Subtype-specific plasma signatures of platelet-related protein releasate in acute pulmonary embolism.

There is evidence that plasma protein profiles differ in the two subtypes of pulmonary embolism (PE), isolated PE (iPE) and deep vein thrombosis (DVT)-associated PE (DVT-PE), in the acute phase. The aim of this study was to determine specific plasma signatures for proteins related to platelets in acute iPE and DVT-PE compared to isolated DVT (iDVT). Within the Genotyping and Molecular Phenotyping of Venous ThromboEmbolism (GMP-VTE) Project, a multicenter prospective cohort study of 693 confirmed VTE cases, a highly sensitive targeted proteomics approach based on dual-antibody proximity extension assay was applied. LASSO-regularized logistic regression analysis selected 33 and 30 of 135 platelet-related candidate proteins in iPE and DVT-PE vs. iDVT, respectively. All regulated proteins were well associated with six prominently released platelet proteins and the majority showed specificity for iPE and DVT-PE compared to iDVT. While iPE-specific proteins were assigned to be predominantly released via shedding mechanisms and extracellular vesicles, granule secretion was identified as a major release mechanism assigned to DVT-associated PE-specific proteins. Network analysis demonstrated three interconnected clusters of specifically regulated proteins in iPE linked to immunoreceptor signaling, pathogen clearance and chemotaxis, whereas for DVT-associated PE one cluster linked to tissue remodeling and leukocyte trafficking. Machine learning-based analysis reveals specific plasma signatures and differential release mechanisms of proteins related to platelets in acute iPE and DVT-associated PE. These data suggest that the platelet protein releasate contributes to the differential regulation of plasma proteins in acute PE compared to iDVT, which may be associated with different platelet activation patterns.

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Déclaration de conflit d'intérêts

Declaration of competing interest S.H., C.G., S.S., and K.L. are employees of Bayer AG. The study was sponsored inter alia by Bayer AG. The sponsors had no role in the design or conduct of the research. H.T.C. received research funding outside the present study from Bayer and received outside the present study honoraria for consultation and/or advisory board participation, from Bayer, Alveron, Galapagos, Portola and Alexion. All reimbursements were transferred to the CARIM institute. H.T.C. and H.M.H.S. are shareholders with Coagulation Profile, a university spinoff small diagnostic company not involved in the present study. P.S.W. has received research funding outside the present study from Boehringer Ingelheim, Sanofi-Aventis, Bayer Healthcare, Daiichi Sankyo Europe and Novartis and received outside the present study honoraria for lectures or consulting from Boehringer Ingelheim, Bayer HealthCare, Evonik, AstraZeneca and Sanofi-Aventis. P.S.W. is principal investigator of the DIASyM research core (BMBF 161L0217A).