Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplantation-Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation, American Society for Transplantation and Cellular Therapy, Asia-Pacific Blood and Marrow Transplantation Group, and Center for International Blood and Marrow Transplant Research

**Background:** Transplantation-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplantation (HCT) driven by microvascular endothelial dysfunction and complement activation. Despite its association with significant morbidity and mortality — with nonrelapse mortality (NRM) rates typically exceeding 50% at 1 year post-HCT — no universally accepted diagnostic or prognostic criteria existed. Multiple proposed criteria (City of Hope, Cho, BMT CTN, Li, IWG, Jodele) differed in required features, timing, and inclusion of organ dysfunction, leading to reported incidences ranging from 0.8% to 36%. This variability precluded multi-institutional studies and hampered interpretation of interventional trials, six of which were using six different eligibility criteria. To address this, the American Society for Transplantation and Cellular Therapy, Center for International Blood and Marrow Transplant Research, Asia-Pacific Blood and Marrow Transplantation, and European Society for Blood and Marrow Transplantation convened an expert panel to harmonize definitions.

**Methods:** Each society nominated two experts to form the TA-TMA Harmonization of Definitions Panel. Panel members performed a literature search focusing on articles from 2000 to 2022, reviewing peer-reviewed studies including ≥10 patients with TA-TMA and prognostic features reported in ≥2 articles. A modified Delphi method was used: panel members voted on statements with options to agree, disagree, or refine; statements were scored on a 5-point Likert scale. Consensus was defined as ≥70% of members responding with 4 (agree) or 5 (strongly agree). Meetings began in September 2021, an initial draft was proposed on April 24, 2022, and the document underwent six revisions.

**Key Results:** Consensus was reached on four key concepts. (1) TA-TMA can be diagnosed using clinical and laboratory criteria or tissue biopsy of kidney or gastrointestinal tissue; biopsy is not required. (2) Consensus diagnostic criteria are proposed using modified Jodele criteria: TA-TMA is diagnosed when ≥4 of 7 features occur twice within 14 days — anemia (failure to achieve transfusion independence despite neutrophil engraftment; hemoglobin decline ≥1 g/dL; or new-onset transfusion dependence), thrombocytopenia (failure to achieve platelet engraftment; higher-than-expected transfusion needs; refractory to platelet transfusions; or ≥50% reduction in baseline platelet count after full engraftment), LDH exceeding ULN, schistocytes, hypertension (≥140/90 mmHg in adults; ≥99th percentile in children), sC5b-9 exceeding ULN, and proteinuria (rUPCR ≥1 mg/mg). (3) Patients with any of the following features are at increased risk of NRM and should be stratified as high-risk TA-TMA: elevated sC5b-9, LDH ≥2× ULN, rUPCR ≥1 mg/mg, multiorgan dysfunction, concurrent grade II–IV acute GVHD, or infection (bacterial or viral). (4) All allogeneic and pediatric autologous HCT recipients with neuroblastoma should be screened weekly for TA-TMA during the first 100 days post-HCT. The panel also identified knowledge gaps, including the need for more specific diagnostic and prognostic biomarkers, development of in vitro and in vivo models, and investigation of TA-TMA-directed therapy in the setting of concurrent GVHD and infection.

**Clinical Implications:** Universal adoption of these harmonized criteria is expected to enable consistent data collection across registries and clinical trials, facilitate early diagnosis through prospective screening, and allow risk-stratified management — with high-risk patients offered TA-TMA-directed therapy (ideally in clinical trials) and standard-risk patients monitored closely. The panel emphasized that these criteria will require continued refinement as data from diverse populations (varying in age, race, ethnicity, and HCT indication) become available. Efforts to identify more specific diagnostic and prognostic biomarkers were identified as a top priority.