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PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

Issued by

National Heart, Lung, and Blood Institute (NHLBI)

Purpose

This Notice of Special Interest (NOSI) aims to accelerate a comprehensive understanding of the mechanisms of COVID-19-Associated Coagulopathy (CAC) which are provoked by vascular endothelial cell injury, hyperimmune responses, and hypercoagulability at genomic, molecular, and cellular levels.

Knowledge obtained from such studies may be applied to the future design of early diagnostics and effective treatment for high-risk patients as well as enable CAC research findings to be applied to on-going COVID-19 clinical trials.

Background

The incidence of thrombosis in COVID-19 ICU patients is estimated to be 20-30%. One of the most striking complications of COVID-19 is acute large vessel occlusion with ischemic stroke in patients under 50 years of age. Rates of venous thromboembolism (VTE) also appear markedly elevated (between 25-49%) in patients with severe COVID-19. These patients frequently exhibit a heavily prothrombotic state with elevated C-Reactive Protein, D-dimer, P-selectin and fibrin(ogen) levels, but, paradoxically, with little change in partial thromboplastin time, prothrombin time, or significant decline in platelet levels. This represents a unique pattern of biomarkers which distinguishes CAC from classical disseminated intravascular coagulopathy (DIC). The aforementioned lab findings in combination with an arterial and/or venous thromboembolic event in a patient with COVID-19 is known as CAC.

Presently, CAC is postulated to result from the interaction between damaged vascular endothelial layers, the immune response, and the coagulation system, resulting in dysregulation of the finely balanced procoagulant/fibrinolytic state. However, the mechanisms linking inflammation in COVID-19 patients to dysregulated hemostasis and thrombosis are yet to be delineated. Hypercoagulability may also be linked to confounding factors such as underlying comorbidities as well as sex and age of patients. Therefore, a better understanding of the pathogenesis of CAC at the genomic, molecular and cellular levels is needed to identify and diagnose patients at risk for CAC, to pinpoint potential therapeutic targets, and to mitigate sequelae of CAC events.

Research Objectives

This NOSI will support research that focuses on the basic mechanisms of COVID-19 associated thrombosis ranging from vascular endothelial cell injury, the host immune responses, to the coagulation and fibrinolysis systems. Identifying risk factors, or co-morbidities that predispose patients to CAC is also of interest.

The scientific objectives of this NOSI include:

• Filling the gaps in our current understanding of the pathophysiology underlying COVID-19-Associated Coagulopathy (CAC) at genomic, molecular and cellular levels
• Elucidating the mechanisms of CAC and its incitement by a hyperinflammatory and immunothrombotic response that is associated with vascular endothelial cell injury following viral entry
• Identifying risk factors predisposing patients to CAC in an effort to develop early diagnostics and more effective treatment for high-risk patients

Applicants are encouraged to establish collaborations among researchers with a multi-disciplinary background, such as cell biology, molecular biology, immunology, hematology, virology, systems biology, multi-omics, and data science.

Research areas of interest include, but are not limited to:

• What is the definition of CAC and distinguishing pathobiology of COVID-19 coagulopathies compared to other procoagulant conditions?
• What roles does CAC play in multi-organ failure?
• What mechanisms are responsible for vascular endothelial cell injury in COVID-19 patients that provoke CAC?
• What roles do the innate or adaptive immune response play in CAC?
• What factors or conditions disturb the hemostatic balance and trigger CAC?
• What roles do megakaryocytes, platelets, and endothelial glycocalyx perturbations play in the immune response and CAC?
• What genetic traits predispose some patients infected with SARS-CoV-2 to hypercoagulability?
• What other risk factors (e.g., age, sex, pregnancy, obesity, diabetes, etc.) predispose some patients with CAC to increased morbidity and mortality?
• What are the short-term and long-term complications of CAC? Is Post-Acute SARS-COV-2 infection (PASC) linked to CAC?
• Can animal models and/or organ-on-chip be developed to study CAC?

Applications aiming to study involvement of CAC in Post-Acute sequelae of SARS CoV-2 infections should consider applying to NOT-OD-22-038 Notice of Special Interest (NOSI): Availability of Administrative Supplements for Research on Pathobiological Mechanisms of Post-Acute Sequelae of SARS-CoV-2 Infection for FY2022.

Additional information regarding sex as a biologic variable can be found at https://orwh.od.nih.gov/

Application and Submission Information

This notice applies to due dates on or after June 5, 2022 and subsequent receipt dates through July 5, 2025. Applications proposing clinical trials are not appropriate for this NOSI, will be deemed nonresponsive and will not proceed to review.

Applications for this NOSI must be submitted using the following opportunity or its reissue:

• PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include NOT-HL-23-002 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will be withdrawn from consideration for this initiative.

Inquiries

Scientific/Research Contacts

Kyung Moon, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Division of Blood Diseases and Resources (DBDR)
Telephone: 301-435-0070
Email: [email protected]

Ronald Warren, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Division of Blood Diseases and Resources (DBDR)
Telephone: 301-435-0070
Email: [email protected]

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Anthony Agresti
National Heart, Lung, and Blood Institute
Telephone: 301-827-8014
Email: [email protected]