<p>Thrombotic microangiopathies (TMA) are rare but highly acute conditions with substantial morbidity and mortality that pose major diagnostic and therapeutic challenges in acute and intensive care medicine. They are defined by the triad of Coombs-negative microangiopathic hemolytic anemia, thrombocytopenia and organ dysfunction, most commonly affecting the kidneys, central nervous system, and heart. Due to overlapping clinical and laboratory features, TMAs are frequently initially misdiagnosed as sepsis or disseminated intravascular coagulation, leading to potentially fatal delays in disease-specific treatment. Pathophysiologically, TMAs result from endothelial injury within the microcirculation, with the formation of platelet-rich microthrombi, mechanical erythrocyte destruction and ischemic organ damage. Key entities include thrombotic thrombocytopenic purpura (TTP), caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency and complement-mediated atypical hemolytic uremic syndrome (aHUS), driven by dysregulation of the alternative complement pathway. Immediate plasmapheresis combined with immunotherapy and caplacizumab is the cornerstone of TTP management, whereas early complement inhibition is crucial for improving outcomes in aHUS. The diagnosis relies on prompt recognition of characteristic laboratory findings, exclusion of relevant differential diagnoses and, in the case of suspected TTP, the use of clinical scoring systems. Given the fulminant disease course, a&#xa0;treat first-confirm later strategy is often required. New treatment approaches, including novel complement inhibitors and plasma-free approaches for TTP, open perspectives for more individualized and targeted treatment strategies, with the potential to further improve survival and long-term organ function.</p>