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Drug-induced Thrombotic Microangiopathy Caused by Gemcitabine.

ABSTRACT: Hemolytic uremic syndrome (HUS) is the triad of nonimmune (Coombs negative) hemolytic anemia, low platelet count, and renal impairment. HUS has been associated with a variety of gastrointestinal malignancies and chemotherapeutic agents. We present a patient with pancreatic cancer treated with gemcitabine for palliation who developed gemcitabine-induced HUS (GiHUS) which responded to some extent to blood and platelet transfusions. With the increase in the use of gemcitabine therapy for pancreatic and other malignancies, it is essential to accurately and timely diagnose GiHUS to avoid the life-threatening complications.

SUBMITTER: Hasan A

PROVIDER: S-EPMC6171780 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other

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Drug-induced Thrombotic Microangiopathy Caused by Gemcitabine.

Hasan Askari A Jain Akriti G AG Naim Huda H Munaf Alvina A Everett George G

Cureus 20180802 8

Hemolytic uremic syndrome (HUS) is the triad of nonimmune (Coombs negative) hemolytic anemia, low platelet count, and renal impairment. HUS has been associated with a variety of gastrointestinal malignancies and chemotherapeutic agents. We present a patient with pancreatic cancer treated with gemcitabine for palliation who developed gemcitabine-induced HUS (GiHUS) which responded to some extent to blood and platelet transfusions. With the increase in the use of gemcitabine therapy for pancreatic ...[more]

PMID: 30324044

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Treatment of Gemcitabine-Induced Thrombotic Microangiopathy Followed by Gemcitabine Rechallenge With Eculizumab.

Project description: Not available

| S-EPMC8116759 | biostudies-literature

Eculizumab in gemcitabine-induced thrombotic microangiopathy: experience of the French thrombotic microangiopathies reference centre.

Project description:BackgroundGemcitabine is a broadly prescribed chemotherapy, the use of which can be limited by renal adverse events, including thrombotic microangiopathy (TMA).MethodsThis study evaluated the efficacy of eculizumab, a monoclonal antibody targeting the terminal complement pathway, in patients with gemcitabine-induced TMA (G-TMA). We conducted an observational, retrospective, multicenter study in 5 French centres, between 2011 and 2016.ResultsTwelve patients with a G-TMA treated by eculizumab were included. The main characteristics were acute renal failure (100%), including stage 3 acute kidney injury (AKI, 58%) and renal replacement therapy (17%), hypertension (92%) and diffuse oedema (83%). Eculizumab was started after a median of 15 days (range 4-44) following TMA diagnosis. A median of 4 injections of eculizumab was performed (range 2-22). Complete hematological remission was achieved in 10 patients (83%) and blood transfusion significantly decreased after only one injection of eculizumab (median of 3 packed red blood cells (range 0-10) before treatment vs 0 (range 0-1) after one injection, P < 0.001). Two patients recovered completely renal function (17%), and 8 achieved a partial remission (67%). Compared to a control group of G-TMA without use of eculizumab, renal outcome was more favourable. At the end of the follow up, median eGFR was 45 vs 33 ml/min/1.73m2 respectively in the eculizumab group and in the control group.ConclusionsThese results suggest that eculizumab is efficient on haemolysis and reduces transfusion requirement in G-TMA. Moreover, eculizumab may improve renal function recovery.

| S-EPMC8293501 | biostudies-literature

Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy

Project description:Spaceflight-related stresses impact health via various body systems, including the hematopoietic and immune systems, with effects ranging from moderate alterations of homeostasis to serious illness. Oxidative stress appears to be involved in these changes, and the transcription factor Nrf2, which regulates expression of a set of cytoprotective and antioxidative stress response genes, has been implicated in the response to spaceflight-induced stresses. Here, we show through analyses of mice from the MHU-3 project, in which Nrf2-knockout mice travelled in space for 31 days, that mice lacking Nrf2 suffer more seriously from spaceflight-induced immunosuppression than wild-type mice. We discovered that a one-month spaceflight triggered the expression of tissue inflammatory marker genes in wild-type mice, an effect that was even more pronounced in the absence of Nrf2. Concomitant with induction of inflammatory conditions, the consumption of coagulation-fibrinolytic factors and platelets was elevated by spaceflight and further accelerated by Nrf2 deficiency. These results highlight that Nrf2 mitigates spaceflight-induced inflammation, subsequent immunosuppression, and thrombotic microangiopathy. These observations reveal a new strategy to relieve health problems encountered during spaceflight.

2023-09-14 | GSE240654 | GEO

Complement C5 inhibition reverses bleomycin-induced thrombotic microangiopathy.

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.

| S-EPMC8023184 | biostudies-literature

Thrombotic microangiopathy in children.

Project description:The syndrome of thrombotic microangiopathy (TMA) is a clinical-pathological entity characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end organ involvement. It comprises a spectrum of underlying etiologies that may differ in children and adults. In children, apart from ruling out shigatoxin-associated hemolytic uremic syndrome (HUS) and other infection-associated TMA like Streptococcus pneumoniae-HUS, rare inherited causes including complement-associated HUS, cobalamin defects, and mutations in diacylglycerol kinase epsilon gene must be investigated. TMA should also be considered in the setting of solid organ or hematopoietic stem cell transplantation. In this review, acquired and inherited causes of TMA are described with a focus on particularities of the main causes of TMA in children. A pragmatic approach that may help the clinician tailor evaluation and management is provided. The described approach will allow for early initiation of treatment while waiting for the definitive diagnosis of the underlying TMA.

| S-EPMC8764494 | biostudies-literature

Thrombotic Microangiopathy and the Kidney.

Project description:Thrombotic microangiopathy can manifest in a diverse range of diseases and is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ injury, including AKI. It can be associated with significant morbidity and mortality, but a systematic approach to investigation and prompt initiation of supportive management and, in some cases, effective specific treatment can result in good outcomes. This review considers the classification, pathology, epidemiology, characteristics, and pathogenesis of the thrombotic microangiopathies, and outlines a pragmatic approach to diagnosis and management.

| S-EPMC5967417 | biostudies-literature

Complement in Secondary Thrombotic Microangiopathy.

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.

| S-EPMC7575444 | biostudies-literature

Activation of Interferon and Complement Pathways in Thrombotic Microangiopathy

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

VEGF inhibition and renal thrombotic microangiopathy.

Project description:The glomerular microvasculature is particularly susceptible to injury in thrombotic microangiopathy, but the mechanisms by which this occurs are unclear. We report the cases of six patients who were treated with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), in whom glomerular disease characteristic of thrombotic microangiopathy developed. To show that local reduction of VEGF within the kidney is sufficient to trigger the pathogenesis of thrombotic microangiopathy, we used conditional gene targeting to delete VEGF from renal podocytes in adult mice; this resulted in a profound thrombotic glomerular injury. These observations provide evidence that glomerular injury in patients who are treated with bevacizumab is probably due to direct targeting of VEGF by antiangiogenic therapy.

| S-EPMC3030578 | biostudies-literature

Thrombotic microangiopathy and associated renal disorders.

Project description:Thrombotic microangiopathy (TMA) is a pathological process involving thrombocytopenia, microangiopathic haemolytic anaemia and microvascular occlusion. TMA is common to haemolytic uraemic syndrome (HUS) associated with shiga toxin or invasive pneumococcal infection, atypical HUS (aHUS), thrombotic thrombocytopenic purpura (TTP) and other disorders including malignant hypertension. HUS complicating infection with shiga toxin-producing Escherichia coli (STEC) is a significant cause of acute renal failure in children worldwide, occurring sporadically or in epidemics. Studies in aHUS have revealed genetic and acquired factors leading to dysregulation of the alternative complement pathway. TTP has been linked to reduced activity of the ADAMTS13 cleaving protease (typically with an autoantibody to ADAMTS13) with consequent disruption of von Willebrand factor multimer processing. However, the convergence of pathogenic pathways and clinical overlap create diagnostic uncertainty, especially at initial presentation. Furthermore, recent developments are challenging established management protocols. This review addresses the current understanding of molecular mechanisms underlying TMA, relating these to clinical presentation with an emphasis on renal manifestations. A diagnostic and therapeutic approach is presented, based on international guidelines, disease registries and published trials. Early treatment remains largely empirical, consisting of plasma replacement/exchange with the exception of childhood STEC-HUS or pneumococcal sepsis. Emerging therapies such as the complement C5 inhibitor eculizumab for aHUS and rituximab for TTP are discussed, as is renal transplantation for those patients who become dialysis-dependent as a result of aHUS.

| S-EPMC3398067 | biostudies-literature

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