Early clinical indicators of transplant-associated thrombotic microangiopathy in pediatric neuroblastoma patients undergoing auto-SCT

Laskin, Benjamin L.; Goebel, Jens; Davies, Stella M.; Khoury, Jane; Bleesing, Jack J.; Mehta, Parinda A.; Filipovich, Alexandra H.; Paff, Zachary; Lawrence, Julia; Yin, Hong; Pinkard, Susan L.; Jodele, Sonata

doi:10.1038/bmt.2010.182

Cited by 78 publications

(80 citation statements)

References 32 publications

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“…Although we previously observed a high risk of TMA after autologous transplantation, especially in children with neuroblastoma, none of the 10 autologous transplant recipients in our cohort developed TMA. 13,26 The overall incidence of TMA that we observed is higher than what has been reported by others, likely because we prospectively monitored all recipients in a uniform manner, in contrast to retrospective reports that likely captured only the most severe cases. 17,25,27 Consistent with our previous retrospective studies, we observed that proteinuria and hypertension were early markers of TMA and were Figure 4.…”

Section: Discussionmentioning

confidence: 58%

“…present in some subjects even before the full hematologic criteria became apparent. 26 Specifically, proteinuria .30 mg/dL as measured by routine dipstick and hypertension .95th percentile were the earliest signs of TMA, along with an elevation in the LDH. In contrast, kidney dysfunction assessed by serum creatinine was a very late marker, highlighting its limitations, as it remains an insensitive marker to detect impaired renal function in HSCT recipients, who potentially have low muscle mass and thus low creatinine generation rates.…”

Section: Discussionmentioning

confidence: 97%

“…In contrast, kidney dysfunction assessed by serum creatinine was a very late marker, highlighting its limitations, as it remains an insensitive marker to detect impaired renal function in HSCT recipients, who potentially have low muscle mass and thus low creatinine generation rates. 17,25,26,28,29 These observations suggest that a diagnosis of TMA should be considered in HSCT recipients with an acute elevation in LDH, proteinuria, and hypertension out of proportion to what would be expected from calcineurin inhibitor and steroid therapy. Importantly, these markers were apparent up to 2 weeks before schistocytes were detected.…”

Section: Discussionmentioning

confidence: 99%

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Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults

Jodele

Davies

Lane

et al. 2014

Blood

342

443

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• Proteinuria and elevated markers of complement activation at TMA diagnosis are associated with poor outcome.• Clinical interventions should be considered in HSCT patients with these high-risk features at the time TMA is diagnosed.Transplant-associated thrombotic microangiopathy (TMA) leads to generalized endothelial dysfunction that can progress to multiorgan injury, and severe cases are associated with poor outcomes after hematopoietic stem cell transplantation (HSCT). Identifying patients at highest risk for severe disease is challenging. We prospectively evaluated 100 consecutive HSCT recipients to determine the incidence of moderate and severe TMA and factors associated with poor overall outcomes. Thirty-nine subjects (39%) met previously published criteria for TMA. Subjects with TMA had a significantly higher nonrelapse mortality (43.6% vs 7.8%, P < .0001) at 1 year post-HSCT compared with those without TMA. Elevated lactate dehydrogenase, proteinuria on routine urinalysis, and hypertension were the earliest markers of TMA. Proteinuria (>30 mg/dL) and evidence of terminal complement activation (elevated sC5b-9) in the blood at the time of TMA diagnosis were associated with very poor survival (<20% at 1 year), whereas all TMA subjects without proteinuria and a normal sC5b-9 serum concentration survived (P < .01). Based on these prospective observations, we conclude that severe TMA occurred in 18% of HSCT recipients in our cohort and propose an algorithm to identify the highest-risk patients who might benefit from prompt clinical interventions. (Blood. 2014;124(4):645-653)

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults

Jodele

Davies

Lane

et al. 2014

Blood

342

443

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“…22 In fact, elevated systolic blood pressure has been identified as an early marker of TA-TMA in pediatric patients undergoing HSCT. 24 In a study, patients with TA-TMA were found to have higher average systolic blood pressure compared to non-TA-TMA group. Systolic hypertension was apparent approximately 1 week before the diagnosis of TA-TMA and persisted, despite aggressive antihypertensive therapy.…”

Section: Screening and Evaluationmentioning

confidence: 99%

Hematopoietic Stem Cell Transplant-Associated Thrombotic Microangiopathy

Elsallabi

Bhatt

Dhakal

et al. 2015

Clin Appl Thromb Hemost

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Hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal, multifactorial disorder, which may present with thrombocytopenia, hemolysis, acute renal failure, mental status changes and involvement of other organs. The pathogenesis of TA-TMA is complex and includes multiple risk factors such as certain conditioning regimens, calcineurin inhibitors (CNIs), graft-versus-host disease (GVHD), human leukocyte antigen mismatch, and opportunistic infections. The end result of these insults is endothelial injury in the kidney and other organs. Recent studies also indicate a role of complement activation in tissue damage. The lack of sensitive and specific diagnostic tests for TA-TMA often results in delayed diagnosis. Biopsy is not always possible for diagnosis because of the risk of complications such as bleeding. Recently, an emerging role of renal-centered screening approach has been demonstrated, which utilize the monitoring of blood pressure, urine protein, serum lactate dehydrogenase and hemogram for early detection. Therapeutic options are limited, and plasma exchange plays a minor role. Withdrawal of offending agent such as CNIs and the use of rituximab can be effective in some patients. However, the current treatment strategy is suboptimal and associated with high mortality rate. Recently, eculizumab has been utilized in a few patients with good outcomes. Patients, who develop TA-TMA, are also at an increased risk of GVHD, infection, renal, cardiovascular, and other complications, which can contribute to high mortality. Better understanding of molecular pathogenesis, improvement in posttransplant management, leading to early diagnosis, and management of TA-TMA are required to improve outcomes of this fatal entity.

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“…TA-TMA occurs in~25-30% of HSCT patients and is characterized by vascular endothelial damage leading to microangiopathic hemolytic anemia, thrombocytopenia and renal injury with multiorgan involvement and polyserositis in severe cases. 5,6 Mortality in patients with severe multiorgan TA-TMA is as high as 90%.…”

mentioning

confidence: 99%

Pericardial effusion in pediatric SCT recipients with thrombotic microangiopathy

Lerner

Dandoy

Hirsch

et al. 2014

Bone Marrow Transplant

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Early clinical indicators of transplant-associated thrombotic microangiopathy in pediatric neuroblastoma patients undergoing auto-SCT

Cited by 78 publications

References 32 publications

Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults

Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults

Hematopoietic Stem Cell Transplant-Associated Thrombotic Microangiopathy

Pericardial effusion in pediatric SCT recipients with thrombotic microangiopathy

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