Full Text HL-95-007 THROMBOTIC THROMBOCYTOPENIC PURPURA AND HIV NIH GUIDE, Volume 23, Number 36, October 14, 1994 RFA: HL-95-007 P.T. 34 Keywords: Blood Diseases AIDS Pathogenesis National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: December 16, 1994 Application Receipt Date: February 16, 1995 PURPOSE 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. 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 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). 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. Applications from minority individuals and women are encouraged. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. MECHANISM OF SUPPORT 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. FUNDS AVAILABLE 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. RESEARCH OBJECTIVES 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 vitro. 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 persons 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 TTP 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 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. 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 meetings. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 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. LETTER OF INTENT 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 APPLICATION PROCEDURES 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 REVIEW CONSIDERATIONS are fulfilled. 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. REVIEW CONSIDERATIONS 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. AWARD CRITERIA 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 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 AUTHORITY AND REGULATIONS 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 people. .
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