Thrombocytopenia with concomitant anemia is a serious condition with a high mortality risk. Destruction of platelets, i.e., thrombocytopenia, can be secondary to either auto-antibodies (immune-mediated) or mechanical destruction (non-immune-mediated). The Coombs test is a widespread tool to differentiate between the two categories, resulting in different specific treatment approaches for each diagnosis. A peripheral blood smear can also help make the diagnosis; for instance, in cases of mechanical destruction such as thrombotic thrombocytopenic purpura (TTP), the red blood cell (RBC) shape looks fragmented, forming schistocytes. In rare instances, TTP can present with both schistocytes and a positive Coombs test, challenging the diagnosis of TTP. TTP is a hematological emergency requiring appropriate anticipation and the initiation of treatment prior to the confirmatory ADAMTS-13 test results. Mild forms of TTP can be managed with glucocorticoids and therapeutic plasma exchange. Refractory cases need more aggressive additional treatment with caplacizumab and rituximab. Caplacizumab is an expensive medication that is usually reserved for use after confirmation of a TTP diagnosis. The advantage of caplacizumab lies in its targeted mechanism of action against the A1 domain of the von Willebrand multimers that are normally destructed by the ADAMTS-13 enzyme. Here, we present a young female patient with confirmed TTP, and the initial diagnosis was challenged by the presence of antibodies with the Coombs test. Very little research has studied this rare instance and the appropriate treatment. Our case will save many future lives, as clinicians should be more aggressive in treating refractory TTP with a positive Coombs test.