A plasma proteomic exploration in the thromboembolic field

Background: The elevated risk on and health burden of thromboembolic events necessitates development of blood-based patient risk monitoring.Objective: We explored the potential of mass spectrometry-based plasma proteomics to provide insights into underlying plasma protein signatures with treatment and occurrence of thromboembolic events.Method: Utilizing a high-throughput, data-independent acquisition, discovery-based proteomics workflow we analysed 434 plasma proteomes from different groups of individuals with elevated risk of thromboembolic events, including individuals I) on vitamin K-antagonists (VKA), II) with a prior venous thromboembolism, III) with acute cerebral venous sinus thrombosis (CVST) and IV) with SARS-CoV-2 infection. Plasma protein levels measured with MS were correlated with international prothrombin time ratio (INR) and conventional clinical laboratory measurements. Plasma profile differences between different groups were assessed using principal component analysis, moderated t-test and clustering analysis.Results: Plasma protein levels were in agreement with conventional clinical laboratory parameters, including albumin and fibrinogen. In addition, levels of vitamin K-dependent proteins inversely correlated with INR. In the individual retrospective studies, we found decreased levels of vitamin K-dependent coagulation proteins in patients on VKAs, alterations in inflammatory signatures among CVST patients and a distinctive signature indicative of SARS-CoV-2 infection. However, no protein signature associated with a thromboembolic event could be identified neither in individual nor combined retrospective studies. Conclusion: Although VKA treatment- and disease-specific signatures were captured, our study highlights that the challenges of discovering biomarkers in patients at risk of thromboembolic events lie in the heterogeneity of individual plasma profiles in relation to treatment and etiology.