ANTIPHOSPHOLIPID ANTIBODY AND LUPUS ANTICOAGULANT

NIH GUIDE, Volume 21, Number 5, February 7, 1992



PA NUMBER:  PA-92-39



P.T. 34



Keywords:

  Autoimmunity 

  Immunology 

  Disease Model 

  Pathophysiology 



National Institute of Arthritis and Musculoskeletal and Skin Diseases

National Heart, Lung, and Blood Institute



PURPOSE



The Arthritis Research Program of the National Institute of Arthritis

and Musculoskeletal and Skin Diseases (NIAMS) supports research on the

autoantibodies found in patients with systemic lupus erythematosus.

The Thrombosis and Hemostasis Branch of the National Heart, Lung, and

Blood Institute (NHLBI) supports research on hypercoagulability and

thrombosis.  The NIAMS and the NHLBI, through this program

announcement, encourage the submission of grant applications for basic

and clinical research related to antiphospholipid antibody and the

lupus anticoagulant.



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 program

announcement, Biology of Autoimmune Antiphospholipid Antibody and Lupus

Anticoagulant, is related to the priority areas of health promotion:

maternal and infant health and heart disease and stroke.  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

202-783-3238).



ELIGIBILITY REQUIREMENTS



Applications may be submitted by foreign and domestic, 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.  Applications from

minority individuals and women are encouraged.  Foreign institutions

are not eligible for the K awards.



MECHANISM OF SUPPORT



Investigators may apply for research project grants (R01), First

Independent Research Support and Transition (FIRST) awards, (R29), and

career development (K04, K08, K11) awards.



RESEARCH OBJECTIVES



Background



Autoimmune antiphospholipid antibody and lupus anticoagulant, two

closely related antibodies, are associated with a clinical syndrome

consisting of recurrent thromboocclusive disease, livedo reticularis,

and repeated in utero fetal deaths.  Many persons with this antibody do

not have systemic lupus erythematosus and some are apparently well.

Among persons with clinical illness attributable to antiphospholipid

antibody, there is considerable heterogeneity of symptoms and of

antibody characteristics.  The mechanisms by which clinical events

occur are unknown.  A serum cofactor, apolipoprotein H, is generally

required for the binding of autoimmune antibody to phospholipid in the

most commonly used solid phase assay, but precise knowledge concerning

the physical nature of the antigen and the relevance of the cofactor in

antibody binding is still lacking.  Animal models for the antibody and

for the syndrome do not currently exist.  Although anticoagulation with

drugs, such as aspirin or warfarin, are frequently used for treatment,

there is as yet no uniform regimen for all clinical conditions

associated with the antibodies and no definitive clinical trials have

yet been conducted.



On September 25, 1991, the NIAMS and the NHLBI co-sponsored an

Antiphospholipid Antibody/Lupus Anticoagulant Workshop.  This Workshop

identified research issues that form the basis of this program

announcement.  These issues include:  the nature of the relationship

between antiphospholipid antibody and lupus anticoagulant; the roles of

apolipoprotein H and of other phospholipid binding proteins in antibody

binding and in clinical illness; the chemical or structural nature of

the antigen or epitope; the (presumably) exogenous trigger for

induction and maintenance of antiphospholipid antibody in patients; the

reasons for patient heterogeneity; and the construction of animal

models.  Treatments for the various clinical manifestations of the

syndrome comprise an additional question.



Research Goals and Scope



The primary goal of this program announcement is to foster research

that enhances knowledge about mechanisms of action of antiphospholipid

antibody.  This goal includes, but is not limited to, studies that

integrate multidisciplinary approaches.



The scope of possible research areas includes, but is not limited to,

the following topics:



o  Studies of phospholipid structure relevant to antigenicity;



o  Studies of the interaction of phospholipid-binding proteins,

including annexins and antiphospholipid antibodies, with phospholipids;



o  Studies of the induction and/or maintenance of antiphospholipid

antibody;



o  Studies defining the differences and/or similarities between

antiphospholipid antibody and lupus anticoagulant;



o  Elucidation of the mechanisms by which lupus anticoagulants and

phospholipid antibodies promote hypercoagulability and thromboembolic

events;



o  Studies of the pathophysiology of fetal death associated with

antiphospholipid antibodies;



o  Animal models;



o  Clinical studies, including differences and/or similarities between

patients with systemic lupus erythematosus and those with primary

antiphospholipid antibody syndrome;



o  Treatment trials.



Investigators are encouraged to use the full range of current

disciplines and techniques available to them.



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 are 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 must 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 must 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 must 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 must be provided.



For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, epidemiology, prevention

(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 review will be deferred until the information is provided.



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.



APPLICATION PROCEDURES



Applicants from institutions that have a General Clinical Research

Center (GCRC) funded by the NIH National Center for Research Resources

may want 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 must be included with the

application.



Applications are to be submitted on the grant application form PHS 398

(rev. 10/88) (applications submitted after May 1 are to use the PHS 398

(rev 9/91)) and will be accepted at the standard application deadlines

as indicated in the application kit.



Application kits are available at most institutional business offices

and may be obtained from the Office of Grants Inquiries, Division of

Research Grants, Westwood Building, Room 449, National Institutes of

Health, Bethesda, MD 20892, telephone 301/496-7441.  The title and

number of the announcement must be typed in Section 2 on the face page

of the application.



The completed original application and six legible copies must be sent

or delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



REVIEW PROCEDURES



Applications will be assigned on the basis of established Public Health

Service referral guidelines.  R01 and R29 applications will be reviewed

for scientific and technical merit by study sections of the Division of

Research Grants, NIH.  Initial review of applications for the K series

will be by the review group of the relevant Institute or Center in

accordance with the standard NIH peer review procedures.  Following

scientific/ technical review, the applications will receive a

second-level review by the appropriate national advisory council.



AWARD CRITERIA



Applications will compete for available funds with all other approved

applications assigned to that ICD.  The following will be considered

making funding decisions:



o  Quality of the proposed project as determined by peer review

o  Availability of funds

o  Program balance among research areas of the announcement.



INQUIRIES



Written and telephone inquiries are encouraged.  The opportunity

to clarify any issues or questions from potential applicants is

welcome.



Direct inquiries regarding programmatic issues to:



Lawrence Petrucelli, Ph.D.

Arthritis Program Director

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Westwood Building, Room 406

Bethesda, MD  20892

Telephone:  (301) 496-7326



or



Carol H. Letendre, Ph.D.

Acting Chief, Thrombosis and Hemostasis Branch

Division of Blood Diseases and Resources

National Heart, Lung and Blood Institute

Federal Building, Room 516

Bethesda, MD  20892

Telephone:  (301) 496-8966



Direct inquiries regarding fiscal matters to:



Diane M. Watson

Grants Management Officer

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Westwood Building, Room 407-A

Bethesda, MD  20892

Telephone:  (301) 496-7495



or



Jane R. Davis

Section Chief, Blood Diseases and Resources

National Heart, Lung and Blood Institute

Westwood Building, Room 4A15C

Bethesda, MD  20892

Telephone:  (301) 496-7257



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic Assistance

Numbers 93.846, Arthritis, Musculoskeletal and Skin Diseases Research

and 93.839, Blood Diseases and Resources Research.  Awards are made

under authorization of the Public Health Service Act, Title IV, Part A

(Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and

285) and administered under PHS grants policies and Federal Regulations

42 CFR 52 and 45 CFR Part 74.  This program is not subject to the

intergovernmental review requirements of Executive Order 12372 or

Health Systems Agency review.



.

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