to start chelation Continue chelation until ferritin <500 ng/dl Desferioxamine was only option until the development of Deferasirox and Deferiprone (not available in US)

44 Iron Overload

45 Vaso-occlusive Crises Factors That Can Precipitate Sickle Cell Crises Infections Low oxygen tension Concomitant medical conditions (e.g., sarcoidosis, diabetes mellitus, herpes) Dehydration Acidosis Extreme physical exercise Physical or psychologic stress Alcohol Pregnancy Cold weather

46 Psychosocial Stressors

47 Coping Skills and Pain Sickle cell disease is the only common pain syndrome in which opioids are considered the major therapy and are started in early childhood and continued throughout adult life. Shapiro, BS in Pain in Infants, Children and Adolescents. 1993

48 Vaso-occlusive (Painful) Crisis Hydration (0.5 NS) Supplemental oxygen if O 2 sat <95% or primary pulmonary process Monitor for complication (CVA; ACS) Alleviate pain Choice of opioid MS or hydromorphone, NO meperidine Use patient controlled mechanism (PCA)

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50 Acute Chest Syndrome Signs/Symptoms Intrapulmonary sickling Often accompanies vaso-occlusive crisis Chest pain Pulmonary infiltrates Hypoxia Leukocytosis Treatment Support oxygenation Avoid fluid overload Simple transfusion If deteriorates (PaO2 < 70% on ABG) exchange transfusion

51 Strokes in SCD Occur in patients with Hb S Children and adults affected, but more common in children Treatment Chronic transfusions Stem cell transplantation

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53 STOP II (Optimizing Stroke Prevention in Sickle Cell Anemia), in 2000 to determine whether transfusion therapy could be safely withdrawn after at least 30 months of transfusions in patients who have converted to normal TCD velocities. Discontinuation of transfusion for the prevention of stroke in children with sickle cell disease results in a high rate of reversion to abnormal bloodflow velocities on Doppler studies and stroke.

54 Secondary Prevention of Stroke Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) This is a Phase III randomized clinical trial for children with SCA. The hypothesis is that hydroxyurea and phlebotomy can maintain an acceptable stroke recurrence rate and significantly reduce the hepatic iron burden. The primary aim is to compare standard therapy (transfusions and chelation) with alternative therapy (hydroxyurea and phlebotomy) for the prevention of secondary stroke and management of iron overload.

55 Disease-modifyng Therapy Stem cell transplantation Modulation of fetal hemoglobin expression Modulation of cell dehydration Modulation of nitric oxide Optimal Gene therapy

56 Stem Cell Transplantation Sole current cure for SCD Primarily offered to children <16 with matched sibling donor 5% incidence of graft rejection 5% mortality Increased risk of stroke or seizure

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58 Conditioning Regimens

59 Protocol 03-DK-0170: Mini-allo stem cell transplant for sickle cell disease Eligibility: Hb SS, SC, or Sb 0 -thal Severe end-organ damage stroke or abnormal CNS vessel pulmonary hypertension (TRV 2.5 m/s) renal damage Or modifiable complication, not ameliorated by hydroxyurea More than 2 hospital admissions per year for pain crises previous acute chest syndromes red cell alloimmunization osteonecrosis of multiple joints

60 Hemoglobin Timeline % of total globin synthesis Birth Post-conceptual age (weeks) Postnatal age (weeks)

61 Hydroxyurea Therapy No Therapy Hydroxyurea 100% Hb S Hb S Hb F Hb S to Hb F hybrid Polymer in cells 75% Hb S and 25% Hb F Flow Hybrid Formation Flow +O 2 O 2 +O 2 O 2 Hb S Polymerization No Flow Flow SS Cells SS Cells

62 Red Blood Cell Longevity Normal SS/HbF SS days days Days days

63 Hydroxyurea in Children Well tolerated No growth deficits Less clinical events (ACS)

64 Benefits of Hydroxyurea The incidence of painful crises was reduced from a median of 4.5 per year to 2.5 per year. The rates of the acute chest syndrome and blood transfusion were also reduced significantly. Follow-up of 233 of the original 299 subjects was performed for up to 9 years and showed a 40% reduction in mortality among those who received hydroxyurea. Am J Hematol 81: 927, 2006

65 Risks of Hydroxyurea

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67 RBC Gardos Channel Schematic Representation of Gardos Channel Activity in Sickle Erythrocytes. All red cells contain Gardos channel proteins in their membranes. Sickle cells accumulate excessive quantities of calcium, that activate the Gardos channel (illustrated as the blue circle on the red cell membrane.) The Gardos channel is a protein "pump" that expels intracellular potassium when activated by calcium. The red cells lose water along with potassium. The result is a higher intracellular hemoglobin concentration. This promotes polymerization of deoxygenated HbS.

68 Modulation of Cell Dehydration Trials utilizing a chemical that inhibits the Gardos channel Blocks water efflux from cell Oral agent with intent to prevent crises Blood. 2008;111:

69 Modulation of Vaso-occlusion with Nitrates

70 DeNOVO study

71 Summary History: determine hemoglobinopathy (SS vs others); ask about past significant clinical events (ACS; stroke); ask about frequency of painful events; ask of transfusions Exam: baseline pulmonary and neuro exams; spleen SC or S/b-thal

72 Summary Laboratory Determine Hb and reticulocytes Determine WBC (correct for presence of nucleated red cells) Determine oxygen saturation Cultures if febrile, symptoms or WBC elevated beyond baseline

73 Summary Alleviate pain (tolerance vs addiction) Judicious transfusions (doesn t alleviate pain) Hydration with hypotonic solutions (don t flood) Supplemental oxygen as needed

74 Summary Survival is being prolonged but adults with Hb S still lag in survival by 2 decades Pulmonary hypertension is the main cause of death Hydroxyurea is the only approved diseasemodifying drug Stem cell transplant remains the only cure Holy Grail gene therapy still a ways off

75 SCD in Africa Neonatal screening sketchy Penicillin prophylaxis scarcely used Hydroxyurea very rarely used Difficulty monitoring Western medicine bias Outpatient narcotics often unavailable Family planning genetic counseling problems Local medicines: Niprisan

76 Blood transfusions contain extra iron Blood transfusions = more healthy red blood cells 1 Red blood cells contain extra iron 1 Too much extra iron leads to excess buildup in the body 1

77 Iron overload, defined The buildup of excess iron in the body s tissues and organs 16,17 The body has no way of getting rid of the extra iron on its own, causing significant damage 16,17 A silent condition with no warning symptoms 16,17

78 Could I be at risk for iron overload? Any patient who has received 10+ transfusions in his/her lifetime is at risk for iron overload 16

79 How iron overload may affect your body Too much iron may damage the body s organs 1 It may lead to serious health problems 18

80 How do I know if I have too much iron? Serum ferritin test 1 a simple blood test measures the amount of iron in your blood 2 Liver biopsy MRI More invasive procedure 16 Bright = high iron concentration Dark = low iron concentration There is a risk of iron overload when you have 10 or more transfusions in your lifetime 1 20 or more transfused units 1 Serum ferritin level of more than 1,000 mcg/l 19

81 What I need to know about my iron levels: important questions 1.Have I received 10 or more blood transfusions? 2.What is my serum ferritin level? Is it above 1,000 mcg/l? 3.How often should I have a serum ferritin test?

82 Treatment for Iron Overload Deferoxamine (Desferal) Available for over 30 years (has been the standard of care) It prolongs survival Unfortunately it must be given by continuous infusion 8 to 12 hours/day, 5 to 7 days/week Compliance is poor because of side effects and quality-of-life issues Survival is correlated with compliance

83 A Newer Treatment: Deferasirox (Exjade) It is taken by mouth It is taken once daily It binds to iron and allows it to be removed by the body through the stools

84 How to Take Deferasirox (Exjade) Stir tablets in orange juice, apple juice or water Take tablets once-daily on empty stomach 30 minutes prior to eating, preferably at the same time each day Tablets should not be chewed or swallowed whole Tasteless and odorless

85 Deferasirox: What are the Risks? Kidney Problems. Exjade may increase blood serum creatinine (a kidney marker) and protein in the urine. Your healthcare professional should monitor you for kidney problems. Liver Problems. Liver problems include hepatitis and changes in blood liver function tests. Your healthcare professional should monitor for liver problems. Ear and Eye Problems. Ear problems include hearing loss and decreased hearing Eye problems include lens opacities, cataracts, increased intraocular pressure, and retina disorders that can cause changes in your eyesight. You should have ear and eye testing done before you start Exjade treatment and at regular times while you are taking this medicine.

86 Common Side Effects stomach area pain nausea vomiting diarrhea skin rash fever headache cough increased blood serum creatinine

87 What Should Patients Tell Their Healthcare Professional? Before you start taking Exjade, tell your healthcare professional if you: have or had kidney problems have or had liver problems Take aluminum-containing antacids (Maalox, Mylanta) are trying to become pregnant, are already pregnant, or are breast-feeding are allergic to Exjade or to any of the ingredients in Exjade

88 Monitoring is important! Marker/AE Measure prior to treatment Measure after treatment has been initiated Monthly Ferritin X X Serum creatinine Proteinuria Liver function testing Auditory & ophthalmic testing X X X X X Monthly monitoring recommended X Annually X

89 The Be Sickle Smart Campaign