1. Sickle Cell Disease: From bench to bedside to prevention
Naomi L. C. Luban, MD Chief, Laboratory Medicine & Pathology
Children's National Medical Center
Professor, Pediatrics and Pathology
Vice Chair for Academic Affairs, Department of Pediatrics
The George Washington University Medical Center

2. Sickle Cell Anemia - Some History
First clinical described in 1910 in a Caribbean student
First disease to be called a “molecular disease” in 1949 by Pauling and Itano on the basis of electrophoresis and later as a single point mutation
Naomi L. C. Luban, MD

3. Sickle Cell Anemia - Some Basics
Most prevalent hgb disorder, world-wide distribution
In African-American population, 17.8% are sickle trait carriers
Estimated incidence of SCA is 1/650
,000 cases among African-Americans
Thymine for adenine substitution in glutamic acid DNA codon (GAG > GTG)
Substitution of valine for glutamic acid in the -6 position
Results in sickled RBC’s
Molecular instability and insolubility
Poor deformability (ISC formation)
Polymerization of hgb to a gel
Naomi L. C. Luban, MD

4. Sickle Cell Anemia – Pathophysiology
Naomi L. C. Luban, MD

5. Sickle Cell Anemia – Pathophysiology
Naomi L. C. Luban, MD

6. Sickle Cell Anemia – Pathophysiology Contributing Factors
Deoxygenation Changes in Temperature
Dehydration Acidosis
Infection Exercise
Pyrexia “Stress’
Naomi L. C. Luban, MD

7. Sickle Cell Anemia – A Vasculopathy: Pathophysiology
Naomi L. C. Luban, MD

8. Factors Effecting Severity of Disease
Naomi L. C. Luban, MD
Miller ST, et al. N Engl J Med 2000;342:83-9

9. Factors Effecting Severity of Disease: Disease Modifiers
Importance of
Saudi-Arabian/Indian and Senegal phenotypes
Co-inheritance of hereditary persistence of fetal hemoglobin
Co-inheritance/induction of disorders of beta globin giving rise to increased HbF levels
Co-inheritance of alpha -Thalassemia trait
Severe iron deficiency
Naomi L. C. Luban, MD

10. SCD in Infancy: “Losing Ground”
Decline in F hgb concentration
Progressive anemia
Dactylitis
Loss of splenic function
Naomi L. C. Luban, MD

11. SCD in Toddler: “Becoming Unhealthy”
Chronic hemolysis / anemia
Chronic hypoxic damage > vasculopathy
Hospitalizations for fever, vaso-occlusive crises, ruling out bacterial / viral disease
Naomi L. C. Luban, MD

12. SCD in School Age: “Organ Damage”
Organs Examples
Brain Stroke, seizures, neurocognitive dysfunction
Lungs Acute chest syndrome, pulmonary hypertension, lower airway disease
Heart Cardiac failure, infarction
Kidneys Renal failure, hyposthenuria, papillary necrosis, medullary CA
Spleen Splenic infarction, sequestration
Hepatobiliary Cholecystitis, hepatic failure
Joints Aseptic necrosis
Naomi L. C. Luban, MD

13. SCD in Adult: “Organ Failure”
Chronic pain
Debilitating organ failure, especially pulmonary, hepatic and kidney
Quality of life issues
Naomi L. C. Luban, MD
NY Times, 2007

14. SCD Morbidity & Mortality
Increased lifespan (14 years to early 40s)
Life expectancy years less than other African Americans
Causes of death
Vary by genotype, age, sex
Infection and sudden death common
Chronic organ injury significant role
Naomi L. C. Luban, MD
Manci et al. British Journal of Hematology, 2003;123:

15. History of Improvement in Care Dependence on Transfusion Through NHLBI Funded Studies
1982 Cooperative Study of Sickle Cell Disease
incidence of allo/auto antibody formation
growth, development; mortality, morbidity
Importance of prophylactic PEN and early ID
1995 Preoperative Transfusion in SCD
optimize % A versus S to decrease postoperative morbidity
1995 Hyroxyurea Trials
increased % F decreases frequency/need for transfusion
1998 STOP I
transfusion prevents stroke
Naomi L. C. Luban, MD

16. Indications for Transfusion
Accepted
Generally accepted
Controversial
Not indicated
Naomi L. C. Luban, MD

17. Accepted Acute stroke Acute splenic sequestration Acute chest syndrome
Acute aplastic crisis
Naomi L. C. Luban, MD

18. Generally Accepted Recurrent stroke Prior to major surgery
Multi system organ failure
Retinal occlusion
Naomi L. C. Luban, MD

19. Controversial Priapism Leg ulcers Chronic organ damage/pain
Acute infection
IV contrast use
Naomi L. C. Luban, MD

20. Not Indicated Normal pregnancy Painful crisis Chronic anemia
Aseptic necrosis
Naomi L. C. Luban, MD

21. Pathophysiology of Transfusion
Decrease % S by dilution
“Normalize” hemoglobin
Improve oxygen delivery
Inhibit erythropoeisis
Decrease sickle cell adhesion and plasma microenvironment
Naomi L. C. Luban, MD

22. Erythrocytapheresis
Naomi L. C. Luban, MD

23. Pathophysiology of Erythrocytapheresis
More rapid % S decrease and hgb normalization
Decrease in viscoelastic properties of whole blood
Thurston et al. Clin Hemorrheal Microcirc 2004;30:61-701
Maintain balance in iron accumulation at expense of higher donor exposure
Kim et al. Blood 1994;83:
Singer et al. J Clin Apher 1999;14:122-5
Decrease cytokines, other proteins that trigger endovascular changes
Naomi L. C. Luban, MD

24. Complications of Transfusion
Iron overload and further organ damage
Allo / autoantibody formation
Transfusion-related infections
Immune dysregulation
Others yet to be identified
Naomi L. C. Luban, MD

25. Actions of Hydroxyurea (HU)
For sure
Increase HbF
Decrease RBC endothelial adherence
Generates NO, a vasodilator
Increase RBC hydration and improves deformability
Possibly
Prevent organ damage if begun in infancy
(Baby HUG NHLBI Trial)
Caveat
25% of individuals are HU nonresponders
Carcinogenic risk
Naomi L. C. Luban, MD

26. Future Improvement in Care Through a Sampling of NHLBI Funded Studies All Ongoing
STOP II (Stroke Prevention Trial)
more information on transfusion preventing stroke
SITT (Silent Cerebral Infarct Trial)
prevent stroke before it occurs
SWITCH (Stroke with Transfusion Changing to HU)
identify methods to decrease TX burden while preventing stroke recurrence
Clinical Trials Network
SCD Clinical Research Network
Transfusion / Hemostasis Clinical Trials Network
Naomi L. C. Luban, MD

27. IBMTR / National Marrow Donor Program
Worldwide experience with SCD and HSCT
Country   
 Belgium 
 United States 
 France 
 Study authors 
 Vermylen et al21 
 Walters et al19,24 
 Current study 
 Period 
 04/86–01/97 
 09/91–03/99 
 11/88–12/04 
 No. of patients 
 50 
 87 
 Median age, y (range) 
 7.7 (0.9–23) 
 9.9 (3.3–14) 
 8.8 (2.2–22) 
 No. of strokes (%) 
 4 (8) 
 14/26 (54) 
 36 (41) 
 Mean ferritin level, ng/mL (range) 
 ? 
 1542 (58–6795) 
 911 (13–3820) 
 Follow-up 
     Median, y (range) 
 5 (0.9–15) 
 3.3 (0.5–7.9) 
 6 (2–17.9) 
     More than 2 y 
 — 
 26 
 Rejections, % 
 10 
 7 
Transplant Related Mortality, % 
 6 
 6.9 
 Event-free Survival, % 
 82 
 84 
 86.1 
     aGvHD above grade II 
 20 
 15 
     cGvHD 
 12 
 13.5 
Cord blood transplantation
Sibling, other hematopoietic stem cell transplantation
Naomi L. C. Luban, MD
Blood 2007;110:2749

28. Future Directions: Predictive Medicine
Is there a clinical phenotype that predicts poor outcome
Is there a laboratory phenotype (other than genotype) that predicts chronic hemolysis and adverse outcome, like LDH
Blood 2006;107:2279
Are there genetic modifiers that predict stroke risk?
Nature Genetics 2005;37:435
Stroke 2007;38:2241
Others
Naomi L. C. Luban, MD

29. Future Directions: Personalized Medicine Applying predictive medicine to health care decisions
Increase and maintain F hgb - HU, analogues
Decrease vasculopathy - Sildenafil, arginine
Decrease transfusion risks - Blood substitutes
RBC membrane channel blockers - Clotrimazole derivatives
Naomi L. C. Luban, MD

30. Future Directions: Preemptive Medicine
Replace the hemoglobin producing cells > hematopoietic stem cell transplantation
Blood 2007;110:2749
Br J Haem 2007;137:479
Replace the defective beta hemoglobin gene, alter it to produce HbF or both > gene therapy
Naomi L. C. Luban, MD

31. In Memoriam Keyoni Danee Carter
Naomi L. C. Luban, MD