Approach to the diagnosis of TTP. Our approach to the diagnosis of TTP involves 3 steps. In the initial step, obvious alternative causes of TMA are excluded. In the second step, if an obvious alternative cause is not present, the patient should be evaluated for TTP, using the PLASMIC score and measurement of ADAMTS13 activity. Our approach assumes that the ADAMTS13 activity result will not be immediately available and that the initial decision about whether to commence PEX must be made on clinical grounds alone. We recommend initiating PEX in patients with an intermediate- or high-risk PLASMIC score, whereas we recommend withholding PEX in those with a low risk score. The ADAMTS13 activity level is used to refine the diagnosis. An ADAMTS13 level of less than 10% confirms the diagnosis of TTP in patients with an intermediate- to high-risk PLASMIC score and supports the diagnosis in those with a low-risk PLASMIC score. The third step involves distinguishing immune-mediated from congenital TTP. We use clinical information, ADAMTS13 inhibitor/antibody assays, measurement of ADAMTS13 activity in remission, and ADAMTS13 mutation analysis to differentiate between these entities. This algorithm aims to provide general guidance to clinicians, but is not a substitute for clinical judgment, which should be individualized for each patient. APS, antiphospholipid syndrome; DIC, disseminated intravascular coagulation; HELLP, Hemolysis, Elevated Liver function tests, and Low Platelets.