Transplantation-associated thrombotic microangiopathy (TA-TMA) is a devastating complication of hematopoietic stem cell transplantation. TA-TMA likely represents the final stage of vascular endothelial injury; however, its pathophysiology is largely unknown, making clinical management difficult. Recently, the association of neutrophil extracellular traps (NETs) with the development of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome has been reported. Thus, we explored whether NETs are also relevant to the occurrence of TA-TMA. We retrospectively analyzed post-transplant trends of serum NET levels in 90 patients, 11 of whom developed TA-TMA. Relative to baseline (before the conditioning regimen), elevated serum NET levels either at 4 weeks after transplantation or as early as the day of transplantation were associated with significantly increased risk of TA-TMA. In contrast, thrombomodulin, a potential marker for TA-TMA, was not helpful to predict the occurrence of TA-TMA in our study. In addition, we directly detected glomerular deposition of NETs in 2 TA-TMA patients. Increased NET levels are a significant risk factor for TA-TMA, suggesting that NET level is a useful biomarker for TA-TMA.
In March 2009, a 17-year-old woman was first diagnosed with acute myelogenous leukemia and myelodysplasia-related changes. She underwent chemotherapy and allogeneic hematopoietic stem cell transplantation, which resulted in complete remission. However, she experienced relapse, and remission was achieved each time with repeated transplantation. In September 2014, a human leukocyte antigen (HLA)-haploidentical transplantation, which was the fifth allogeneic transplantation, was performed to treat the third relapse. Platelet transfusion refractoriness, hemolytic anemia with schistocytes, and renal dysfunction were observed from approximately the day of engraftment; therefore, transplantation-associated thrombotic microangiopathy (TA-TMA) was diagnosed. Recombinant human soluble thrombomodulin (rTM) was administered, and fresh-frozen plasma (FFP) was infused; this resulted in gradual improvement of TA-TMA. Treatment with rTM and FFP was discontinued on the 70th day after transplantation. Because the HLA-haploidentical transplantation was the fifth allogeneic transplantation, the risk of aggravation of TA-TMA was very high. Combined treatment with rTM and FFP, however, resulted in improvement of TA-TMA. Further investigation of similar cases is necessary for clarifying the usefulness of rTM for TA-TMA.
Granulocyte/macrophage colony-stimulating factor (GM-CSF) inhibits Fas-induced apoptosis of neutrophils. However, the exact step in the apoptotic pathway blocked by GM-CSF remained unclear. Here, we found that pretreatment of neutrophils with GM-CSF inhibits the recruitment of Fas-associated protein with death domain (FADD) to Fas, abolishing the formation of the death-inducing signaling complex required for Fas-induced apoptosis. Two-dimensional electrophoresis revealed that GM-CSF modifies the ratio of FADD subspecies. These GM-CSF-triggered changes were abrogated, and Fas-induced apoptosis was restored by an inhibitor of classical protein kinase C (PKC), Go6976, and by the combination of a phosphatidylinositol 3-kinase (PI-3K) inhibitor, LY294002, and an inhibitor of mitogen-activated protein kinase kinase (MEK)1, PD98059. Go6976 blocked GM-CSF-elicited phosphorylation of Akt/PKB and extracellular signal-regulated kinase (ERK)1/2. These results indicated that GM-CSF suppresses Fas-induced neutrophil apoptosis by inhibiting FADD binding to Fas, through redundant actions of PI-3K and MEK1-ERK1/2 pathways downstream of classical PKC.
FMS-like tyrosine kinase 3 (FLT3), a class III tyrosine kinase receptor, plays an important role in the pro- liferation, survival, and differentiation of hematopoietic stem/progenitor cells. Approximately 30% of pa- tients with cytogenetically normal acute myeloid leukemia (CN-AML) harbor FLT3 mutations. The most frequent FLT3 mutations are internal tandem duplications (ITDs) in the juxtamembrane domain. FLT3-ITD mutations cause ligand-independent dimerization of FLT3 and the constitutive activation of its downstream signaling pathways, such as PI3K/AKT, A4APK/ERK, and STAT5, leading to dysregulated cellular prolifera- tion. The relapse risk of CN-AML patients with FLT3-ITD is higher and the overall survival (OS) of such patients is shorter than those of patients with wild-type FLT3. Recently genome-wide studies with next-generation sequencing have suggested that mutational combinations of genes related to signal transduction, transcription, splicing, cancer suppressors, and epigenetics contribute to the pathogenesis of AML. These mutations including FLT3-ITD may be prognostic factors facilitating the risk stratification for CN-AML. The point mutations D835/I836 in the tyrosine kinase domain (TKD) are detected in 5-7% of AML patients. The clinical relevance of these FLT3-TKD mutations remains unclear. FLT3-TKD mutations are detected even in patients treated with FLT3 inhibitors as secondary mutations, suggesting that the mutations are as- sociated with the resistance. Therefore, the detection of these mutations might provide us with the opportunity to consider appropriate treatment for patients. The molecular abnormalities in AML patients give us insights into the pathology of AML and clinically significant information required for the diagnosis, prognosis, and treatment decisions. [Review].
The rate at which patients are accurately diagnosed with hereditary angioedema (HAE), as well as diagnosed patients access to modern treatments differs greatly among countries. Moreover, the severity and burden of HAE on patients have been reported mostly on the basis of physician-reported surveys. To gain insight into the real-world conditions of patients with HAE through a patient-reported survey in Japan and identify any unmet needs.A questionnaire was distributed to 121 patients with HAE via a Japanese HAE patient organization during 2016-2017. Responses were collected from 70 patients (57.9%) and subjected to analysis.The average periods from the initial appearance of symptoms (e.g. edema) to a HAE diagnosis was 15.6 years (min-max, 0-53). Patients visited an average of 4.6 different departments until receiving a definitive diagnosis. The average age at the first visit was 25.6 years (3-73) and at diagnosis 32.8 years (0-73). Patients reported an average of 15.7 (0-100) attacks per year, but only 53.1% of attacks were treated. The days of hospitalization due to severe attacks was 14.3 (0-200) before diagnosis, but these declined to 4.3 (0-50) after diagnosis. In the treatment for attacks, 82% of the patients were treated with the plasma-derived C1 inhibitor concentrate, and 69% of the patients reported experiencing a therapeutic effect.There is a long gap between first attack and diagnosis of HAE, and the number of non-treated attacks is high in Japan. Steps are needed to improve the diagnostic and treatment environments to address these issues.
