Systemic coagulation parameters in mice after treatment with vascular targeting agents
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Published on: September 30, 2021
Maike Unruh1, Andrea Grunow, Claudia Gottstein
1Department of Internal Medicine I/Experimental Oncology and Vascular Biology, University Hospital Cologne, Joseph-Stelzmann-Strasse, 50924 Cologne, Germany. m_unruh@gmx.de
Background:
Vascular targeting of malignant tumors has become a clinically validated new treatment approach with clear patient benefit. However clinical studies have also revealed that some types of vascular targeting agents (VTAs) are prone to coagulation system side effects. It is therefore essential to predetermine coagulation parameters in preclinical studies. As of to date, this has rarely been done, predominantly due to technical issues. The goal of this study was to establish and apply a standardized process, whereby systemic coagulation activation can be routinely measured in mice.
Results:
We have evaluated a number of sampling techniques and coagulation tests regarding their suitability for this purpose. We were able to adapt two assays measuring soluble fibrin, a marker for a prethrombotic status. Thus, soluble fibrin could be measured for the first time in mice. All assays were validated in a positive control model for systemic coagulation activation, i.e. lipopolysaccharide-induced endotoxemia. Based on our results, we selected a panel of coagulation tests, which are both feasable and informative for preclinical testing of VTAs: soluble fibrin, thrombin-antithrombin complexes, free antithrombin III, white blood cell counts and platelet counts. The effect of tumor transplants on coagulation parameters was evaluated using this panel. We then applied this set of assays in treatment studies with a VTA developed in our laboratory to investigate a potential systemic coagulation activation.
Conclusion:
We have established a standardized panel of assays that can be used to test murine blood samples for coagulation activation in preclinical studies. All tests are feasible to perform in any research laboratory without specialized equipment. In addition, this is the first report to measure soluble fibrin, an early marker of systemic coagulation activation, in mice. The panel was applied on tumor bearing mice and mice treated with a VTA. We suggest its general application for coagulation activation analyses in mice.
Insights
This study establishes a standardized method for measuring blood clotting activation in mice, crucial for evaluating new cancer therapies. The new assay panel, including soluble fibrin measurement, aids in preclinical safety assessments of vascular targeting agents.
Area of Science:
- Biomedical Research
- Oncology
- Hematology
Background:
- Vascular targeting agents (VTAs) offer clinical benefits for malignant tumors but can cause coagulation side effects.
- Preclinical assessment of coagulation parameters is essential for VTA safety but technically challenging.
- A standardized method for measuring systemic coagulation activation in mice is needed.
Purpose of the Study:
- To establish and validate a standardized panel of coagulation assays for routine measurement in mice.
- To enable reliable preclinical assessment of coagulation activation induced by VTAs.
- To investigate the impact of tumor burden and VTA treatment on coagulation.
Main Methods:
- Evaluation of various sampling techniques and coagulation assays for suitability in mice.
- Adaptation and validation of assays for soluble fibrin, a marker of prethrombotic status.
- Selection and application of a panel including soluble fibrin, thrombin-antithrombin complexes, free antithrombin III, white blood cell, and platelet counts.
Main Results:
- Successfully adapted and validated assays for measuring soluble fibrin in mice for the first time.
- Identified a feasible and informative panel of coagulation tests for preclinical VTA evaluation.
- Demonstrated the application of the panel in tumor-bearing mice and in studies with a VTA.
Conclusions:
- A standardized, feasible assay panel for murine coagulation activation analysis has been established.
- This panel facilitates routine preclinical safety testing of VTAs.
- The ability to measure soluble fibrin in mice represents a significant advancement in assessing coagulation activation.
