# Biomarkers for 12-lipoxygenase inhibition as a therapeutic intervention for heparin-induced thrombocytopenia and thrombosis (HIT/T)

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $208,600

## Abstract

The goal of this project is to develop highly sensitive and reproducible biomarkers for assessment of VLX-1005
treatment of heparin-induced thrombocytopenia and thrombosis (HIT/T). VLX-1005, a 12-LOX inhibitor that
potently inhibits immune-mediated thrombosis including HIT/T, has the potential to treat HIT/T in patients.
HIT/T is an acquired life-threatening thrombocytopenic and thrombotic complications that occur in patients
exposed to unfractionated heparin (UFH) or low molecular weight heparin (LMWH): the most widely used
anticoagulants in the world. Approximately 12 million patients are exposed to UFH and LMWH annually in the
US alone with ~24,000 developing HIT/T every year. HIT/T often results in aberrant platelet activation and
aggregation leading to a) platelet-derived microparticle release, b) increased thrombin generation leading to
catastrophic arterial and venous thrombosis that results in venous limb gangrene, c) deep venous thrombosis,
and d) pulmonary embolism and death. Current treatment of HIT/T is limited to argatroban (a direct thrombin
inhibitor). Unfortunately, this carries a significant risk of severe bleeding limited its effectiveness. Recent
evidence has established that the enzyme 12- lipoxygenase (12-LOX), and its metabolic product, 12-
hydroxyeicosatetraenoic acid (12-HETE) are key contributors to the underlying pathology of HIT/T including
promoting platelet reactivity, thrombus formation/stability as well as vessel occlusion. VLX-1005 selectively and
potently inhibits 12-LOX, halts aberrant platelet activation and thrombosis and has shown efficacy in numerous
animal models, including mesenteric arteriole injury and laser-induced cremaster arteriole thrombosis. While
the development of VLX-1005 for treatment of HIT/T is rapidly progressing, it will be important to have highly
sensitive biomarkers for assessment of VLX-1005 as it intervenes and prevents morbidity and mortality often
observed with the disease. To this end, we propose 2 Aims to address this concern for clinical trial readiness.
In Aim 1, several biomarkers for coagulation state and platelet activation will be assessed including the
thrombin-antithrombin (TAT) ELISA assay, 12-HETE assay, light transmission aggregometry (LTA), and whole
blood impedance aggregometry (WBIA) in mouse models of HIT/T. These biomarkers will serve as an indicator
of VLX-1005 effects on both coagulation and platelet activation. As VLX-1005 has not been shown to effect
coagulation or fibrin formation, we do not expect VLX-1005 to alter coagulation conditions in the patient,
however since a decreased platelet activation environment may result in decreased thrombin activation, these
biomarker will inform if VLX-1005 is altering upstream coagulation. Aim 2 will take the biomarker optimization
from Aim 1 and apply it to human blood samples ex vivo to determine the efficacy of the biomarkers to report
VLX-1005 effects in the blood. The biomarker assay profile is essential for the planne...

## Key facts

- **NIH application ID:** 10177358
- **Project number:** 1R21TR003185-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** MICHAEL Allan HOLINSTAT
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $208,600
- **Award type:** 1
- **Project period:** 2021-06-11 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10177358

## Citation

> US National Institutes of Health, RePORTER application 10177358, Biomarkers for 12-lipoxygenase inhibition as a therapeutic intervention for heparin-induced thrombocytopenia and thrombosis (HIT/T) (1R21TR003185-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10177358. Licensed CC0.

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