Diagnostic approach to the patient with a catastrophic thrombotic presentation. The presenting history and physical examination, initial imaging studies, and laboratory studies are used to determine the most likely etiology of the patient’s thrombotic diathesis. Initial laboratory studies should include a complete blood count and blood film, a comprehensive metabolic panel (including blood urea nitrogen, creatinine, and liver function studies), an LDH, a prothrombin time, partial thromboplastin time, fibrinogen, and D-dimer, and testing for aPLs. Additional diagnostic laboratory studies that might be obtained in selected subsets of these patients would include testing for anti-PF4/heparin antibodies (to evaluate for HIT), an ADAMTS13 level (to evaluate for an atypical presentation of TTP), additional testing for aPLs (to evaluate for catastrophic APS), and selected additional tests that may direct or alter therapy (eg, antithrombin level). There can be considerable overlap between these disorders, particularly at initial presentation. aPL, antiphospholipid antibody; APS, antiphospholipid syndrome; HITT, heparin-induced thrombocytopenia with thrombosis; LDH, lactate dehydrogenase; MAHA, microangiopathic hemolytic anemia; TMA, thrombotic microangiopathy; TP, thrombocytopenia; TTP, thrombotic thrombocytopenic purpura.