MINUTES OF THE SEVENTY-SECOND MEETING
OF THE
SICKLE CELL DISEASE ADVISORY COMMITTEE
Bethesda, Maryland
June 9, 1997

COMMITTEE MEMBERS PRESENT

Dr. Kenneth Bridges
Dr. Jessica Davis
Dr. Joseph DeSimone
Dr. James Eckman
Dr. Mary Fabry
Dr. Cage Johnson
Dr. Vipul Mankad
Dr. William Mentzer
Ms. June Vavasseur

COMMITTEE MEMBERS ABSENT

Dr. Iris Buchanan

EX-OFFICIO MEMBERS PRESENT

Dr. Jane Lin-Fu
Dr. Martin Steinberg
Dr. Scott Wegner

EX-OFFICIO MEMBERS ABSENT

Dr. William Hannon

PROGRAM STAFF AND AFFILIATED ORGANIZATION REPRESENTATIVES:

Dr. Clarice D. Reid, DBDR; Duane Bonds,SCRG; Dr. Junius Adams, SCRG; Dr. Carol H.
Letendre, DBDR; Ms. Susan Pucie; Dr. Helena Mishoe, Ms. Sonya I. Ross, Maryland, DHMH,
Office of Hereditary Diseases ; Ms. Patricia Penn, Maryland, DHMH, Office of Hereditary
Diseases, Ms. Lisa Douglas, Georgetown, Ms. C. Siegal, Alpha Therapeutics, Dr. John Boucher,
RTL.

Executive Secretary    - Dr. Clarice D. Reid
Secretary                    - Ms. Petronella A. Barrow

I. INTRODUCTORY REMARKS

Dr. Cage Johnson, Chairman, called the 72nd meeting of the Sickle Cell Disease Advisory
Committee to order at 9:00 am. He welcomed the new member,  Dr. Vipul Mankad, Chairman  
and Professor of Pediatrics, University of Kentucky, Louisville. He thanked the outgoing member,
Ms. June Vavasseur for her service to the committee.  

II.  ANNOUNCEMENTS

Dr. Clarice Reid, Executive Secretary, read the mandatory conflict of interest statement and
reminded members to sign and return forms to Ms. Barrow. 

III.  CONSIDERATION OF MINUTES

The minutes of the last meeting were unanimously approved without modification. 

IV.  CHAIRMAN'S REPORT

Dr. Johnson briefly summarized highlights of activities since the last meeting. The Special 
Emphasis Panel on Bone Marrow Transplantation for Sickle Cell Disease held in April considered
a number of research and social issues.  Of particular interest was the discrepancy between the
large number of patients on the clinical center rosters of the national collaborative study
supported by the NHLBI and the relative small number of  transplants. This led to a discussion
regarding eligibility criteria,  lack of available matched sibling donors, and how physicians provide
education about transplantation as a  potential therapeutic option.  The financing of bone marrow
transplants has not been a major problem, although reimbursement differs in states. 

DIRECTOR'S REPORT

Dr. Clarice Reid, presented information on the latest cycle of  grant funding at the recent meeting
of the NHLBI Advisory Council.  While grants were funded to the 23rd percentile, there were
fewer investigator-initiated grants submitted  in the Blood Division during the entire year. This
translates to fewer grants to identify for select pay,  in addition to a smaller number of fundable
grants within the established payline.  Hopefully, this is a one time occurrence and not a trend for
future years. The DBDR presented two program initiatives that were approved by Council. One
encourages clinical research for  Cooley's anemia in areas of oral chelators, non-invasive
techniques for  measuring body iron and other therapeutic approaches.  The second program
presented  focused on platelet storage.   Dr. Reid reviewed with the committee several updates
on pending legislation, Dr. Varmus's testimony on setting priorities, and the new peer review 
grading system that includes a consideration of innovation. In closing, the committee was
reminded of the 50th anniversary of the NHLBI  and the upcoming September Conference
highlighting NHLBI and the 25th anniversary of the National Sickle Cell Disease Program. 
 
VI.     Hemostatic Factors and Sickle Cell Diseases - Dr. Jay Degen, Children's Hospital   
         Research Foundation, Cincinnati,OH.

Dr. Degen's research is based on an accumulation of indirect evidence that hemostatic factors
participate in sickle cell disease pathology.  He presented studies that will be carried out in
transgenic mouse animal models.  The sickle cell animal model is the SAD mouse, which has a
human beta-globin transgene containing the mutations for Hb S, Hb Antilles, and Hb D Punjab. 
These animals develop severe sickling problems under ambient oxygen tension, especially in the 
spleen and bone marrow.  The SAD mouse line will be crossed with each of three transgenic
mouse lines which have recently been developed in Dr. Degen's laboratory:  1) no circulating
fibrinogen due to disruption of the Aalpha-chain gene; 2) a truncation of the fibrinogen
gamma-chain, which ablates platelet aggregation; and 3) no circulating plasminogen due to gene
disruption.  If fibrinogen-dependent functions (fibrin clot formation and platelet aggregation)
contribute to the vasoocclusive process in sickle cell disease, the pathological manifestations of
sickle cell disease in SAD mice should be ameliorated in  that have both the SAD gene and
either of the genes that result in decreased fibrinogen function.  In contrast, the SAD mice with
the plasminogen mutation will reveal the postulated role of coagulation in sickle cell disease by
manifesting worsened vasoocclusive pathology due to deficiency in fibrinolysis.  The results of
these genetic manipulations of coagulation on sickle cell disease pathology in the SAD mouse
should elucidate the role of thrombosis in sickle cell vasoocclusion and will provide a foundation
for the application of new anticoagulant, antiplatelet, and thrombolytic therapies to the treatment
of sickle cell patients.
     

     Thrombotic Markers in Vasoocclusive Crises - Dr. James Eckman Emory University School of 
     Medicine.
     
Dr. Eckman and colleagues have shown that individuals with sickle cell disease exhibit enhanced
thrombosis in vivo, and that thrombosis is substantially increased during painful episodes. 
Furthermore, in a controlled clinical study evaluating n-3 fatty acids in individuals with frequent
painful episodes, thrombosis decreased to near basal control levels, and the frequency of painful
episodes decreased significantly.  However, the changes in laboratory values were somewhat
less dramatic.  These encouraging preliminary results suggest that more extensive studies with
more patients should be carried out to determine whether or not the beneficial effects of n-3 fatty
acid administration are due to changes in blood coagulation.  Dr. Eckman suggested that these
studies should  include intervention trials with a preventive component, as well as acute
intervention with anti-thrombin therapy during acute painful episodes.

VII.    COMMITTEE REPORTS

           Sickle Cell Trait Results

Dr. Eckman reviewed with the committee the guidelines developed by the Council of Regional
Networks (CORN)  to assure follow up of individuals identified with sickle cell trait through
newborn screening programs. The SCDAC officially approved  this document as the official
statement of the committee and discussed ways to disseminated the information. Dr.Jane Lin-Fu
suggested sending the guidelines with a cover letter to all the state maternal and child health
directors.  It should also be included in the genetics Clearinghouse and placed on the MCH
electronic superhighway.  Dr. Davis emphasized the continued need for education of primary
care providers with respect to hemoglobinopathies.The pilot project funded by HRSA to her
center has confirmed the knowledge deficit and the ability to improve this through a well directed
educational program. 

           Update on Genetic Screening

Dr. Jessica Davis reported on the Task Force, a subcommittee of ELSI, working on guidelines for 
genetic testing and screening. The first part of the report was a follow up to issues raised by the
IOM on genetics in the early nineties regarding the pitfalls and problems of genetic testing. The
final report will be forwarded to the Secretary level through Dr. William Raub whose office is
coordinating the input from PHS agencies. . It includes a section on education, laboratory
provisions and consumer and provider issues related to informed consent. One of the disturbing
points was the lack of any federal laboratory regulations regarding genetic testing. Other issues
that remain unresolved involve discrimination, not just in health and life insurance, but also in 
employment and educational opportunities. It is a challenge to the genetics community to work
with Congress and others to assure that these problems are properly addressed. It was
suggested that an entirely different group should examine the issue of public health and genetics. 

     Pediatric Hydroxyurea Follow up (PED-HUG)

Dr. Duane Bonds briefly reported on preliminary data from the PED-HUG study. It is  designed to
determine the maximum tolerated dose of hydroxyurea and overall safety in young children with
sickle cell disease and overall safety.  The children entered range in ages 5-15 years.   The
children had similar responses to hydroxyurea as the adults with increases in total hemoglobin,
MC and MCHC. Fetal hemoglobin data are not available. There have been no significant
changes in growth and development. The committee discussed the future follow up of these
children and it was the consensus that pediatric patients in the study should be closely followed
and evaluated. In addition, a registry with all the pediatric patients on hydroxyurea is needed to
capture untoward effects of this drug. The possible mechanism would be to attach a pediatric
component to the ongoing  MSH adult follow up study.

VIII.  AGENCY REPORTS

Department of Veterans Affairs

Dr. Martin Steinberg reported that the VA screening and education program continues to function
at a low level.  In the area of research, there are few grants in red cell or sickle cell disease,
however, the VA is still interested in supporting good basic and clinical research in the area of
red cells and mechanisms of disease. 

Health Resources and Services Administration

Dr. Jane Lin-Fu reported on the Genetic Services Program. The current budget is $9.2 million
and the focus of grant solicitations is  to integrate community health services, strengthen
genetics in primary care and overcoming ethnocultural barriers.  The overall goal is to improve
genetic services nationwide. The largest number of applications were in the areas of sickle cell
disease (12) grants  and primary care (11) grants. There were very few in managed care. 

Dr. Lin-Fu discussed the managed care conference, convened by CORN, in April. A protocol
was presented by Dr. Peter Lane that had been used successfully to negotiate with managed
care organizations in Colorado for sickle cell children. It appears that other states are developing
similar relationship with managed care organizations.  

Centers for Disease Control

There was not a representative from the CDC. 

Department of Defense (DoD)

Dr. Wegner indicated that the entire Department of Defense will be transitioned to managed care
by the end of 1997. All beneficiaries will be in a managed care network, some operated by the
military and others outside of the military. This will likely affect the pediatric population. 

IX.  UPDATE ON PROGRAM  ACTIVITIES

Dr. Adams highlighted opportunities for research under the use of the Small Business
mechanism with particular emphasis on collaborations with the academic community. 
He reported on new exciting areas of potential research with the zebrafish pointing out the
advantages of this model from the standpoint of developmental biology and genetics. 
The program initiative on vascular biology in sickle cell disease has been updated to
eliminate overlap with coagulation and input was requested from committee members.
The initiative on lung disease will be reviewed by several committee members and discussed
 at the next meeting. 

Dr. Bonds gave a brief update of ongoing clinical trials. The CSSCD is in the last phase of 
the study and there are no plans for continuation. The major unanswered question is the lack
of specific indices of clinical severity. The committee discussed the importance of even some
"soft" outcome variables that  would be helpful. Dr. Bonds introduced the concept of a pediatric 
clinical trial with hydroxyurea with surrogate markers of chronic end organ disease as the
endpoints. There was considerable discussion by the committee of other potential therapies that
could be used in younger asymptomatic children.  One possible selection process for children
could be based on genetic markers as haplotypes, alpha thalassemia genotype and F cell locus.  
 
 Dr. Mankad shared with the committee his experience on the FDA committee that supports
small  clinical research studies through the orphan drug program. He pointed out the opportunity
for research  on sickle cell disease and suggested the possibility of inviting an FDA official to a
meeting of this committee to provide an overview of this process. 

The meeting was adjourned at 3:15 pm . 

FUTURE MEETING DATES

November 14, 1997
June 8, 1998

I hereby certify that to the best of  our knowledge, the foregoing minutes are accurate and
complete.

___________________________                                    _____________
Cage S. Johnson, M.D.                                                             Date
Chairman
Sickle Cell Disease Advisory Committee

___________________________                                     ______________
Clarice D. Reid, M.D.                                                                 Date
Executive Secretary
Sickle Cell Disease Advisory Committee
.