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

Abstract

Transplantation-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplantation (HCT) associated with significant morbidity and mortality. However, TA-TMA is a clinical diagnosis, and multiple criteria have been proposed without universal application. Although some patients have a self-resolving disease, others progress to multiorgan failure and/or death. Poor prognostic features also are not uniformly accepted. The lack of harmonization of diagnostic and prognostic markers has precluded multi-institutional studies to better understand incidence and outcomes. Even current interventional trials use different criteria, making it challenging to interpret the data. To address this urgent need, the American Society for Transplantation and Cellular Therapy, Center for International Bone Marrow Transplant Research, Asia-Pacific Blood and Marrow Transplantation, and European Society for Blood and Marrow Transplantation nominated representatives for an expert panel tasked with reaching consensus on diagnostic and prognostic criteria. The panel reviewed literature, generated consensus statements regarding diagnostic and prognostic features of TA-TMA using the Delphi method, and identified future directions of investigation. Consensus was reached on 4 key concepts: (1) TA-TMA can be diagnosed using clinical and laboratory criteria or tissue biopsy of kidney or gastrointestinal tissue; however, biopsy is not required; (2) consensus diagnostic criteria are proposed using the modified Jodele criteria with additional definitions of anemia and thrombocytopenia. TA-TMA is diagnosed when ≥4 of the following 7 features occur twice within 14 days: anemia, defined as failure to achieve transfusion independence despite neutrophil engraftment; hemoglobin decline by ≥1 g/dL or new-onset transfusion dependence; thrombocytopenia, defined as failure to achieve platelet engraftment, higher-than-expected transfusion needs, refractory to platelet transfusions, or ≥50% reduction in baseline platelet count after full platelet engraftment; lactate dehydrogenase (LDH) exceeding the upper limit of normal (ULN); schistocytes; hypertension; soluble C5b-9 (sC5b-9) exceeding the ULN; and proteinuria (≥1 mg/mg random urine protein-to-creatinine ratio [rUPCR]); (3) patients with any of the following features are at increased risk of nonrelapse mortality and should be stratified as high-risk TA-TMA: elevated sC5b-9, LDH ≥2 times the ULN, rUPCR ≥1 mg/mg, multiorgan dysfunction, concurrent grade II-IV acute graft-versus-host disease (GVHD), or infection (bacterial or viral); and (4) all allogeneic and pediatric autologous HCT recipients with neuroblastoma should be screened weekly for TA-TMA during the first 100 days post-HCT. Patients diagnosed with TA-TMA should be risk-stratified, and those with high-risk disease should be offered participation in a clinical trial for TA-TMA-directed therapy if available. We propose that these criteria and risk stratification features be used in data registries, prospective studies, and clinical practice across international settings. This harmonization will facilitate the investigation of TA-TMA across populations diverse in race, ethnicity, age, disease indications, and transplantation characteristics. As these criteria are widely used, we expect continued refinement as necessary. Efforts to identify more specific diagnostic and prognostic biomarkers are a top priority of the field. Finally, an investigation of the impact of TA-TMA-directed treatment, particularly in the setting of concurrent highly morbid complications, such as steroid-refractory GVHD and infection, is critically needed.

Keywords: Complement; Diagnostic criteria; Nonrelapse mortality; Risk stratification; Transplantation-associated thrombotic microangiopathy.

Figure 1.

Proposed pathophysiology of TA-TMA and potential biomarkers. Endothelial cells (ECs) are thought to be damaged by chemotherapy administered as part of the preparative regimen, medications, and complications of BMT. Damaged ECs release ANG-2, leading to vascular destabilization and release of IL-8. Local recruitment of antigen-presenting cells (APCs) and lymphocytes results from the expression of increased adhesion molecules by activated APCs. APCs also express TNF-α and INF-γ, which further activate neutrophils and T cells, which then release neutrophil extracellular traps (NETs). This leads to the activation of a component of the alternative complement pathway, C3b, which binds to the endothelial surface, leading to formation of the membrane activating complex (MAC) on ECs, further contributing to direct ongoing damage of the ECs. The formation of microthrombi ensues next, whereby tissue factor released from the damaged ECs binds factor VIIA and von Willebrand factor (vWF), promoting platelet activation and subsequent thrombus formation. Microthrombi then lead to organ ischemia and end-organ damage (eg, renal failure). Markers of any of these pathways may have diagnostic or prognostic implications in TA-TMA. sC5b-9 and dsDNA (marker of NETs) have been tested for diagnostic utility, but the other markers have not. Potential biomarkers include soluble selectins, markers of endothelial injury, inflammatory cytokines, components of complement cascade other than sC5b-9, and markers of thrombosis. V-CAM indicates vascular cell adhesion molecule; I-CAM, intercellular adhesion molecule (Figure created using Biorender). Figure modified with permission from Schoettler, et al. Current Opinion Hematology, 2021. Schoettler M, Chonat S, Williams K, Lehmann L. Emerging therapeutic and preventive approaches to transplant-associated thrombotic microangiopathy. Curr Opin Hematol. 2021 Nov 1;28 (6):408–416. doi: 10.1097/MOH.0000000000000687. PMID: 34534983.

Figure 2.

Recommended screening and diagnostic workup for TA-TMA. There is sufficient evidence supporting routine screening of all allogeneic and pediatric autologous HCT recipients with an underlying diagnosis of neuroblastoma through day 100 post-HCT. Screening also should be considered after day 100 in patients who develop a known risk factor for TA-TMA, including acute GVHD, chronic GVHD, or infection. In patients with ≥3 abnormal screening laboratory test results or clinical manifestations or organ dysfunction concerning for TA-TMA, additional testing should be done. In patients who meet the criteria for high-risk TA-TMA, treatment with TA-TMA-directed therapy should be considered. Patients who do not meet high-risk criteria should be monitored closely, and treatment may be initiated at the discretion of the clinician if cytopenia or other manifestations persist. Triggers of TA-TMA (eg, infection, GVHD) should be aggressively managed. *sC5b-9 is not available at all centers. If sC5b-9 testing is not available, screening of urine and other organ function should continue, and treatment offered to patients meeting high-risk TA-TMA criteria.