# Role of myeloid KLF2 in antiphospholipid antibody-mediated thrombosis

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $466,929

## Abstract

Project Summary:
The Antiphospholipid Antibody Syndrome (APS) is characterized by recurrent arterial and venous thrombosis
in small and large vessels accompanied by persistently positive antiphospholipid antibody tests. This condition
often affects young patients (particularly women of child-bearing age) and is associated with significant
morbidity and mortality. Classically, studies of thrombosis have focused largely on platelets (arterial clots), red
blood cells (venous clots) and the coagulation factors. However a growing body of data gathering over the past
decade supports an intimate link between inflammation and thrombosis such that inflammation begets
thrombosis and thrombosis amplifies the inflammatory response. Specifically, neutrophil activation and
generation of neutrophil extracellular traps (NETs) have been shown to contribute to thrombosis in the setting
of antiphospholipid antibodies. Further, NETs prime macrophages for inflammasome activation and release of
cytokines and tissue factor implicating cross talk between members of the myeloid system to generate a
proinflammatory and prothrombotic milieu. Presently, thrombosis risk is managed with lifelong anticoagulant
therapy that is only modestly effective and associated with a high risk of bleeding, suggesting that alternate or
novel approaches are necessary. These observations fuel the momentum for the view that therapies targeting
the myeloid lineage may have potential impact on both arterial and venous thrombosis. However, the
molecular mechanisms underlying myeloid cell activation in orchestrating this thrombo-inflammatory response
is poorly understood.
 Our observations (both published and nascent) establish transcription factor KLF2 as a potent tonic
repressor of myeloid cell activation and inflammation as well as an essential determinant of both arterial and
venous thrombosis. Mechanistically, KLF2 is found to regulate two conserved ancient programs — generation
of neutrophil extracellular traps (NETs) and activation of the inflammasome. Specific to this proposal, we find
that (i) APLA infusion increases both arterial and venous thrombosis in mice; (ii) APLA treatment leads to
decreased KLF2 expression and inflammasome activation of macrophages and increased NET generation in
neutrophils; (iii) myeloid-specific overexpression of KLF2 offers thromboprotection in the presence of APLA.
Finally, the therapeutic potential of targeting KLF2 is revealed by our discovery that the anti-cancer agent
bortezomib (BZ), at low non-toxic doses, induces myeloid KLF2 and confers potent anti-thrombotic effects
(without altering hemostasis) in both arterial and venous beds that are KLF2-dependent. These observations
provide the foundation for the central hypothesis that myeloid KLF2 is a central determinant of
vascular thrombosis in APS that can be targeted for therapeutic gain. To explore this hypothesis, the
following aims are proposed: (1) To investigate the effect of altering myeloid KLF2 o...

## Key facts

- **NIH application ID:** 10213122
- **Project number:** 5R01HL142647-04
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Lalitha Nayak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $466,929
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213122

## Citation

> US National Institutes of Health, RePORTER application 10213122, Role of myeloid KLF2 in antiphospholipid antibody-mediated thrombosis (5R01HL142647-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10213122. Licensed CC0.

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