The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy

Jodele, Sonata; Zhang, Kejian; Zou, Fanggeng; Laskin, Benjamin L.; Dandoy, Christopher E.; Myers, Kasiani C.; Lane, Adam; Meller, Jaroslav; Medvedovic, Mario; Chen, Jenny; Davies, Stella M.

doi:10.1182/blood-2015-08-663435

Cited by 157 publications

(156 citation statements)

References 33 publications

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“…Factor H autoantibodies or gene variations or mutations are present in some patients with TA-TMA after SCT [12, 30]. Our findings suggest a role of complement activation in pathogenesis of TA-TMA following allo-SCT.…”

Section: Discussionmentioning

confidence: 74%

“…Three of the six patients with TA-TMA after allo-SCT also demonstrated the presence of factor H autoantibodies [2]. Another study also showed that allo-SCT recipients with multiple complement gene variants (≥ 3) were at high risk for development of TA-TMA [12]. These results implied that increased numbers of complement gene variants predispose to TA-TMA, which contributes to the transplant-related mortality [12].…”

Section: Introductionmentioning

confidence: 99%

“…Another study also showed that allo-SCT recipients with multiple complement gene variants (≥ 3) were at high risk for development of TA-TMA [12]. These results implied that increased numbers of complement gene variants predispose to TA-TMA, which contributes to the transplant-related mortality [12]. Arteriolar C4d deposition was found in the kidney disease following SCT [13].…”

Section: Introductionmentioning

confidence: 99%

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Plasma levels of complement activation fragments C3b and sC5b-9 significantly increased in patients with thrombotic microangiopathy after allogeneic stem cell transplantation

Wang

Chen

et al. 2017

Ann Hematol

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Transplantation-associated thrombotic microangiopathy (TA-TMA) is an uncommon but severe complication in patients undergoing allogeneic stem cell transplantation (allo-SCT). However, the mechanism is unclear. From 2011 to 2014, 20 patients with TA-TMA, 20 patients without, and 54 patients with various other complications, including veno occlusive disease (VOD), graft-versus-host disease (GVHD), and infection, were recruited in the study. Plasma vWF antigen (vWFAg), vWF activity (vWFAc), and ADAMTS13 activity were determined in these patients by ELISAs and FRETS-vWF73 assay, respectively. Plasma C3b, sC5b-9, and CH50 were also determined by ELISAs. Plasma levels of C3b were significantly increased in patients with either TA-TMA (p < 0.0001) or GVHD (p < 0.01). Plasma sC5b-9 and CH50 levels in patients with TA-TMA were also significantly increased (p < 0.001). Plasma ADAMTS13 activity was lower in patients with VOD, but normal with other complications. Both plasma vWFAg and vWFAc levels were not elevated in patients with TA-TMA or VOD compared with those of other groups. Complement activation likely via an alternative pathway (increased C3b, sC5b-9, and CH50) may play a role in the pathogenesis of TA-TMA. ADAMTS13 activity is reduced in VOD, but the ADAMTS13/vWF axis appears to be unaffected in patients with TA-TMA.

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Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Plasma levels of complement activation fragments C3b and sC5b-9 significantly increased in patients with thrombotic microangiopathy after allogeneic stem cell transplantation

Wang

Chen

et al. 2017

Ann Hematol

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“…For example, sirolimus, cyclosporine or tacrolimus have been associated with PRES and may be withdrawn if they are felt to be contributing to the development of PRES. 118 TMA and genetic susceptibility to TMA 119 can also be associated with neurocognitive dysfunction and also require prompt identification and management. 120 …”

Section: Interventionsmentioning

confidence: 99%

Neurocognitive dysfunction in hematopoietic cell transplant recipients: expert review from the late effects and Quality of Life Working Committee of the CIBMTR and complications and Quality of Life Working Party of the EBMT

Buchbinder

Kelly

Duarte

et al. 2018

Bone Marrow Transplant

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Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and non-malignant diseases. Despite increasing survival rates, long-term morbidity following HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction following HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction following HCT. In this review, we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and to help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Lastly, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae following HCT.

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“…The diagnosis of intestinal TMA relies primarily on histopathologic evaluation demonstrating hyaline thrombi in the capillaries of intestinal biopsies, or the presence of thrombonecrotic arteriolar lesions in the intestine on autopsy (44,45). Recent reports have revealed that activation and dysregulation of the complement alternative pathway may be a major contributor to endothelial damage incurred during TA-TMA (46,47). These findings are significant as they may identify a genetic susceptibility for disease development and ultimately guide the institution of novel treatment strategies to improve outcomes.…”

Section: Hematopoietic Stem Cell Transplantationmentioning

confidence: 99%

Specific Etiologies Associated With the Multiple Organ Dysfunction Syndrome in Children: Part 1

Upperman

Lacroix

Curley

et al. 2017

Pediatric Critical Care Medicine

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Objective To describe a number of the conditions associated with multiple organ dysfunction syndrome (MODS) presented as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development MODS Workshop (March 26–27, 2015). Data Sources Literature review, research data, and expert opinion. Study Selection Not applicable. Data Extraction Moderated by an expert from the field, issues relevant to the association of MODS with a variety of conditions were presented, discussed and debated with a focus on identifying knowledge gaps and research priorities. Data Synthesis Summary of presentations and discussion supported and supplemented by relevant literature. Conclusions There is a wide range of medical conditions associated with MODS in children. Traditionally, sepsis and trauma are the two conditions most commonly associated with MODS both in children and adults. However, there are a number of other pathophysiologic processes that may result in MODS. In this paper, we discuss conditions such as cancer, congenital heart disease and acute respiratory distress syndrome. In addition, the relationship between MODS and clinical therapies such as hematopoietic stem cell transplantation and cardiopulmonary bypass are also considered. The purpose of this manuscript is to describe the association of MODS with a variety of conditions in an attempt to identify similarities, differences and opportunities for therapeutic intervention.

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The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy

Abstract: Key Points HSCT recipients with multiple complement gene variants (≥3) are at high risk for severe TA-TMA. Increased numbers of complement gene variants predisposing to TMA might contribute to racial disparities in transplant-related mortality.

Cited by 157 publications

References 33 publications

Plasma levels of complement activation fragments C3b and sC5b-9 significantly increased in patients with thrombotic microangiopathy after allogeneic stem cell transplantation

Plasma levels of complement activation fragments C3b and sC5b-9 significantly increased in patients with thrombotic microangiopathy after allogeneic stem cell transplantation

Neurocognitive dysfunction in hematopoietic cell transplant recipients: expert review from the late effects and Quality of Life Working Committee of the CIBMTR and complications and Quality of Life Working Party of the EBMT

Specific Etiologies Associated With the Multiple Organ Dysfunction Syndrome in Children: Part 1

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