In vitro evidence of complement activation in transplantation-associated thrombotic microangiopathy.
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ABSTRACT:
SUBMITTER: Rotz SJ
PROVIDER: S-EPMC5728339 | biostudies-literature | 2017 Sep
REPOSITORIES: biostudies-literature
Publications
In vitro evidence of complement activation in transplantation-associated thrombotic microangiopathy.
Rotz Seth J SJ Luebbering Nathan N Dixon Bradley P BP Gavriilaki Eleni E Brodsky Robert A RA Dandoy Christopher E CE Jodele Sonata S Davies Stella M SM
Blood advances 20170823 20
Transplantation-associated thrombotic microangiopathy is associated with complement activation in vitro.This data further supports the use of eculizumab for the treatment of patients with TA-TMA. ...[more]
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Project description:Transplant-associated thrombotic microangiopathy (TA-TMA) is a significant cause of mortality after hematopoietic stem cell transplant (HSCT). Complement blockade is an effective therapeutic strategy for TA-TMA, but some patients with severe disease lack a complete response, prompting a search for additional targetable endothelial injury pathways. We performed transcriptome analysis of peripheral blood mononuclear cells collected prior to HSCT and at onset of TA-TMA and observed significant up-regulation of classical and alternative complement pathways during active TA-TMA. At resolution of TA-TMA after eculizumab therapy, essentially all up-regulated genes and pathways returned to baseline expression levels, supporting the clinical practice of successfully discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling. To confirm our observations, we documented a high incidence of clinically significant TMA in children with hemophagocytic lymphohistiocytosis (HLH), an interferon gamma-driven disease, outside the setting of transplantation. We also confirmed increased interferon signaling in a separate cohort of patients by measuring CXCL9 and CXCL10 in urine. Our data suggest a key relationship between increased interferon signaling, complement activation, and TMA in two distinct clinical settings, HLH and TA-TMA. Combined anti-complement and anti-interferon treatment may facilitate disease control in patients with refractory TA-TMA. These data cast light on the occurrence of TMA in persons receiving therapeutic interferons, and possibility of TMA in other interferon-driven diseases where interferon may be a novel therapeutic target.
2020-03-30 | GSE134979 | GEO
Project description:Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling that resolved after complement blockade. In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome (aHUS), where complement activation occurs largely via the alternative pathway. Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. We propose a model of an "interferon-complement loop" that can perpetuate endothelial injury and thrombotic microangiopathy. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.
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Project description:Thrombotic microangiopathy (TMA) is a condition characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA) with varying degrees of organ damage in the setting of normal international normalized ratio and activated partial thromboplastin time. Complement has been implicated in the etiology of TMA, which are classified as primary TMA when genetic and acquired defects in complement proteins are the primary drivers of TMA (complement-mediated TMA or atypical hemolytic uremic syndrome, aHUS) or secondary TMA, when complement activation occurs in the context of other disease processes, such as infection, malignant hypertension, autoimmune disease, malignancy, transplantation, pregnancy, and drugs. It is important to recognize that this classification is not absolute because genetic variants in complement genes have been identified in patients with secondary TMA, and distinguishing complement/genetic-mediated TMA from secondary causes of TMA can be challenging and lead to potentially harmful delays in treatment. In this review, we focus on data supporting the involvement of complement in aHUS and in secondary forms of TMA associated with malignant hypertension, drugs, autoimmune diseases, pregnancy, and infections. In aHUS, genetic variants in complement genes are found in up to 60% of patients, whereas in the secondary forms, the finding of genetic defects is variable, ranging from almost 60% in TMA associated with malignant hypertension to less than 10% in drug-induced TMA. On the basis of these findings, a new approach to management of TMA is proposed.
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Project description:Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a life-threatening syndrome that occurs in adult and pediatric patients after hematopoietic stem cell transplantation. Nonspecific symptoms, heterogeneity within study populations, and variability among current diagnostic criteria contribute to misdiagnosis and underdiagnosis of this syndrome. Hematopoietic stem cell transplantation and associated risk factors precipitate endothelial injury, leading to HSCT-TMA and other endothelial injury syndromes such as hepatic veno-occlusive disease/sinusoidal obstruction syndrome, idiopathic pneumonia syndrome, diffuse alveolar hemorrhage, capillary leak syndrome, and graft-versus-host disease. Endothelial injury can trigger activation of the complement system, promoting inflammation and the development of endothelial injury syndromes, ultimately leading to organ damage and failure. In particular, the lectin pathway of complement is activated by damage-associated molecular patterns (DAMPs) on the surface of injured endothelial cells. Pattern-recognition molecules such as mannose-binding lectin (MBL), collectins, and ficolins-collectively termed lectins-bind to DAMPs on injured host cells, forming activation complexes with MBL-associated serine proteases 1, 2, and 3 (MASP-1, MASP-2, and MASP-3). Activation of the lectin pathway may also trigger the coagulation cascade via MASP-2 cleavage of prothrombin to thrombin. Together, activation of complement and the coagulation cascade lead to a procoagulant state that may result in development of HSCT-TMA. Several complement inhibitors targeting various complement pathways are in clinical trials for the treatment of HSCT-TMA. In this article, we review the role of the complement system in HSCT-TMA pathogenesis, with a focus on the lectin pathway.
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Project description:Activation of Interferon and Complement Pathways in Thrombotic Microangiopathy
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Project description:Whether C5 blocking may improve the outcomes of patients developing chemotherapy-induced thrombotic microangiopathy (TMA) remains elusive. Lung fibrosis is a well-known complication of bleomycin, whereas TMAs are very rare (<20 cases described). Here, we report an exceptional case of a male patient that developed acute respiratory distress syndrome and TMA following administration of bleomycin, cisplatin and etoposide . Refractoriness to plasma exchanges prompted us to use eculizumab as salvage therapy. Eculizumab led to complete remission of the TMA before Day 2. However, the patient progressed towards refractory respiratory failure, suggesting that pathophysiological mechanisms of bleomycin-induced lung fibrosis and TMA differ.
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Project description:Complement activation has a major role in thrombotic microangiopathy (TMA), a disorder that can occur in a variety of clinical conditions. Promising results of recent trials with terminal complement-inhibiting drugs call for biomarkers identifying patients who might benefit from this treatment. The primary aim of this study was to determine the prevalence and localization of complement factor C4d in kidneys of patients with TMA. The secondary aims were to determine which complement pathways lead to C4d deposition and to determine whether complement activation results in deposition of the terminal complement complex. We examined 42 renal sections with histologically confirmed TMA obtained from a heterogeneous patient group. Deposits of C4d, mannose-binding lectin, C1q, IgM, and C5b-9 were scored in the glomeruli, peritubular capillaries, and arterioles. Notably, C4d deposits were present in 88.1% of TMA cases, and the various clinical conditions had distinct staining patterns within the various compartments of the renal vasculature. Classical pathway activation was observed in 90.5% of TMA cases. C5b-9 deposits were present in 78.6% of TMA cases and in 39.6% of controls (n=53), but the staining pattern differed between cases and controls. In conclusion, C4d is a common finding in TMA, regardless of the underlying clinical condition. Moreover, C5b-9 was present in >75% of the TMA samples, suggesting that terminal complement inhibitors may have a beneficial effect in these patients. C4d and C5b-9 should be investigated as possible diagnostic biomarkers in the clinical work-up of patients suspected of having complement-mediated TMA.
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Project description:Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous reports suggest that TA-TMA is caused by complement activation by complement-related genetic variants; however, this needs to be verified, especially in adults. Here, we performed a nested case-control study of allo-HSCT-treated adults at a single center. Fifteen TA-TMA patients and 15 non-TA-TMA patients, matched according to the propensity score, were enrolled. Based on a previous report showing an association between complement-related genes and development of TA-TMA, we first sequenced these 17 genes. Both cohorts harbored several genetic variants with rare allele frequencies; however, there was no difference in the percentage of patients in the TA-TMA and non-TA-TMA groups with the rare variants, or in the average number of rare variants per patient. Second, we measured plasma concentrations of complement proteins. Notably, levels of Ba protein on Day 7 following allo-HSCT were abnormally and significantly higher in TA-TMA than in non-TA-TMA cases, suggesting that complement activation via the alternative pathway contributes to TA-TMA. All other parameters, including soluble C5b-9, on Day 7 were similar between the groups. The levels of C3, C4, CH50, and complement factors H and I in the TA-TMA group after Day 28 were significantly lower than those in the non-TA-TMA group. Complement-related genetic variants did not predict TA-TMA development. By contrast, abnormally high levels of Ba on Day 7 did predict development of TA-TMA and non-relapse mortality. Thus, Ba levels on Day 7 after allo-HSCT are a sensitive and prognostic biomarker of TA-TMA.
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