Dive into the future of thrombosis management

01 Sep 2020

At the 25th European Hematology Association Annual Congress (EHA25), three researchers presented the latest findings on the role of gut microbiome, microvesicles (MVs) and neutrophil extracellular traps (NETs) in thrombosis. Understanding the implications of these key players would enable a more comprehensive prevention and management of thrombosis in the future.

A gnotobiotic mice study revealed that commensal microbiota augmented atherothrombosis and vascular inflammation among mice in late atherosclerosis. In carotid arteries, the gut microbiota also enhanced arterial thrombosis and plaque rupture-induced thrombus growth.1 “Interestingly, the vascular inflammatory phenotype of those animals was influenced by the presence of gut microbiota,” said Dr. Christoph Reinhardt, junior professor at the Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany.

Hepatic synthesis of von Willebrand factor (VWF) is regulated by the gut microbiota through endothelial toll-like receptor 2 (TLR2) signaling. At sites of vascular injury, plasma VWF promotes platelet adhesion to the extracellular matrix and platelet aggregation. Diminished VWF plasma levels are decisive for reduced platelet deposition in germ-free mice, indicating that gut microbiota is linked to arterial thrombus formation through TLR2-dependent regulation of endothelial VWF synthesis in the liver endothelium.2 Dr. Reinhardt pointed out, “We have a route of microbial patterns that activates the liver endothelium that can influence arterial thrombus growth in case of vascular injury in the carotid artery.”

Besides gut microbiome, MVs were also found to play a role in thrombus formation. In cancer patients, endogenous MVs accumulate at injury sites and promote the formation of thrombus.3 Particularly, tissue factor (TF)-positive MVs were found to activate platelets to enhance  venous thromboembolism (VTE).4

MVs are involved in the regulation of endothelial TF expression through miRNA transfer, yet the lack of prospective and standardized study design restricts the confidence in identifying procoagulant MVs as biomarkers for VTE prediction.5 “MVs are multifaceted protagonists interconnecting cellular and soluble actors of vascular homeostasis. They can be considered as a potential biomarker for (thrombotic) risks,” noted by Prof. Françoise Dignat-George, professor of immunology and hematology at Aix-Marseille University, France. Regarding the current paradigm of technical strategies for MV measurement, Prof. Dignat-George stated, “Functional assays are more sensitive, whereas MV-associated antigen detection is still a challenge.”

NETs are another player in the formation of thrombus. Platelets bound by NETs were activated, to promote thrombin generation and binding of plasma proteins. The fibrin clots bound by NETs were tissue plasminogen activator (tPA)-resistant that could only be digested by the combination of DNAse and tPA, highlighting the role of NETs independent of fibrin.6

As a biomarker for NETs formation and VTE risk prediction, citrullinated histone is formed by the mediation of peptidylarginine deiminase 4 (PAD4), which emphasize the key role of PAD4 in NETs formation and thrombosis.7 “NETs were contributing to thrombus formation by providing a procoagulant scaffold, and PAD4-mediated citrullination plays a key role in this process,” explained by Dr. Kimberly Martinod, Assistant Professor at KU Leuven, Belgium.

“Disease states with PAD4 hyperactivation may increase the thrombotic risk. This is a really interesting topic to investigate, for example in the context of COVID-19, where we observed a strong increase of VTE events in infected patients,” added Dr. Martinod to highlight the importance of delineating the role and application of gut microbiome, MVs and NETs in thrombosis to help identify high-risk individuals for better thrombosis management and reduce disease morbidity and mortality.

  1. Kiouptsi K, et al. The microbiota promotes arterial thrombosis in low-density lipoprotein receptor-deficient mice. mBio. 2019 Sep-Oct;10(5):e02298-19.
  2. Jäckel S, et al. Gut microbiota regulate hepatic von Willebrand factor synthesis and arterial thrombus formation via toll-like receptor-2. Blood. 2017 Jul 27;130(4):542-53.
  3. Thomas GM, et al. Cancer cell-derived microparticles bearing P-selectin glycoprotein ligand 1 accelerate thrombus formation in vivo. J Exp Med. 2009 Aug 31;206(9):1913-27.
  4. Thomas GM, et al. Tissue factor expressed by circulating cancer cell-derived microparticles drastically increases the incidence of deep vein thrombosis in mice. J Thromb Haemost. 2015 Jul;13(7):1310-9.
  5. Laffont B, et al. Activated platelets can deliver mRNA regulatory Ago2•microRNA complexes to endothelial cells via microparticles. Blood. 2013 Jul 111;122(2):253-61.
  6. Fuchs TA, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15880-5.
  7. Mauracher LM, et al. Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients. J Thromb Haemost. 2018 Mar;16(3):508-18.