Full Text HL-92-06-B

THROMBOCYTOPENIAS IN WOMEN AND NEONATES

NIH GUIDE, Volume 21, Number 6, February 14, 1992

RFA:  HL-92-06-B

P.T. 34, AA, II

Keywords: 
  Cardiovascular Diseases 
  Immunology 
  Biology, Cellular 
  Biology, Molecular 
  Hematology 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  March 20, 1992
Application Receipt Date:  May 7, 1992

PURPOSE

The Division of Blood Diseases and Resources (DBDR), National Heart,
Lung, and Blood Institute (NHLBI) invites applications for studies to
better define the properties and clinical relevance of the antiplatelet
antibodies in alloimmune and autoimmune thrombocytopenias in women and
neonates.  The knowledge gained is expected to lead to improved therapy
for this patient population.

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 Request
for Applications (RFA), Thrombocytopenias in Women and Neonates, is
related to the priority area of maternal and infant health.  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).

ELIGIBILITY REQUIREMENTS

All domestic public and private, for-profit and non-profit institutions
or organizations are eligible to apply in response to this RFA.  Awards
in connection with this announcement will be made to foreign
institutions only for research of very unusual merit, need, and
promise, and in accordance with Public Health Service policy governing
such awards.  Applications from minority individuals and women are
encouraged.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research grant (R01) and is a one-time solicitation.  Applicants will
plan and execute the research programs and are requested to furnish
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 unsolicited grant program of the NIH.  It is
anticipated that support for the present program will begin in
September, 1992.  Administrative adjustments in project period and/or
amount of support may be required at the time of the award.  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

Although the financial plans for fiscal year 1992 include $1.5 million
for this program, award of grants pursuant to this RFA is contingent
upon receipt of funds for this purpose.  It is anticipated that about
six grants will be awarded.  The specific amount to be funded will,
however, depend on the merit and scope of the applications received and
on the availability of funds.  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.  If
collaborative arrangements involve sub-contracts with other
institutions, the NHLBI Grants Operations Branch (telephone:
301-496-7257) must be consulted regarding procedures to be followed.

RESEARCH OBJECTIVES

Background

Immune thrombocytopenia is characterized by platelet destruction due to
antiplatelet antibodies that result in platelet phagocytosis by the
reticuloendothelial system. The platelet specific target antigen may be
an alloantigen or an autoantigen.  Immunization against platelet
alloantigens leads to neonatal alloimmune thrombocytopenic purpura
(NATP) and post-transfusion purpura (PTP).  Both conditions are rare
and transient, but they may lead to severe, life-threatening hemorrhage
during the period of thrombocytopenia.  Idiopathic (or immune)
thrombocytopenic purpura (ITP) may be associated with other autoimmune
diseases, such as lymphoma, or may occur as an isolated disorder.
Chronic ITP is a relatively common hematologic problem with a peak
incidence in the third and fourth decades; women are affected more
frequently than men.  Thrombocytopenia is one of the more frequent
complications noted during pregnancy and may present as an incidental
finding in an otherwise healthy pregnant woman or may be associated
with clinical hemorrhage.  Chronic ITP in remission may be exacerbated
during pregnancy in some women.  Whether a pregnant woman with ITP is
symptomatic or not, her newborn infant is at risk for transient
thrombocytopenia due to transplacental passage of platelet
autoantibodies.  The factors determining whether or not a particular
infant will be affected are not well established.

Cyclic thrombocytopenia has been known to occur in women in phase with
the menstrual cycle.  Based on the reported capacity of estrogenic
hormones to modulate macrophage Fc gamma receptor expression, it has
been proposed that hormonal changes during the menstrual cycle may
alter receptor-mediated platelet clearance by macrophages, modulate
platelet survival and cause cyclical thrombocytopenia.

In NATP, fetal and neonatal thrombocytopenia result from the formation
of maternal antibody to a paternally derived antigen expressed on the
surface of the fetal platelets.  The pathophysiologic process involved
is similar to Rh disease of the newborn in which severe fetal anemia
caused by maternal antibodies to red cells occurs as early as 20 weeks
of gestation.  NATP occurs in approximately 1 in 2000 to 1 in 5000
births, but the condition may be life threatening with the possibility
of severe hemorrhage during the period of thrombocytopenia.

A diagnosis of NATP may be suspected in the setting of unexpected
petechiae, purpura, and severe thrombocytopenia in an otherwise healthy
neonate whose mother is well and has no history of autoimmune
thrombocytopenia.  The thrombocytopenia is usually isolated with a
normal white cell count and hematocrit.  Previous antigenic exposure
for sensitization is not required and a first born infant may be
affected.  Other diagnoses to be considered are effects of drugs, viral
infections, and the possibility of the presence of a maternal
autoantibody.  Bone marrow megakaryocytes tend to be higher in infants
with NATP.  However, some infants with NATP lack megakaryocytes,
apparently because they are damaged by the alloantibody.  There are
estimated to be about 800 to 2000 cases of NATP in a year of 4 million
deliveries.  The exact incidence of intracranial hemorrhage among
affected infants is not known, but estimates range between 10 to 20
percent of all cases.  Thus, there may be 300 babies per year, 20
percent of 1,500, who suffer serious intracranial hemorrhage associated
with NATP.

Recently, there has been significant improvement in the understanding
of platelet membrane biochemistry and several new platelet alloantigens
have been identified.  The antigen Pl(A1), located on platelet membrane
glycoprotein IIIa (GPIIIa), appears to be the most common antigen
associated with published cases of NATP.  The amino acid substitution
underlying the Pl(A1) and Pl(A2) polymorphism has been determined and
specific oligonucleotide probes for diagnosis have been developed.  An
important question here is whether the specificity or properties of the
platelet antibodies predispose to intracranial hemorrhage.  Can
hemorrhage be predicted prior to its occurrence?  Some fetuses appear
to be severely thrombocytopenic only immediately prior to term while
others are thrombocytopenic by the 20th week of gestation.  The
antenatal duration of severe thrombocytopenia may be influenced by the
quality or the quantity of the maternal antibody and could be an
important factor in the risk of antenatal intracranial hemorrhage.

Although approximately 2 percent of pregnancies are at risk for NATP
because of Pl(A1) incompatibility, the syndrome is diagnosed in only 1
of 2000 to 5000 births.  Women sensitized during pregnancy to Pl(A1)
antigen have a high frequency of the HLA markers DRw3 and DR52.  This
association is more striking than for any other defined alloimmune
response in humans.  Important information about NATP and alloimmune
responses in general might be obtained by determining the basis for
this relationship.

Most autoantibodies in patients with chronic ITP appear to recognize
epitopes on the platelet GP IIb/IIIa or GP Ib/IX complexes, but recent
studies have implicated several other platelet membrane glycoproteins
(GPIa/IIa, GPIV, CD9) as targets.  Patients with systemic lupus
erythematosus and thrombocytopenia appear to recognize platelet
membrane glycoproteins.  It is important that the range of target
epitopes for which platelet autoantibodies are specific be defined and
that the relationship between target epitopes, platelet dysfunction,
and thrombocytopenia be characterized.

The choice of therapy for NATP is not clear and each therapy has its
own risks and benefits.  Transfusion of platelets lacking the
incompatible antigen, usually obtained from the mother, seems to be the
preferred treatment.  Transfusion of unmatched platelets from a random
donor may be helpful if matched platelets cannot be obtained.  IV gamma
globulin and steroids, alone or in combination with other modalities,
have also been utilized.  Platelet transfusion in utero for the
management of NATP has been described.  However, some clinicians
consider this to be an invasive and risky procedure.

Autoimmune neonatal thrombocytopenia is also caused by the passive
transfer of maternal antibody against platelets, but clinically the
disease appears to be less serious than NATP.  Moreover, all mothers
with ITP do not have thrombocytopenic babies.  Comparative studies on
the nature of the platelet antibodies in auto- and allo-immune neonatal
thrombocytopenias could yield important information on the etiology and
severity of these diseases.  An important difference in the management
of the two diseases is that, in the second case, the physician is
likely to be aware that the baby is at risk because of the mother's
ITP.  In some centers these pregnancies are considered for possible
cesarean section delivery, but recently more centers have recommended
avoiding surgery by using alternative management including fetal scalp
sampling or percutaneous umbilical blood sampling, steroids, IV gamma
globulin, anti-D infusions or combinations of these diagnostic and
therapeutic modalities.  The characterization of the antibodies
involved in NATP and PTP, certain drug-induced thrombocytopenias,
cyclical thrombocytopenia, and better assessment of the pathophysiology
of platelet destruction may lead to a more effective choice of therapy
for these patients.

True maternal ITP has been differentiated from "periparturient
thrombocytopenia" or "benign thrombocytopenia of pregnancy."  This
latter syndrome, reported in the past five years, is characterized by
a negative history for thrombocytopenia prior to pregnancy and the
incidental finding of mild thrombocytopenia (95,000/mm3).  Infants born
of these women are rarely, if ever, thrombocytopenic, leading to the
recommendation that these pregnancies may not require special
interventions such as operative delivery aimed at protecting a
potentially thrombocytopenic fetus.  It is not clear whether this
syndrome is actually a 'mild' form of ITP or a separate entity with a
different pathogenic mechanism.  The possibility of drug-induced
thrombocytopenia must also be considered in the differential diagnosis
of ITP and benign thrombocytopenia of pregnancy.

Examples of Research Areas

The following are examples of research areas, and prospective
applicants are urged to use their own ideas regarding the area of
research to be explored.

o  characterize the etiology and improve the diagnosis of autoimmune
thrombocytopenia in women, especially during pregnancy; develop
improved methods for differentiating autoimmune thrombocytopenia from
"incidental" thrombocytopenia in pregnant women and for assessing the
risk that an infant will be born thrombocytopenic and suffer
hemorrhagic complications.

o  increase knowledge of the prevalence and pathogenesis of neonatal
alloimmune thrombocytopenic purpura and develop improved methods for
diagnosis and treatment and for assessment of the risk of neonatal
thrombocytopenia and hemorrhagic complications.

o  better define the biochemical nature and clinical relevance of the
antigens and antiplatelet antibodies involved in immune
thrombocytopenia including immunoglobulin subclasses, cytotoxic
mechanisms, target antigens, epitope specificity, antigen frequency
amongst minority populations, and cross reactivity with endothelial and
other cells.

o  improved understanding of platelet production and clearance in women
and infants with thrombocytopenia and developmental aspects of allo-
and auto-antigen expression on fetal platelets and on megakaryocytic
precursors.

o  prevalence, pathogenesis, and treatment of other forms of
thrombocytopenia associated with pregnancy such as the thrombocytopenia
of preeclampsia and the HELLP syndrome (hemolysis, elevated liver
function tests, and low platelets).

Disciplines and Expertise

Among the disciplines and expertise that may be appropriate for this
program are hematology, immunology, biochemistry, cell biology,
medicine, and molecular biology.

Exclusions

Epidemiological studies and large-scale clinical trials are
specifically excluded from this RFA.

SPECIAL REQUIREMENTS

Upon initiation of the program, the NHLBI will sponsor annual meetings
to encourage and exchange of information among investigators who
participate in this program.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements will be required to include
minorities and women in study populations so that research findings can
be of benefit to all persons at risk of the disease, disorder or
condition under study; special emphasis should be placed on the need
for inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of the
study.  This information should be included in the form PHS 398 in
Section 2, A-D of the Research Plan AND summarized in Section 2, E,
Human Subjects.  Applicants/offerors are urged to assess carefully the
feasibility of including the broadest possible representation of
minority groups.  However, NIH recognizes that it may not be feasible
or appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority populations
(i.e., Native Americans (including American Indians or Alaskan
Natives), Asian/Pacific Islanders, Blacks, Hispanics).  The rationale
for studies on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, (and
preventive strategies), diagnosis, or treatment of diseases, disorders
or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the  results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and will be reflected in
assigning the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.

LETTER OF INTENT

The NHLBI requests that prospective applicants submit a letter of
intent that includes a descriptive title of the proposed research and
identification of any other participating institutions.  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 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 application.  This
letter of intent, is to be received by March 20, 1992, and is to be
sent to:

Dr. Charles L. Turbyfill
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 553
Bethesda, MD  20892
Telephone:  (301) 496-7351
FAX:  (301) 496-7033

APPLICATION PROCEDURES

Applications are to be submitted on the traditional research project
grant application form PHS 398 (rev. 9/91).  This form is available in
an applicant institution's office of sponsored research or business
office and from the Office of Grant Inquiries, Division of Research
Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449,
Bethesda, MD 20892, telephone: 301/496-7441.  Use the conventional
format for research project grant applications and ensure that the
points identified in the Section on Review Considerations are
fulfilled.

To identify the application as a response to this RFA, check "YES" on
Item 2 of page 1 of the application and enter the title and RFA Number:

"THROMBOCYTOPENIAS IN WOMEN AND NEONATES HL-92-06-B."

THE RFA LABEL (AVAILABLE IN APPLICATION FORM 398) MUST BE AFFIXED TO
THE BOTTOM OF THE FACE PAGE OF THE ORIGINAL COPY OF THE APPLICATION.
FAILURE TO USE THIS LABEL COULD RESULT IN DELAYED PROCESSING OF THE
APPLICATION.

In the preparation of the budget for the grant application, applicants
should REQUEST ADDITIONAL TRAVEL FUNDS for one meeting each year that
will be held in Bethesda, Maryland.  Applicants should also include a
statement in the applications indicating their willingness to
participate in such meetings.

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

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

SEND AN ADDITIONAL TWO COPIES OF THE APPLICATION TO DR. CHARLES
TURBYFILL AT THE ADDRESS LISTED UNDER LETTER OF INTENT.  IT IS
IMPORTANT TO SEND THESE TWO COPIES AT THE SAME TIME AS THE ORIGINAL AND
FOUR 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 May 7, 1992.  An application not
received by this date will be returned to the applicant.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for responsiveness to the
objectives of this RFA.  If an application is judged unresponsive, the
applicant will be contacted to withdraw the application or have it
submitted as an unsolicited grant application for the next review
cycle.  If the application submitted in response to this RFA is
substantially similar to a grant application already submitted to the
NIH for review, but has not yet been reviewed, the applicant will be
asked to withdraw either the pending application or the new one.
Simultaneous submission of identical applications will not be allowed,
nor will essentially identical applications be reviewed by different
review committees.  Therefore, an application cannot be submitted in
response to this RFA that is essentially identical to one that has
already been 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.

Applications judged to be responsive will be reviewed for scientific
and technical merit by an initial review group, that will be convened
by the Division of Extramural Affairs, NHLBI, solely to review these
applications.

This initial review will include a preliminary evaluation to determine
scientific merit relative to the other applications received in
response to the RFA (triage).  The NHLBI will withdraw from further
consideration applications judged to be noncompetitive and promptly
notify the Principal Investigator/program director and the official
signing for the applicant organization.  Those applications judged to
be competitive will be further evaluated for scientific/technical merit
by the usual peer review procedures, including, if deemed appropriate,
a reverse site visit at the applicant's expense.

Review Criteria:  The factors to be considered in the evaluation of
scientific merit of each application will be those used in the review
of traditional research-project grant applications:  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; and the
appropriateness of the requested budget to the work proposed.

The second level review will be by the National Heart, Lung, and Blood
Advisory Council.

AWARD CRITERIA

The anticipated date of award is September, 1992.

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.

INQUIRIES

Inquiries regarding this RFA may be directed 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) 402-1622

For fiscal and administrative matters, contact:

Ms. Jane R. Davis
Chief, Blood Division Grants Management Section
Divison of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A11
Bethesda, MD  20892
Telephone:  (301) 496-7257
FAX:  (301) 402-1200

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 grants
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.

.

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