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

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

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 32 - 50,000 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

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

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

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

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

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

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

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

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

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

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

SCD Morbidity & Mortality Increased lifespan (14 years to early 40s) Life expectancy 20-30 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;123:359-365

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

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

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

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

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

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

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

Erythrocytapheresis Naomi L. C. Luban, MD

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;83:1136-42 Singer et al. J Clin Apher 1999;14:122-5 Decrease cytokines, other proteins that trigger endovascular changes Naomi L. C. Luban, MD

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

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

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

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

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

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

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

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