Visual Universitätsmedizin Mainz

TRP X42 The role of inflammation for primary and secondary venous thromboembolic events

Funding period: 01.08.2019 – 31.07.2020

Project Summary

Venous thromboembolism (VTE), defined as deep vein thrombosis (DVT), pulmonary embolism (PE), or both, is a common condition characterized by the formation of an occlusive blood clot in the venous vascular system with a complex, multicausal etiology accompanied by serious short- and long-term complications, including death.

Evidence is accumulating that the factors influencing VTE formation are not restricted to the coagulation system alone. In particular, inflammation and the immune response are known to be closely involved in the formation and resolution of thrombi. Effective cardiovascular drugs with anti-inflammatory effects such as statins have been shown to reduce the risk of incident and recurrent arterial and venous thrombosis. However, a substantial proportion remains at risk for recurrent events, despite low LDL-cholesterol levels. This is argued to be attributable to the presence of a prolonged inflammatory response (exemplarily reflected by persistently elevated levels of high sensitive C-reactive protein), a concept, which is known as “residual inflammatory risk”. The recent CANTOS trial provides evidence that IL-1b along with other cytokines play central roles in the inflammatory reaction that drives the IL-6 signaling pathway and have profound effects on cardiovascular outcomes. Several other ongoing studies are focused on multiple immune mediators involved in this process to support the inflammatory hypothesis of cardiovascular diseases.

Of clinical importance, VTE is associated with a high risk of recurrence after a first episode of VTE (5%–7% per year), and it is more than 50 times higher than in patients without previous VTE. Though continued oral anticoagulation therapy, reduces the risk of recurrence, recurrent VTE episodes or extension of the disease occur in a nonnegligible portion of patients (≈4% after a DVT), even in the presence of adequate therapy. The risk of recurrence must be carefully weighed against the risk of anticoagulant-related bleeding. Thus, it is very important to assess the risk of recurrence in each individual patient as to be able to adequately weigh this risk against the risks of long-term anticoagulation. A better understanding of the role of inflammation in different clinical manifestations of VTE (e.g. primary versus secondary prevention) has high potential for better risk assessment and individualized therapeutic approaches of VTE.

The overarching objective of this project is to evaluate the potential role of inflammation for primary and secondary VTE by exploring the pathophysiological mechanism with an innovative, data-driven multi-omics approach. This is achieved by high-throughput multiplex technology that covers broad spectra of mechanisms within specific biological systems involved in inflammation. These mechanisms are also hypothesized to be involved in venous thrombosis, and proteins will be explored for significant under- or overexpression in primary and secondary VTE events. Application of these technologies to VTE enables identification of protein biomarkers for prediction in the clinical setting, and understanding on a molecular level.

Overall, this project provides the opportunity to advance the understanding of molecular and cellular players triggering occlusion of veins in initial and recurrent VTE, which is important for the development of strategies to diagnose, prevent and treat VTE, identify cardiovascular-inflammation cross links and ultimately improve patients outcomes. Funding the proteomic profiling of incident VTE individuals provides the opportunity to identify proteomic combinations that might enhance tools for clinical risk stratification.

Principal Investigator