Rationale: Protocols for regional citrate anticoagulation with the hypertonic 4% trisodium citrate solution have been recently described as an anticoagulation strategy during membrane therapeutic plasma exchange (mTPE). The effect of citrate in the patient’s systemic hemostasis is negligible, thus regional citrate anticoagulation application is advantageous in circumstances in which heparin-based protocols are deemed unsafe for patients with a high risk of bleeding. The downsides of using hypertonic citrate solutions are mainly hypocalcemia and hypernatremia that ultimately can cause adverse clinical events. Presenting concerns of the patient: (1) A 57-year-old Caucasian female with a history of active vaginal bleeding secondary to endometrial hyperplasia. She had a history of antiphospholipid syndrome, and systemic lupus erythematosus with marked refractory autoimmune thrombocytopenia. Her platelet count was persistently below 4,000/mm³ even after different immunosuppressive regimens and daily platelet transfusions. (1) A 70-year-old Caucasian female was hospitalized presenting acute kidney injury stage 3 due to rapidly progressive antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, however without the need for renal replacement therapy. At admission, serum creatinine (sCr) was 3.56 mg/dL (normal range: 0.53-1.00 mg/dL). Her baseline sCr was 0.8 mg/dL obtained 6 months earlier. Chest tomography revealed bilateral masses compatible with granulomatous lesions and no signs of alveolar bleeding. Since severe cases of ANCA vasculitis involving the lungs may evolve with alveolar hemorrhage, heparin was avoided. Diagnoses: (1) Systemic lupus erythematosus-associated autoimmune thrombocytopenia and (2) ANCA-associated vasculitis with kidney and lung involvement. Interventions: Herein, we describe a case series of 12 consecutive mTPE treatments in 2 different patients using regional 4% trisodium citrate anticoagulation. Outcomes: All the sessions were uneventful, presented only minor electrolyte imbalances, and were effectively completed without early interruptions due to clotting of the plasmafilter. Teaching points: In our 2 cases, extracorporeal regional citrate anticoagulation was successful in optimizing plasmafilter patency without bleeding events in 2 high-risk patients using established protocols for the citrate and calcium infusions.