Management of aTTP in patients who refuse or are intolerant to plasma remains challenging, but new drugs can be implemented with success. A 39-year-old woman presented to the Emergency department for bruises at the upper and lower limbs together with worsening anemia and thrombocytopenia; PLASMIC score was seven, indicative of high risk to have a thrombotic microangiopathy due to severe ADAMTS-13 deficiency: indeed, it was 1.4%. We immediately started Plasma Exchange, but after the third procedure she developed severe anaphylaxis to Octaplas plasma, so PEXs were discontinued. We proceeded to a salvage strategy with rituximab and caplacizumab that was rapidly effective to resolve symptoms and hemolysis. It has been already reported a case in which a patient developed severe reactions to fresh-frozen plasma that required discontinuation of PEX. Differently from this case, our patient was already using the less immunogenic pooled plasma units Octaplas, therefore a strategy with caplacizumab was the only available option. Moreover, rituximab is associated with a shorter time to obtain a durable remission in aTTP and a faster time (15 days) to final ADAMTS13 activity recovery >10%. To our knowledge, this is the first case of early discontinuation of caplacizumab in a patient allergic to PEX by actively monitoring ADAMTS13 activity, allowing optimization of healthcare resources during COVID-19 pandemic. © 2021 Wiley Periodicals LLC.