Sima Fotouhi Pathology Grand Rounds April 19th, 2011 On April 19th, 2011, I attended Dr.

India Sisler's Grand Round entitled Sickle Cell Disease- Transition from Pediatric to Adult Care. Dr. Sisler Graduated from UVA and did her residency at MCV. She began her presentation with general statistics. There are about 70,000 to 100,000 SCD (Sickle Cell Disease) patients in the US, with 1/12 African-Americans having the trait. She explains the hemoglobin alpha and beta connections as an overview into the disease. She explains that a single amino acid gene switch on the beta gene structure is what causes hemoglobin S which is what causes SCD. Hemoglobin S is 25 times less soluble then regular hemoglobin, and the polymerization begins when it is deoxygenated, they polymers begin lining up in rows changing the structure of the red blood cell itself. There are 3 ways that sickle cell disease affects a patient: anemia, impaired oxygenation, inflammation or vascular damage. With anemia, we learn that the lifespan of a red blood cell in a patient without SCD is 120 days, a patient with SCD is less than ten days. Also anemia, she adds, is chronic and lifelong. An SCD patient will also get impaired blood flow because of the sickled shape of the cell, which causes difficulty passing through microcirculation, which causes impaired oxygenation. Sickled cells generate twice the normal amounts of oxidants and free radicals which cause inflammation and endothelial damage. SCD is cumulative increases throughout life. In the last 100 years, the medical community has had few precious medical advancements in the field of SCD. Newborn screening has helped immensely, as well as prophylactic penicillin, and pneumococcal disease vaccination. About 40 years ago the average life expectancy for patients with sickle cell anemia was 14.3 years, about twenty years ago it was approximately 45, and now the average is about 50. She then spoke about the Georgia Comprehensive Sickle Cell Center study which looked at 387 patients transitioned from adolescent to adult care from 1996-2006. They found that 5.8% of the patients died in the first 10 years following the transition, and the mean age of death was only 23.4 years old. Dr. Sisler next spoke of how adolescence is a socially high risk period as it is, because the movement into adulthood by itself is difficult, due to dependence on parents, selfesteem problems, and relationships. Also a big set up for failure is that the responsibility of their own medical care is a rude awakening, and many have a hard time adjusting to a lifestyle of taking care of themselves. Adolescences with SCD have an increased amount of emergency room utilization in comparison to any other phase in their lives, according to a study presented at a hematology conference last year. The percentage of 20-30 year olds utilizing the emergency room who were uninsured was much higher than that of any other age group. Dr. Sisler then spoke about the history of transition in general, first talking about the US Surgeon General's 1989 conference surrounding the needs of older adolescents with chronic conditions, then talking about how according to the AAP over half a million children in the US with special health care needs cross the threshold into adulthood a year. To wrap up her presentation Dr. Sisler spoke of the Stages of Transition: beginning, decision to begin a transition, middle, actions taken to build capacity of adolescent to undergo transition, and the end, transitioned to adult care and actively participating in adult care.

Sima Fotouhi Pathology Grand Rounds April 19th, 2011 Article 1: Protective Role of Hemoglobin and Fetal Hemoglobin in Early Kidney Disease for Children with Sickle Cell Anemia. Most patients with sickle cell anemia are at risk for organ damage including kidney disease. Microalbuminuria may be an early marker of disease progression. Microalbuminuria occurs when the kidney leaks small amounts of albumin into the urine (in other words, when there is an abnormally high permeability for albumin in the glomerulus). In most cases, in order to determine the appropriate intervention for these at risk children, a better understanding of the pathophysiology of renal damage is needed (Lebensburger et.al. 430).. This study analyzed laboratory and clinical findings in children with sickle cell anemia according to the presence or absence of MA (microalbuminuria) during well clinic sickle cell visits. Results were analyzed in sum as well as by therapeutic intervention (not on therapy, hydroxyurea therapy (a chemotherapy agent with potent effects on the bone marrow), or chronic transfusion therapy) (Lebensburger et.al. 430). Thirty two of 144 (about 22%) children had MA, including 20 of 82 (24%) children not on a therapeutic intervention (or chronic transfusion or hydroxyurea). In children not on therapy, low hemoglobin, low fetal hemoglobin and high lactate dehydrogenase were associated with MA (Lebensburger et.al. 431). The numbers of positive screens for MA for the different treatment groups were: Hydroxyurea 13%; chronic transfusion 26% and children on no treatment 24%. However, the difference between the hydroxyurea group and the chronic transfusion or no treatment groups did not reach statistical significance. In conclusion the researchers determined that increased hemoglobin and fetal hemoglobin may provide protection against kidney disease in sickle cell anemia and should be evaluated (Lebensburger et.al. 432). Article 2: Inhibition of Phosphodiesterase 9A Reduces Cytokine-Stimulated in Vitro Adhesion of Neutrophils from Sickle Cell Anemia Individuals. It is commonly known that leukocyte adhesion to vessel walls may initiate vasoocclusion in sickle cell anemia; however, the extent to which inflammation participates in this mechanism is not understood. This in vitro study investigated whether inflammatory molecules, commonly enlarged in sickle cell anemia, can affect neutrophil (white blood cells) adhesive properties and whether cyclic guanosine monophosphate (cGMP)-elevating agents can inhibit such adhesion (Miguel et. al. 1). The effects of Interleukin 8, tumor necrosis factor (TNF)-, and BAY 41-2271 (a guanylate-cylase stimulator) on the adhesive properties of neutrophils from healthy control and steady-state sickle cell anemic individuals were determined using static-adhesion assays (cellular matrixes) (Miguel et. al. 1). Neutrophils demonstrated increased adhesive properties, compared to control neutrophils; Interleukin-8, TNF-. The PDE9A inhibitor, BAY-73-6691, significantly reduced basal control neutrophil and sickle cell anemia neutrophil adhesion; this was accompanied by decreased sickle cell anemia neutrophil surface expressions of several adhesion molecules (Miguel et. al. 2). The chronic inflammatory nature of SCA may contribute to leukocyte adhesive functions in SCA. Furthermore, elevation of leukocyte cGMP may be an interesting approach for inhibition of leukocyte adhesion to the vessel wall, even in the presence of inflammatory stimuli (2).

Sima Fotouhi Pathology Grand Rounds April 19th, 2011 Reference List: Lebensburger, J. S Johnson, M Askenazi, D Rozario, N Howard, L Hilliard. Protective Role Of Hemoglobin And Fetal Hemoglobin In Early Kidney Disease For Children With Sickle Cell Anemia. American Journal of Hematology 86 (2011) 430432. Web. 20 April 2011. Miguel, L. CB Almeida, F Traina, AA Canalli, VM Dominical, ST Saad, FF Costa, N Conran. Inhibition Of Phosphodiesterase 9A Reduces Cytokine-Stimulated in Vitro Adhesion of Neutrophils from Sickle Cell Anemia Individuals. Inflammation Research. Epub Ahead of Print. (2011) Web. 20 April 2011.