Following the widespread use of anti SARS-CoV-2 vaccines, there have been reports of thrombocytopenia developing after the administration of different types of vaccine. We report a case of a 63-year-old male who developed neurological symptoms after receiving the second dose of the bnt162b2 vaccine. Blood tests performed upon admission to the Emergency Department revealed severe thrombocytopenia and microangiopathic hemolytic anemia. ADAMTS13 activity was undetectable and antibody titer was high. Due to the rapid neurological deterioration, steroid therapy with prednisone was started at an initial dose of 1 mg/kg/day. Rituximab therapy was started to prevent the formation of new antibodies. Given the slow response to this therapy, we added Caplacizumab, (a monoclonal antibody anti-Von Willebrand factor) in order to inhibit platelet hyperaggregation, combined with standard plasma exchange. The patient experienced repeated episodes of intolerance to fresh frozen plasma (FFP). Switching from plasma exchange to plasma filtration, remission was attained in this unusual case of vaccine-related thrombocytopenia with microangiopathic hemolytic anemia.