Thrombotic thrombocytopenic purpura (TTP) is a rare form of microangiopathic hemolytic anemia with high rates of mortality without treatment. Common risk factors for TTP include immunosuppression, pregnancy, and female gender. However, several case reports show that TTP may have an association with autoimmune conditions such as Sjögren's syndrome (SS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). We present a similar case of a 41-year-old female with a past medical history of RA, SLE, and SS, who arrived at the hospital with hematuria, flank pain, slow speech, and altered mental status. Based on her presentation, there were concerns for TTP, hemolytic uremic syndrome, glomerulonephritis, or sepsis secondary to urinary tract infection. After diagnosis was narrowed to TTP, treatment was initiated for TTP with plasmapheresis, methylprednisolone, and rituximab infusions prior to receiving diagnostic confirmation due to high clinical suspicion. Upon further workup, her autoimmune and immunology panels returned several days post-admission with low ADAMTS13 activity, confirming the TTP diagnosis. Her autoimmune conditions were also confirmed for SS, RA, and SLE based on positive serology for anti-SSA/Ro antibodies, anti-CCP antibodies, and speckled ANA, respectively. With treatment, the platelet counts increased, and the symptoms present at admission resolved over a prolonged hospital course. Initiating treatment for TTP should be based on findings of clinical and routine laboratory testing rather than confirmatory test results due to the delay in receiving results, such as the ADAMTS13 level. In patients with a history of autoimmune disease, the association between TTP and autoimmune diseases can help formulate a clinical diagnosis of TTP early in the hospital course, allowing for treatment initiation and decreased mortality.