# An integrated computational and experimental approach to understanding the hemostatic response during treatment of bleeding

> **NIH NIH R01** · COLORADO SCHOOL OF MINES · 2020 · $735,695

## Abstract

Individuals with hemophilia or taking anticoagulants are at risk for bleeding, but where they bleed is different.
Understanding how these two types of perturbations to the hemostatic system interact in distinct vascular beds
(VBs) will inform decisions about bleeding treatment. Bleeding is treated using prohemostatic agents, but
individual responses to these agents are highly variable and the mechanisms underlying the variability are
unknown. Hemostasis is a nonlinear process involving complex coagulation biochemistry coupled to platelet
function, VBs, and biophysical mechanisms including blood flow; it is well suited for study with an integrated
computational and experimental approach. The long-term goal of this research is to develop mathematical
models that improve the treatment of bleeding. The overall objective is to develop and validate mathematical
models of bleeding that will identify mechanisms underlying variable responses to prohemostatics and in
different VBs. The central hypothesis is that global sensitivity analysis (GSA) applied to mechanistic
mathematical models of bleeding will elucidate synergies and/or cooperation among platelet, vascular, and
plasma components and predict experimentally-verified hemostatic responses. This hypothesis is based on
preliminary data produced using exactly this approach in the applicants’ laboratories. The rationale is that the
proposed quantitative methods and the identification of modifiers of the hemostatic response will together
provide a foundation for developing assays that test for specific and previously unidentified biomarkers. Guided
by strong preliminary data, this hypothesis will be tested in three specific aims: 1) Develop and refine
mathematical models of hemostasis, 2) Determine the mechanistic link between bleeding site and bleeding
cause, and 3) Identify modifiers of hemostasis that regulate responses to prohemostatics in hemophilia A. In
Aim 1, existing models will be extended to include essential features of platelet and fibrin dynamics and
validated with microfluidic assays. In Aim 2, submodels of anticoagulants will be developed and incorporated
into the hemostasis models. Experimental measurements of VB characteristics will be acquired. GSA will
identify the causes of VB site-specific variability in the hemostatic response. In Aim 3, submodels of
prohemostatics will be developed and incorporated into the hemostasis models. GSA will identify the causes of
variability in responses to them during treatment of hemophilia A. The approach is innovative because (1) the
mathematical models and experimental assays will be developed in tandem to iteratively and optimally inform
one another, and (2) novel submodels of anticoagulants and prohemostatics will be added to a comprehensive
model of the hemostatic system that includes platelet, fibrin, and VB dynamics coupled to coagulation and flow.
The proposed research is significant because it is expected to (1) provide mechanistic explanati...

## Key facts

- **NIH application ID:** 9946263
- **Project number:** 1R01HL151984-01
- **Recipient organization:** COLORADO SCHOOL OF MINES
- **Principal Investigator:** AARON L FOGELSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $735,695
- **Award type:** 1
- **Project period:** 2020-04-10 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9946263

## Citation

> US National Institutes of Health, RePORTER application 9946263, An integrated computational and experimental approach to understanding the hemostatic response during treatment of bleeding (1R01HL151984-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9946263. Licensed CC0.

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