Full Text HL-95-010 COAGULATION, PLATELETS AND THROMBOSIS IN SICKLE DISEASE PATHOPHYSIOLOGY NIH GUIDE, Volume 23, Number 36, October 14, 1994 RFA: HL-95-010 National Heart, Lung, and Blood Institute P.T. 34 Keywords: Blood Diseases Cardiovascular Diseases Pathogenesis Letter of Intent Receipt Date: December 20, 1994 Application Receipt Date: January 24, 1995 PURPOSE The Division of Blood Diseases and Resources (DBDR) of the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), invites research grant applications to support basic research on the role of hemostasis and thrombosis in the pathophysiology of sickle cell disease vasculopathy. 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), Coagulation, Platelets and Thrombosis in Sickle Cell Disease Pathophysiology, is related to the priority areas of clinical prevention services, chronic disabling conditions, and maternal and infant health. The goal of this program is basic research leading to approaches that ameliorate the long term debilitating effects of this disease. 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 (R29) awards. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) individual research project grant (R01) and FIRST award (R29) 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 46 months of support may be requested for R01 applications, but 58 months of support must be requested for R29 applications. 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 July 1, 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, $1,500,000 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. It is anticipated that about six new grants will be awarded under this program. The specific number 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 (telephone: (301) 594-7436) should be consulted regarding procedures to be followed. RESEARCH OBJECTIVES Vascular occlusive events account for much of the morbidity and mortality associated with sickle cell disease. Despite significant advances in clinical observation and experimental investigation, however, the pathogenesis of these vaso- occlusive events remains ill-defined and the subject of much speculation. Factors contributory to the initiation of vaso-occlusion may include rheological abnormalities related to sickling, abnormal adhesiveness of sickle red cells to endothelium, dehydration and poor deformability of sickle red cells, various vascular factors, and activation of hemostatic systems. Despite various observations that are consistent with a pathogenetic role for hemostasis and thrombosis in sickle vaso-occlusive events, the incompleteness of existing data leaves important but unanswered hypotheses regarding this neglected area of sickle disease pathophysiology. Further understanding of the role of thrombosis and/or hemostatic activation in sickle cell disease pathophysiology is likely to facilitate the rational design of therapeutic trials and approaches and to thereby improve clinical care of affected individuals. Clinical Involvement Cerebrovascular disease contributes significant morbidity in up to 17 percent of patients with sickle cell anemia, with stroke resulting from thrombosis usually developing at sites of underlying intimal hyperplasia. Suggestive, albeit inconclusive, evidence suggests that thrombosis may contribute to the acute chest syndrome and pulmonary hypertension in sickle cell disease. Whether this disease includes an increased risk for venous thrombosis and thromboembolism has not been resolved. The possibility that thrombosis and/or hemostatic activation contributes to other manifestations such as the acute painful vaso-occlusive crisis has not been excluded. Limited trials have failed to find benefit in prophylactic aspirin, although this approach could leave thrombin-induced platelet activation unimpeded. Very small trials have claimed lack of benefit from warfarin therapy but discernible benefit from long-term subcutaneous heparin. There have been no studies of antiplatelet or anticoagulant agents in the primary or secondary prevention of stroke in sickle cell disease, nor has the efficacy of thrombolytic agents been tested. Pathophysiology Insofar as thrombotic complications occur in sickle cell disease, they may be uniquely widespread in their anatomical distribution, with abnormal clotting occurring in the venous (e.g., thrombosis with pulmonary embolus), arterial (e.g., stroke), and microvascular (e.g., painful vaso-occlusive crisis) circulations. Such heterogeneity of clinical phenomena is distinctly unusual (i.e., in inherited hypercoagulable states such as protein S or C deficiency) and conceivably could derive from participation of multiple hemostatic disturbances. Virchow's triad (altered blood flow, disturbed vascular integrity, and alterations in the blood) encompasses our understanding of the pathogenesis of thrombosis, irrespective of the anatomical vascular bed in question. Therefore, it is reasonable to consider the potential role of hemostasis and thrombosis in sickle cell disease in terms of the components of Virchow's triad. Blood flow augments mass transport of blood borne elements beyond that resulting from diffusion alone and may thereby influence the thrombotic process. In a normal laminar flow situation, the effective concentration of platelets is increased several fold towards the periphery of a normal vessel. This cellular distribution is a function of both red cell concentration and wall shear rate. Flow models have been employed to study a combination of normal red blood cells and platelets, but nothing is known about sickle erythrocytes and their interaction with platelets in such models. The complex interplay of abnormalities in erythrocyte deformability, membrane characteristics, vascular factors (e.g., flow rate, vessel diameter and reactivity, and so on), and tendency to adhere to the vascular endothelium has not been directly studied in the context of the genesis of thrombosis. The disturbance in normal laminar blood flow in sickle vessels might directly influence endothelial cell function; for example, it has been previously demonstrated that shear stresses regulate the synthesis and expression of prostacyclin, tissue plasminogen activator, and von Willerbrand factor by endothelial cells. Studies have also shown that platelets exposed to physiological shear forces ex vivo (in viscometers) aggregate without the addition of exogenous agonists, a phenomenon not seen in standard platelet aggregation assays. Further studies specifically examining shear stresses in interrelationships between sickle red cells, platelets, endothelial cells, and coagulation factors may enhance our understanding of this disease. Normal vascular endothelium plays an important role in resisting thrombosis. It is likely that endothelial cell dysfunction (and possibly denudation) contributes significantly to the thrombotic manifestations of sickle cell disease. Increased numbers of circulating endothelial cells have been observed during crisis, and elevated levels of prostacyclin metabolites have been variably observed in sickle plasmas, possibly suggesting that endothelial injury occurs in vivo. Vascular intimal hyperplasia of large cerebral arteries, sometimes with superimposed thrombosis, is thought to be the most frequent cause of stroke in sickle cell disease. It is now possible with a combination of magnetic resonance imaging and angiography to demonstrate the presence of vascular intimal lesions in the cerebral vascular circulation of children with sickle cell disease. In order to extend our knowledge of the role of altered vascular integrity in some of the other complications of sickle cell disease, further histopathological and clinical-pathological data are necessary to define the frequency and significance of intimal hyperplasia in other vascular beds. This in turn raises the question of the pathogenesis of this vascular lesion and whether it may derive from endothelial injury caused by adherent sickle erythrocytes or molestation of the endothelium by pathologic or biologic modifiers that impact upon its anticoagulant/procoagulant balance. For example, elevated levels of tumor necrosis factor, IL1 and endotoxin have been noted in sickle plasmas, although the temporal relationship of such changes to clinical or vascular events is undefined. The state of endothelial activation or integrity, either in general or in relationship to specific clinical events, is wholly undefined in sickle cell disease. Numerous clinical studies have documented that the coagulation system is in a state of activation in "steady state" sickle disease as well as during painful crisis. In particular it seems clear that ongoing thrombin generation and fibrinolysis occurs in these patients (e.g., as evidenced by increased prothrombin F 1.2 fragment, fibrinopeptide A, thrombin/antithrombin complexes, and D-dimer), even in steady state; whether this change is in relationship to acute vaso-occlusive crisis is less clear. D-dimer levels are reported to be commonly elevated in sickle patients with leg ulcers, aseptic necrosis, or stroke. Diminished levels of anti-thrombotic substances (proteins S and C and antithrombin III) are often observed in sickle patients. Since plasmatic coagulation is initiated by tissue factor in vivo, it is significant that recent observation of accelerated Factor VII turnover has provided indirect evidence for abnormal tissue factor expression in sickle disease patients. Direct demonstration of tissue factor expression, verification of its location (e.g., monocytes versus endothelium), and identification of stimulants underlying its apparent expression in sickle cell disease have not been attempted. The extent to which hemostatic changes are contributed to in vivo by abnormality of the sickle cell membrane (in which negatively charged phospholipids are available to enhance coagulation reactions) or the circulating red cell membrane spicular fragments in sickle plasma is essentially unknown. Other studies have provided suggestive evidence for platelet activation (e.g., elevated plasma -thromboglobulin, decreased platelet thrombospondin, and preliminary observation of abnormal expression of platelet activation antigens) even in steady state sickle patients, but unambiguous proof of this using modern, optimal platelet collection methodology has not been provided. The precise reason for apparent platelet activation in these patients has not been established, nor have the circumstances of its occurrence. In particular, the degree to which platelet abnormalities change relative to specific clinical events is not defined, nor is the relationship, if any, between platelet activation and thrombin generation. The recent demonstration that platelet-derived thrombospondin could be a major factor in adhesion of sickle red cells to endothelium identifies one potential link between the hemostatic systems and vascular occlusion in this disease. The extent to which platelet release products impact upon the endothelium and vessel wall in sickle disease has not been defined. This RFA is intended to stimulate research on the role of hemostasis and thrombosis in the pathophysiology of sickle cell disease. Examples of research areas that would be responsive to this RFA are given below. This list is intended to provide guidance as to areas suitable for study; it is not intended to be all inclusive. Investigators are encouraged to consider other topics relevant to this program. o Investigation of endothelial function/dysfunction as it pertains to the anticoagulant/procoagulant balance of the endothelial surface in sickle patients. What is the state of endothelial activation in sickle cell patients? Does endothelial dysfunction contribute to the coagulopathy and vasculopathy of sickle cell disease? Do other known factors peculiar to sickle disease (e.g., red cell adhesivity, elevation of certain acute phase reactants) impact upon endothelial cell hemostatic function? o Investigation of the reason(s) for coagulation abnormalities in sickle cell disease. What causes apparent activation of tissue factor? Where and under what circumstances is it expressed? Does the abnormal sickle red cell membrane or the presence of circulating spicular fragments contribute to in vivo hemostatic abnormalities? What explains apparent deficiencies of antithrombotic proteins in these patients? o Investigation of the extent to which hemostatic abnormalities contribute to sickle vascular disease. What vascular events do (and which do not) involve hemostatic abnormalities in their primary pathogenesis? For which events does hemostatic activation and/or thrombosis play an important secondary role? Does coagulopathy in sickle disease precede or follow vasculopathy? o Investigation of platelet physiology in sickle cell disease. What is the extent of platelet activation in sickle patients? Under what circumstances does it occur, and what triggers it? Is there any relationship between platelet activation and specific vascular events? o Investigation of the biochemical distinction (or similarity) between acute painful crisis and inter-critical periods. Does the "steady-state" really exist vis a vis hemostatic systems? What are the precise hemostatic differences between apparent steady state and acute painful crisis? Do any hemostatic abnormalities play a different role in vaso- occlusive events other than the acute painful episode? Can detailed longitudinal studies of hemostatic systems elucidate cause from effect, risk factor from primary trigger, acute from chronic? o Can pharmacologic manipulation of hemostasis impact favorably upon any vaso-occlusive manifestations of sickle cell disease? The primary intent of this RFA is to solicit basic rather than clinical studies. However, in recognition of the fact that the long term goal of such work is to develop successful therapeutic approaches, inclusion of some clinical investigation as a necessary and integral part of a basic scientific program would be considered to be responsive to this RFA. 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 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 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 20, 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: Chief, Review Branch 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 an applicant institution's office of sponsored research and 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. FIRST applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST applications submitted without the required number of references will be considered incomplete and will be returned without 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. 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: COAGULATION IN SICKLE CELL DISEASE RFA HL-95-010. 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. 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: 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 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 January 24, 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 determine 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 (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 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. Applications should be prepared so that they can be reviewed without the necessity of interaction between the applicants and the reviewers, since no site visit or reverse site visit will be part of the technical 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 The anticipated date of award is July 1, 1995. 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. In order to more evenly distribute administrative workload and reduce the number of awards with July 1 or September 30 start dates, the NHLBI will award ten months of time and money for the first competing budget period of this project. This action results in a project period of 46 months rather than 48 months. Investigators should plan their research projects and budgets within these timeframes. 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 concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. Junius G. Adams, III Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute Federal Building, Room 508 7550 Wisconsin Avenue MSC 9090 Bethesda, MD 20892-9090 Telephone: (301) 496-6931 FAX: (301) 402-4843 Internet: Junius_Adams@NIH.GOV For fiscal and administrative matters, contact: Ms. Jane R. Davis Blood Division Grants Management Section National Heart, Lung, and Blood Institute Westwood Building, Room 4A11 Bethesda, MD 20892 Telephone: (301) 594-7436 FAX: (301) 594-7492 Internet: Jane_Davis@NIH.GOV AUTHORITY AND REGUALTIONS 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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