Incidence and outcomes of thromboembolic and bleeding events in patients with liver cirrhosis in the USA.

BACKGROUND & AIMS: Understanding the epidemiology of bleeding and thromboembolism (clotting) in liver cirrhosis provides important data for future studies and policymaking; however, head-to-head comparisons of bleeding and clotting remain limited. METHODS: This is a populational retrospective cohort study using the US National Readmission Database of 2018 to compare the incidence and outcomes of bleeding and clotting events in patients with liver cirrhosis. The primary outcomes were the 11-month incidence proportion of bleeding and clotting events. RESULTS: Of 1 304 815 participants, 26 569 had liver cirrhosis (45.0% women, mean age 57.2 [SD, 12.7] years). During the 11-month follow-up, in patients with cirrhosis, for bleeding and clotting events, the incidence proportions was 15.3% and 6.6%; the risk-standardized all-cause mortality rates were 2.4% and 1.0%; the rates of intensive care intervention were 4.1% and 1.9%; the rates of rehabilitation transfer were .2% and .2%; the cumulative length of stays were 45 100 and 23 566 days; total hospital costs were 147 and 84 million US dollars; total hospital charges were 620 and 365 million US dollars. Compared to non-cirrhosis, liver cirrhosis was associated with higher rates of bleeding (adjusted hazard ratio, 3.02 [95% CI, 2.85-3.20]) and portal vein thrombosis (PVT) (18.46 [14.86-22.92]), and slightly lower risks of other non-PVT venous thromboembolic events (.82 [.75-.89]). CONCLUSIONS: Bleeding is more common than thromboembolism in patients with liver cirrhosis, causes higher morbidity, mortality and resource utilization. Liver cirrhosis is an independent risk factor for bleeding and PVT, but not non-PVT thromboembolism including venous thromboembolism, acute myocardial infarction and ischemic stroke.

Citrullination in the pathology of inflammatory and autoimmune disorders: recent advances and future perspectives.

Numerous post-translational modifications (PTMs) govern the collective metabolism of a cell through altering the structure and functions of proteins. The action of the most prevalent PTMs, encompassing phosphorylation, methylation, acylations, ubiquitination and glycosylation is well documented. A less explored protein PTM, conversion of peptidylarginine to citrulline, is the subject of this review. The process of citrullination is catalysed by peptidylarginine deiminases (PADs), a family of conserved enzymes expressed in a variety of human tissues. Accumulating evidence suggest that citrullination plays a significant role in regulating cellular metabolism and gene expression by affecting a multitude of pathways and modulating the chromatin status. Here, we will discuss the biochemical nature of arginine citrullination, the enzymatic machinery behind it and also provide information on the pathological consequences of citrullination in the development of inflammatory diseases (rheumatoid arthritis, multiple sclerosis, psoriasis, systemic lupus erythematosus, periodontitis and COVID-19), cancer and thromboembolism. Finally, developments on inhibitors against protein citrullination and recent clinical trials providing a promising therapeutic approach to inflammatory disease by targeting citrullination are discussed.

Cause of death based on systematic post-mortem studies in patients with positive SARS-CoV-2 tissue PCR during the COVID-19 pandemic.

IMPORTANCE: Assessment of the causative association between the COVID-19 and cause of death has been hampered by limited availability of systematically performed autopsies. We aimed to present autopsy-confirmed causes of death in patients who died with COVID-19 and to assess the association between thrombosis and diffuse alveolar damage consistent with COVID-19 (DAD). METHODS: Consecutive forensic (n = 60) and clinical (n = 42) autopsies with positive post-mortem SARS-CoV-2 PCR in lungs (age 73 ± 14 years, 50% men) were included. The cause of death analysis was based on a review of medical records and histological reports. Thrombotic phenomena in lungs were defined as pulmonary thromboembolism (PE), thrombosis in pulmonary artery branches or microangiopathy in capillary vessels. RESULTS: COVID-19 caused or contributed to death in 71% of clinical and 83% of forensic autopsies, in whom significant DAD was observed. Of the patients with COVID-19 as the primary cause of death, only 19% had no thrombotic phenomena in the lungs, as opposed to 38% amongst those with COVID-19 as a contributing cause of death and 54% amongst patients whose death was not related to COVID-19 (p = 0.002). PE was observed in 5 patients. Two patients fulfilled the criteria for lymphocyte myocarditis. CONCLUSIONS: Vast majority of all PCR-positive fatalities, including out-of-hospital deaths, during the SARS-CoV-2 pandemic were related to DAD caused by COVID-19. Pulmonary artery thrombosis and microangiopathy in pulmonary tissue were common and associated with the presence of DAD, whilst venous PE was rarely observed. Histology-confirmed lymphocyte myocarditis was a rare finding.

Aberrant cytokine expression in COVID-19 patients: Associations between cytokines and disease severity.

Cytokines play pleiotropic, antagonistic, and collaborative in viral disease. The high morbidity and mortality of coronavirus disease 2019 (COVID-19) make it a significant threat to global public health. Elucidating its pathogenesis is essential to finding effective therapy. A retrospective study was conducted on 71 patients hospitalized with COVID-19. Data on cytokines, T lymphocytes, and other clinical and laboratory characteristics were collected from patients with variable disease severity. The effects of cytokines on the overall survival (OS) and event-free survival (EFS) of patients were analyzed. The critically severe and severe patients had higher infection indexes and significant multiple organ function abnormalities than the mild patients (P < 0.05). IL-6 and IL-10 were significantly higher in the critically severe patients than in the severe and mild patients (P < 0.05). IL-6 and IL-10 were closely associated with white blood cells, neutrophils, T lymphocyte subsets, D-D dimer, blood urea nitrogen, complement C1q, procalcitonin C-reactive protein. Moreover, the IL-6 and IL-10 levels were closely correlated to dyspnea and dizziness (P < 0.05). The patients with higher IL-10 levels had shorter OS than the group with lower levels (P < 0.05). The older patients with higher levels of single IL-6 or IL-10 tended to have shorter EFS (P < 0.05), while the patients who had more elevated IL-6 and IL-10 had shorter OS (P < 0.05). The Cox proportional hazard model revealed that IL-6 was the independent factor affecting EFS. IL-6 and IL-10 play crucial roles in COVID-19 prognosis.

Unfractionated heparin using actual body weight without dose capping in obese pediatric patients-Subgroup analysis from an observational cohort study.

To evaluate the correlation between an uncapped, actual body weight-based unfractionated heparin dosing strategy, we performed a body mass index-based subanalysis of a previously reported pediatric cohort. Nearly half (45%) of obese patients were supra-therapeutic on initial anti-FXa assessment. Obese patients achieved therapeutic anti-FXa significantly faster than nonobese patients (median 4 vs 12 hours, P = .0192) and were more likely to have any supra-therapeutic anti-FXa levels (77% vs 35%; P = .0021). There was no statistically significant difference in major or clinically relevant nonmajor bleeding rates between weight categories (P = .69). Prospective pediatric studies are warranted to confirm our findings.

Management of Anticoagulation Therapy in Patients With Thromboembolism in the Context of Renal Dysfunction: Challenging Cases and Practical Algorithms.

BACKGROUND: Low-molecular-weight heparin is cleared through the kidneys and is commonly used for anticoagulation in the pediatric population. OBSERVATION: We present 3 challenging cases of children requiring anticoagulation in the context of acute kidney injury, nephrotic syndrome, and hemodialysis. CONCLUSIONS: A significant change in anti-factor Xa (anti-Xa) levels-used for drug monitoring-should prompt an assessment of renal function. In nephrotic syndrome, anti-Xa levels should be closely monitored when there is a change in the status of nephrotic disease activity. In hemodialysis patients, enoxaparin at once daily reduced dosing should be considered with trough and peak anti-Xa levels monitoring.

Histopathologic Evaluation of COVID-19 Patients With Peripheral Arterial Thromboembolism: Does Clot Composition Make Any Sense?

BACKGROUND: Coronavirus disease 2019 (COVID-19) causes thromboembolic complications during or post-infection period despite a lack of conventional risk factors. The study aims to learn fundamental changes in COVID-19 patients who underwent embolectomy in terms of clinical characteristics and clot composition. METHODS: In a retrospective cohort study design, we evaluated 21 patients who underwent embolectomy in our clinic between March 12, 2020, and December 31, 2020. Demographics, characteristics, and laboratory values were abstracted and analyzed. Histopathological assessment was held in the pathology department. RESULTS: Of these 21 patients, 11 (52.3%) were SARS-CoV-2 positive and 10 (47.6%) were SARS-CoV-2 negative. There is no statistical difference in terms of anatomic distribution, diagnostic method, length of hospital stay, amputation or mortality levels. Thromboembolic material of COVID-19 patients include significantly less red blood cell (RBC) (21.2-32.6%; P= 0.01), more lymphocyte (14.1-2.6%; P< 0.001), and more leukocyte (27.1-22.1%; P= 0.05). There was no statistical difference between the fibrin ratio. CONCLUSIONS: Inflammatory cells are prominent in arterial thromboembolic material of COVID-19 patients. A combination of hyperinflammation and prothrombotic status may be responsible for this phenomenon.

Obesity in women: anaesthetic implications for peri-operative and peripartum management.

The prevalence, healthcare and socio-economic impact of obesity (defined as having a body mass index of ≥ 30 kg.m-2 ) are disproportionately higher in women than men. A combination of biological and social factors, including the adaptation of energy homeostasis to the increased demands of pregnancy and lactation and poor access to healthy foods or exercise facilities, contribute to the increasing prevalence of obesity in women. Obesity-related physiological changes stem from mass loading and increased metabolism of adipose tissue, as well as secretion of bioactive substances from adipocytes leading to chronic low-grade inflammation. As a result, obesity is associated with increased risks of: infertility; malignancy; sleep-disordered breathing; cardiovascular disease; diabetes; and thromboembolism. Hence, obese women are at markedly increased risk of peri-operative morbidity and mortality and require comprehensive evaluation and targeted comorbidity optimisation by a multidisciplinary team. In addition to routine obstetric challenges, pregnancy in women with obesity further exacerbates the above risks, making multidisciplinary management starting at pre-conception even more important. Weight loss, lifestyle management and optimisation of comorbidity are the cornerstone of reducing obesity-related risks. The anaesthetist plays a vital role within the multidisciplinary team by emphasising weight loss as part of pre-operative comorbidity optimisation, formulation of individualised peri-operative management plans, supervising postoperative care in the high dependency or intensive care settings and providing safe labour analgesia and careful peripartum management for obese parturients.

Clinicopathologic Features of COVID-19: A Case Report and Value of Forensic Autopsy in Studying SARS-CoV-2 Infection.

ABSTRACT: As of August 23, 2020, the 2019 novel coronavirus disease (COVID-19) has infected more than 23,518,340 people and caused more than 810,492 deaths worldwide including 4,717 deaths in China. We present a case of a 53-year-old woman who was admitted to the hospital because of dry coughs and high fever on January 26, 2020, in Wuhan, China. She was not tested for SARS-CoV-2 RNA until on hospital day 11 (illness day 21) because of a significant shortage of test kits at the local hospital. Then, her test was positive for COVID-19 on hospital day 20. Despite intensive medical treatments, she developed respiratory failure with secondary bacterial infection and expired on hospital day 23 (3 days after she was tested positive for SARS-CoV-2 RNA). A systemic autopsy examination, including immunohistochemistry and ultrastructural studies, demonstrates that SARS-CoV-2 can infect multiple organs with profound adverse effect on the immune system, and the lung pathology is characterized by diffuse alveolar damage. Extrapulmonary SARS-CoV-2 RNA was detected in several organs postmortem. The detailed pathological features are described. In addition, this report highlights the value of forensic autopsy in studying SARS-CoV-2 infection and the importance of clinicopathological correlation in better understanding the pathogenesis of COVID-19.

Thromboembolic Adverse Drug Reactions in Janus Kinase (JAK) Inhibitors: Does the Inhibitor Specificity Play a Role?

Recent advances in immunology enabled the characterization of several signal transmitting pathways responsible for proper cytokine and chemokine signaling. Among them, Janus kinases (JAKs) are essential components of receptor activation systems. The discovery of JAK kinases enabled the synthesis of JAK kinase inhibitors (JAKi or Jakinibs), which have proven to be efficacious in the treatment of hematologic malignancies and several rheumatological disorders and continue to be investigated in many clinical indications. Blocking multiple cytokines belonging to several cytokine families with a single small molecule may, however, create a potential risk for the patients. Recently, a higher risk of thromboembolic complications, namely, deep vein thrombosis and pulmonary embolism, has been recognized as the main concern during treatment with Jakinibs. At present, it is not entirely clear whether this increased risk is related to direct cytokine blockade, the presence of concomitant diseases in treated patients or other unknown circumstances that work together to increase the risk of this side effect. In this review, we discuss data on the risk of thromboembolic side effects, with special emphasis on the mechanism that may be responsible for this increased risk. Many indirect data indicate that higher thromboembolic risk may be related to the specificity of JAK inhibitor action, such that preferentially blocking one signaling pathway upsets the balance between pro and anti-thrombotic activities.

High Mobility Group Box 1 Protein in Cerebral Thromboemboli.

High-mobility group box 1 protein (HMGB1) is a damage-associated molecular pattern (DAMP) involved in neutrophil extracellular trap (NET) formation and thrombosis. NETs are regularly found in cerebral thromboemboli. We here analyzed associated HMGB1 expression in human thromboemboli retrieved via mechanical thrombectomy from 37 stroke patients with large vessel occlusion. HMGB1 was detected in all thromboemboli, accounting for 1.7% (IQR 0.6-6.2%) of the total thromboemboli area and was found to be colocalized with neutrophils and NETs and in spatial proximity to platelets. Correlation analysis revealed that the detection of HMGB1 was strongly related to the number of neutrophils (r = 0.58, p = 0.0002) and platelets (r = 0.51, p = 0.001). Our results demonstrate that HMGB1 is a substantial constituent of thromboemboli causing large vessel occlusion stroke.

Coagulation factor XII in thrombosis and inflammation.

Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. The factor XII-driven contact system starts coagulation and inflammatory mechanisms via the intrinsic pathway of coagulation and the bradykinin-producing kallikrein-kinin system, respectively. The biochemistry of the contact system in vitro is well understood; however, its in vivo functions are just beginning to emerge. Challenging the concept of the coagulation balance, targeting factor XII or its activator polyphosphate, provides protection from thromboembolic diseases without interfering with hemostasis. This suggests that the polyphosphate/factor XII axis contributes to thrombus formation while being dispensable for hemostatic processes. In contrast to deficiency in factor XII providing safe thromboprotection, excessive FXII activity is associated with the life-threatening inflammatory disorder hereditary angioedema. The current review summarizes recent findings of the polyphosphate/factor XII-driven contact system at the intersection of procoagulant and proinflammatory disease states. Elucidating the contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory disorders.

Proteomic Analyses of Endarterectomized Tissues from Patients with Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is largely unknown. Proteomics offers an approach to overview the molecular activities and signal transduction pathways involved in specific disease processes. OBJECTIVES: In this study, the expression of proteins in endarterectomized tissues from patients with CTEPH was investigated in a novel strategy to explore the pathophysiology of this disease. METHODS: We used the iTRAQ (isobaric tag for relative and absolute quantitation) approach combined with a Thermo Scientific Q Exactive MS analysis to compare the protein profiles in endarterectomized tissues from CTEPH patients and that of the control samples (mixture of cultured human pulmonary artery endothelial cells, human pulmonary artery smooth muscle cells, and human pulmonary fibroblasts). GO and KEGG analyses were performed to understand the functional classification and molecular activities of all the tissue-specific proteins, and the involved signal transduction pathways. RESULTS: Six hundred and seventy-nine tissue-specific proteins were detected. Bioinformatic analysis showed that the major biological processes involving these proteins were: response to wounding, defense response, acute inflammatory response, immune response, complement activation, and blood coagulation. The main pathways involved were: complement and coagulation cascade, systemic lupus erythematosus, extracellular matrix-receptor interaction, cell adhesion molecules, FcεRI signaling, and leukocyte transendothelial migration. CONCLUSIONS: The present study revealed that immune and defense response might play an important role in CTEPH.

Characteristics of Acute Stroke in Patients with Coronavirus Disease 2019 and Challenges in Stroke Management during an Epidemic.

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic infection associated with high morbidity and mortality. The Korean city of Daegu endured the first large COVID-19 outbreak outside of China. Since the report of the first confirmed case in Daegu on February 18, 2020, a total of 6,880 patients have been reported until May 29, 2020. We experienced five patients with ischemic stroke and COVID-19 during this period in four tertiary hospitals in Daegu. The D-dimer levels were high in all three patients in whom D-dimer blood testing was performed. Multiple embolic infarctions were observed in three patients and suspected in one. The mean time from stroke symptom onset to emergency room arrival was 22 hours. As a result, acute treatment for ischemic stroke was delayed. The present case series report raises the possibility that the coronavirus responsible for COVID-19 causes or worsens stroke, perhaps by inducing inflammation. The control of COVID-19 is very important; however, early and proper management of stroke should not be neglected during the epidemic.

The Pathogenic Role of Very Low Density Lipoprotein on Atrial Remodeling in the Metabolic Syndrome.

Atrial fibrillation (AF) is the most common persistent arrhythmia, and can lead to systemic thromboembolism and heart failure. Aging and metabolic syndrome (MetS) are major risks for AF. One of the most important manifestations of MetS is dyslipidemia, but its correlation with AF is ambiguous in clinical observational studies. Although there is a paradoxical relationship between fasting cholesterol and AF incidence, the beneficial benefit from lipid lowering therapy in reduction of AF is significant. Here, we reviewed the health burden from AF and MetS, the association between two disease entities, and the metabolism of triglyceride, which is elevated in MetS. We also reviewed scientific evidence for the mechanistic links between very low density lipoproteins (VLDL), which primarily carry circulatory triglyceride, to atrial cardiomyopathy and development of AF. The effects of VLDL to atria suggesting pathogenic to atrial cardiomyopathy and AF include excess lipid accumulation, direct cytotoxicity, abbreviated action potentials, disturbed calcium regulation, delayed conduction velocities, modulated gap junctions, and sarcomere protein derangements. The electrical remodeling and structural changes in concert promote development of atrial cardiomyopathy in MetS and ultimately lead to vulnerability to AF. As VLDL plays a major role in lipid metabolism after meals (rather than fasting state), further human studies that focus on the effects/correlation of postprandial lipids to atrial remodeling are required to determine whether VLDL-targeted therapy can reduce MetS-related AF. On the basis of our scientific evidence, we propose a pivotal role of VLDL in MetS-related atrial cardiomyopathy and vulnerability to AF.

Platelet-Rich Emboli in Cerebral Large Vessel Occlusion Are Associated With a Large Artery Atherosclerosis Source.

Background and Purpose- Nearly 30% of large vessel occlusion acute ischemic stroke clots are from an unknown source. We assessed histological clot composition in a series of patients with large vessel occlusion and investigated correlations between clot composition and stroke pathogenesis. Methods- As part of the multi-institutional STRIP registry (Stroke Thromboembolism Registry of Imaging and Pathology), consecutive emboli retrieved during mechanical thrombectomy were stained using Martius Scarlett Blue and analyzed using machine learning software. We assessed proportions of red blood cells, fibrin, platelets, and white blood cells. Correlations between clot components and stroke pathogenesis (large artery atherosclerosis, cardioembolism, and stroke of undetermined pathogenesis) were assessed using SPSS22. Results- One hundred five patients were included. The proportion of platelet-rich clots (55.0% versus 21.2%; P=0.005) and percentage of platelet content (22.1±4.2% versus 13.9±14.2%; P=0.03) was significantly higher in the large artery atherosclerosis group compared with the cardioembolic group. The proportion of platelet-rich clots (50.0% versus 21.2%; P=0.024) was also significantly higher in the cryptogenic group compared with cardioembolic cases. Large artery atherosclerosis and cryptogenic cases had a similar proportion of platelet-rich clots (55.0% versus 50.0%; P=0.636). There was no significant difference between stroke pathogenesis and the other major clot components. Conclusions- High platelet content of emboli is associated with a large artery atherosclerosis etiology of large vessel occlusion.

Tamoxifen treatment for male breast cancer and risk of thromboembolism: prospective cohort analysis.

PURPOSE: Thromboembolism is a common adverse event in women treated with tamoxifen (TAM) for breast cancer. The risk in male breast cancer patients is poorly investigated. We aimed to examine the risk of thrombotic events after TAM in male breast cancer patients. PATIENTS AND METHODS: In this prospective cohort study, 448 patients treated between May 2009 and July 2017 for male breast cancer (BC) were assessed for eligibility. Patients with follow-up shorter than 6 months were excluded. The cumulative risk of thromboembolism was evaluated. RESULTS: The median follow-up was 47 months (range 6-101 months) with a median age of 69.4 years (range 27-89 years). Oestrogen receptor and progesterone receptor expression levels were observed in 98.3 and 94.9% of cases, respectively. During the follow-up period, thrombotic events were documented in 21 (11.9%) of 177 patients receiving TAM and in 1 (2.5%) of 41 patients who did not receive tamoxifen. The estimated incidence was 51.9 per 1000 person-years and 21.5 per 1000 person-years, respectively. Notably, the highest risk was identified in the first 18 months, where 81% of the observed thrombotic events occurred. Patients aged older than 71 years had a significantly increased risk of thrombotic event under TAM treatment than their younger counterparts (p = 0.033). History of thrombotic event, cardiovascular and liver disease, as well as additional adjuvant treatment were not associated with increased thrombotic risk. CONCLUSION: The risk of thrombotic event in men treated with TAM for breast cancer is markedly increased in the first 18 months of treatment, and should be considered during treatment decisions.

Neurologic Complications of Infective Endocarditis: A Joint Model for a Septic Thromboembolism and Inflammatory Small Vessel Disease.

OBJECTIVES: Embolic events from vegetations are commonly accepted as the main mechanism involved in neurologic complications of infective endocarditis. The pathophysiology may imply other phenomena, including vasculitis. We aimed to define the cerebral lesion spectrum in an infective endocarditis rat model. DESIGN: Experimental model of Staphylococcus aureus or Enterococcus faecalis infective endocarditis. Neurologic lesions observed in the infective endocarditis model were compared with three other conditions, namely bacteremia, nonbacterial thrombotic endocarditis, and healthy controls. SETTING: Research laboratory of a university hospital. SUBJECTS: Male Wistar rats. INTERVENTIONS: Brain MRI, neuropathology, immunohistochemistry for astrocyte and microglia, and bacterial studies on brain tissue were used to characterize neurologic lesions. MEASUREMENTS AND MAIN RESULTS: In the infective endocarditis group, MRI revealed at least one cerebral lesion in 12 of 23 rats (52%), including brain infarctions (n = 9/23, 39%) and cerebral microbleeds (n = 8/23, 35%). In the infective endocarditis group, neuropathology revealed brain infarctions (n = 12/23, 52%), microhemorrhages (n = 10/23, 44%), and inflammatory processes (i.e., cell infiltrates including abscesses, vasculitis, meningoencephalitis, and/or ependymitis; n = 11/23, 48%). In the bacteremia group, MRI studies were normal and neuropathology revealed only hemorrhages (n = 2/11, 18%). Neuropathologic patterns observed in the nonbacterial thrombotic endocarditis group were similar to those observed in the infective endocarditis group. Immunochemistry revealed higher microglial activation in the infective endocarditis group (n = 11/23, 48%), when compared with the bacteremia (n = 1/11, 9%; p = 0.03) and nonbacterial thrombotic endocarditis groups (n = 0/7, 0%; p = 0.02). CONCLUSIONS: This original model of infective endocarditis recapitulates the neurologic lesion spectrum observed in humans and suggests synergistic mechanisms involved, including thromboembolism and cerebral vasculitis, promoted by a systemic bacteremia-mediated inflammation.

Emphysematous pyelonephritis in renal allograft related to antibody-mediated rejection: A case report and literature review.

Emphysematous pyelonephritis (EPN) is a rare condition which can rapidly progress to sepsis and multiple organ failure with high mortality. We experienced a rare case of EPN in a renal allograft related to antibody-mediated rejection (AMR). The patient received a deceased donor kidney transplant due to end-stage renal disease secondary to diabetes mellitus. Cross-match test was negative but she had remote history of anti-HLA-A2 antibody corresponding with the donor HLA. Surgery concluded without any major events. Anti-thymoglobulin was given perioperatively for induction. She was compliant with her immunosuppressive medications making urine of 2 L/d with serum creatinine of 1.9 mg/dL at discharge on post-operative day (POD) 6. She did well until POD 14 when she presented to the clinic with features of sepsis, pain over the transplanted kidney area and decline in urine volume with elevated serum creatinine. CT revealed extensive gas throughout the transplanted kidney. Renal scan revealed non-functional transplant kidney with no arterial flow. Based on these findings, a decision to perform transplant nephrectomy was made. At laparotomy, the kidney was completely necrotic. Pathology showed non-viable kidney parenchyma with the tubules lacking neutrophilic casts suggestive of ischemic necrosis. Donor-specific antibody (DSA) returned positive with high intensity anti-HLA-A2 antibody. This is the first case of early EPN in allograft considered to have occurred as a result of thrombotic ischemia secondary to AMR. This case suggests consideration of perioperative anti-B-cell and/or anti-plasma cell therapies for historical DSA and strict post-operative follow-up in immunologically high-risk recipients to detect early signs of rejection and avoid deleterious outcomes.

Renin-angiotensin system regulates pulmonary arterial smooth muscle cell migration in chronic thromboembolic pulmonary hypertension.

Pulmonary arterial smooth muscle cell (PASMC) migration plays a key role in vascular remodeling, which occurs during development of chronic thromboembolic pulmonary hypertension (CTEPH). Activation of the renin-angiotensin system (RAS) contributes to vascular remodeling observed in many diseases, including idiopathic pulmonary arterial hypertension. However, the role of RAS imbalance in CTEPH has not been characterized. Here, we hypothesize that RAS imbalance regulates vascular remodeling by promoting PASMC migration in CTEPH. Serum renin and angiotensin II levels in patients with CTEPH were quantified by ELISA. The pulmonary endarterectomy tissues were stained and analyzed by immunohistochemistry. PASMCs were isolated and verified by immunofluorescence staining. PASMC migration was determined by Transwell assay. Phosphorylation and protein level were detected by Western blotting. Serum levels of renin and angiotensin II were increased in patients with CTEPH {renin [median (25th percentile, 75th percentile) in pg/ml], 1,199.94 [690.85, 1,656.90] vs. 595.43 [351.48, 936.43], P < 0.001; angiotensin II [in pg/ml], 63.97 [45.97, 345.24] vs. 56.85 [11.20, 90.37], P < 0.05}. The migration of PASMCs isolated from patients with CTEPH was enhanced compared with control. Angiotensin II promoted the migration of PASMCs via activation of angiotensin II receptor 1 and phosphorylation of ERK1/2, whereas angiotensin-(1-7) counteracted this effect through activation of the Mas receptor and ERK1/2. These results demonstrate that the renin-angiotensin system regulates migration of PASMCs from patients with CTEPH via the ERK1/2 pathway. Our findings suggest that angiotensin-(1-7) or reagents targeting the renin-angiotensin system will be beneficial in the development of novel therapies for CTEPH.