Bleeding crises are common complications in hemato-oncological patients undergoing chemotherapy and stem cell transplantation. Platelet transfusions are frequently administered to treat and prevent bleeding events at low platelet counts. However, the association between thrombocytopenia and bleeding events remains unclear, arguing for an improved understanding of pathophysiological changes underpinning bleeding events. Therefore, this study aims to identify plasma protein levels associated with bleeding events in a hemato-oncological patient population using unbiased mass spectrometry-based plasma profiling. Plasma samples and clinical records from 176 hemato-oncological patients included in the Pathogen Reduction Evaluation & Predictive Analytical Rating Score (PREPAReS) study were analyzed. Out of 600 identified proteins, abundance levels of 55 proteins were found to be associated with bleeding severity at time of sampling. Among these, a large cluster of platelet proteins (n = 48) as well as coagulation factor 7 (F7) and vitamin-K dependent protein C (PROC) were observed. Interestingly, nine out of these 55 proteins were also associated with time-to-major bleeding event (WHO grade 2 or higher). Platelet protein levels correlated with platelet counts, but not with white cell counts nor platelet transfusions. Taken together, our results suggest that lower abundance of platelet- and coagulation proteins in plasma are associated with increased bleeding grade and time-to-major bleeding events in hemato-oncological patients. This highlights the potential for improved hemostatic monitoring of hemato-oncological patients at risk of bleeding, beyond platelet count alone.