Thrombotic thrombocytopenic purpura (TTP), caused by severely reduced activity of the von Willebrand factor-cleaving protease ADAMTS13, is a medical emergency with life-threatening complications and a 90% mortality rate if left untreated. It presents a diagnostic challenge given the multiorgan involvement of the cardiovascular, gastrointestinal, and central nervous systems. Furthermore, the well-known full pentad of fever, hemolytic anemia, bleeding associated with thrombocytopenia, neurological signs, and renal disease is often absent in patients with TTP. We present a 51-year-old male adult with TTP. We utilized the PLASMIC scoring system, which predicts the likelihood of ADAMST13 activity in adults with features of thrombotic microangiopathy and thrombocytopenia with high sensitivity and specificity. We further review the literature supporting the expert statement on ICU management of patients with TTP that plasma exchange (PEX) should be initiated within 6 hours of diagnosis with adjunctive glucocorticoids, rituximab, and caplacizumab. If PEX is unavailable, plasma infusion can be started while the patient awaits transfer to a center with PEX capabilities.