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Ninth Cooley's Anemia Symposium

Ninth Cooley's Anemia Symposium

Wednesday, October 21, 2009 - Saturday, October 24, 2009

The New York Academy of Sciences

Presented By

Presented by the Cooley's Anemia Foundation and the New York Academy of Sciences


Thanks to scientific advances, individuals with thalassemia—a group of genetic blood disorders which includes Cooley's Anemia—are now living into their 40s and 50s. Not only are individuals living longer, but their quality of life has increased. Scientific and clinical advancements have resulted in new iron-chelating drugs, early detection of organ failure, an understanding of adult complications associated with living with thalassemia (osteoporosis, heart failure, growth hormone defi ciency, pulmonary hypertension, and in fertility) and promising progress towards the ultimate magic bullet—a cure in the form of bone marrow and cord blood transplants, or gene therapy.

The symposium will integrate basic science and clinical research so that both scientists and clinicians can develop a mutual understanding of recent progress in thalassemia. Patients are also welcome to attend the symposium and are eligible for discounted prices. Please email or call 800.522.7222 for more information.

The Thalassemia Action Group (TAG), the only national patient support group for thalassemia patients, will host a one-day meeting in conjunction with this conference. The meeting, to be held on Saturday October 24th from 9:00 am to 5:00 pm, is intended for patients and family members in order to educate them on presentations and scientific advancements discussed during the symposium. It is a chance for patients to hear experts on thalassemia, ask questions and discuss the concerns that face those afflicted with thalassemia. For more information please visit or email For information about registration to the TAG meeting please call 800.522.7222 (ext 205)

Presented by


For a complete list of sponsors, please click the Sponsorship tab.


*Presentation times are subject to change

Day 1: Wednesday, October 21, 2009

4:00 PM


5:00 PM

Welcome Remarks


Kathy Granger, PhD, The New York Academy of Sciences
Elliott Vichinsky, MD, Childrens Hospital Oakland
Anthony J. Viola, Cooley's Anemia Foundation National President

5:15 PM

Keynote Lecture


Thalassemia Progress and Potential - An Overview
Alan Cohen, MD, Children's Hospital of Philadelphia

6:00 PMKeynote Lecture
 Pathogenesis and Management of Iron Toxicity in Thalassemia
 Chaim Hershko, MD, Shaare Zedek Medical Center, Jerusalem, Israel

6:45 PM

Welcome Reception

Day 2: Thursday, October 22, 2009

7:45 AM

Registration and Poster Session I Set-up

8:00 AM

Concurrent Breakfast Workshops


Cultural Influences on Compliance and Care
Kathleen Durst, MA, LMSW, Cooley's Anemia Foundation


Pregnancy and Chelation: Iron Regulation and Metabolism
Melody Cunningham, MD, University of Tennessee Health Sciences Center


Antioxidants and Innovative Approaches to Treating the Pathophysiology in Thalassemia
Eliezer Rachmilewitz, MD, The Edith Wolfson Medical Center, Holon, Israel

9:00 AM

Keynote Lecture


Thalassemia as a Global Health Problem: Recent Progress towards its Control in the Developing Countries
Sir David Weatherall, MD, FRS, University of Oxford, Headington, UK

Session I: Iron Regulation and Metabolism

Session Chair: Melody Cunningham, MD, University of Tennessee Health Sciences Center

9:30 AM

Iron Regulation and Ineffective Erythropoiesis, JAK 2
Stefano Rivella, PhD, Weill Cornell Medical Center

9:50 AM

Hepcidin in Thalassemia
Elizabeta Nemeth, PhD, UCLA David Geffen School of Medicine

10:10 AM

TMPRSS6: A Modifier of  Hepcidin Production in Relation to Iron Stores
Mark D. Fleming, MD, PhD, Children's Hospital Boston

10:30 AM

Coffee Break

Session II: Gene Regulation and Therapy

Session Chair: Jeffrey L. Miller, MD, National Institute of Diabetes and Digestive and Kidney Diseases

11:00 AM

The Identification of Factors Regulating γ-globin Gene Transcription
Frank Grosveld, PhD, Erasmus Medical Center, Rotterdam, The Netherlands

11:20 AM

Lentivirus Vector-Based Gene Therapy for Beta-Clobinopathies
Punam Malik, MD, Cincinnati Children's Hospital Medical Center

11:40 AM

Cell Therapies in a Humanized Mouse Model of Cooley's Anemia
Thomas M. Ryan, PhD, University of Alabama at Birmingham

12:00 PM

Identifying CIS-acting Elements to Improve Vectors for Gene Therapy of Hemoglobin Disorders
David Bodine, PhD, National Human Genome Research

12:20 PM

Globin Gene Transfer in Subjects with β-Thalassemia-Progress, Challenges, and Clinical Implementation
Michel Sadelain, MD, Memorial Sloan-Kettering Cancer Center

12:40 PM

Lunch and Poster Session I

2:30 PM

Conversion to Transfusion Independence with Partial Clonal Dominance after Lentiviral Gene Therapy for Severe Human Beta-Thalassemia
Philippe LeBoulch, MD, Harvard Medical School and Brigham & Women's Hospital, Fontenay-aux-Roses, France

2:50 PM

Safety and Efficacy of G-CSF Mobilization in Major Beta-Thalassemia 
Evangelia Yannaki, MD, George Papanicolaou Hospital, Thessaloniki, Greece

3:10 PM

Transcriptional Silencing of HBF by BCL 11A
Stuart H. Orkin, MD, Children's Hospital Boston

3:30 PM

Gene Therapy for Sickle Cell Disease and Beta-Thalassemia Using Lentiviral Vectors to Enhance Fetal Hemoglobin Production
Derek A. Persons, MD, PhD, St. Jude Children's Research Hospital

3:50 PM

Coffee Break

Session III: Iron Overload and Chelation Therapy

Session Chair: Robert W Grady, PhD, Weill Cornell Medical College

4:20 PM

Antonio Piga, MD, University of Turin, Orbassano, Italy

4:40 PM

Combined Therapy
Renzo Galanello, MD, University of Cagliari, Cagliari, Italy

5:00 PM

Deferasirox:An update
John Porter, MD, University College London

5:20 PM

Monitoring the Efficiency of Iron Chelation Therapy
Robert C. Hider, PhD, King's College London

5:40 PM

Survival Trends Using Combination Therapy (CCT)
Paul Telfer, DM, FRCP, Barts and The London School of Medicine and Dentistry

6:00 PM

Current Strategies for Chelation Therapy- How will we Choose the Best Approaches in Thalassemia?
Ellis Neufeld, MD,PhD, Children's Hospital of Boston

6:20 PM

Sessions Conclude

Day 3: Friday, October 23, 2009

7:45 AM

Registration and Poster Session II Set-up

8:00 AM

Concurrent Breakfast Workshops


Ongoing and Upcoming Clinical Trials
Janet L. Kwiatkowski, MD, MSCE, Children's Hospital of Philadelphia


Growth Hormones/Endocrine Therapy
Ratna Chatterjee, MD, PhD, University College Hospital, London, UK


Pain as an Emergent Issue in Thalassemia
Susan Carson, Thalassemia Research Network

Session IV: Iron Imaging

Session Chair: Roland Fischer, PhD, University Clinic Hamburg-Eppendorf, Germany

9:00 AM

Rapid Monitoring of Iron-Chelating Therapy in Cooley's Anemia by Magnetic Resonance Imaging (MRI) of Myocardial Ferritin Iron
Gary Brittenham, MD, Columbia University College of Physicians and Surgeons

9:20 AM

Interpreting Liver Iron Concentration Measurements and Imaging
Tim St. Pierre, PhD, The University of Western Australia

9:40 AM

Predicting Pituitary Iron and Endocrine Damage using MRI
John C. Wood, MD, Children's Hospital Los Angeles


Data Blitz Session I
Four 15-minute presentations from young investigators selected from the poster abstracts

11:00 AM

Coffee Break

Session V: New Advances in Stem Cell Transplantation

Session Chair: Mark Walters, MD, Children’s Hospital & Research Center, Oakland, CA

11:30 AM

Introduction and Overview of HCT for Thalassemia Major
Mark Walters, MD, Children's Hospital & Research Center, Oakland, CA

11:50 AM

Multiple Unit Cord Blood Transplantation
Joanne Kurtzberg, MD, Duke University Medical Center, Durham, NC

12:10 PM

Novel Preparative Regimens with Reduced Toxicity before Transplantation of Patients with Thalassemia
Franco Locatelli, MD, University of Pavia

12:30 PM

Progress in Hematopoietic Stem Cell Transplantation as Allogeneic Cellular Gene Therapy in Thalassemia
Antonella Isgrò, MD, PhD, International Centrer for Transplantation in Thalassemia and Sickle Cell Anemia, Rome, Italy

12:50 PM

Lunch and Poster Session II

Session VI: New Therapy for Hemoglobin F

Session Chair: Ellis Neufeld, MD,PhD, Children's Hospital of Boston

2:30 PM

Hemoglobin E/Beta-Thalassaemia: From North America to Sri Lanka
Vivekanandan Thayalasuthan, Toronto General Hospital

2:50 PM

Fetal Globin Induction Therapies for Beta Thalassemia: Principles and Potential 

3:10 PM

Data Blitz Presentation selected from poster abstracts

3:30 PM

Coffee Break

Session VII: Cardiac Dysfunction

Session Chair: Thomas Coates, MD, Children's Hospital Los Angeles

4:00 PM

Early Prediction of Cardiac Dysfunction in Thalassaemia Major
John Malcolm Walker, MD, FRCP, University College Hospital, London, UK

4:20 PM

Role of Cardiovascular MRI in Thalassemia Major
John C. Wood, MD, Children's Hospital Los Angeles, Los Angeles, CA

4:40 PM

Pulmonary Hypertension in Thalassemia
Claudia R. Morris, MD, Children's Hospital and Research Center Oakland

5:00 PM

Sessions Conclude

Day 4: Saturday, October 24, 2009

7:45 AM


8:00 AM

Concurrent Breakfast Workshops


Elliott Vichinsky, MD, Childrens Hospital Oakland


Liver Disease
Paul Harmatz, MD, Children's Hospital Oakland


Cardiac Disease
John C. Wood, MD, Children's Hospital Los Angeles


Cord Blood Registries: Role in Thalassemia
Burt Lubin, MD, Children's Hospital Oakland Research Institute

Session VIII: Nutrition and Antioxidant Therapies

Session Chair: Alexis A. Thompson, MD, MPH, Children's Memorial Hospital, Northwestern University, Chicago, IL

9:00 AM

Nutritional Deficiencies in Patients with Thalassemia
Ellen B. Fung, PhD, RD, Children's Hospital and Research Center Oakland

9:20 AM

Nutrition and Antioxidant Therapies in Thalassemia
Ashutosh Lal, MD, Children's Hospital and Research Center Oakland

9:40 AM

Ferritin Regulation for Antioxidant Protection,and Iron Nutrition
Elizabeth Theil, PhD, Children's Hospital Oakland Research Institute

Session IX: Clinical Syndromes in Thalassemia and Disease Severity

Session Chair: David Chui, MD, Boston University School of Medicine

10:00 AM

Alpha-Thalassemia Syndromes
Elliott Vichinsky, MD, Childrens Hospital Oakland

10:20 AM

Phenotype/Genotype correlation in Thalassemia Intermedia
Caterina Borgna-Pignatti, MD, University of Ferrara, Ferrara, Italy

10:40 AM

Data Blitz Session II
Three 15-minute presentations from young investigators selected from the poster abstracts

11:30 AM


Session X: The Adult Thalassemia Patient

Session Chair: Patricia Giardina, MD, New York Presbyterian Hospital-Weill Cornell Medical Center

12:30 PM

Reproductive Issues in Females with Thalassemia
Sylvia Titi Singer, MD, Children's Hospital and Research Center Oakland

12:50 PM

Thrombosis, Stroke, and their Prevention
Maria Domenica Cappellini, MD, University of Milan

1:10 PM

Osteoporosis in Beta-Thalassemia: Pathophysiology and Management
Evangelos Terpos, MD, PhD, University of Athens School of Medicine

1:30 PM

Panel Discussion: Adults with Thalassemia in a Pediatric World
Dawn F. Adler, MA, Thalassemia International Federation, Davis, CA
Laurice Levine, MA, CCLS, Child Life Specialist in Radiology, Seattle Children's Hospital
Gargi Pahuja, JD, MPH, Treasurer Thalassemia Action Group ( TAG ), Jersey City, NJ

1:55 PM

Symposium Summary
Arthur W. Nienhuis, MD, St. Jude Children's Research Hospital, Memphis, TN

2:15 PM

Closing Remarks

2:20 PMCooley's symposium ends - Coffee Break in Lobby



Elliott Vichinsky, MD

Children's Hospital and Research Center

Ellis Neufeld,MD, PhD

Children's Hospital Boston

Kathy Granger, PhD

The New York Academy of Sciences

Keynote Speakers

Alan Cohen, MD

Children’s Hospital of Philadelphia

Chaim Hershko, MD

Shaare Zedek Medical Center

Sir David Weatherall, MD

University of Oxford


Dawn F. Adler, MA

Thalassemia International Federation

David Bodine, PhD

National Human Genome Research

Caterina Borgna-Pignatti, MD

University of Ferrara

Gary Brittenham, MD

Columbia University College of Physicians and Surgeons

Maria Domenica Cappellini, MD

University of Milan

Mark D. Fleming, MD, PhD

Children’s Hospital Boston

Ellen B. Fung, PhD, RD

Children's Hospital and Research Center Oakland

Renzo Galanello, MD

University of Cagliari

Frank Grosveld, PhD

Erasmus Medical Center

Robert C. Hider, PhD

King's College London

Antonella Isgro, MD, PhD

Mediterranean Institute of Hematology

Joanne Kurtzberg, PhD

Duke University Medical Center

Ashutosh Lal, MD

Children’s Hospital and Research Center Oakland

Philippe LeBoulch, MD

Harvard Medical School and Brigham & Women's Hospital

Laurice Levine, MA, CCLS

Children's Hospital and Research Center Oakland

Franco Locatelli, MD

University of Pavia

Punam Malik, MD

Cincinnati Children's Hospital Medical Center

Claudia R. Morris, MD

Children’s Hospital and Research Center Oakland

Elizabeta Nemeth, PhD

UCLA David Geffen School of Medicine

Arthur W. Niehuis, MD

St. Jude’s Children’s Research Hospital

Vivekanandan Thayalasuthan

Toronto General Hospital

Stuart H. Orkin, MD

Children's Hospital Boston

Gargi Pahuja, JD, MPH

Treasurer Thalassemia Action Group (TAG)

Susan P. Perrine, MD

Boston University School of Medicine

Derek A. Persons, MD

St. Jude Children’s Research Hospital

Tim St. Pierre, PhD

The University of Western Australia

Antonio Piga, MD

University of Turin

John Porter, MD

University College London

Michel Sadelain, MD

Memorial Sloan Kettering Cancer Center

Stefano Rivella, PhD

Weill Cornell Medical Center

Thomas M. Ryan, PhD

University of Alabama at Birmingham

Paul Telfer, DM, FRCP

Barts and The London School of Medicine and Dentistry

Evangelos Terpos, MD, PhD

University of Athens School of Medicine

Elizabeth Theil, PhD

Children’s Hospital Oakland Research Institute

Sylvia Titi Singer, MD

Children's Center and Research Center Oakland

John Malcolm Walker, MD, FRCP

University College Hospital

Mark Walters, MD

Children’s Hospital & Research Center

John C. Wood, MD

Children's Hospital Los Angeles

Evangelia Yannaki, MD

George Papanicolaou Hospital

Workshops Leaders

Kathleen Durst, MA

Cooley’s Anemia Foundation

Melody Cunningham, MD

University of Tennessee Health Sciences Center

Eliezer Rachmilewitz, MD

The Edith Wolfson Medical Center

Janet L. Kwiatkowski, MD

Children’s Hospital of Philadelphia

Ratna Chatterjee, MD, PhD

University College Hospital

Dru Foote, RN, PNP

Children's Hospital & Research Center Oakland

Paul Harmatz, MD

Children’s Hospital of Oakland

John C. Wood

Children's Hospital Los Angeles

Bert Lubin, MD

Children’s Hospital Oakland Research Institute



For sponsorship opportunities please contact Sonya Dougal at or 212.298.8682.

Presented by


  • • This program is supported by an educational grant from Novartis Oncology.

Academy Friends

Ferrokin BioSciences

HemaQuest Pharmaceuticals, Inc.


Resonance Health

The project described was supported by Award Number R13HL096359 from the National Heart, Lung, And Blood Institute, and The National Institute Of Diabetes And Digestive And Kidney Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, And Blood Institute or the National Institutes of Health

Day 4: Saturday, October 24

Nutritional Deficiencies in Patients with Thalassmia

Ellen B. Fung, PhD RD, Elliott Vichinsky, MD, Children’s Hospital & Research Center at Oakland, Oakland, CA

Optimal nutritional status is imperative for achieving the genetic potential for growth and pubertal development in children as well as for robust immune function and bone health in adults. Patients with thalassemia are known to have abnormal growth, altered pubertal development and immune function as well as deficits in bone mineral acquisition. The etiology of these co-morbidites is typically ascribed to the toxic effects of transfusion related iron-overload. Though the relationship of nutritional status to abnormal growth, pubertal development, immune status and bone health has been shown in other chronic diseases, few studies have specifically focused on aspects of nutritional status and its relationship to health in patients with thalassemia.
Over the last decade, our group and others have observed deficiencies of up to 75% of patients studied in vitamins C, D, and selenium and up to 40% of patients appear deficient in copper, zinc, folate and other B vitamins. Typically, depleted circulating levels of nutrients have been observed despite seemingly adequate dietary intake. This disconnect between intake and circulating levels suggest that patients with thalassemia may have increased needs for certain nutrients due to either poor nutrient absorption, elevated losses or increased nutrient turnover.

Dairy intake and weight bearing physical activity are reduced in subjects with thalassemia and are related to poor bone health. Alternatively, higher fat mass has been shown to be protective in both transfused and non-transfused patients. These preliminary findings will be shared, in addition to results from an ongoing placebo controlled trial of zinc supplementation on bone health. Alternative therapies which utilize nutrient and antioxidant supplementation in addition to increased physical activity may improve nutritional status and overall health in this population, as well as decrease long term co-morbidities such as reduced bone mass.

Nutrition and Antioxidant Therapies in Thalassemia

Ashutosh Lal, M.D1,2, Novie Ko, BS1, Elliott Vichinsky, MD2, Bruce Ames, PhD1, Jung H Suh, MPH PhD1. 1Children’s Hospital Oakland Research Institute, 2Hematology/Oncology, Children’s Hospital & Research Center at Research Center Oakland, Oakland, CA

The contribution of micronutrient deficiencies to the disease burden experienced by individuals with thalassemia may be considerable. Micronutrient depletion in thalassemia is appropriately considered in the context of iron overload and chelation therapy, and antioxidant defenses have received the most attention. The prevalence of certain deficiencies, particularly vitamin C, vitamin E, vitamin D, zinc and copper, is common, and can promote or worsen pathophysiologic mechanisms such as oxidative stress, immune dysfunction and bone mineral deficits. Chronic increase in free radical production can interfere with metabolism through oxidative modification of proteins and lipids. A metabolomics approach utilizing high-throughput liquid chromatography linked tandem mass spectrometric analysis of metabolites can demonstrate metabolic changes in response to sub-optimal nutrition. Using this approach, differences in the sulfur amino acid metabolism between thalassemia major and control subjects were detected in the plasma and also within the transfused donor red blood cells. The glutathione pool is expanded with accumulation of precursor compounds, but a significantly higher proportion of glutathione and cysteine exist in the oxidized state. Characterization of the compensatory mechanisms would help towards targeted interventions to restore the plasma and red cell redox balance. We propose gauging the utility of antioxidant therapy based on its remediating effects on altered metabolism, instead of specific markers of oxidative damage. Nutritional interventions should occur in the background of stable and effective chelation and transfusion therapies. The eventual goal is to evaluate whether target organ damage in thalassemia can be diminished through maintenance of optimal micronutrient status and the control of systemic oxidative stress.

Ferritin Regulation For Antioxidant Protection, And Iron Nutrition

Elizabeth C. Theil, CHORI (Children's Hospitals and Research Center Oakland), Oakland, USA; University of California, Berkeley, CA

Iron/oxygen reactions, the source of much oxidant damage, are also the substrates for cellular ferritin catalysis used to make the ferritin iron and oxygen mineral, ferrihydrite. Cellular ferritin functions as an oxidant protector by consuming iron and oxygen. Recent data show that ferritin genes are regulated by the same inducers that regulate oxidant protection enzymes such as quinone reductase and thioredoxin reductase.

In normal health, the cellular ferritin mineral i is a biological iron concentrate, inside the protective ferritin protein cage, that is used to synthesize iron–proteins such as hemoglobin and metabolic enzymes. During iron overload cellular ferritin also traps excess iron. Most of the iron in iron overload is in cellular ferritin and degraded ferritin (hemosiderin). Cellualr ferritin synthesis is increased in iron overload by removing a regulator that inhibits ferritin mRNA function. Usually the effect is so small that the iron content of ferritin increases causing protein damage and ferritin conversion to toxic hemosiderin.

Three novel ways to manipulate ferritin that can minimize effects of excess iron are:
1. Increase rates of removal of iron from ferritin by unfolding ferritin protein pores.
2. Increase rates of synthesis by targeting ferritin mRNA.
3. Decrease nutritional iron uptake with ferritin-rich (whole legume) foods, since the absorption mechanism is different than for iron salts or heme.
The stage of development of each of the three approaches will be described and new directions defined. Part Support: NIH, Cooley’s anemia and CHORI Foundations

Session IX: Clinical Syndromes in Thalassemia and Disease Severity

Alpha Thalassemia Syndromes

Elliott Vichinsky, MD, Children’s Hospital & Research Center Oakland, CA

Alpha thalassemia is the most common genetic disorder of hemoglobin synthesis, affecting up to 5% of the world’s population. It represents a group of conditions resulting from reduced or absent synthesis of one to all four of the alpha globin genes. Deletional or non-deletional mutations occur on chromosome 16. The severity of the syndrome ranges from completely asymptomatic to fatal in utero. Hemoglobin H disease, a mutation of three alpha globin genes, is more severe than previously recognized. Anemia, hypersplenism, hemosiderosis, growth failure, and osteoporosis are commonly noted as the patient ages. It can occur in all ethnic groups. In California, one in 9000 births has Hemoglobin H disease. Alpha thalassemia major, a usually fatal in utero disease, is now recognized to have a complex molecular and phenotypic expression with increasing births being reported. Surviving newborns without intrauterine transfusion often have congenital anomalies and neurocognitive injury. Serious maternal complications often accompany pregnancy. Doppler ultrasonography with intrauterine transfusion ameliorates these complications.  The high incidence of this disorder in many populations mandates population screening and prenatal diagnosis of at-risk couples. Universal newborn screening has been adopted in several regions, with necessary DNA confirmatory testing.

Phenotype/Genotype Correlation in Thalassemia Intermedia

C.Borgna-Pignatti, MD, Pediatric Department, University of Ferrara, Ferrara, Italy

Thalassemia intermedia is an heterogeneous clinical syndrome, spanning from an almost asymptomatic condition in which the slight anemia is diagnosed during a routine check-up, to a severe disease, often transfusion-independent only at the price of intense medullary expansion and extramedullary erythropoiesis. The pathophysiology of beta-thalassemia depends on the degree of alpha/non alpha globin chain imbalance. Any factor able to decrease the imbalance in homozygous beta thalassemia will improve the clinical picture. These factors include milder thalassemia alleles, increased production of fetal hemoglobin, concurrent alpha thalassemia. On the other hand, there are individuals with heterozygous beta thalassemia in whom the imbalance, and therefore the clinical picture, is made more severe by the co-inheritance of one or more supernumerary alpha globins. Genetic modifiers can also have a role in the development of complications in patients with thalassemia intermedia. The metabolism of bilirubin is influenced by the common A(TA)(n)TAA promoter mutation at the UGT1A1 locus, that has been demonstrated to be a risk factor for gallstones formation. The inheritance of the C282Y or the H63D polymorphism in the HFE gene can increase the iron absorption and make the hemosiderosis, often present in these patients, more severe. Several mutations at the basis of increased thrombophilia in the non thalassemic population could increase the already present thrombotic predisposition. Other as yet nonconclusive studies have investigated the correlation between osteoporosis and genes involved in bone metabolism, or between cardiac disease and the polymorphisms of apolipoprotein ε-4allele or glutathione S-transferase. There is no doubt, however, that the genetic heterogeneity at the basis of the phenotypic variability thalassemia intermedia will continue to be elucidated

Session X: The Adult Thalassemia Patient

Reproductive Issues in Females with Thalassemia

Sylvia T. Singer, MD1, Annie Higa1, Nancy Sweeters PNP1, Olivia Vega BSc1, Tiffany Chin BAIB1, Deborah Trevithick PNP2, Marcel Cedars MD2

1Hematology/Oncology and Clinical Research Center at Children’s Hospital and Research Center Oakland CA; 2Division for Reproductive Endocrinology, UCSF,  Oakland, CA

Achievement of reproductive capacity and creating a family has become a great mission for many thalassemia major (TM) patients. Despite recent progress in assessment of reproductive function–there is limited implementation for females with thalassemia. Though infertility is thought to results primarily from iron toxicity to the pituitary-gonadal axis function, the extent of direct toxicity to the ovaries and amount of the ovarian function preserved in TM females is unknown. Since the natural mechanism of follicle aging is thought to result from oxidative stress, it is likely that in thalassemia females iron-induced oxidative damage can result in earlier follicular aging. Currently, there is no good data on the relation of reproductive potential-both pituitary function and ovarian reserve-to iron overload during puberty and adult life. We studied the predictors of reproductive impairment in 23 adult females with TM (median age 29 years, range 17-42). 20/23 had primary or secondary amenorrhea. FSH, LH and estradiol were low or undetectable in 16/23 women. Ovarian reserve testing (ORT) was determined by ultrasound for an antral follicular count (AFC), obtained in 16 women, and showed a poor AFC for age (4-7 follicles) in 10/16 (66%) women, intermediate AFC (8-12) in 3 and a normal AFC in 3 women. Anti-mullerian-hormone (AMH) levels were low (mean=2.9 ng/ml) and declined with age, correlating with AFC (R2=0.006). These findings demonstrate a low ovarian reserve in a majority of adult females with TM. Elevated LIC and NTBI were more prevalent in women with a low ovarian reserve and hypogonadotropic hypogonadism. Further study on the extent of iron load and toxicity and how it relates to ovarian reserve through puberty and adulthood, are needed.

Thrombosis, Stroke and their Prevention

M. Domenica Cappellini, MD1, Giovanna Graziadei MD1 , Khaled M. Musallam, MD2, Ali T. Taher, MD2, 1Universitá di Milano, Policlinico Foundation IRCCS, Milan, Italy, 2American University of Beirut Medical Center, Beirut, Lebanon

The presence of a high incidence of thromboembolic events (TEE) has led to the identification of a hypercoagulable state in the thalassemia syndromes.1 However, there are relatively few epidemiological data on the overall frequency of these complications. The largest clinical study to date, by Taher et al.2, on 8860 thalassemia patients demonstrated that TEE occurred 4.38 times more frequently in thalassemia intermedia (TI) than thalassemia major (TM) patients, with more venous events occurring in TI and more arterial events (including stroke) occurring in TM. The study described age beyond 20 years, splenectomy, transfusion naïvety, family history and previous thrombotic events as the main risk factors for developing TEE. Moreover, in a study done to assess the rate of brain damage in patients with benign hemoglobinopathies, 37.5% of patients with TI showed asymptomatic brain damage on magnetic resonance imaging (MRI).3 More recently, unpublished data by Taher et al.4 on splenectomized TI patients observed a 60% rate of silent brain abnormality by MRI rising to 86.7% when combining MRI to position emission tomography (PET). The main risk factors for the development of silent strokes were increasing age and transfusion naïvety. Autopsy findings in thalassemia patients have confirmed hypercoagulability as a pathologic state. Autopsy series in patients with TM and TI describe the presence of DVT, pulmonary embolism and recurrent arterial occlusion, with thrombi in small and large pulmonary vessels.1 Current understanding of the underlying pathophysiology describes a procoagulant activity of damaged circulating red blood cells (RBCs), co-inheritance of coagulation defects, depletion of antithrombotic factors, endothelial inflammation and conditions that increase thrombotic burden. These factors have been observed at a higher rate in splenectomized patients.5 Several studies have identified a role for transfusion therapy to control the rate of TEE since it decreased numbers of pathological RBC exhibiting indices of membrane damage.1 The available data on the use of anticoagulants, antiplatelet, or other agents in thalassemia are either lacking or involve small, poorly controlled and/or relatively low-quality studies. However, TI patients who experience TEE and receive aspirin afterwards had a lower recurrence.2 Treatment with the fetal hemoglobin-inducing agents, hydroxycarbmide and decitabine, results in decreases in plasma markers of thrombin generation. Hydroxycarbamide may decrease coagulation activation by reducing phospholipid expression on the surface of both RBC and platelets and decreasing RBC adhesion to thrombospondin. In addition to being a nitric oxide donor, hydroxycarbamide may also decrease hemostatic activation by its effect in decreasing the white blood cell count and particularly monocytes that express transcription factor. Another approach would be to correct the reactive oxygen species-induced RBC membrane damage using antioxidants, although this approach has not yet been verified in clinical trials.1 It may also be possible to design a thalassemia-tailored thrombosis risk-assessment model (RAM) to estimate thrombotic risk as a function of intrinsic and extrinsic factors. Moreover, tests for predisposing factors could also be performed, particularly in high-risk patients. If clinically verified, this type of model could serve as a guideline for possible preventative treatment to decrease the incidence of TEE, which can cause significant morbidity and mortality.1

Osteoporosis in Beta-Thalassemia: Pathophysiology and Management

Evangelos Terpos, MD, PhD1 & Ersi Voskaridou, MD, PhD2
1Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece & 2Thalassemia Center, Laikon General Hospital, Athens, Greece

Osteoporosis represents a prominent cause of morbidity in patients of both genders with beta-thalassemia major (TM) or thalassemia intermedia. The pathogenesis of bone loss in thalassemia is multifactorial. The delay in sexual maturation, the presence of diabetes and hypothyroidism, the parathyroid gland dysfunction, the accelerated hemopoiesis with progressive marrow expansion, the direct iron toxicity on osteoblasts, the iron chelators, the deficiency of growth hormone or insulin growth factors have been identified as major causes of osteoporosis in thalassemia.

Osteoporosis is a progressive disease; thus prevention and early diagnosis are very important. Adequate hormonal replacement, effective iron chelation, improvement of hemoglobin levels, calcium and vitamin D administration, physical activity, and no smoking consist the main to-date measures for the management of the disease. However, despite the normalization of hemoglobin levels, adequate hormone replacement and effective iron chelation, patients continue to show an unbalanced bone turnover resulting in seriously diminished bone mineral density (BMD). During the last decade, novel pathogenetic data suggest that the reduced osteoblastic activity, which is believed to be the basic mechanism of bone loss in TM, is accompanied by a comparable or even greater increase in bone resorption. Increased levels of receptor activator of nuclear factor-kappaB ligand (RANKL) and bone resorption markers (N- and C-terminal cross-linking telopeptide of collagen type-I) support the presence of increased osteoclast activity in thalassemia patients. Therefore, the role of bisphosphonates, that are potent inhibitors of osteoclast activation, arises as major in the management of osteoporosis in these patients. Oral alendronate and intravenous pamidronate and zoledronic acid have shown efficacy in increasing BMD in thalassemia patients. However, many aspects have to be clarified before the broad use of bisphosphonates in TM-induced osteoporosis: which one? how long? and at what dose?

Other novel agents that stimulate bone formation such as teriparatide, a recombinant peptide fragment of parathyroid hormone and strontium ranelate, a second anabolic agent that prevents osteoporotic fractures in postmenopausal women are being studied but their effects in TM-induced osteoporosis have not been reported to-date. Antibodies against RANKL, such as denosumab, with proven efficacy in postmenopausal osteoporosis and antibodies against dickkopf-1, which has been found to be increased in TM patients with osteoporosis, or against sclerostin (SOST) may be future agents for the effective management of this difficult complication of thalassemia.

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