Coagulation disorders display a major clinical concern of diseases accompanied by the intravascular release of high heme concentrations. In addition, early investigations on heme administration as a treatment of porphyria patients highlighted the thromboinflammatory side effects of locally high heme levels. As a regulatory molecule, heme is well-known to affect the function and/or stability of proteins through binding to short, surface-exposed amino acid stretches, so-called ‘heme-binding motifs’. As such, the stimulation of the complement and coagulation system through direct heme binding to participating proteins (e.g., C3 and fibrinogen) has been described in the past and correlated with the respective clinical symptoms. Herein, we started to analyze the network of clotting factors as potential heme-regulated proteins by screening for heme-binding motifs using the webserver HeMoQuest. Subsequently, these motifs were synthesized as model peptides and analyzed for heme binding by UV/vis spectroscopy. Promising sites were further evaluated by molecular docking and dynamics simulations of the respective heme-protein complexes. Apart from these computational studies, the heme-binding capacity of these proteins was experimentally studied by UV/vis and/or SPR spectroscopy. Structural investigations were conducted by single-particle cryo-electron microscopy. Finally, the effect of heme binding towards the function of the respective protein was analyzed by diverse physiologically relevant as well as biochemical activity assays. In summary, heme binding to select blood coagulation proteins (e.g., FVIII) is demonstrated by applying a combination of biochemical, spectroscopic, bioinformatic, structural, and clinically relevant approaches. The results provided extend our understanding of heme as a regulator in the blood coagulation system on molecular level, which will support the knowledge on the progression of thrombosis under pathophysiological conditions of high intravascular heme levels.