NEW APPROACHES TO IMPROVE THE VIABILITY AND FUNCTION OF TRANSFUSED
PLATELETS

NIH Guide, Volume 26, Number 35, October 17, 1997

RFA:  HL-97-016

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  November 28,1997
Application Receipt Date:  January 22, 1998

THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  THIS
FULL RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION
INSTRUCTIONS THAT MUST BE USED WHEN PREPARING RESPONSES TO THIS
RFA.

PURPOSE

The Transfusion Medicine Scientific Research Group, Division of
Blood Diseases and Resources, National Heart, Lung, and Blood
Institute (NHLBI), announces the availability of a Request for
Applications (RFA) on the above subject.  The purpose of this
initiative is to encourage the conduct of research on the
alterations produced in blood platelets during collection/
processing and storage, on the development of detection techniques
for monitoring viability and function of platelets after
collection/processing and during storage, and on the prevention of
defects responsible for loss of function.  The recent availability
of sophisticated tools and analytical techniques to study the
platelet surface components, evidence that platelet storage and
viability can probably be improved, and need to make maximum use of
blood products, make it possible and timely to pursue such
questions in an important area of hematologic research and national
health need.  Thus, the intent of this solicitation is to: (a)
encourage established investigators with available tools to devote
resources to this area; (b) attract new scientific expertise such
as cell biology, biochemistry, molecular biology,  into studies of
platelet viability and function; and (c) promote inter-disciplinary
collaborative research in helping to solve a fundamental question
in hematology; i.e., what biologic events result in loss of
platelet viability and/or function after collection/processing and
during storage and how can these events be prevented.  The ultimate
goal will be to define the conditions which will provide better
hemostatic function as a result of platelet transfusions to
thrombocytopenic patients.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the
health promotion and disease prevention objectives of "Healthy
People 2000", a PHS-led national activity for setting priority
areas.  This RFA, New Approaches to Improve the Viability and
Function of Transfused Platelets, is related to the priority areas
of heart diseases and stroke, and cancer.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report: Stock No.
017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing
Office, Washington, DC 20402-9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit
and non-profit organizations, public and private, such as
universities, colleges, hospitals, laboratories, units of state or
local governments, and eligible agencies of the federal government. 
Awards in response to this RFA will be made to foreign institutions
only for research of very unusual merit, need, and promise, and in
accordance with PHS policy governing such awards.  Minority
individuals and women are encouraged to apply.

MECHANISM OF SUPPORT

This RFA will use the NIH individual research project grant (R01)
mechanism of support.  Newly independent investigators who may wish
to consult with a program representative (see "INQUIRIES" section)
are encouraged to apply.  Specific application instructions have
been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME"
streamlining efforts being examined by the NIH.  The MODULAR GRANT
concept establishes specific modules in which direct costs may be
requested as well as a maximum level for requested budgets.  Only
limited budgetary information is required under this approach.  The
JUST-IN-TIME concept allows applicants to submit certain
information only when there is a possibility for an award. It is
anticipated that these changes will reduce the administrative
burden for the applicants, reviewers, and Institute staff.

For this RFA, funds must be requested in $25,000 direct cost
modules and a maximum of seven modules ($175,000 direct costs) per
year may be requested.  Any necessary escalation must be included
within the number of modules being  requested.  Only limited budget
information will be required and any budget adjustments made by the
Initial Review Group will be in modules of $25,000.  Instructions
for completing the Biographical Sketch have also been modified.  In
addition, Other Support information and the application Checklist
page are not required as part of the initial application.  If there
is a possibility for an award, necessary budget, Other Support and
Checklist information will be requested by NHLBI staff following
the initial review.  The APPLICATION PROCEDURES section of this RFA
provides specific details of modifications to standard PHS 398
application kit instructions.

Applicants, who will plan and execute their own research programs,
are requested to furnish their own estimates of the time required
to achieve the objectives of the proposed research project.  Up to
4 years of support may be requested.  At the end of the official
award period, renewal applications may be submitted for peer review
and competition for support through the regular grant program of
the NHLBI.  It is anticipated that support for the present program
will begin September 1998.  Administrative adjustments in project
period or amount of support may be required at the time of the
award.  Since a variety of approaches would represent valid
responses to this announcement, it is anticipated that there will
be a range of costs among individual grants awarded.  All current
policies and requirements that govern the research grant programs
of the NIH will apply to grants awarded in connection with this
RFA.

FUNDS AVAILABLE

It is anticipated that for fiscal year 1998, $1,200,000 total costs
will be available for the first year of support for this
initiative.  The award of grants pursuant to this RFA is contingent
upon receipt of such funds for this purpose.  It is anticipated
that approximately four to six new grants will be awarded under
this program.  Applicants may request up to four years of support. 
The specific number to be funded will, however, depend on the merit
and scope of the applications received and on the availability of
funds.  Direct costs will be awarded in modules of $25,000, less
any overlap or other necessary administrative adjustments. 
Facilities and Administrative costs will be awarded based on the
negotiated rates.  If collaborative arrangements involve
subcontracts with other institutions, Ms. Jane R. Davis of the
NHLBI Grants Operations Branch (telephone: (301) 435-0166) should
be consulted regarding procedures to be followed.

RESEARCH OBJECTIVES

BACKGROUND

Platelets are enucleated cell fragments produced from
megakaryocytes and are essential to prevent or stop microvascular
bleeding.  Platelet transfusions  to treat hemorrhagic
thrombocytopenia have increased dramatically from 410,000 units in
1971 to 7,258,000 units in 1989.  Recently, a marked increase has
been noted in transfusions of single donor apheresis platelets. 
Between 1992 and 1994, single donor apheresis platelet 
transfusions increased from 3,642,000 to 4,284,000 unit equivalents
(expressed as platelets harvested from one unit of donated blood),
an increase of 23.6%.  In 1994, transfusions of single donor
platelets actually exceeded transfusions of platelet concentrates
for the first time.

Platelets demonstrate a progressive loss in viability during
storage. At one large regional blood center, 156 consecutive
platelet transfusion-refractory patients were examined to determine
the mechanism of their platelet refractoriness.  Of these, 108
(69%) had no evidence of platelet-reactive antibodies. Only 3 of
these non-alloimmune platelet-refractory patients did not show
improved responses when they were given "fresh" platelets that were
stored for less than 30 hours.  Responses to fresh vs. stored
platelets were as much as a 4-fold increase in posttransfusion
platelet increment, and a 2-fold increase in platelet survival. 
Thus, the frequency with which patients may develop refractoriness
to stored platelets and the magnitude of the differences in
patients' responses to fresh and stored platelets all suggest that
improvements in the quality of stored platelets would result in
major improvements in the management of thrombocytopenic patients,
accompanied by cost savings

At least part of this loss in platelet viability may represent
activation during collection/processing and storage resulting in
platelets that are prematurely removed from circulation.  To begin
to improve or extend the shelf-life of platelets, it is essential
to understand and define better the alterations that take place in
these cells.  Therefore, it is important to conduct basic research
on the cellular and molecular changes leading to the loss of
platelet viability and/or function in vitro. Previous studies have
demonstrated that stored platelets gradually lose their ability to
aggregate or secrete cytoplasmic granular materials upon activation
with physiologic stimulants. This loss could, in part, be due to a
general decay in the metabolic activities of the cell. Some
investigators have reported alterations in the contractile
proteins, e.g., myosin or actin-binding platelet proteins.  Others
have observed changes in specific surface glycoproteins of stored
platelets.  However, these studies have been sporadic, and the
results reported by one investigator have not always been
reproduced in another laboratory.

There are accumulating data to suggest that it may now be possible
to identify an artificial medium that will meet the metabolic needs
of platelets during storage much better than the anticoagulated
plasma with red cell preserving capabilities that is currently
used.  In some studies, inhibitors that prevent platelet activation
during storage have been added to the medium, resulting in further
improvements in platelet viability.  These results indicate that
there are newer approaches for storing platelets that need to be
developed, tested, and refined with the expectation that the
quality of stored platelets will be significantly enhanced.

The clinical relevance for understanding the biological changes
during platelet storage is well-recognized.  The demand for
platelets to support patients: 1) with dilutional thrombocytopenia
due to massive blood transfusions; 2) being treated with aggressive
cancer and marrow transplant chemotherapy regimens causing bone
marrow suppression; or 3) with other specific thrombocytopenic
episodes, is steadily increasing.  In addition to the already-
identified need for platelet therapy, the platelet demands are
expected to increase as more hematopoietic abnormalities occur in
AIDS patients such as bone marrow dysplasia, anemia,
thrombocytopenia, and leukopenia.

This special grant program is for the support of research
addressing fundamental questions concerning: 1) how  normal
platelet function is maintained; 2) what alterations in platelet
biology, physiology, or biochemistry develop during collection and
storage; 3) how these changes during storage can be prevented ; and
4) does prevention of these storage changes result in improved
posttransfusion viability and/or storage for long periods of time
in the cold, and 5) can systems be developed that will detect non-
viable platelets in storage and prevent their transfusion.  The
emphasis of this program is clearly on the cellular and molecular
properties of platelets.  Extensive clinical trials are not deemed
appropriate for this solicitation although investigators are
encouraged to propose some extension of basic studies into a
clinical setting to correlate in vitro changes with in vivo events. 
Particular encouragement is offered to investigators possessing
modern tools who are well-trained in relevant techniques and are
currently pursuing other research interests.  It is hoped that
inter-disciplinary and collaborative approaches may be developed
which will complement the efforts of workers in the field.

Collaborative research among disciplines such as hematology,
biochemistry, cell biology, pharmacology, and molecular biology may
be necessary to achieve some of the goals of this study. Examples
of topics that might be appropriate for this program are:

o  Storage-related changes in platelet internal structures
including the cytoskeleton and contractile proteins.

o  Role of proteases, especially calcium-activated proteases, in
causing structural alterations leading to loss of platelet
function.

o  Correlations of in vitro changes with alterations in platelet
viability or function in vivo.

o  Development of conditions for storing platelets in the cold
without inducing the "platelet lesion".

o  Development of conditions which might circumvent storage-induced
changes and improve platelet viability and  function.

o  Development of procedures and parameters to more accurately
assess the viability and/or function of stored platelets.

o  Effect of additives on the changes produced on  the platelet
surface due to collection/processing and storage.

SPECIAL REQUIREMENTS

Upon initiation of the program, the NHLBI will sponsor annual
meetings to encourage the exchange of information among
investigators who participate in this program.  Travel funds for a
one day meeting each year, most likely to be held in Bethesda,
Maryland, should be included in the modules. Applicants should also
include a statement in the applications indicating their
willingness to participate in such meetings.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of the NIH that women and members of minority
groups and their subpopulations must be included in all NIH
supported biomedical and behavioral research projects involving
human subjects, unless a clear and compelling rationale and
justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of research. 
This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).  All investigators proposing
research involving human subjects should read the "NIH Guidelines
for Inclusion of Women and Minorities as Subjects in Clinical
Research", which have been published in the Federal Register of
March 28, 1994 (FR 59 14508-14513), and in the NIH GUIDE FOR GRANTS
AND CONTRACTS of March 18, 1994, Volume 23, Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact person listed below.  Program staff may
also provide additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by November 28, 1997,
a letter of intent that includes a descriptive title of the
proposed research, the name, address, and telephone number of the
Principal Investigator, the identities of other key personnel and
participating institutions and the number and title of the RFA in
response to which the application may be submitted.  Such letters
are requested only for the purpose of providing an indication of
the number and scope of applications to be received; therefore,
their receipt is usually not acknowledged.  A letter of intent is
not binding, and it will not enter into the review of any
application subsequently submitted, nor is it a necessary
requirement for the application.

The letter of intent is to be sent to:

Dr. C. James Scheirer
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0266
FAX:  (301) 480-3541
Email:  james_scheirer@nih.gov

APPLICATION PROCEDURES

Application Receipt Date: January 22, 1998

Applications are to be submitted on the research grant application
form PHS 398 (revised 5/95).  This form is available in at most
institutional offices of sponsored research and from the Division
of Extramural Outreach and Information Resources, National
Institutes of Health, 6701 Rockledge Drive - MSC 7910, Bethesda, MD
20892-7910, telephone 301-435-0714, email: asknih@od.nih.gov.

BUDGET INSTRUCTIONS

The total direct costs must be requested in accordance with the
program guidelines and the modifications made to the standard PHS
398 application instructions described below:

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD
Do not complete Form Page 4 of the PHS 398 (rev 5/95).  It is not
required nor will it be accepted at the time of application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT
Do not complete the categorical budget tables on Form page 5 of the
PHS 398 (rev. 5/95). Only the requested total direct costs line for
each year must be completed based on the number of $25,000 modules
being requested.  Applicants may not request a change in the amount
of each module.  A maximum of seven modules ($175,000) direct costs
per year may be requested and each applicant may request up to five
years of support for this RFA.  Direct cost budgets will remain
constant throughout the life of the project (i.e. the same number
of modules requested for all budget periods).  Any necessary
escalation should be considered when determining the number of
modules to be requested.  However, in the event that the number of
modules requested must change in any future year due to the nature
of the research proposed, appropriate justification must be
provided.  Total Direct Costs for the entire Proposed Project
Period should be shown in the box provided.

o  BUDGET JUSTIFICATION
- Budget justifications should be provided under "Justifications"
on Form Page 5 of the PHS 398.
- List the names, role on the project and proposed percent effort
for all project personnel (salaried or unsalaried) and provide a
narrative justification for each person based on his/her role on
the project.
- Identify all consultants by name and organizational affiliation
and describe the services to be performed.
- Provide a general narrative justification for individual
categories (equipment, supplies, etc.) required to complete the
work proposed.  More detailed justifications should be provided for
high cost items.  Any large one-time purchases, such as large
equipment requests, must be accommodated within these limits.  No
specific costs for items or categories should be shown.

o  CONSORTIUM/CONTRACTUAL COSTS - If collaborations or subcontracts
are involved that require transfer of funds from the grantee to
other institutions, it is necessary to establish formal subcontract
agreements with each collaborating institution.  A letter of intent
from each collaborating institution should be submitted with the
application.  Only the percentage of the consortium/contractual
TOTAL COSTS (direct and indirect) relative to the total DIRECT
COSTS of the overall project needs to be stated at this time. The
following example should be used to indicate the percentage cost of
the consortium, "The consortium agreement represents 27% of overall
$175,000 direct costs requested in the first year.".  A budget
justification for the consortium should be provided as described in
the "Budget Justification" section above (no Form Page 5 required
for the consortium).  Please indicate whether the consortium will
be in place for the entire project period and identify any future
year changes in the percentage relative to the parent grant.

If there is a possibility for an award, the applicant will be
requested to identify actual direct and indirect costs for all
years of the consortium.  Please note that total subcontract costs
need not be calculated in $25,000 modules.  However, when
subcontract funds are added to the parent grant budget, the total
direct cost amount must be included in the number of $25,000
modules requested.

o  BIOGRAPHICAL SKETCH - A biographical sketch is required for all
key personnel, following the modified instructions below.  Do not
exceed the two-page limit for each person.
- Complete the educational block at the top of the form page;
- List current position(s) and those previous positions directly
relevant to the application;
- List selected peer-reviewed publications directly relevant to the
proposed project, with full citation;
- The applicant has the option to provide information on research
projects completed and/or research grants participated in during
the last five years that are relevant to the proposed project.

o  OTHER SUPPORT - Do not complete the "Other Support" pages (Form
Page 7).  Selected other support information relevant to the
proposed research may be included in the Biographical Sketch as
indicated above.  Complete Other Support information will be
requested by NHLBI staff if there is a possibility for an award.

o  CHECKLIST - No "Checklist" page is required as part of the
initial application.  A completed Checklist will be requested by
NHLBI staff if there is a possibility for an award.

o  The applicant should provide the name and phone number of the
individual to contact concerning fiscal and administrative issues
if additional information is necessary following the initial
review.

Sample budgets and justification page will be provided upon request
or following the submission of a letter of intent.

APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED
UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER
REVIEW.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for
conducting the proposed research.  If so, a letter of agreement
from either the GCRC program director or principal investigator
could be included with the application.

The RFA label available in the PHS 398 application kit must be
affixed to the bottom of the face page of the application.  Failure
to use this label could result in delayed processing of the
application such that it may not reach the review committee in time
for review.  In addition, the RFA title and number must be typed on
line 2 of the face page of the application form and the YES box
must be marked.

Send or deliver the completed application and three signed, exact
photocopies of it to the following, making sure that the original
application with the RFA label attached is on top:

CENTER FOR SCIENTIFIC REVIEW (formerly Division of Research Grants)
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application
must be sent to the Dr. C. James Scheirer at the address listed
under Letter of Intent.  It is important to send these two copies
at the same time as the original and three copies are sent to the
Center for Scientific Review.  Otherwise the NHLBI cannot guarantee
that the application will be reviewed in competition for this RFA.

Applications must be received by January 22, 1998.  If an
application is received after that date, it will be returned to the
applicant without review.  The Center for Scientific Review (CSR)
will not accept any application in response to this rfa that is
essentially the same as one currently pending initial review,
unless the applicant withdraws the pending application.  The CSR
will not accept any application that is essentially the same as one
already reviewed.  This does not preclude the submission of
substantial revisions of applications already reviewed, but such
applications must include an introduction addressing the previous
critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the
CSR and responsiveness by the NHLBI.  Incomplete applications will
be returned to the applicant without further consideration.  If
NHLBI staff determines that the application is not responsive to
the RFA, it will be returned to the applicant without further
consideration.

Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NHLBI in accordance with the review
criteria stated below.  As part of the initial merit review, a
process may be used by the initial review group in which
applications will be determined to be competitive or non-
competitive based on their scientific merit relative to other
applications received in response to the RFA.  Applications judged
to be competitive will be discussed and be assigned a priority
score.  Applications determined to be non-competitive will be
withdrawn from further consideration and the principal
investigator/program director and the official signing for the
applicant organization will be promptly notified.

Review Criteria

Criteria for the scientific and technical merit review are as
follows:

Significance:  Does this study address an important problem?  If
the aims of the application are achieved, how will scientific
knowledge be advanced? What will be the effect of these studies on
the concepts or methods that drive this field?

Approach:  Are the conceptual framework, design, methods, and
analyses adequately developed, well-intergrated, and appropriate to
the aims of the project?  Does the applicant acknowledge potential
problem areas and consider alternative tactics?

Innovation:  Does the project employ novel concepts, approaches or
methods? Are the aims original and innovative?  Does the project
challenge existing paradigms or develop new methodologies or
technologies?

Investigator:  Is the investigator appropriately trained and well-
suited to carry out this work?  Is the work proposed appropriate to
the experience level of the principal investigator and other
researchers (if any)?

Environment:  Does the scientific environment in which the work
will be done contribute to the probability of success?  Do the
proposed experiments take advantage of unique features of the
scientific environment or employ useful collaborative arrangements? 
Is there evidence of institutional support?

Budget:  Is the requested budget and estimation of time to
completion of the project appropriate for the proposed research?

The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.

The personnel category will be reviewed for appropriate staffing
based on the requested percent effort.  The direct costs budget
request will be reviewed for consistency with the proposed methods
and specific aims.  Any budgetary adjustments recommended by the
reviewers will be in $25,000 modules.  The duration of support will
be reviewed to determine if it is appropriate to ensure successful
completion of the requested scope of the project.

The roster of the reviewers for this RFA may be found at:
http://www.nhlbi.nih.gov/nhlbi/meet.htm Link:[ under Peer Review:
Special Emphasis Panels (SEPs)].

AWARD CRITERIA

The anticipated date of award is September 1998.  Funding decisions
will be made on the basis of scientific and technical merit as
determined by peer review, program needs and balance, and the
availability of funds.

Awards in response to this RFA will be made to foreign institutions
only for research of very unusual merit, need, and promise, and in
accordance with PHS policy governing such awards. Designated
funding levels are subject to change at any time prior to award,
due to unforeseen budgetary, administrative and/or scientific
developments.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is
welcome.

Inquiries regarding this programmatic issues may be directed to:

Dr. Luiz H. Barbosa
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10146
Bethesda, MD  20892-7950
Telephone:  (301) 435-0075
FAX:  (301) 480-0868
Email:  lb30o@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Jane R. Davis
Grants Management Office
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7926
Bethesda, MD  20897-796
Telephone:  (301) 435-0166
FAX:  (301) 480-3310
Email:  jane_davis@nih.gov

AUTHORITY AND REGULATIONS

The programs of the Division of Blood Diseases and Resources,
NHLBI, are described in the Catalog of Federal Domestic Assistance
Number 93.839.  Awards will be made under the authority of the
Public Health Service Act, Section 301 (42 USC 241) and
administered under PHS grant policies and Federal regulations, most
specifically 42 CFR Part 52 and 45 CFR Part 74.  This program is
not subject to the intergovernmental review requirements of
Executive Order 12372, or to Health Systems Agency Review.

The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all
tobacco products.  In addition, Public Law 103-227, the Pro-
Children Act of 1994, prohibits smoking in certain facilities (or
in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early
childhood development services are provided to children.  This is
consistent with the PHS mission to protect and advance the physical
and mental health of the American people.


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