Thromb Haemost 2021; 121(04): 433-448
DOI: 10.1055/s-0040-1718414
Coagulation and Fibrinolysis

Chemical Modulators of Fibrinogen Production and Their Impact on Venous Thrombosis

Rui Vilar
1  Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, Geneva, Switzerland
,
Samuel W. Lukowski
1  Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, Geneva, Switzerland
2  Institute for Molecular Bioscience, The University of Queensland, Saint Lucia, Queensland, Australia
,
Marco Garieri
1  Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, Geneva, Switzerland
,
Corinne Di Sanza
1  Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, Geneva, Switzerland
,
Marguerite Neerman-Arbez
1  Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, Geneva, Switzerland
3  iGE3, Institute of Genetics and Genomics in Geneva, Geneva, Switzerland
,
Richard J. Fish
1  Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, Geneva, Switzerland
› Author Affiliations
Funding This study was supported by a Swiss National Science Foundation grant (#31003A_152633) to M. Neerman-Arbez and a Novartis Foundation for Medical-Biological Research grant to R.J. Fish. We thank the University of Geneva Faculty of Medicine Proteomics, Flow Cytometry and Bioimaging services for their technical assistance and advice.

Abstract

Thrombosis is a leading cause of morbidity and mortality. Fibrinogen, the soluble substrate for fibrin-based clotting, has a central role in haemostasis and thrombosis and its plasma concentration correlates with cardiovascular disease event risk and a prothrombotic state in experimental models. We aimed to identify chemical entities capable of changing fibrinogen production and test their impact on experimental thrombosis. A total of 1,280 bioactive compounds were screened for their ability to alter fibrinogen production by hepatocyte-derived cancer cells and a selected panel was tested in zebrafish larvae. Anthralin and all-trans retinoic acid (RA) were identified as fibrinogen-lowering and fibrinogen-increasing moieties, respectively. In zebrafish larvae, anthralin prolonged laser-induced venous- occlusion times and reduced thrombocyte accumulation at injury sites. RA had opposite effects. Treatment with RA, a nuclear receptor ligand, increased fibrinogen mRNA levels. Using an antisense morpholino oligonucleotide to deplete zebrafish fibrinogen, we correlated a shortening of laser-induced venous thrombosis times with RA treatment and fibrinogen protein levels. Anthralin had little effect on fibrinogen mRNA in zebrafish larvae, despite leading to lower detectable fibrinogen. Therefore, we made a proteomic scan of anthralin-treated cells and larvae. A reduced representation of proteins linked to the canonical secretory pathway was detected, suggesting that anthralin affects protein secretion. In summary, we found that chemical modulation of fibrinogen levels correlates with measured effects on experimental venous thrombosis and could be investigated as a therapeutic avenue for thrombosis prevention.

Supplementary Material



Publication History

Received: 08 May 2020

Accepted: 02 September 2020

Publication Date:
10 December 2020 (online)

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