Transplantation-Associated Thrombotic Microangiopathy Risk Stratification: Is There a Window of Opportunity to Improve Outcomes?

Jodele, Sonata; Dandoy, Christopher E.; Sabulski, Anthony; Koo, Jane; Lane, Adam; Myers, Kasiani C.; Wallace, Gregory; Chima, Ranjit S.; Teusink‐Cross, Ashley; Hirsch, Russel; Ryan, Thomas; Benoit, Stefanie; Davies, Stella M.

doi:10.1016/j.jtct.2022.04.019

Cited by 20 publications

(26 citation statements)

References 18 publications

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“…This study lastly suggests that scheduled soluble C5b-9 measurements could promptly identify patients at risk for poor outcomes and would facilitate early TA-TMA-directed therapy to prevent organ injury. Moreover, an updated TA-TMA risk algorithm incorporating laboratory biomarkers, clinical findings, and comorbid conditions was generated using this study’s findings for managing TA-TMA ( 127 ). Lastly, the measurement of haptoglobin in blood samples from TA-TMA patients has been proposed as diagnostic criteria.…”

Section: Biomarkers Of Endothelial Damage For the Diagnosis Prognosti...mentioning

confidence: 99%

Early vascular endothelial complications after hematopoietic cell transplantation: Role of the endotheliopathy in biomarkers and target therapies development

Moreno-Castaño

Salas²,

Palomo³

et al. 2022

Front. Immunol.

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This work aims to review the role of endothelial dysfunction underlying the main complications appearing early after autologous and allogeneic hematopoietic cell transplantation (HCT). The endothelial damage as the pathophysiological substrate of sinusoidal obstruction syndrome (SOS) is well established. However, there is growing evidence of the involvement of endothelial dysfunction in other complications, such as acute graft-versus-host disease (aGVHD) and transplant-associated thrombotic microangiopathy (TA-TMAs). Moreover, HCT-related endotheliopathy is not only limited to the HCT setting, as there is increasing evidence of its implication in complications derived from other cellular therapies. We also review the incidence and the risk factors of the main HCT complications and the biological evidence of the endothelial involvement and other linked pathways in their development. In addition, we cover the state of the art regarding the potential use of the biomarkers of endotheliopathy in the prediction, the early diagnosis, and the follow-up of the HCT complications and summarize current knowledge points to the endothelium and the other linked pathways described as potential targets for the prevention and treatment of HCT-complications. Lastly, the endothelium-focused therapeutic strategies that are emerging and might have a potential impact on the survival and quality of life of post-HCT-patients are additionally reviewed.

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Section: Biomarkers Of Endothelial Damage For the Diagnosis Prognosti...mentioning

confidence: 99%

Early vascular endothelial complications after hematopoietic cell transplantation: Role of the endotheliopathy in biomarkers and target therapies development

Moreno-Castaño

Salas²,

Palomo³

et al. 2022

Front. Immunol.

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“… 51 Furthermore, Jodele et al published an updated risk stratification for TA-TMA that identifies concurrent grades 2 to 4 GVHD as a high-risk feature of TA-TMA. 52 These findings suggest the exact type of hits present are important in the disease progression of TA-TMA. Because of the limited number of patients in the autopsy study, we were unable to investigate these specific hits and their impact on CNS TA-TMA, and we therefore recommend further investigation.…”

Section: Discussionmentioning

confidence: 90%

Cerebral vascular injury in transplant-associated thrombotic microangiopathy

et al. 2022

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Transplant-associated thrombotic microangiopathy (TA-TMA) and atypical hemolytic uremic syndrome (aHUS) are complement-mediated TMAs. The central nervous system (CNS) is the most common extrarenal organ affected by aHUS, and, despite mechanistic overlap between aHUS and TA-TMA, CNS involvement is rarely reported in TA-TMA, suggesting that CNS involvement in TA-TMA may be underdiagnosed and that these patients may benefit from complement blockers. In addition, there are no widely used histologic or radiologic criteria for the diagnosis of TMA in the brain. Thirteen recipients of pediatric hematopoietic cell transplants (HCTs) who had TA-TMA and who underwent autopsy were studied. Seven of 13 brains had vascular injury, and 2 had severe vascular injury. Neurologic symptoms correlated with severe vascular injury. Classic TMA histology was present and most often observed in the cerebellum, brainstem, and cerebral white matter. Abnormalities in similar anatomic regions were seen on imaging. Brain imaging findings related to TMA included hemorrhages, siderosis, and posterior reversible encephalopathy syndrome. We then studied 100 consecutive HCT recipients to identify differences in neurologic complications between patients with and those without TA-TMA. Patients with TA-TMA were significantly more likely to have a clinical concern for seizure, have an electroencephalogram performed, and develop altered mental status. In summary, our study confirms that TA-TMA involves the brains of recipients of HCT and is associated with an increased incidence of neurologic symptoms. Based on these findings, we propose that patients with low- or moderate-risk TA-TMA who develop neurologic complications should be considered for TA-TMA–directed therapy.

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“…Outcomes included death, non-relapse mortality, and neurological dysfunction ( 50 ). Four studies reported prognostic implications of sC5b-9 including (1) values ≥ 244 ng/dl at the time of diagnosis ( 2 ); (2) a change in level of 1.8-fold from baseline to diagnosis ( 51 ); (3) an increase of a log at the time of TA-TMA ( 51 ); and (4) levels of sC5b-9 ≥300 ng/l and ANG-2 > 3000 pg/ml in patients with concurrent TA-TMA and GVHD ( 36 ). Markers of microangiopathy including decreased levels of haptoglobin ( 52 ), elevated levels of LDH ( 15 , 53 ), and scores that use laboratory values of microangiopathy, including BATAP (bilirubin, age, thrombocytopenia, anemia, proteinuria) ( 54 ) TMA index (LDH/platelets), and an EASIX score ( 55 ), all portended a poor prognosis.…”

Section: Resultsmentioning

confidence: 99%

A systematic review of diagnostic, prognostic, and risk blood and urine biomarkers of transplant-associated thrombotic microangiopathy

2023

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Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of allogeneic and autologous hematopoietic cellular therapy (HCT), associated with significant morbidity and mortality. Although the central drivers of the disease are thought to be endothelial damage and complement activation, no specific diagnostic biomarkers have been identified. TA-TMA is typically diagnosed using criteria comprised of non-specific clinical and laboratory features. Some patients will have a self-remitting course, but more than half develop multi-organ dysfunction or die, making prognostic biomarkers critical. Prevention of TA-TMA, an approach central to other HCT complications such as graft-versus-host disease, is largely untested in part due to a lack of identified early high-risk biomarkers. We conducted a systematic review to summarize the diagnostic, early risk, and prognostic biomarkers of TA-TMA. We screened the titles and abstracts of 1524 citations. After screening out duplications, we read the abstracts of 979 papers and fully reviewed 132 full-text publications. Thirty-one publications fulfilled the inclusion criteria of more than five patients with TA-TMA and a reported measure of association with diagnosis, prognosis, or risk of later development of the disease. Fourteen studies (45%) were with adults, 12 (39%) were with children <18 years old, three included both children and adults, and two did not report age. There were 53 biomarker or biomarker signature entries, and a total of 27 unique biomarkers. Only four biomarkers reported sensitivity and specificity. The single biomarker with the most robust data was sC5b-9, which conferred diagnostic, prognostic, and risk implications. Studies of combinations of biomarkers were rare. No meta-analyses were performed because of significant heterogeneity between studies. The limitations of studies included small sample size, study designs with a high risk of bias (i.e., case–control), the timing of sample collection, and the selection of controls. Furthermore, only two (6%) studies included a training and validation cohort. Cut-off points are needed to stratify groups, as most biomarkers do not have normal values, or normal values cannot be assumed in the HCT setting. In the future, multi-institutional, collaborative efforts are needed to perform rigorously designed, prospective studies with serially enrolled patients, with samples collected at the time of TA-TMA diagnosis, careful selection of controls, and validation of selected biomarkers and cut-off points in a separate cohort.

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Transplantation-Associated Thrombotic Microangiopathy Risk Stratification: Is There a Window of Opportunity to Improve Outcomes?

Cited by 20 publications

References 18 publications

Early vascular endothelial complications after hematopoietic cell transplantation: Role of the endotheliopathy in biomarkers and target therapies development

Early vascular endothelial complications after hematopoietic cell transplantation: Role of the endotheliopathy in biomarkers and target therapies development

Cerebral vascular injury in transplant-associated thrombotic microangiopathy

A systematic review of diagnostic, prognostic, and risk blood and urine biomarkers of transplant-associated thrombotic microangiopathy

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