Potent inhibition of breast cancer by bis-indole-derived nuclear receptor 4A1 (NR4A1) antagonists.

BACKGROUND: Nuclear receptor 4A1 (NR4A1) is overexpressed in mammary tumors, and the methylene-substituted bis-indole derivative 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) acts as an NR4A1 antagonist (inverse agonist) and inhibits NR4A1-regulated pro-oncogenic pathways/genes in breast and other cancer cells. METHODS: Buttressed analogs of DIM-C-pPhOH were synthesized by condensation of the substituted p-hydroxybenzaldehydes with indole. Breast cancer cell growth, survival, and migration assays were carried out by cell counting, Annexin V staining, and Boyden chamber assays, respectively. Changes in RNA and protein expression were determined by RT-PCR and western blots, respectively. Analysis of RNAseq results was carried out using Ingenuity Pathway Analysis, and in vivo potencies of NR4A1 antagonists were determined in athymic nude mice bearing MDA-MB-231 cells in an orthotopic model. RESULTS: Ingenuity Pathway analysis of common genes modulated by NR4A1 knockdown or treatment with DIM-C-pPhOH showed that changes in gene expression were consistent with the observed decreased functional responses, namely inhibition of growth and migration and increased apoptosis. DIM-C-pPhOH is rapidly metabolized and the effects and potencies of buttressed analogs of DIM-C-pPhOH which contain one or two substituents ortho to the hydroxyl groups were investigated using NR4A1-regulated gene/gene products as endpoints. The buttressed analogs were more potent than DIM-C-pPhOH in both in vitro assays and as inhibitors of mammary tumor growth. Moreover, using 1,1-bis(3'-indolyl)-1-(3-chloro-4-hydroxy-5-methoxyphenyl)methane (DIM-C-pPhOh-3-Cl-5-OCH3) significant tumor growth inhibition was observed at doses as low as 2 mg/kg/d which was at least an order of magnitude more potent than DIM-C-pPhOH. CONCLUSIONS: These buttressed analogs represent a more potent set of second generation NR4A1 antagonists as inhibitors of breast cancer.

A 15-year review of characteristics and outcomes of patients leaving against medical advice.

PURPOSE: Discharging against medical advice can have significant, detrimental effects on burn patient outcomes as well as higher hospital readmission rates and healthcare expenditures. The goal of this study is to identify characteristics of patients who left against medical advice and suggest solutions to mitigate these factors. Data were collected at our American Burn Association verified Burn Unit over a 15-year period. RESULTS: Between 2007 and 2022, 37 patients were identified as having left against medical advice from the burn unit. The average patient age was 37 years old with 64.9% being male, and 70.2% were identified as having a substance abuse history. The majority (51.4%) had Medicaid or State health insurance, 29.7% had no insurance, and 18.9% had private insurance. The mechanism of injury was most commonly frostbite (43.2%). The majority sustained < 1% total body surface area injuries. Most (83.7%) had social work and/or case management involved during their admission, and all (100%) had their involvement if the length of admission was greater than one day. Over half (59.5%) returned to the ED within 2 weeks with complications. CONCLUSIONS: This study found that patients discharging against medical advice from the burn unit suffered from smaller injuries, often due to cold related injuries. These patients had comorbid substance abuse or psychiatric histories, and the majority had Medicaid or state health insurance. Recruiting interdisciplinary care members, including social work, psychiatry, and addiction medicine, early may help these patients by encouraging completion of their hospital care and setting up crucial follow-up care.

Venous Thromboembolism Incidence, Risk Factors, and Prophylaxis in Burn Patients: a National Trauma Database Study.

Comprehensive studies on the incidence, risk factors, and prophylactic measures related to venous thromboembolism (VTE) are lacking in burn care. This study characterizes VTE risk and existing prevention measures to improve and inform overall patient care in the field of burn care on a national scale. The US National Trauma Data Bank (NTDB) was queried from 2007 to 2021 to identify burn-injured patients. Descriptive statistics and multivariate regression analyses were used to explore the association between demographic/clinical characteristics and VTE risk as well as compare various VTE chemoprophylaxis types. There were 326,614 burn-injured patients included for analysis; 5,642 (1.7%) experienced a VTE event during their hospitalization. Patients with VTE were significantly older, had greater BMIs and %TBSA, and were more likely to be male (p<0.001). History of smoking, hypertension or myocardial infarction, and/or substance use disorder were significant predictors of VTE (p<0.001). Patients who received low molecular weight heparin (LMWH) were less likely to have VTE compared to patients treated with heparin when controlling for other VTE risk factors (OR: .564 95% CI .523-.607, p<0.001). Longer time to VTE chemoprophylaxis (>6 hours) initiation was significantly associated with VTE (OR=1.04 95% CI 1.03=1.07, p<0.001). This study sheds light on risk factors and chemoprophylaxis in VTE to help guide clinical practice when implementing prevention strategies in burn patients. This knowledge can be leveraged to refine risk stratification models, inform evidence-based prevention strategies, and ultimately enhance the quality of care for burn patients at risk of VTE.

Bleeding Complications in Patients With Severe Frostbite Injury.

Frostbite is caused by exposure to cold temperatures and can lead to severe injury resulting in amputations. Tissue plasminogen activator (tPA) is a thrombolytic agent that has demonstrated efficacy preventing amputation in frostbite patients. The goal of frostbite management with tPA is to salvage tissue without causing clinically significant bleeding complication. The purpose of this study was to characterize bleeding complications in severe frostbite patients managed with and without tPA. Retrospective chart review of severe frostbite patients admitted to a single ABA verified burn center. Bleeding events were grouped: category 0: no bleed; category 1: bleed not resulting in change or intervention; category 2: bleed resulting in change of management; and category 3: bleed resulting in change of management and intervention. Over a 7-year period, 188 patients were included in the study. Most patients had no documentation suggesting a bleeding complication: 69.7% category 0, 19.1% category 1, 4.8% category 2, and 6.4% category 3. There was no significant difference in category 2 or 3 bleeding complications between patients treated with or without tPA. Overall, 9 of the 143 patients (6.3%) treated with tPA had a category 2 or 3 bleeding complication within 12 hours of tPA completion and 12 of 143 (8.4%) within 24 hours of tPA completion. Based on the low risk of severe bleeding and significant benefit relative to limb or digit salvage demonstrated in this study, we conclude that tPA is safe and effective for the treatment of frostbite in appropriately selected patients.

American Burn Association Clinical Practice Guidelines on the Treatment of Severe Frostbite.

This Clinical Practice Guideline addresses severe frostbite treatment. We defined severe frostbite as atmospheric cooling that results in a perfusion deficit to the extremities. We limited our review to adults and excluded cold contact or rapid freeze injuries that resulted in isolated devitalized tissue. After developing population, intervention, comparator, outcomes (PICO) questions, a comprehensive literature search was conducted with the help of a professional medical librarian. Available literature was reviewed and systematically evaluated. Recommendations based on the available scientific evidence were formulated through consensus of a multidisciplinary committee. We conditionally recommend the use of rapid rewarming in a 38 to 42°C water bath and the use of thrombolytics for fewer amputations and/or a more distal level of amputation. We conditionally recommend the use of "early" administration of thrombolytics (≤12 hours from rewarming) compared to "later" administration of thrombolytics for fewer amputations and/or a more distal level of amputation. No recommendation could be formed on the use of vascular imaging studies to determine the use of and/or the time to initiate thrombolytic therapy. No recommendation could be formed on the use of intravenous thrombolytics compared to the use of intra-arterial thrombolytics on fewer amputations and/or a more distal level of amputation. No recommendation could be formed on the use of iloprost resulting in fewer amputations and/or more distal levels of amputation. No recommendation could be formed on the use of diagnostic imaging modalities for surgical planning on fewer amputations, a more distal level of amputation, or earlier timing of amputation.

The Effects of Rapid Rewarming on Tissue Salvage in Severe Frostbite Injury.

Frostbite is a high morbidity injury caused by soft tissue freezing, which can lead to digit necrosis requiring amputation. Rapid rewarming is a first-line treatment method that involves placing affected digits into a warm water bath. This study aims to assess the clinical practices for frostbite at facilities outside of dedicated burn centers, and any impact these practices have on tissue salvage. Retrospective chart review at a single burn center identified frostbite patients admitted directly or as transfers over a 7-year period. Records were reviewed to identify initial treatment strategies. If given, time to thrombolytics from admit was noted. Tissue salvage rates were calculated from radiologically derived tissue at-risk scores and final amputation scores. One-hundred patients were transferred from outside facilities, and 108 were direct admissions (N = 208). There was no significant difference in group demographics. Rapid rewarming was the initial treatment modality more commonly in direct admit patients (P = .016). The use of rapid rewarming did not correlate with tissue salvage (P = .112). Early use of thrombolytics had a positive impact on tissue salvage (P = .003). Thrombolytics were given 1.2 hours earlier in direct admit patients (P = .029), however there was no difference in tissue salvage rates between the groups (P = .127). Efforts should focus on larger scale study to further assess the effectiveness of rapid rewarming. Although rapid rewarming did not significantly impact tissue salvage in this study, we continue to recommend its use over less studied treatment methods, and continue to view it as an important bridge to burn center transfer and administration of thrombolytic therapy.

A Fatal Case of Toxic Epidermal Necrolysis Combined With Vanishing Bile Duct Syndrome and Hemophagocytic Lymphohistiocytosis.

This case report describes a case of fatal toxic epidermal necrolysis complicated by both vanishing bile duct syndrome and hemophagocytic lymphohistiocytosis due to Influenza B infection. Here we highlight the potential for complex morbidity secondary to underlying autoimmune hypersensitivity. Furthermore, the stepwise progression of these pathologies is noted, with the initial epidermal lesions first progressing to cholestatic injury and then subsequently to the hematologic manifestations.

An Institutional Protocol for the Treatment of Severe Frostbite Injury-A 6-Year Retrospective Analysis.

The treatment of severe frostbite injury has undergone rapid development in the past 30 years with many different diagnostic and treatment options now available. However, there is currently no consensus on the best method for management of this disease process. At our institution, we have designed a protocol for severe frostbite injury that includes diagnosis, medical treatment, wound cares, therapy, and surgery. This study assess the efficacy of our treatment since its implementation six years ago. During this time, all patients with severe frostbite injury were included in prospective observational trial of the protocol. We found that this protocol results in significant tissue salvage with over 80.7% of previously ischemic tissue becoming viable and not requiring amputation. We also were able to improve our center's efficiency over the course of six years and now our current average time from rapid rewarming to delivery of thrombolytics is under six hours.

Intermediate Skin Substitutes Are Unnecessary in Small (<10% TBSA) Burns.

The use of intermediate skin substitutes between debridement and final autografting is routine for many practitioners. Materials such as xenografts and allografts have been promoted to help with wound coverage before autografting. However, there is limited data for their use in relatively small burn wounds (<10% TBSA). In this study, we analyzed the outcomes of 100 consecutive patients who underwent autografting for burns <10% TBSA at our American Burn Association-verified burn unit in the absence of intermediate skin substitute use. We retrospectively analyzed 100 patients who underwent split thickness skin graft autografting for burns <10% TBSA between November 2017 and June 2019. No patients were treated with intermediate skin substitutes. Analysis included basic demographics, comorbidities, TBSA burned, mechanism of burn, time to grafting, if grafting was performed in a single procedure or staged, graft loss (>50% graft failure), and time to complete healing (no further wound care required). Twelve patients (12%) had unpredictable graft beds, and their procedure was staged. These patients underwent surgical debridement and were dressed in antimicrobial dressing for an average of 5 days before autografting. No patients had intermediate skin substitutes between procedures. Eighty-eight patients (88%) were debrided and grafted in a single stage. In the staged group, there was a 0% rate of graft failure compared with 9.1% rate of graft failure in the primarily grafted group (P = .004). There was a similar length of stay and time to complete healing in the staged group and primarily grafted group (P = .496 and P = .571). There was a significantly shorter time from injury to first procedure between the staged group and the primarily grafted group (8.7 days and 13.5 days, P = .014). In the eight instances of graft failure, infection or inadequate debridement was the cause. Seven of these eight cases required further surgical intervention. Intermediate skin substitutes are an unnecessary step in grafting small burns. These add only complexity and cost to patient care. Many patients can be debrided and grafted in a single stage. Debridement alone with delayed grafting is a highly effective surgical method when the wound bed is not suitable for immediate grafting. The use of intermediate skin substitutes in small burns requires further investigation as this study finds low benefit for this product.

Small Pediatric Burns Can Be Safely Managed on an Outpatient Basis.

American Burn Association (ABA) guidelines recommend that all pediatric burns be transferred to a burn center if their presenting hospital lacks the necessary personnel or equipment for their care. Our institution often treats small burns (<10% TBSA) in pediatric patients in an ambulatory setting with a nondaily dressing. The aim of this study was to determine whether small pediatric burns could be safely managed on an outpatient basis. A retrospective review at a single ABA-verified burn center was conducted, including 742 pediatric patients presenting to the burn evaluation clinic in a 3-year period. Postburn day, age, sex, TBSA, burn etiology, body area burned, burn dressing type, outpatient versus inpatient management, reason(s) for admission, and any operative intervention were collected. Overall, the most common burn etiologies were scald (68%), contact (20%), and flame (5%). In this cohort, 14% (101) of patients were admitted on evaluation to the burn center with a mean TBSA of 9%. The remaining 86% (641) of patients were treated outpatient with a mean TBSA of 3%. Of those who were treated outpatient, 96% (613) successfully completed outpatient care and 4% (28) were subsequently admitted. The patients who were successfully managed in an ambulatory setting had a mean TBSA of 3%, whereas the patients who failed outpatient care had a mean TBSA of 4%. The primary reason for the subsequent admission of these patients was nutrition optimization (61%). The vast majority of small pediatric burns can be effectively treated on an outpatient basis with a nondaily dressing.

Inhibition of NR4A1 Promotes ROS Accumulation and IL24-Dependent Growth Arrest in Rhabdomyosarcoma.

Nuclear receptor 4A1 (NR4A1, Nur77) is overexpressed in rhabdomyosarcoma (RMS), and inactivation of NR4A1 (siNR4A1) or treatment with the NR4A1 antagonist 1,1-bis(3'-indoly)-1-(p-hydroxy-phenyl)methane (DIM-C-pPhOH) has antiproliferative and proapoptotic effects on RMS cells. However, the mechanism by which NR4A1 inhibition exerts these effects is poorly defined. Here, we report that NR4A1 silencing or inhibition resulted in accumulation of reactive oxygen species (ROS) and ROS-dependent induction of the tumor suppressor-like cytokine IL24 in RMS cells. Mechanistically, NR4A1 was found to regulate the expression of the proreductant genes thioredoxin domain-containing 5 (TXNDC5) and isocitrate dehydrogenase 1 (IDH1), which are downregulated in RMS cells following NR4A1 knockdown or inhibition. Silencing TXNDC5 and IDH1 also induced ROS accumulation and IL24 expression in RMS cells, suggesting that NR4A1 antagonists mediate their antiproliferative and apoptotic effects through modulation of proreductant gene expression. Finally, cotreatment with the antioxidant glutathione or IL24-blocking antibody reversed the effects of NR4A1 inhibition, demonstrating the importance of both ROS and IL24 in mediating the cellular responses. IMPLICATIONS: Overall, these data elucidate the mechanism by which NR4A1 inhibition functions to inhibit the proliferation, survival, and migration of RMS cells.

Reactive Oxygen Species (ROS)-Inducing Triterpenoid Inhibits Rhabdomyosarcoma Cell and Tumor Growth through Targeting Sp Transcription Factors.

Methyl 2-trifluoromethyl-3,11-dioxo-18ß-olean-1,12-dien-3-oate (CF3DODA-Me) is derived synthetically from glycyrrhetinic acid, a major component of licorice, and this compound induced reactive oxygen species (ROS) in RD and Rh30 rhabdomyosarcoma (RMS) cells. CF3DODA-Me also inhibited growth and invasion and induced apoptosis in RMS cells, and these responses were attenuated after cotreatment with the antioxidant glutathione, demonstrating the effective anticancer activity of ROS in RMS. CF3DODA-Me also downregulated expression of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 and prooncogenic Sp-regulated genes including PAX3-FOXO1 (in Rh30 cells). The mechanism of CF3DODA-Me-induced Sp-downregulation involved ROS-dependent repression of c-Myc and cMyc-regulated miR-27a and miR-17/20a, and this resulted in induction of the miRNA-regulated Sp repressors ZBTB4, ZBTB10, and ZBTB34. The cell and tumor growth effects of CF3DODA-Me further emphasize the sensitivity of RMS cells to ROS inducers and their potential clinical applications for treating this deadly disease. IMPLICATIONS: CF3DODA-Me and HDAC inhibitors that induce ROS-dependent Sp downregulation could be developed for clinical applications in treating rhabdomyosarcoma.

Microangiography: An Alternative Tool for Assessing Severe Frostbite Injury.

Assessment of frostbite injury typically relies on computed tomography, angiography, or nuclear medicine studies to detect perfusion deficits prior to thrombolytic therapy. The aim of this study was to evaluate the potential of a novel imaging method, microangiography, in the assessment of severe frostbite injury. Patients with severe frostbite were included if they received a post-thrombolytic Technetium 99 (Tc99) bone scan, a Tc99 bone scan without thrombolytic therapy, and/or post-thrombolytic microangiography (MA) study. We included all patients from the years 2006 to 2018 with severe frostbite injury who had received appropriate imaging for diagnosis: Tc99 scan alone (N = 82), microangiography alone (N = 22), and both Tc99 and microangiography (N = 26). The majority of patients received thrombolytic therapy (76.2%), and the average time to thrombolytics was 6.9 hours. Tc99 scans showed strong correlation with amputation level (r = .836, P < .001), and microangiography showed a slightly stronger positive correlation with amputation level (r = .870, P < .001). In the subset who received both Tc99 scan and microangiography (N = 26), we observed significant differences in the mean scores of perfusion deficit (z = 3.20, P < .001). In this subset, a moderate correlation was found between level of perfusion deficit on Tc99 bone scan and amputation level (r = .525, P = .006). A very strong positive correlation was found between the microangiography studies and the amputation level (r = .890, P < .001). These results demonstrate that microangiography is a reliable alternative method of assessing severe frostbite injury and predicting amputation level.

Interleukin-24 (IL24) Is Suppressed by PAX3-FOXO1 and Is a Novel Therapy for Rhabdomyosarcoma.

Alveolar rhabdomyosarcoma (ARMS) patients have a poor prognosis, and this is primarily due to overexpression of the oncogenic fusion protein PAX3-FOXO1. Results of RNA-sequencing studies show that PAX3-FOXO1 represses expression of interleukin-24 (IL24), and these two genes are inversely expressed in patient tumors. PAX3-FOXO1 also regulates histone deacetylase 5 (HDAC5) in ARMS cells, and results of RNA interference studies confirmed that PAX3-FOXO1-mediated repression of IL24 is HDAC5-dependent. Knockdown of PAX3-FOXO1 decreases ARMS cell proliferation, survival, and migration, and we also observed similar responses in cells after overexpression of IL24, consistent with results reported for this tumor suppressor-like cytokine in other solid tumors. We also observed in double knockdown studies that the inhibition of ARMS cell proliferation, survival, and migration after knockdown of PAX3-FOXO1 was significantly (>75%) reversed by knockdown of IL24. Adenoviral-expressed IL24 was directly injected into ARMS tumors in athymic nude mice, and this resulted in decreased tumor growth and weight. Because adenoviral IL24 has already successfully undergone phase I in clinical trials, this represents an alternative approach (alone and/or combination) for treating ARMS patients who currently undergo cytotoxic drug therapies.

PAX3-FOXO1A Expression in Rhabdomyosarcoma Is Driven by the Targetable Nuclear Receptor NR4A1.

Alveolar rhabdomyosarcoma (ARMS) is a devastating pediatric disease driven by expression of the oncogenic fusion gene PAX3-FOXO1A. In this study, we report overexpression of the nuclear receptor NR4A1 in rhabdomyosarcomas that is sufficient to drive high expression of PAX3-FOXO1A there. RNAi-mediated silencing of NR4A1 decreased expression of PAX3-FOXO1A and its downstream effector genes. Similarly, cell treatment with the NR4A1 small-molecule antagonists 1,1-bis(3-indolyl)-1-(p-hydroxy or p-carbomethoxyphenyl)methane (C-DIM) decreased PAX3-FOXO1A. Mechanistic investigations revealed a requirement for the NR4A1/Sp4 complex to bind GC-rich promoter regions to elevate transcription of the PAX3-FOXO1A gene. In parallel, NR4A1 also regulated expression of ß1-integrin, which with PAX3-FOXO1A, contributed to tumor cell migration that was blocked by C-DIM/NR4A1 antagonists. Taken together, our results provide a preclinical rationale for the use of NR4A1 small-molecule antagonists to treat ARMS and other rhabdomyosarcomas driven by PAX3-FOXO1A. Cancer Res; 77(3); 732-41. ©2016 AACR.

Time Matters in Severe Frostbite: Assessment of Limb/Digit Salvage on the Individual Patient Level.

Severe frostbite is associated with high levels of morbidity through loss of digits or limbs. The aim of this study was to examine the salvage rate following severe frostbite injury. Frostbite patients from 2006 to 2014 were identified in the prospectively maintained database at a single urban burn and trauma center. Patients with imaging demonstrating a lack of blood flow in limbs/digits were included in the analysis (N = 73). The Hennepin Frostbite Score was used to quantify frostbite injury and salvage. This score provides a single value to assess each individual patient's salvage rate. The majority of patients with perfusion deficits were male (80%) with an average age of 42 years (range 11-83 years). Patients requiring amputation tended to be older (P = .002), have more tissue impacted by frostbite (P < .001), and experienced a longer time from rewarming to thrombolytic therapy (P = .001). A majority of patients (62%) received thrombolytic treatment. The percentage of patients requiring amputation was lower and the salvage rate was higher in patients treated with thrombolytics; however, the differences failed to reach statistical significance (P = .092 and P = .061, respectively). The rate of salvage decreases as the time from rewarming to thrombolytic therapy increases. Regression analysis demonstrates an additional 26.8% salvage loss with each hour of delayed treatment (P = .006). When the amount of tissue at risk for amputation is included in the model, each hour delay in thrombolytic treatment results in a 28.1% decrease in salvage (P = .011). This study demonstrates a significant decrease in limb/digit salvage with each hour of delayed administration of thrombolytics in patients with severe frostbite.

Nuclear receptor 4A1 (NR4A1) as a drug target for treating rhabdomyosarcoma (RMS).

The orphan nuclear receptor NR4A1 is expressed in tumors from rhabdomyosarcoma (RMS) patients and Rh30 and RD RMS cell lines, and we used RNA interference (RNAi) to investigate the role of this receptor in RMS cells. Knockdown of NR4A1 in Rh30 cells decreased cell proliferation, induced Annexin V staining and induced polyADPribose polymerase (PARP) cleavage and these results were similar to those observed in other solid tumors. Previous studies show that NR4A1 regulates expression of growth promoting/pro-survival genes with GC-rich promoters, activates mTOR through suppression of p53, and maintains low oxidative stress by regulating expression of isocitrate dehydrogenase 1 (IDH1) and thioredoxin domain containing 5 (TXNDC5). Results of RNAi studies demonstrated that NR4A1 also regulates these pathways and associated genes in RMS cells and thereby exhibits pro-oncogenic activity. 1,1-Bis(3-indolyl)-1-(p-substituted phenyl)methane (C-DIM) analogs containing p-hydroxyl (DIM-C-pPhOH) and p-carboxymethyl (DIM-C-pPhCO2Me) substituents are NR4A1 ligands that decreased NR4A1-dependent transactivation in RMS cells and inhibited RMS cell and tumor growth and induced apoptosis. Moreover, the effects of NR4A1 knockdown and the C-DIM/NR4A1 antagonists were comparable as inhibitors of NR4A1-dependent genes/pathways. Both NR4A1 knockdown and treatment with DIM-C-pPhOH and DIM-C-pPhCO2Me also induced ROS which activated stress genes and induced sestrin 2 which activated AMPK and inhibited mTOR in the mutant p53 RMS cells. Since NR4A1 regulates several growth-promoting/pro-survival pathways in RMS, the C-DIM/NR4A1 antagonists represent a novel mechanism-based approach for treating this disease alone or in combination and thereby reducing the adverse effects of current cytotoxic therapies.

Hemolysis, pump thrombus, and neurologic events in continuous-flow left ventricular assist device recipients.

BACKGROUND: An ongoing challenge in the management of patients with heart failure who receive left ventricular assist devices (LVADs) is achieving optimal anticoagulation. Adverse prothrombotic events include hemolysis or pump thrombus (H/T) and neurologic events (NEs), and all limit the success of LVAD therapy. Our aim was to study the incidence and clinical outcomes associated with these events in a large single-center cohort. METHODS: We retrospectively reviewed our prospectively collected database of all patients receiving a HeartMate II (Thoratec Corp, Pleasanton, CA) LVAD from 2005 to 2012. Demographic, clinical, and outcome data were analyzed using standard statistical methods. All adverse events were recorded. RESULTS: Of 193 patients receiving LVADs, we identified 39 H/T events in 26 (13.4%) patients and 22 NEs in 19 (9.8%) patients. Seventy-four percent of events occurred in the last 3 years of the series, during which time 63% of implants were placed. Of patients with H/T, 8 (31% of those having H/T, 4.1% of total) had more than 1 event and 4 (15.4% of those having H/T, 2.1% of total) underwent pump exchanges. Five (23%) patients had NEs after H/T, and 6 (32%) died as a result of the NE. Of patients with H/T, 27% had preceding episodes of infection, 31% had an international normalized ratio (INR) of less than 1.5, 31% had an INR of 1.5 to 2, 15% had a history of clotting or were hypercoagulable, and 4% had anticoagulation intentionally withheld. Lactate dehydrogenase (LDH), plasma hemoglobin, INR, and platelet determinations were significantly different at the time of H/T compared with baseline values. The survival at 6 months (alive or having undergone transplantation) for those with a prothrombotic event compared with those without was 70% versus 75.2% (p = 0.5). CONCLUSIONS: The incidence of H/T or NEs is significant and results in major morbidity after LVAD placement. Infection and suboptimal anticoagulation are associated with the majority of these events. Identification of patients at higher risk for hemolysis (ie, infection) may allow for modification of anticoagulation regimens to reduce these risks and improve clinical outcomes.