Thromboinflammation as a Driver of Venous Thromboembolism

AbstractThrombus formation has been identified as an integral part in innate immunity, termed immunothrombosis. Activation of host defense systems is known to result in a procoagulant environment. In this system, cellular players as well as soluble mediators interact with each other and their dysregulation can lead to the pathological process of thromboinflammation. These mechanisms have been under intensified investigation during the COVID-19 pandemic. In this review, we focus on the underlying mechanisms leading to thromboinflammation as one trigger of venous thromboembolism.

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ST Elevation Infarction after Heart Transplantation Induced by Coronary Spasms and Mural Thrombus Detected by Optical Coherence Tomography

Case Reports in Transplantation ◽

10.1155/2016/1863869 ◽

2016 ◽

Vol 2016 ◽

pp. 1-4 ◽

Cited By ~ 3

Author(s):

Tor Skibsted Clemmensen ◽

Niels Ramsing Holm ◽

Hans Eiskjær ◽

Steen Hvitfeldt Poulsen ◽

Michael Maeng ◽

...

Keyword(s):

Myocardial Infarction ◽

Optical Coherence Tomography ◽

Coronary Artery ◽

Thrombus Formation ◽

Coronary Intervention ◽

Suspected Coronary Artery Disease ◽

Optical Coherence ◽

Mural Thrombus ◽

Clinical Value ◽

Underlying Mechanisms

The case illustrates the possible link between coronary spasms, intraluminal thrombus formation, and widespread organized and layered thrombi in HTx patients. Furthermore, the case underlines the clinical value of OCT as a novel method for high-resolution vessel imaging in heart-transplanted (HTx) patients with coronary spasms and suspected coronary artery disease. Coronary spasms and sudden death are frequent complications after HTx. The underlying mechanisms leading to these complications are unknown. The present case displays the clinical course of a 19-year-old HTx patient who was hospitalized due to acute myocardial infarction induced by severe coronary spasms. The patients remained unstable on conservative therapy. Therefore, an optical coherence tomography (OCT) was performed and revealed massive, organized thrombi in the left main coronary artery, the circumflex coronary artery, and the left anterior descending coronary artery. The patient was stabilized after percutaneous coronary intervention. As a mural thrombus often goes undetected by coronary angiography, OCT may prove benefit in HTx patients with myocardial infarction or suspected coronary spasms.

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Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like Receptor 4

Scientific Reports ◽

10.1038/srep31936 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 13

Author(s):

Zhijuan Qiu ◽

Jorge L. Cervantes ◽

Basak B. Cicek ◽

Subhajit Mukherjee ◽

Madhukumar Venkatesh ◽

...

Keyword(s):

Innate Immunity ◽

Bacterial Infection ◽

Host Defense ◽

Negative Impact ◽

Pregnane X Receptor ◽

Negative Regulator ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Chemokine Production ◽

Inflammatory Monocytes

Abstract The nuclear pregnane X receptor (PXR) plays a central role in regulating xenobiotic metabolism. We now report a novel role for PXR as a critical negative regulator of innate immunity after infection. Pxr −/− mice exhibited remarkably elevated pro-inflammatory cytokine and chemokine production following infection with Listeria monocytogenes (Lm). Despite the more robust innate immune response, Pxr −/− mice were highly susceptible to Lm infection. Surprisingly, disruption of the Toll-like receptor 4 (TLR4) but not TLR2 signaling restored the inflammation to normal levels and the ability to clear Lm in Pxr −/− mice. Mechanistically, the heightened inflammation in Pxr −/− mice resulted in the death of inflammatory monocytes that led to the enhanced susceptibility to Lm infection. These data demonstrated that PXR regulated pathogen-induced inflammation and host defense against Lm infection through modulating the TLR4 pathway. In summary, we discovered an apical role for PXR in regulating innate immunity. In addition, we uncovered a remarkable negative impact of the TLR4 pathway in controlling the quality of the inflammatory response and host defense against a gram-positive bacterial infection.

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Host Defense Systems

10.1007/springerreference_32327 ◽

2011 ◽

Keyword(s):

Host Defense ◽

Defense Systems

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Role of microRNAs in Venous Thromboembolism

International Journal of Molecular Sciences ◽

10.3390/ijms21072602 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2602 ◽

Cited By ~ 1

Author(s):

Vânia M. Morelli ◽

Sigrid K. Brækkan ◽

John-Bjarne Hansen

Keyword(s):

Venous Thromboembolism ◽

Animal Models ◽

Statistical Power ◽

Current Knowledge ◽

Thrombus Formation ◽

Therapeutic Targets ◽

Small Sample ◽

Future Research ◽

Gene Expressions

MicroRNAs (miRNAs) are non-coding RNAs that execute their function by targeted downregulation of gene expressions. There is growing evidence from epidemiological studies and animal models suggesting that the expression level of miRNAs is dysregulated in venous thromboembolism (VTE). In this review, we summarize the current knowledge on the role of miRNAs as biomarkers for VTE and provide general insight into research exploring the modulation of miRNA activity in animal models of venous thrombosis. Up to now, published studies have yielded inconsistent results on the role of miRNAs as biomarkers for VTE with most of the reports focused on diagnostic research. The limited statistical power of the individual studies, due to the small sample sizes, may substantially contribute to the poor reproducibility among studies. In animal models, over-expression or inhibition of some miRNAs appear to influence venous thrombus formation and resolution. However, there is an important gap in knowledge on the potential role of miRNAs as therapeutic targets in VTE. Future research involving large cohorts should be designed to clarify the clinical usefulness of miRNAs as biomarkers for VTE, and animal model studies should be pursued to unravel the role of miRNAs in the pathogenesis of VTE and their potential as therapeutic targets.

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Interferon-induced guanylate-binding proteins: Guardians of host defense in health and disease

Journal of Experimental Medicine ◽

10.1084/jem.20182031 ◽

2019 ◽

Vol 216 (3) ◽

pp. 482-500 ◽

Cited By ~ 29

Author(s):

Kyle Tretina ◽

Eui-Soon Park ◽

Agnieszka Maminska ◽

John D. MacMicking

Keyword(s):

Innate Immunity ◽

Bacterial Infection ◽

Host Defense ◽

Tissue Damage ◽

Binding Proteins ◽

Wide Spectrum ◽

Cell Types ◽

Microbial Pathogens ◽

Health And Disease ◽

Basic Biology

Guanylate-binding proteins (GBPs) have recently emerged as central orchestrators of immunity to infection, inflammation, and neoplastic diseases. Within numerous host cell types, these IFN-induced GTPases assemble into large nanomachines that execute distinct host defense activities against a wide variety of microbial pathogens. In addition, GBPs customize inflammasome responses to bacterial infection and sepsis, where they act as critical rheostats to amplify innate immunity and regulate tissue damage. Similar functions are becoming evident for metabolic inflammatory syndromes and cancer, further underscoring the importance of GBPs within infectious as well as altered homeostatic settings. A better understanding of the basic biology of these IFN-induced GTPases could thus benefit clinical approaches to a wide spectrum of important human diseases.

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Classification of inflammatory skin diseases: A proposal based on the disorders of the three-layered defense systems, barrier, innate immunity and acquired immunity

Journal of Dermatological Science ◽

10.1016/j.jdermsci.2014.08.010 ◽

2014 ◽

Vol 76 (2) ◽

pp. 81-89 ◽

Cited By ~ 33

Author(s):

Teruki Dainichi ◽

Sho Hanakawa ◽

Kenji Kabashima

Keyword(s):

Innate Immunity ◽

Skin Diseases ◽

Acquired Immunity ◽

Inflammatory Skin Diseases ◽

Defense Systems ◽

Inflammatory Skin

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Caspase-6 Is a Key Regulator of Innate Immunity, Inflammasome Activation, and Host Defense

Cell ◽

10.1016/j.cell.2020.03.040 ◽

2020 ◽

Vol 181 (3) ◽

pp. 674-687.e13 ◽

Cited By ~ 27

Author(s):

Min Zheng ◽

Rajendra Karki ◽

Peter Vogel ◽

Thirumala-Devi Kanneganti

Keyword(s):

Innate Immunity ◽

Host Defense ◽

Inflammasome Activation ◽

Caspase 6

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Association of mean platelet volume with risk of venous thromboembolism and mortality in patients with cancer

Thrombosis and Haemostasis ◽

10.1160/th13-07-0603 ◽

2014 ◽

Vol 111 (04) ◽

pp. 670-678 ◽

Cited By ~ 53

Author(s):

Alexandra Kaider ◽

Ilse Schwarzinger ◽

Julia Riedl ◽

Eva-Maria Reitter ◽

Christine Marosi ◽

...

Keyword(s):

Venous Thromboembolism ◽

Cancer Patients ◽

Mean Platelet Volume ◽

Multivariable Analysis ◽

Observation Time ◽

Newly Diagnosed ◽

Platelet Volume ◽

Observational Cohort ◽

Study Population ◽

Underlying Mechanisms

SummaryVenous thromboembolism (VTE) is a frequent complication in cancer patients. Mean platelet volume (MPV) has been associated with arterial and venous thrombosis in patients without cancer. We analysed MPV in cancer patients and investigated the association of MPV with risk of VTE and mortality. MPV was routinely determined in the Vienna Cancer and Thrombosis Study, a prospective, observational cohort study of patients with newly diagnosed or progressive cancer after remission. Study endpoints were occurrence of symptomatic VTE or death during a maximum follow-up of two years. Out of 1,544 included patients, 114 (7.4%) developed VTE and 573 (37.1%) died during a median observation time of 576 days. High MPV ≥75th percentile of the study population; ≥10.8 fL) was associated with decreased risk of VTE compared to MPV below the 75th percentile (HR [95% CI]: 0.59 [0.37–0.95], p=0.031). In multivariable analysis, including age, sex, cancer groups, newly diagnosed vs recurrent disease, platelet count and soluble P-selectin, this association remained statistically significant (0.65 [0.37–0.98], p=0.041). Mortality of patients with MPV (≥75th percentile was significantly decreased compared to those with lower MPV (0.72 [0.59–0.88], p=0.001). Two-year probability of VTE and overall survival was 5.5% and 64.7% in patients with high MPV compared to 9% and 55.7% in those with lower MPV. In conclusion, high MPV is associated with decreased VTE risk and improved survival in cancer patients. This finding is contrary to results observed in patients without cancer. Further studies are needed to confirm our results and elucidate underlying mechanisms.Previous presentations of this manuscript: Data from this study were presented in part at the Annual Spring Meeting of the Austrian Society for Haematology and Oncology (OeGHO) in Linz, Austria, and as an oral presentation at the XXIV. Congress of the International Society on Thrombosis and Haemostasis (ISTH) 2013 in Amsterdam, the Netherlands.

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