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(9202-S)

Tibor Greenwalt Memorial Award and

Lectureship: They Are Not Just Little

Adults 

 

October 7, 2012 9:15 AM - 10:00 AM  

 

Event Faculty List

Event Title: 9202-S: Tibor Greenwalt Memorial Award and Lectureship: They Are Not Just Little Adults

Event Date: Sunday, October 7, 2012 Event Time: 9:15 AM to 10:00 AM

Director/Moderator Karina Yazdanbakhsh, PhD Associate Member New York Blood Center KYazdanbakhsh@NYBloodCenter.org Disclosures: No

Award Recipient/Speaker Naomi Luban, MD Chief , Division of Laboratory Medicine Children's Hospital NLUBAN@CNMC.ORG Disclosures: No

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Naomi L. C. Luban, MDChief, Division of Laboratory Medicine

Director, Transfusion Medicine / The Edward J. Miller Donor Center Vice Chair for Academic Affairs, Department of Pediatrics

Children's National Medical CenterProfessor, Pediatrics and Pathology

George Washington University School of Medicine and Health Science

Tibor Greenwalt Memorial Award and Lectureship

October, 2012

They Are Not Just Small Adults

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Tibor Greenwalt as Mentor and Advisor

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Background and Training: Threads of a Career

Best friend with ALL, treated by Dr. Sidney Farber at Boston Children’s

Parents who supported science and mathematics

NSF summer high school experience in regenerative biology at Brandeis

College summers in cancer biology lab at Tufts

First rotation in medical school in pediatrics at Mt. Sinai

Fellowship at Cornell / Sloan Kettering / Rockefeller

Sidney Farber Abraham Jacobi Alexander Wiener

Karl Landsteiner Hans Popper

Sanford Leiken Margaret Hilgartner Anthony Cerami

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Reflections on What Constitutes the Discipline

Blood banking: the collection, processing and storage of peripheral blood, bone marrow and hematopoietic stem cells (HSCs)

Clinical transfusion medicine: transfusion / transplantation of blood / blood products, HSC and progenitor blood cells

Transfusion biology: cellular and molecular biology of blood cells, immunopathology of transfusion, engineering of stem and immunocompetent cells

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Infants and Children Are Not Just Small Adults

Unique pathophysiology Progress from fetus to adolescent Are often born too soon Suffer unique complications Live long lives Are our future

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Infants and Children Are Not Just Small Adults: Pathophysiology

Specific to Developmental Hematology• Adaptive responses to anemia and thrombocytopenia• Coagulation and anticoagulation proteins• Humoral and cellular immunity• Glucuronidation and other protein-bound excretory

pathwaysSpecific to Size

• Total blood and plasma volumes• Pharmacokinetics of volume distribution and excretion

Specific to Neonatal Physiology• Neurodevelopmental immaturity • Permeability of blood / brain and blood / testis barriers• Response to toxicants, additives and medications

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Infants and Children Are Not Just Small Adults: Real Life Examples

Average volume RBC unit = 250 mL Blood volume of premature infant of 500 gm at 100 mL/kg = 50 mL Usual transfusion volume at 10 mL/kg = 5 mL

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Andrews M. Developmental Hemostasis: Relevance to thromboembolic complications in pediatric patients. Thromb Haemost. 1995;74 (1 Suppl):415-425

Reverdiau-Moalic P, et al. Evolution of blood coagulation activators and inhibitors in the healthy human fetus. Blood. 1996;88:900-906

Fetuses, Infants and Children Are Not Just Small Adults: Real Life Examples

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Career Goals: Apply Principles and Practices of Pediatrics to Transfusion Medicine

To develop a program of clinical, epidemiological and translational research, education and service directed toward the safe, efficacious delivery of blood, blood products and hematopoietic stem cells to vulnerable populations, recognizing their uniqueness.

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Hemolytic Anemia, Coagulation and Stem Cell Biology

Established: • Focus on congenital hemolytic anemia,

coagulation and transplantation biology• Opportunity over time to serve NIH, FDA

and CDC in DSMB’s, SEPs and review panels

Challenges: • Maximizing therapy for iron related organ

toxicity• Improving HSC transplantation outcomes,

especially Graft vs. Host Disease• RBC allo- / autoantibody development

LIC 24.7 mg/gm

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Transfusion-related Immune Modulation in Hemophilia

Established: • Commitment to dissecting adverse

immunological consequences of transfusion• Involvement as regional Hemophilia Treatment

Center director and participant in clinical trials and epidemiological outcome studies in hemophilia

• Plasma derived hemophilia products replaced by recombinant products, obviating concern for HIV / HCV / Parvo

Challenges:• Inhibitor development and Immune Tolerance

Induction protocols• Initiation of prophylaxis to prevent joint disease• Gene therapy and long acting products

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Adapting Transfusion Practice to Meet Needs of Infants

Established:• Challenging bag and device manufacturers to recognize

the transfused neonate as an “underserved” population• Involvement with AABB: Technical Manual, SSCC,

Pediatric Hemotherapy Committee and the Board• Collaborations with Drs. Strauss, Sacher, Roseff and

PisciottoChallenges:• Guidelines and criteria for transfusion in neonates still

unsettled• New anticoagulant / storage solutions and devices require

neonatal / pediatric considerations• Importance of age of blood still in flux

R. Strauss R. Sacher S. Roseff P. Pisciotto

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Transfusion Transmitted Infections in Pediatric Patients

Established:• Ongoing partnership with Dr. Harvey Alter and DTM / NIH

colleagues• Use of molecular methods to identify transfusion transmitted

diseasesChallenges:• CMV and Parvo B19 “safe” product selection for fetus / neonate

still questioned • New and emerging infectious and other risks continue• Paucity of longitudinal risk assessment for neonates for drugs,

devices, and “off label” processes

Supported by: 5R01HL067229 and HHSF223200910021C through FDA

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Immune Dysregulation Results in RBC Allo-and Autoantibody Development in SCD

Established:• Molecular phenotyping focus and investigations on

molecular basis of alloimmunization• Consultant roles in SCD transfusion studies: CSSCD,

STOP I and II; SWiTCH and TWiTCHChallenges:• Discrepancy between animal and human models of

alloimmunization• Responder versus non-responder phenotype still not

identifiable• Computerization of molecular donor/ recipient matching

ABO/Rh

Type

RBC transfused

Hgb S pattern

Serological Rh CE phenotype Molecular Rh CE phenotype

C c E e C c E e

B Neg 8 SS (SF) Pos Pos Neg Pos Neg Pos Neg Pos

Known Antibodies

Rh Variant

Extended Phenotype

Anti-"e" like (hrS/hrB)

r's + "e" variant

K-, k+, Fya-, Fyb-, Jka+, Jkb+, M+, N-, S-, s+ / Lea-, Leb-, P1+

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Transfusion-associated Graft vs. Host Disease: Applying Transplantation and Radiation Biology

Concepts to Blood IrradiationEstablished:• Consideration of dosimetry and use of LDA to assess irradiation

effect• Contribution to FDA regulation

“The dose of irradiation delivered should be 2500 cGy targeted to the central portion of the container and the minimum dose should be 1500 cGy at any other point.”

http://www.fda.gov/cber/guidelines.htm• Expanded indications to include premature infant and othersChallenges:• Immunobiology of the premature / neonate not well studied • Cause of adverse effect of irradiation on RBC and storage lesion• Product availability and advisability of universal irradiation or

equivalent process for all patients

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Increasing Blood Donors with a Commitment to Specific Patient Populations

Established:• Efficacy of focused donor recruitment: “Buddy” Programs• Self sufficiency of blood / blood products unique to needs of

selected patientsChallenges:• Indications for prophylactic transfusion for SCD will increase

need for antigen phenotyped products • Future of molecular phenotyping• Effect of toxicants, drugs and metals (Pb) in donor blood• Focus on “age of blood” and inventory management

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In Learning You Will Teach, And In Teaching You Will Learn … Phil Collins

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Importance of Research in Infants and Children: Why Are They a Unique Population and Not Just Small Adults

They have diseases adults don’t haveRh Hemolytic Disease, Necrotizing Enterocolitisand Neonatal AlloimmuneThrombocytopenia

They have diseases adults have, but with different pathophysiology

- Hypertension in Complex Congenital Heart Disease- Stroke in Sickle Cell Disease

They have access to off-label use of drugs which improve outcome, but can be taken away due to adult complications

Drug Research and ChildrenMost drugs prescribed for children have not been tested in children.

http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm143455.htm

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Small sample size and small subjects make collaboration vital

- multiple illnesses- epigenetic confounders- risk-benefit, a parental concern

“Hand-me-down” medications often not optimal

Developmental origins of disease can be identified

Significant prevention opportunities

Challenges and Opportunities in Pediatric Research

2020

How Can We Improve the Research We Perform in Kids?

Careful observational and epidemiologic research

Elegant basic science research

Development of animal models

Careful clinical “phenotyping”

Quality investigator-initiated clinical trials

Collaboration between epidemiologists, basic scientists, and clinicians

Technical advances which focus on infants and children

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The Future of Pediatric Research: Leveling the Playing Field

Research networks will broaden patient availability

“No More Hand-Me-Downs”: Children and Clinical Studies campaign (http://www.nhlbi.nih.gov/childrenandclinicalstudies/index.php)

Pediatric devices: incentivizing small business through SBIR grants

Prevention: evidence-based pediatric guidelines

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The Future of Pediatric Research in Transfusion Medicine: Federally Funded Clinical Trials and Studies Relevant to

Transfusion Medicine

Hemophilia RESIST:Plasma derived vs. monoclonal product

SIPPET: Inhibitors in toddlers with hemophilia

Blood transfusionTransfusion of Preemies (TOP) TrialIOWA Program Project in Neonatal TransfusionTT: CMV Observational Birth Cohort StudyTransfusion Medicine / Hemostasis Clinical Trials Network: Pediatric Subgroup and Pedi-PLADORed Cell Storage duration Study (RECESS)

Sickle Cell DiseaseTWiTCH: TCD With Transfusion Changing to HydroxyureaSITT: Silent Cerebral Infarct Transfusion Trial

At this meeting ARIPI: Age of Red Blood Cells In Premature Infants: P3-030A

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Mentorship of Junior Faculty: Contributing to New Knowledge

Molecular characterization of RBC alloimmunization in SCD

Application of RBC molecular phenotyping andD variants

Cytochrome C oxidase and platelet storage defects

Coagulopathy of neonatal hypothermia usingThromboelastogram (TEG)

Di(2-Ethylhexl)phthalate and Bisphenol A Exposure inpediatric cardiac surgery

Expression patterns of fetal hemoglobin and reticulocytephenotype in children with SCD and during HSCT

Genomics and metabolomics of necrotizing enterocolitis

Inflammatory markers in Extracorporeal Photopheresis

Longitudinal assessment of transfusion-transmitteddiseases

Supported by: 1T32HL110841-01 and UL1RR031988 / UL1TR000075

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With Thanks to All Who Have Made Our Work and This Award Possible

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And to Children of the District of Columbia and the NIH’s Science Education Partnership Award: “Being Me”

http://www.childrensnational.org/beingme/

Our Next Generation of Scientists

Funded by: 8R25OD010969-04

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With Gratitude to My Family: “Always have someone to love, something to do and something to look forward to”

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And to Duffy Who Always Made Us Smile

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“To laugh often and much; to win the respect of intelligent people and the attention of children…to leave the world a better place…to know one life has breathed easier because you have lived. This is to have succeeded.”

Ralph Waldo Emerson

And First Do No Harm