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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