Thrombotic Microangiopathy: Multi-Institutional Review of Pediatric Patients Who Underwent HSCT

Abstract

Thrombotic microangiopathy (TMA) is a rare but serious complication of hematopoietic stem cell transplantation (HSCT). The purpose of our study is to estimate the incidence, prevalence, and analyze the risk factors and outcome of TMA in children receiving HSCT. Patients under the age of 21 who underwent HSCT at one of the 42 Pediatric Health Information System (PHIS) hospitals from 2000–2012 were analyzed, including demographics, hospitalizations, TMA, and other HSCT-related complications. From 2000 to 2012, a total of 12,369 unique pediatric patients who received HSCT were identified. Among these, 93 (0.8%) children were identified to have the diagnosis of TMA. TMA was significantly associated with allogeneic HSCT, peripheral blood stem cell trasnplants (PBSCT), cytomegalovirus (CMV), human herpes virus 6 (HHV6), fungal infection, graft-versus-host disease (GVHD), and veno-occlusive disease (VOD) (p = 0.01). Multivariate logistic regression analysis of mortality showed only HHV6 was an independent risk factor associated with increased mortality in patients with TMA (hazard ratio: 2.86 [1.01, 8.39], p = 0.05). The prevalence of TMA in our study is 0.8% with a mortality in our pediatric TMA cohort of 30%, which is in contrast to the higher mortality reported in previously published, small-case series. HHV6 emerged as not only a risk factor for TMA but also as associated with increased mortality in these patients.

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy and the role of advanced practice providers and pharmacists

“…A historic lack of consensus on diagnostic criteria has been a likely contributor to the wide range of incidences reported in clinical research [20,21]. Several clinical signs have been proposed as supporting a diagnosis of HSCT-TMA, including thrombocytopenia, hemolytic anemia, absence of antibodies, tissue damage, kidney dysfunction, and hypertension (Table 1) [19,[22][23][24][25][26].…”

“…HSCT-TMA is often underdiagnosed, with one study reporting confirmed diagnoses in fewer than half of patients with suspected cases [ 9 ]. This is particularly evident in real-world clinical practice, where fewer than 1% of pediatric patients receiving HSCT are diagnosed with HSCT-TMA [ 20 ].…”

Rare variants in complement system genes associate with endothelial damage after pediatric allogeneic hematopoietic stem cell transplantation

“…Endothelial cells can be damaged and activated during the HSCT process by several mechanisms, including previous chemotherapy, conditioning (e.g. irradiation), drugs used in the transplantation process (such as G-CSF or calcineurin inhibitors), cytokines produced by activated immune cells or the injured tissues, infections, engraftment and alloreactivity (9)(10)(11). Injury and inflammation involve neutrophil activation leading to formation of neutrophil extracellular traps (NETs).…”

“…Although not emphasized earlier, the second hit could, in addition to procoagulant activity, also involve “procomplement” activity with changes in the ability of endothelial cells to protect themselves against complement attack ( 5 ). Currently a “three hit” –hypothesis, where the first hit is the patients´ genetic predisposition to endothelial complications, is considered most relevant to the disease pathogenesis ( 5 , 11 , 20 , 21 ).…”