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Thrombosis, when considering all its manifestations including myocardial infarction, stroke, and venous thromboembolism, constitutes the leading cause of death world-wide. Treatment of thrombotic diseases has been revolutionised by direct oral anticoagulants (DOACs) targeting thrombin and FXa. However, the therapeutic or prophylactic use of DOACs is not without limitations, including persistent and significant bleeding risks. In this review, we summarise and discuss current state-of-the-art of novel and experimental anticoagulation and fibrino/thrombolytic therapies beyond DOACs. In particular, we review studies investigating contact pathway inhibition, including in-vitro and in-vivo studies of FXIIa and FXIa inhibition, and clinical trials of contact pathway inhibition. We review in-vitro and in-vivo studies investigating inhibition of common pathway coagulation targets, including FV, FVIII, and FIX. This is followed by analysis of options for the therapeutic targeting of fibrin or fibrinogen, and FXIII. Next, we explore opportunities for the therapeutic harnessing of naturally occurring anticoagulant pathways as well as fibrinolytic mechanisms. The current state-of-the-art research for each of these mechanisms is summarised, including whether studies have progressed from in-vitro to in-vivo experimentation, and whether clinical trials have been performed. We highlight particularly novel areas of interest and include evaluation of the relative preclinical and clinical trial progress for the selected targets. The increased understanding of mechanisms driving thrombosis holds promise for future developments in novel anticoagulants that may contribute to reducing the impact and burden of thrombotic diseases while improving safety of current therapeutic options.