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Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
Hemoglobinopathy & sickle cell disease
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Hemoglobinopathy & sickle cell disease

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  • 1. Hemoglobin Disorders and the Sickle Hemoglobinopathies Babette B. Weksler MD May 8, 2013 No conflict of interest to disclose
  • 2. RBC Microparticles Increase in Stored Blood and Can Scavenge Vascular Nitric Oxide, Favoring Vasoconstriction and Platelet Activation Red cell microparticles react with the important signaling molecule NO almost as fast as cell-free hemoglobin, about 1000 times faster than red-cell-encapsulated hemoglobin Liu, Free Rad Biol Med 65:1164, 2013
  • 3. Increased Coagulation during VOC in Sickle Cell Disease Inpatient=VOC D dimer 3077+ 3655 Outpatient= steadu state D dimer 1041 + 619 Shah Thr. Res. 130:3241,2012
  • 4. Polymerization Delay Times in Human Hemoglobin Mixtures HbS= 100% S; HbF= 75%S. 25%F; HbAS3= 75%S. 25%AS3 Levasseur JBC 2004
  • 5. HbAS3 Gene Therapy Corrects Sickling in Sickle Mice Levasseur JBC 2004 Recipient mice expressed 20-30% HbAS3
  • 6. Antisickling Properties of Mutated Hb globin Chain asp16 stabilizes interaction glu87 decreases polymerization ala22 decreases polymerization Levasseur JBC 279:27518, 2004 Fig 1
  • 7. Cross Section of Polymerized Hemoglobin SS Fiber
  • 8. Lentiviral Provirus Carrying Modified Beta Globin Casette Human Hb globin gene modified at 3 sites to impede sickling globin locus control region FB insulators
  • 9. Erythroid Differentiation of Transduced CD34+ Cells from Healthy (HD) or Sickle Cell Donors (SCD) Romero JCI 123:3319, 8/2013
  • 10. Expression of Transduced HBBAS3 in HD and SCD Erythroid Differentiated CD34+ Cells HBBAS3 RNA Romero JCI 123:3319, ‘13 Fig 4 Hb Tetramer
  • 11. Deoxygenated RBC from HBBAS3-Transduced SCD CD34+ Cultures Romero JCI 123:3319 Fig 5
  • 12. Hemoglobin Genes and Products Hgb is a tetramer of the products of two genes, alpha globin and non-alpha globin. 2 identical chain genes on chromosome 16p chain genes clustered on chromosome 11p Hemoglobin Genotype Hb A Hb A2 Hb F Amount 96% 3% 1% If a-chain synthesis is decreased, see Hb Barts = 4 or Hb H = 4
  • 13. Two Human Globin Gene Clusters Exist on Different Chromosomes EMBRYONIC α2ε2 Gower 1 Portland δ2ε2 Gower 2 FETAL δ2γ2 α2γ2 F ADULT α2δ2 A2 α2β2 A
  • 14. Timeline and Sites of Synthesis of the Different Hemoglobin Chains
  • 15. In Vivo Detection of Engrafted HBBAS3-Transduced CD34+ Cells Transplanted into NSG Mice SCD SCD Romero JCI:123,3319;’13 HD Mock HD SCD HD HBBAS3
  • 16. Hemoglobin Dissociation Shift oxyHb The affinity of Hgb for O2 is regulated by temperature, pH, and bisphosphoglycerate (BPG, or 2,3 DPG) sick patient deoxyHb
  • 17. Hemoglobin Abnormalities 1. Quantitative defects: imbalance of chain synthesis  thalassemia syndromes 2. Qualitative defects: additions, substitutions or deletions of amino acids e.g. sickle cell disease or altered oxygen affinity, stability 3. Failure to silence genes: hereditary persistence of fetal hemoglobin (HPFH)
  • 18. Itano, Singer, Wells, and Pauling - 1949 demonstated abnormal electrophoretic mobility of Hb S and predicted molecular charge alteration
  • 19. A single invariant point mutation in the beta globin gene is the basis for sickle cell disease GAG GTG glu6 val6 Yet the phenotype is extremely variable
  • 20. Rheologic effect of intravascular sickling
  • 21. Natural History of Sickle Cell Disease 1960’s Disease of childhood 1973 Median age at death = 14 yr (1/6 cases>50) 1990 Survival >20 yr of 85%, if SC 95% 1994* Median age at death 42 for men, 48 for women 2001 Median age at death 53 for men, 58 for women Main causes of death: organ failure 18%, stroke 22%, acute event 32% * when hydroxyurea became available
  • 22. Mortality rate per 100,000 Afr-Amer population Mortality Rates for Adults and Children (<19yr) with SCD in the US 1979-2005 3 2.5 Adult 2.0 1.5 1.0 Child 0.5 1980 1985 1990 1995 2000 2005 Lanzkron, Pub Health Repts 128:110, 2013
  • 23. Bone infarcts and marrow expansion in SCD Fishbone vertebrae Infarction of humeral head
  • 24. Stroke in SCD
  • 25. Acute Chest Syndrome in SCD
  • 26. Functional 5 months Asplenia 7 months
  • 27. Sickle cell ulcer
  • 28. Modulating Factors in Sickle Cell Disease High Hb F (interferes with sickling) Other non-S hemoglobins Beta thalassemia trait/ alpha thalassemia trait Beta globin haplotype: Senegal>Benin>Bantu>Cameroon (correlates with Hb F levels and to X-linked F-cell production locus)
  • 29. Sickle/Beta+ Thal has milder phenotype due to low MCV, residual Hb A and lower Hb S content but Sickle/Beta-zero Thal is as severe as SS
  • 30. a-Thalassemia: 1 or 2 Gene Deletion if combined with SS, ameliorates phenotype by decreasing MCH
  • 31. Target Cells in Hb CC 56 yo AA man, Hb 10.8, MCV 78, normal LFTs, spleen palpable
  • 32. Hemoglobin SC Disease % Hb S is greater than in sickle trait, so more severe Crises less frequent than SS, Hb level higher and ranges from ~8 g/dL to normal. RBC lifespan longer than in SS RBC dehydration High rate of aseptic necrosis and retinal disease Splenomegaly common Anemia, crises common in pregnancy Responds to hydroxyurea
  • 33. Predictors of Increased Mortality in Sickle Cell Disease Persistent high WBC and platelet count Acute chest syndrome Pulmonary hypertension Renal impairment Hb < 7 g/dL
  • 34. Coagulopathy in SCD Activated vascular endothelium = prothrombotic Decreased vascular NO favors platelet activation Prothrombotic microparticles from RBC and platelets Increased blood tissue factor level VWF activating factor increased (Activated A1 domain that binds platelets) Total VWF increased High WBC and positive surface PS also favor thrombosis Pulmonary hypertension favors silent pulmonary emboli
  • 35. Mainstays of Therapy in SCD Analgesics Fluid, Oxygen Blood Immunizations Penicillin Hydroxyurea
  • 36. Hydroxyurea in Sickle Cell Disease Raises Hb F --- decreases Hb S polymerization in rbc Decreases sickling, crises, ACS Decreases inflammatory cytokines Lowers WBC Induces eNOS-cGMP pathway in endothelium Reduces procoagulant state of endothelium Decreases stroke incidence in SCD children
  • 37. How Hydroxyurea Works in SS disease
  • 38. Longterm Adult Use of Hydroxyurea in SCD median >10 yrs No HU HU Crises/yr 7.4 + 6.5 0.2 + 0.4 Tx/yr 1.5 + 5.9 ~0 Hosp/yr 2.1 + 2.9 0.6 + 0.2 ACS 6.1% 0.8% OS 65% 86% AVN No difference Stroke No difference Pulmonary HT No difference Voskaridou, Blood 115:2354, 2010
  • 39. Transfusion High level matching to avoid alloimmunization Exchange vs simple transfusion Blood viscosity Pre-operative transfusion goal to reduce Hb S to 30% Hb ~ 10 Phlebotomy Iron overload management—Exjade in SS, less tissue iron deposition than thal
  • 40. Is Gene Therapy Feasible for SCD? Need for safe and effective vector Requirement for LCR as well as coding region for human bA-globin gene Harvest sufficient HSC from recipient Stable expansion of transduced HSC
  • 41. Adenosine A2A Receptor Agonists for Inflammation Control in SCD During VOC, NFKb p65, IFN, A2AR are elevated in iNKT cells (0.5% of all T cells) Regadenoson (Lexiscan) an A2AR agonist, is FDA approved for myocardial perfusion studies Low dose Regadenoson infusion x 24 h in SCD patients lowers iNKT inflammatory markers to normal during VOC Mechanism is via deactivation of iNK-T cells No toxicity 21 pts steady state, 6 VOC reported in Blood 4/25/13 Phase II study started April 2013. Clin Trials Gov #NCT1788631
  • 42. What’s New and Hopeful in SCD Management Better understanding of inflammatory and procoagulant pathophysiology Better management of pediatric SCD-transcranial doppler, transfusion programs, early hydroxyurea New concepts about role of hydroxyurea Microfluidic techniques for probing rheology Better grasp on how to raise HbF Novel pharmacologic approaches
  • 43. Case Presentation History: 20 yo Afro-American male 10 year H/O leg ulcers, otitis media, pneumonia, and attacks of abdominal pain with jaundice 1 prior episode joint swelling and pain Presented with fever, cough and anemia Physical Exam: pallor, scleral icterus, round and oval scars over lower extremities bilateral rales, dullness both bases cardiomegaly with soft systolic murmur
  • 44. Case Presentation, continued Urinalysis: trace albumin; few granular casts Peripheral blood: WBCs 15,250/mm3 72 P, 1 Band, 15L, 7 M, 5 Eo RBCs 2,800,000/mm3 74 nRBCs/100 WBC
  • 45. Case Presentation, continued. This was the first description of sickle cell anemia, 100 yrs ago in a dental student from Granada who presented with pneumonia to Cook County Hospital in Chicago in 1909 on Christmas eve. James R. Herrick “Peculiar elongation and sickle-shaped red blood corpuscles in a case of severe anemia.” Arch Int Med 6:517, 1910. “…some change in the composition of the corpuscle itself may be the determining factor”
  • 46. Peripheral Blood

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