Plasma from blood is a very accessible sample; therefore it is very valuable to discover the existence of molecular markers in plasma associated with disease. Such markers are of course helpful to detect or categorize diverse disease states, and additionally may offer insights about the mechanisms responsible for the disease, the possible therapeutic actions and the effects of therapies and lifestyles on disease outcomes.
Venous thromboembolism (VTE), or formation of blood clots, includes pulmonary embolism (PE), formation of clots in the lungs, and deep vein thrombosis (DVT), formation of clots in the deep veins. PE can occur in individuals with or without DVT. While both types of PE are relatively common, it is suspected that the causes of PE could be different in each case, with consequences for the choice of a therapy. To evaluate possible differences in these diseases at the molecular level, we used a targeted proteomics approach (Olink technology) to assess the levels of a panel of inflammation related proteins to compare individuals with PE occurring in isolation to individuals with PE occurring with DVT [1]. Our results indicated five protein markers in isolated PE: IFNG, GDNF, GALNT3, PADI2 and IL-15Ralpha. These proteins suggest that the mechanisms involved in isolated PE are more related to inflammatory processes (e.g. inhibition of the NF-kappaB signaling by GALNT3) and less to the general mechanisms of VTE, supporting the local pulmonary origin of PE.
Although obesity is a risk factor for VTE, mortality from VTE in obese patients is half: this is known as the obesity paradox in VTE. To discover mechanisms protecting obese individuals from VTE, we obtained an 11-protein signature of circulating proteins comparing obese and non-obese individuals with VTE: CLEC4C, FABP4, FLT3LG, IL-17C, LEP, LYVE1, MASP1, ST2, THBS2, THBS4, TSLP [2]. This signature does not explain the paradox. However, we found that one of these proteins, leptin (LEP), protects against disease recurrence and death in VTE obese patients, which was abrogated if there was leptin resistance (as indicated by high levels of circulating MMP-2 protein). Thus, the protective effect is not due to the obesity.
Coagulation factors are proteins that are critical in the development of VTE. To investigate research that suggests that inhibition of coagulation factor XIa (FXIa) prevents VTE, we measured the plasma protein profile of patients during an acute VTE event and 12 months after, and correlated changes in protein expression with factor XI activity (clotting assay) measured at both time points [3]. A total of 21 and 66 proteins associated with FXI activity at the VTE event and the 12 months follow-up time points, respectively, with 7 proteins associated at both time points. Proteins identified included modulators of cells of the immune system, and known activators of FXI through the contact activation system using extracellular matrix modification, neutrophil degeneration, apoptosis and the metabolism of various biomolecules, and are involved in signaling pathways related to thrombo-inflammation such as IL-1, NF-kappaB and TLR4.
References
[1] Ten Cate, V., J.H. Prochaska, A. Schulz, T. Koeck, A. Pallares Robles, M. Lenz, L. Eggebrecht, S. Rapp, M. Panova-Noeva, H.A. Ghofrani, F.J. Meyer, C. Espinola-Klein, K.J. Lackner, M. Michal, A.K. Schuster, K. Strauch, A.M. Zink, V. Laux, S. Heitmeier, S.V. Konstantinides, T. Münzel, M.A. Andrade-Navarro, K. Leineweber and P.S. Wild. 2021. Protein expression profiling suggests relevance of noncanonical pathways in isolated pulmonary embolism. Blood. 137, 2681-2693.
[2] Ten Cate, V., T. Koeck, J.H. Prochaska, A. Schulz, M. Panova-Noeva, S. Rapp, L. Eggebrecht, M. Lenz, J. Glunz, M. Sauer, R. Ewert, M. Halank, T. Münzel, S. Heitmeier, M.A. Andrade-Navarro, K.J. Lackner, S.V. Konstantinides, K. Leineweber, P.S. Wild. 2021. A targeted proteomics investigation of the obesity paradox in venous thromboembolism. Blood Advances. 5, 2909-2918.
[3] Pallares Robles, A., V. ten Cate, A. Schulz, J.H. Prochaska, S. Rapp, T. Koeck, M. Panova-Noeva, S. Heitmeier, S. Schwers, K. Leineweber, H.J. Seyfarth, C.F. Opitz, H. Spronk, C. Espinola-Klein, K.J. Lackner, T. Münzel, M.A. Andrade-Navarro, S.V. Konstantinides, H. ten Cate and P.S. Wild. 2022. Association of FXI activity with thrombo-inflammation, extracellular matrix, lipid metabolism and apoptosis in venous thrombosis. Sci. Rep. 12, 9761.