Full Text HL-95-007


NIH GUIDE, Volume 23, Number 36, October 14, 1994

RFA:  HL-95-007

P.T. 34

  Blood Diseases 

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  December 16, 1994
Application Receipt Date:  February 16, 1995


The objectives of this initiative are to (1) support studies on the
pathogenesis of thrombotic thrombocytopenic purpura (TTP) and (2)
stimulate development of new approaches for determining
predisposition, early diagnosis and treatment of TTP associated with
HIV infection.  The goal of this program is to understand the
pathogenesis of TTP and the development of better therapy for TTP
patients with HIV.


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 Request
for Application (RFA), Thrombotic Thrombocytopenic Purpura and HIV,
is related to the priority areas of heart disease and stroke, and HIV
infection.  Potential applicants may obtain a copy of "Healthy People
2000" (Full Report:  Stock No. 017-001-00474-0) or "Healthy People
2000" (Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202-782-3238).


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.  Applications from minority
individuals and women are encouraged.  Foreign institutions are not
eligible for First Independent Research Support and Transition
(FIRST) (R29) awards.


This RFA will use the National Institutes of Health (NIH) individual
research project grant (R01) and FIRST (R29) awards and is a one-time
solicitation.  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 five 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 in July 1995.  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 RFA, 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.


It is anticipated that for fiscal year 1995, $2,000,000 (total costs)
will be available for this initiative. It should be noted that award
of grants pursuant to this RFA is contingent upon receipt of such
funds for this purpose.  Designated funding levels are subject to
change at any time prior to final award, due to unforeseen budgetary,
administrative, and/or scientific development.  It is anticipated
that about seven new grants will be awarded under this program.  The
specific amount to be funded will, however, depend on the merit and
scope of the applications received and on the availability of funds.
If collaborative arrangements involve sub-contracts with other
institutions, the NHLBI Grants Operations Branch (tel: 301- 594-7436)
should be consulted regarding procedures to be followed.


Thrombotic thrombocytopenic purpura (TTP) is characterized by
thrombocytopenia, hemolytic anemia, fluctuating neurological signs,
renal dysfunction, fever, and other signs of organ failure.
Histologically, there are widespread micro-thrombi and reactive
endothelial proliferation.  Thrombi consist of masses of platelets
and entrapping erythrocytes and fibrin.

The etiology and mechanism of this disorder is unclear and past
studies dealing with etiology and treatment of the disorder have been
flawed or inconclusive.  TTP occurs in a very heterogenous group of
persons and has been associated with cancer, pregnancy, collagen
vascular disorders, bacterial infection, and most recently HIV-1
infection.  It is unclear if all cases of TTP arise by a similar
mechanism to produce the same constellation of symptoms or if each
represents a different disorder with similar clinical manifestations.
It has been reported that plasma obtained from patients with TTP
contains a platelet aggregatory factor.  Moreover, calpain, a
calcium-dependent protease, is thought to be present in the serum of
individuals with active TTP, but not normal controls or persons with
the disease in remission.  vWF proteolyzed by calpain binds to
activated platelets and causes platelet aggregation.  Other
investigators also documented 170 kD and 150 kD fragments after
treating vWF with calpain.  Of interest is the fact that normal
plasma prevented calpain-associated abnormal fragmentation of vWF.
Recently, very large vWF multimers, that disappeared during relapses
of the disease, have been isolated from the plasma of individuals
with TTP.  These large vWF multimers are absent in normal plasma and
probably reflect the endothelial damage that occurs during the course
of the disease, resulting in the secretion of unusually large vWF
multimers from Weibel-Palade bodies during the episode of TTP.  These
findings suggest that an abnormal calpain-like protease activity in
TTP plasma might cause abnormal fragmentation of these unusually
large vWF multimers.  Other investigators have demonstrated decreased
prostacyclin generation from the blood vessel walls of individuals
with this disorder, as well as in their first degree relatives
without the disease.  The hemolytic anemia in this disorder is
thought to be caused by the mechanical trauma that red cells sustain
as they pass through abnormal blood vessels.  Other investigators
believe that platelets obtained from individuals with TTP promote
hemolysis of normal red cells when they are incubated together in

There has been significant progress in the basic understanding of the
cell biology of both platelets and endothelial cells, the two
components that appear to be intimately involved in the
pathophysiology of TTP.  The technology and probes necessary to
determine the activation status of these cells are now routinely
available in a number of laboratories.  Similarly, progress has been
made in understanding the structure-function of von Willebrand
factor, a plasma protein that may play a key role in the development
of TTP.  It thus appears to be timely to apply this knowledge and the
available tools to determine the etiology of TTP, which is being
increasingly reported in the HIV-positive population.

Plasmapheresis was developed as a therapeutic modality after it was
observed that individuals with TTP receiving repeated whole blood
transfusion underwent a remission. Subsequently, marked improvement
was noted in some patients within hours following plasma exchange.
Alternatively, some investigators have noted a response to plasma
exchange in patients who have previously failed to respond to fresh
frozen plasma.  This has fueled the debate about whether the clinical
manifestations of TTP result from a missing plasma factor that
inhibits aggregation (which is replaced during plasma infusion) or a
platelet aggregatory factor that is not normally present in plasma
(which is removed during plasmapheresis).  A recent controlled trial
of plasma exchange versus plasma infusion in patient with TTP of all
origins, except HIV infection, demonstrated the superiority of plasma
exchange, although proponents of plasma infusion argue that plasma
exchange merely allows a greater volume of plasma to be infused.  The
role of steroids, splenectomy, vincristine, and anti-platelet agents
in the treatment of this disorder is controversial.  Most studies
using these agents also used many other different treatments and it
is not clear what part of the clinical response could be attributed
to these agents.

In a disease that was considered uniformly fatal before 1968, it is
clear that the prognosis for thrombotic thrombocytopenic purpura
appears to have improved greatly in recent years. This decreased
mortality may result from more effective therapy, earlier or better
diagnosis of milder cases, or a change in the natural history of the
disease.  Certainly there have been a number of cases with apparent
indolent course reported in the literature.  The effectiveness of
various therapies may differ with the underlying disease.

Examples of promising research topics include:

Controlled clinical studies addressing the effective treatment of TTP
and its etiology are clearly warranted.  This initiative will support
research designed to determine the most effective treatment of TTP
related to HIV infection as well as to examine the factors which lead
to its expression.  The aim of this initiative is to encourage basic
research that will increase the understanding of the pathophysiology
of TTP in all patients.  Special emphasis will be placed on the
determination of safe and effective treatment for this disorder in
HIV-positive persons.  Because of the relatively small numbers of
persons afflicted with TTP, collaborative arrangements among centers
are encouraged.

The following are examples of research areas for this initiative.

o  Elucidation of the pathogenesis of TTP

o  Studies on the mechanism of platelet activation in vivo with
emphasis on the platelet surface

o  Elucidation of the influence of HIV infection on the development
of TTP

o  Studies to determine the optimal treatment of TTP in HIV infected

o  Development of animal models of TTP and evaluation of specific
agents (antibodies, peptides) that could be beneficial in the
treatment of TTP

o  Investigation of the relationship between TTP and HIV and CMV
viremia, and other markers of immune function

o  Studies of the status of the endothelium in patients with active

o  Critical studies of possible abnormalities in plasma from patients
with TTP, e.g., large vWf multimers, platelet aggregators and
inhibitors, proteolytic enzymes and methods of their inhibition


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


It is the policy of 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 the research.  This new policy results from the NIH
Revitalization Act of 1993 (Section 492B of Public Law 103-43) and
supersedes and strengthens the previous policies (Concerning the
Inclusion of Women in study populations, and Concerning the Inclusion
of Minorities in Study Populations), which have been in effect since
1990.  The new policy contains some new provisions that are
substantially different from the 1990 policies.

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 reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.

Investigators also may obtain copies from the program staff listed
under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.


Prospective applicants are asked to submit, by December 16, 1994, 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.  Although a letter of intent
is not required, is not binding, and does not enter into the review
of a subsequent application, the information that it contains allows
IC staff to estimate the potential review workload and avoid conflict
of interest in the review.

The letter of intent is to be sent to:

Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 553
Bethesda, MD  20892
Telephone:  (301) 594-7478
FAX:  (301) 594-7407
Internet:  James_Scheirer@NIH.GOV


Applications are to be submitted on the research grant application
form PHS 398 (rev. 9/91).  This form is available in most
institutional offices of sponsored research from the Office of Grants
Information, Division of Research Grants, National Institutes of
Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone
(301) 710-0267.  Use the conventional format for research grant
applications and ensure that the points identified in the section on

To identify the application as a response to this RFA, check "YES" on
Item 2a of page 1 of the application and enter the title and RFA
number:  Thrombotic Thrombocytopenic Purpura and HIV: HL-95-007.

The RFA label available in the PHS 398 (rev. 9/91) application form
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 2a of the face page of the application form and the YES box must
be marked.

Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.

Send or deliver the completed application and three signed, exact
photocopies to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

Send an additional two copies of the application to the Chief,
Centers and Special Projects Review Section 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
Division of Research Grants.  Otherwise the NHLBI cannot guarantee
that the application will be reviewed in competition for this RFA.

Applications must be received by February 16, 1995.  If an
application is received after that date, it will be returned to the
applicant without review.  The Division of Research Grants (DRG) 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 DRG 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.


Upon receipt, applications will be reviewed for completeness by the
DRG and responsiveness by the NHLBI.  Incomplete applications will be
returned to the applicant without further consideration.  If NHLBI
staff find that the application is not responsive to the RFA, it will
be returned 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 Division of Extramural Affairs, NHLBI in
accordance with the review criteria stated below.  As part of the
initial merit review, a process (triage) 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 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 notified.

Applications should be prepared so that they can be reviewed without
the necessity of interaction between applicants and reviewers since
no site visit or reverse site visit will be part of the technical
merit review.

Review Criteria

The factors to be considered in the evaluation of scientific merit of
each application will be similar to those used in the review of
traditional research grant applications, including the novelty,
originality, and feasibility of the approach; the training,
experience and research competence of the investigator(s); the
adequacy of the experimental design; the suitability of the
facilities; the appropriateness of the requested budget to the work
proposed; and adequacy of plans to include both genders and
minorities and their subgroups as appropriate for the scientific
goals of the research.


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.


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

Direct inquiries regarding programmatic issues to:

Dr. Pankaj Ganguly
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Federal Building, Room 5C14
Bethesda, MD  20892
Telephone:  (301) 402-2237
FAX:  (301) 496-9940
Internet:  Pankaj_Ganguly@NIH.GOV

For fiscal and administrative matters, contact:

Ms. Jane R. Davis
Grants Operation Branch
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A15
Bethesda, MD  20892
Telephone:  (301) 594-7436
FAX:  (301) 594-7492
Internet:  Jane_Davis@NIH.GOV


The programs of the Division of Blood Diseases and Resources, NHLBI,
are described in the Catalog of Federal Domestic Assistance No
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 Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non-use
of all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American


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