Beyond the assays: Managing unresolvable TMA and the pharmacokinetic cost of plasma exchange Free

Introduction: Thrombotic microangiopathies (TMAs) encompass a spectrum of life-threatening disorders that share overlapping clinical features yet require distinct therapies, underscoring the importance of timely and accurate differentiation. We report a diagnostically challenging case of a rapidly progressive TMA in an elderly patient presenting with new-onset disease.

Case presentation: A 73-year-old man with history of Tetralogy of Fallot with bioprosthetic aortic valve replacement on warfarin and CKD stage IIIb (baseline creatinine 1.7–1.8 mg/dL) presented with two weeks of progressive jaundice, anorexia, and fatigue. On admission he was afebrile, oriented, and hemodynamically stable. Initial bloodwork revealed LDH 2,500 U/L, hemoglobin 7.3 g/dL, platelets 23 x 10³/µL, BUN/creatinine 65/2.21 mg/dL, total bilirubin 5.8 mg/dL (indirect 1.1), AST 171 U/L, ALT 30 U/L, RPI 2.1, INR 2.56, and negative direct antiglobulin test. A peripheral blood smear demonstrated marked anisocytosis with schistocytes and abundant polychromatophilic cells. The right upper quadrant abdominal US showed a solitary 2.3 cm gallstone without any evidence of cholecystitis. Transthoracic echocardiogram excluded prosthetic valve dysfunction, and extensive infectious workup including Shiga-toxin PCR was unremarkable. Complement levels, ADAMTS13 activity, and autoimmune serologies were obtained. Given PLASMIC score of 5, he was started on daily corticosteroids and underwent plasma exchange (PLEX) along with Fresh Frozen Plasma resulting in improving LDH at 1,612 U/L. However, the patient's hemoglobin and platelets continued to downtrend despite PLEX requiring frequent blood products transfusions. Additional findings included C3 of 53 mg/dL, C4 of 9 mg/dL, CH50 of 41 U/mL, and ADAMTS13 activity of 61%. Under the suspicion of complement-mediated Hemolytic Uremic Syndrome (HUS), PLEX was held, meningococcal vaccination administered, and penicillin V prophylaxis initiated. A single dose of Ravulizumab was given, but LDH rose to 2,339 U/L, creatinine increased to 3.2 mg/dL, and bleeding complications developed. PLEX was resumed followed by Rituximab infusion and a 7-day steroid taper. ANA, centromere, chromatin, dsDNA, JO-1, ribosomal P, RNP, Scl-70, Smith, SSA, SSB were all negative. A second dose of Ravulizumab was administered two weeks after the initial dose, at which point PLEX was discontinued. Despite this intervention, the patient experienced clinical deterioration with persisting hemolysis, worsening anemia, hemoptysis, and hematochezia. Given his poor prognosis and lack of therapeutic response, care was transitioned to comfort measures only.

Discussion: This case underscores that even with comprehensive testing and aggressive management for both TTP and complement-mediated HUS, current diagnostics may remain inconclusive, leaving clinicians without a clearly effective therapy. Our patient's intermediate ADAMTS13 activity and low complement levels created an overlap zone where evidence-based guidance is scant. Moreover, PLEX for the suspected TTP posed a pharmacokinetic challenge in this patient. By removing monoclonal agents, there was a need for careful coordination of dosing, PLEX timing, and potential redosing. Therefore, beyond emphasizing pre-PLEX sampling to avoid dilutional false negatives, this case highlights the need for rapid, discriminatory biomarkers and protocols that reconcile the competing demands of urgent PLEX and sustained complement inhibition. Finally, elderly patients with limited reserve may sustain permanent organ damage even with optimal therapy, reinforcing the imperative for clearer diagnostic algorithms and drug-delivery strategies in mixed-mechanism TMAs.