# The Monocyte/Macrophage Role in Experimental Deep Vein Thrombosis Resolution and Vein Wall Injury

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $577,399

## Abstract

ABSTRACT
Post-thrombotic syndrome (PTS) is the most common sequelae from deep vein thrombosis (DVT),
characterized by vein wall fibrosis, valve destruction, and often occlusion. It is estimated to occur in ~40 –
50% of those suffering a DVT. No direct medical therapy exists to treat PTS, highlighted by the recent failure
of graded compression stockings to prevent PTS (SOX trial). The ATTRACT trial suggested that even those
patients treated with thrombolysis still have a ~40% incident PTS at 2 years, and invasive pharmaco-
mechanical thrombus removal did not improve outcomes. Significant bleeding risks remain even with the new
non-vitamin-K antagonists. Monocyte/macrophages (Mo/MΦ) are the primary leukocyte directing two key
pathobiologic processes: venous thrombosis resolution and the associated vein wall fibrotic injury. Mo/MΦ are
classified by their inflammatory or anti-inflammatory functions, which is a dynamic process in vivo. For
example, interleukin-1 (IL-1), IL-12 secreting and cell surface Ly6Chi, CCR2++, CX3CR1+ antigen expression
characterizes classically activated, or pro-inflammatory Mo/MΦ. Conversely, IL-10 secreting, transcription
factor Nr4a1 dependent, and cell surface Ly6Clo, CCR2-, CX3CR1++ antigen expression characterizes
alternatively activated Mo/MΦ with pro-healing and inflammation resolving activities. From published and
preliminary data, pro-inflammatory Ly6Chi Mo/MΦ are involved with early VT, followed by a later transition to
Ly6Clo. We show that in a stasis murine model of VT that a pro-inflammatory cytokine milieu exists, that early
LyC6hi Mo/MΦ changes over to a LyC6lo content, and that Ly6Clo Mo/MΦ may drive both VT resolution as well
as vein wall fibrotic injury. However, the mechanism of Mo/MΦ actions in VT resolution and vein wall injury, as
well as whether this is thrombogenic model, sex and age dependent is not known. Our overall hypothesis is
that VT resolution and vein wall fibrotic injury is dependent on Mo/MΦ actions, is dependent on model, age,
and sex, and can be ameliorated with increasing Ly6Clo Mo/MΦ in the thrombosed vein. We will address this
hypothesis by three specific aims. Specific Aim 1: To define the local environmental and cellular factors that
drive Ly6Chi and Ly6Clo Mo/MΦ phenotypes in the thrombosed vein, with sex, age, and thrombogenic model
variation. Specific Aim 2: To directly determine the Mo/MΦ mediated mechanisms of VT resolution and vein
wall injury. Specific Aim 3: To determine if targeted Mo/MΦ polarization within the thrombus environment can
promote VT resolution and vein wall healing. Murine models of VT, with variations of age and sex, Mo/MΦ
conditional deleted and transgenic mice and molecular, immunological, and in vivo imaging will be used to
accomplish these aims. The proposed experiments herein will significantly move the field forward by defining
the mechanisms of Mo/MΦ mediated actions in VT resolution and vein wall injury, and will test novel
assessments and agents to in...

## Key facts

- **NIH application ID:** 9883290
- **Project number:** 1R01HL144550-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** PETER K HENKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $577,399
- **Award type:** 1
- **Project period:** 2020-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9883290

## Citation

> US National Institutes of Health, RePORTER application 9883290, The Monocyte/Macrophage Role in Experimental Deep Vein Thrombosis Resolution and Vein Wall Injury (1R01HL144550-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9883290. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*