Platelet activation and ferroptosis mediated NETosis drives heme induced pulmonary thrombosis.

Cell-free heme (CFH) is a product of hemoglobin, myoglobin and hemoprotein degradation, which is a hallmark of pathologies associated with extensive hemolysis and tissue damage. CHF and iron collectively induce cytokine storm, lung injury, respiratory distress and infection susceptibility in the lungs suggesting their key role in the progression of lung disease pathology. We have previously demonstrated that heme-mediated reactive oxygen species (ROS) induces platelet activation and ferroptosis. However, interaction of ferroptotic platelets and neutrophils, the mechanism of action and associated complications remain unclear. In this study, we demonstrate that heme-induced P-selectin expression and Phosphatidylserine (PS) externalization in platelets via ASK-1-inflammasome axis increases platelet-neutrophil aggregates in circulation, resulting in Neutrophil extracellular traps (NET) formation in vitro and in vivo. Further, heme-induced platelet activation in mice increased platelet-neutrophil aggregates and accumulation of NETs in the lungs causing pulmonary damage. Thus, connecting CFH-mediated platelet activation to NETosis and pulmonary thrombosis. As lung infections induce acute respiratory stress, thrombosis and NETosis, we propose that heme -mediated platelet activation and ferroptosis might be crucial in such clinical manifestations. Further, considering the ability of redox modulators and ferroptosis inhibitors like FS-1, Lpx-1 and DFO to inhibit heme-induced ferroptotic platelets-mediated NETosis and pulmonary thrombosis. They could be potential adjuvant therapy to regulate respiratory distress-associated clinical complications.

Case report: Primary hepatocellular carcinoma with portal vein tumor thrombus characterized by active tumor immune microenvironment achieving a complete response following treatment of combined immunotherapy.

Portal vein tumor thrombus (PVTT) is a frequent complication in hepatocellular carcinoma (HCC). HCC patients with PVTT have the characteristics of less treatment tolerance and poor prognosis. Immunotherapy, especially combined immunotherapy, has been successfully used in advanced HCC. However, there are no recognized universally indicators that can predict response or resistance to immunotherapy for HCC. Herein, we reported a 58-year-old HCC patient with PVTT, cirrhosis and chronic viral hepatitis, who achieved complete response (CR) after combined immunotherapy (camrelizumab combined with sorafenib or regorafenib), according to his high enrichment of tumor-infiltrating immune cells and tertiary lymphoid structure (TLS). In this case, we revealed the characteristics of the baseline tumor immune microenvironment (TIME) in a HCC patient who responded well to combined immunotherapy, suggesting that TIME can be used to assist in clinical decision making of immunotherapy for HCC.

α-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt.

BACKGROUND: Phospho-Akt1 (pAkt1) undergoes prolyl hydroxylation at Pro125 and Pro313 by the prolyl hydroxylase-2 (PHD2) in a reaction decarboxylating α-ketoglutarate (αKG). We investigated whether the αKG supplementation could inhibit Akt-mediated activation of platelets and monocytes, in vitro as well as in vivo, by augmenting PHD2 activity. METHODS: We treated platelets or monocytes isolated from healthy individuals with αKG in presence of agonists in vitro and assessed the signalling molecules including pAkt1. We supplemented mice with dietary αKG and estimated the functional responses of platelets and monocytes ex vivo. Further, we investigated the impact of dietary αKG on inflammation and thrombosis in lungs of mice either treated with thrombosis-inducing agent carrageenan or infected with SARS-CoV-2. FINDINGS: Octyl αKG supplementation to platelets promoted PHD2 activity through elevated intracellular αKG to succinate ratio, and reduced aggregation in vitro by suppressing pAkt1(Thr308). Augmented PHD2 activity was confirmed by increased hydroxylated-proline and enhanced binding of PHD2 to pAkt in αKG-treated platelets. Contrastingly, inhibitors of PHD2 significantly increased pAkt1 in platelets. Octyl-αKG followed similar mechanism in monocytes to inhibit cytokine secretion in vitro. Our data also describe a suppressed pAkt1 and reduced activation of platelets and leukocytes ex vivo from mice supplemented with dietary αKG, unaccompanied by alteration in their number. Dietary αKG significantly reduced clot formation and leukocyte accumulation in various organs including lungs of mice treated with thrombosis-inducing agent carrageenan. Importantly, in SARS-CoV-2 infected hamsters, we observed a significant rescue effect of dietary αKG on inflamed lungs with significantly reduced leukocyte accumulation, clot formation and viral load alongside down-modulation of pAkt in the lung of the infected animals. INTERPRETATION: Our study suggests that dietary αKG supplementation prevents Akt-driven maladies such as thrombosis and inflammation and rescues pathology of COVID19-infected lungs. FUNDING: Study was funded by the Department of Biotechnology (DBT), Govt. of India (grants: BT/PR22881 and BT/PR22985); and the Science and Engineering Research Board, Govt. of India (CRG/000092).

Rutaecarpine, an Alkaloid from Evodia rutaecarpa, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3ß Signal Axis through a Cyclic Nucleotides/VASP-Independent Mechanism.

The role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. Evodia rutaecarpa (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bioactive component with substantial beneficial properties including vasodilation. To address a research gap, we investigated the inhibitory mechanisms of Rut in washed human platelets and experimental mice. At low concentrations (1-5 µM), Rut strongly inhibited collagen-induced platelet aggregation, whereas it exerted only a slight or no effect on platelets stimulated with other agonists (e.g., thrombin). Rut markedly inhibited P-selectin expression; adenosine triphosphate release; [Ca2+]i mobilization; hydroxyl radical formation; and phospholipase C (PLC)γ2/protein kinase C (PKC), mitogen-activated protein kinase, and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3ß (GSK3ß) phosphorylation stimulated by collagen. SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor) did not reverse Rut-mediated antiplatelet aggregation. Rut was not directly responding to vasodilator-stimulated phosphoprotein phosphorylation. Rut significantly increased the occlusion time of fluorescence irradiated thrombotic platelet plug formation. The findings demonstrated that Rut exerts a strong effect against platelet activation through the PLCγ2/PKC and PI3K/Akt/GSK3ß pathways. Thus, Rut can be a potential therapeutic agent for thromboembolic disorders.

The Net Clinical Benefit of Rivaroxaban Compared to Low-Molecular-Weight Heparin in the Treatment of Cancer-Associated Thrombosis: Systematic Review and Meta-Analysis.

Cancer-associated thrombosis (CAT) carries significant morbidity and mortality. Low-molecular-weight heparin (LMWH) remains the standard of care, with recent systematic studies suggesting the efficacy and safety of rivaroxaban in the treatment of CAT. Uncertainty, however, remains regarding rivaroxaban efficacy and safety in real-world settings. We performed a systematic review and meta-analysis of studies comparing rivaroxaban to LMWH. We searched PubMed, MEDLINE, and EMBASE. The primary outcome was the net clinical benefit (NCB), while rates of major bleeding (MB), venous thromboembolism (VTE), clinically relevant nonmajor bleeding (CRNMB), and all-cause mortality events were secondary outcomes. Seventeen studies were included in the final analysis. Rivaroxaban had a better NCB (relative risk [RR] = 0.82; 95% CI = 0.75-0.89, Q = 10.51, I 2 = 0%), less VTE events (RR = 0.73, 95% CI = 0.65-0.82, Q = 6.76, I 2 = 0%), and lower all-cause mortality (RR = 0.72, 95% CI = 0.57-0.91, Q = 32.8, I 2 = 79%) compared to LMWH. Additionally, comparable MB events (RR = 1.07, 95% CI = 0.85-1.33, Q = 16.9, I 2 = 11%). However, CRNMB events were higher in the rivaroxaban group (RR = 2.02, 95% CI = 1.46-2.80, Q = 9.9, I 2 = 19%). Additional analyses demonstrated consistency of results. Our review encompassing data from randomized and real-world data suggested rivaroxaban superiority compared to LMWH in terms of a better NCB, fewer VTE events, lower all-cause mortality, and comparable MB risk while carrying a higher risk of CRNMB. These findings support the use of rivaroxaban in the treatment of CAT. Additionally, it warrants a sizable randomized controlled study testing the superiority of rivaroxaban versus LMWH formulation and ascertaining bleeding outcomes according to cancer type and site.

Nutritional Indices for Assessing Fatty Acids: A Mini-Review.

Dietary fats are generally fatty acids that may play positive or negative roles in the prevention and treatment of diseases. In nature, fatty acids occur in the form of mixtures of saturated fatty acid (SFA), monounsaturated fatty acid (MUFA), and polyunsaturated fatty acid (PUFA), so their nutritional and/or medicinal values must be determined. Herein, we do not consider the classic indices, such as ∑SFA, ∑MUFA, ∑PUFA, ∑n-6 PUFA, ∑n-3 PUFA, and n-6 PUFA/n-3 PUFA; instead, we summarize and review the definitions, implications, and applications of indices used in recent years, including the PUFA/SFA, index of atherogenicity (IA), the index of thrombogenicity (IT), the hypocholesterolemic/hypercholesterolemic ratio (HH), the health-promoting index (HPI), the unsaturation index (UI), the sum of eicosapentaenoic acid and docosahexaenoic acid (EPA + DHA), fish lipid quality/flesh lipid quality (FLQ), the linoleic acid/α-linolenic acid (LA/ALA) ratio, and trans fatty acid (TFA). Of these nutritional indices, IA and IT are the most commonly used to assess the composition of fatty acids as they outline significant implications and provide clear evidence. EPA + DHA is commonly used to assess the nutritional quality of marine animal products. All indices have their advantages and disadvantages; hence, a rational choice of which to use is critical.

Use of Direct Oral Anticoagulants in the Treatment of Left Ventricular Thrombus: Systematic Review of Current Literature.

BACKGROUND: Left ventricular thrombus (LVT) is an important complication in the setting of systolic dysfunction, particularly after acute myocardial infarction. Current guidelines recommend the vitamin-K antagonist, warfarin, for the treatment of LVT. AREA OF UNCERTAINTY AND STUDY QUESTION: The direct oral anticoagulants (DOACs) are being increasingly used for the management of this entity, despite lack of randomized trials in support of it or knowledge about their efficacy. We aimed to assess the frequency of use and the efficacy of DOACs in the treatment of LVT. DATA SOURCES: We searched published articles in Google Scholar, PubMed, MEDLINE, and Embase from the introduction of DOACs in any therapy until April 2018. Reports describing patients diagnosed with LVT and who were treated with a DOAC were examined. Patient characteristics, comorbidities, pharmacologic treatments, and outcomes were collected. The primary end points of this study were thrombus resolution and time to resolution. Other end points were bleeding and thromboembolic events. RESULTS: Thirty articles describing 41 patients were analyzed. The most common risk factors for LVT formation were male gender, ischemic heart disease, and low ejection fraction. Most patients were treated with rivaroxaban (51.2%), followed by apixaban (26.8%) and dabigatran (22%). Patients were treated with DOAC alone (46.3%), DOAC and aspirin (12.2%), DOAC and clopidogrel (2.4%), and triple therapy (39%). Thrombus resolution success rate was 81%, 100%, and 88.9% for rivaroxaban, apixaban, and dabigatran, respectively. The median time of thrombus resolution was 40 days, 36 days, and 24 days for rivaroxaban, apixaban, and dabigatran, respectively. One nonfatal bleeding event and one stroke event were reported while on a DOAC. CONCLUSIONS: The use of DOACs is a reasonable alternative to vitamin-K antagonists in the management of LVT.

A magnetically modified black phosphorus nanosheet-based heparin delivery platform for preventing DVT accurately.

A new heparin targeting delivery platform was developed based on iron oxide (Fe3O4) nanoparticles and polyethyleneimine (PEI) functionalized black phosphorus nanosheets (BP NSs). Both in and ex vivo studies suggested that this drug delivery platform (PEI/Fe3O4@BP NSs) possessed high heparin loading capacity (≈450%), accurate magnetic enrichment capacity, and good biocompatibility. With the aid of near-infrared (NIR) laser irradiation, this BP NS based delivery platform could further enhance the photothermal thrombolysis effect. Most importantly, the experiments in vivo confirmed that the proposed PEI/Fe3O4@BP NSs could considerably prolong the effective drug concentration duration of heparin. By which means, accurate, long-acting, and effective thromboprophylaxis could be accomplished with limited drug dosage, which could radically reduce the perniciousness of drug overdose.

Leaf-Inspired Authentically Complex Microvascular Networks for Deciphering Biological Transport Process.

The vascular transport of molecules, cells, and nanoconstructs is a fundamental biophysical process impacting tissue regeneration, delivery of nutrients and therapeutic agents, and the response of the immune system to external pathogens. This process is often studied in single-channel microfluidic devices lacking the complex tridimensional organization of vascular networks. Here, soft lithography is employed to replicate the vein system of a Hedera elix leaf on a polydimethilsiloxane (PDMS) template. The replica is then sealed and connected to an external pumping system to realize an authentically complex microvascular network. This satisfies energy minimization criteria by Murray's law and comprises a network of channels ranging in size from capillaries (∼50 µm) to large arterioles and venules (∼400 µm). Micro-PIV (micro-particle image velocimetry) analysis is employed to characterize flow conditions in terms of streamlines, fluid velocity, and flow rates. To demonstrate the ability to reproduce physiologically relevant transport processes, two different applications are demonstrated: vascular deposition of tumor cells and lysis of blood clots. To this end, conditions are identified to culture cells within the microvasculature and realize a confluent endothelial monolayer. Then, the vascular deposition of circulating breast (MDA-MB 231) cancer cells is documented throughout the network under physiologically relevant flow conditions. Firm cell adhesion mostly occurs in channels with low mean blood velocity. As a second application, blood clots are formed within the chip by mixing whole blood with a thrombin solution. After demonstrating the blood clot stability, tissue plasminogen activator (tPA) and tPA-carrying nanoconstructs (tPA-DPNs) are employed as thrombolytics. In agreement with previous data, clot dissolution is equally induced by tPA and tPA-DPNs. The proposed leaf-inspired chip can be efficiently used to study a variety of vascular transport processes in complex microvascular networks, where geometry and flow conditions can be modulated and monitored throughout the experimental campaign.

The antithrombotic activity of the active fractions from the fruits of Celastrus orbiculatus Thunb through the anti-coagulation, anti-platelet activation and anti-fibrinolysis pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine Celastrus orbiculatus Thunb (C. orbiculatus) with peel and seeds is mainly composed of flavonoids, sesquiterpenes and tripenes. According to the Traditional Chinese medicine standard of Liaoning province (2009), it has been long used to invigorate blood circulation. AIM OF THE STUDY: To identify the antithrombus fraction and components of C. orbiculatus, and to investigate the underlying mechanisms. MATERIALS AND METHODS: The antithrombus effects of C. orbiculatus fractions were evaluated in vitro by plasma recalcification time (PRT). The antithrombus effect of NST-50, the most effective fraction, was further investigated in acute pulmonary embolism (APE) mice and FeCl3-induced carotid arterial thrombus rats. Bleeding assessment was also carried out to assess the side effects of NST-50. In addition, the content of total flavonoids and active components of NST-50 was also quantified. RESULTS: Nine flavonoids were detected in NST-50 as main components with the content of 44.70%. Next, NST-50 was found with significant anticoagulation activity by prolonging the plasma recalcification time (PRT), activated partial thromboplastin time (APTT), thrombin time (TT) and prothrombin time (PT) and decreasing the content of fibrinogen (FIB). Furthermore, NST-50 administration markedly suppressed the level of TXB2 and PAI-1, while significantly up-regulated the level of 6-keto-PGF1a and t-PA (p < 0.05). CONCLUSION: The results demonstrated that NST-50 could be valuable in clinical application against acute coronary syndrome, venous thromboembolisms and cerebrovascular thrombosis. It was possible that the anticoagulation action of NST-50 could be related to the regulation of TXA2 - PGI2 and t-PA - PAI-1 pairs.

Lipiodol deposition in portal vein tumour thrombus predicts treatment outcome in HCC patients after transarterial chemoembolisation.

OBJECTIVE: To study lipiodol deposition in portal vein tumour thrombus (PVTT) in predicting the treatment outcome of hepatocellular carcinoma (HCC) patients after transarterial chemoembolisation (TACE). METHODS: We retrospectively reviewed data from 379 HCC patients with PVTT who underwent TACE as the initial treatment at Sun Yat-Sen University Cancer Center from January 2008 to December 2015. Patients were grouped by positive and negative lipiodol deposition based on the extent of lipiodol deposition in PVTT. The overall survival (OS) and progression-free survival (PFS) were compared between negative and positive lipiodol deposition groups; furthermore, the value of the combinatorial evaluation of tumour responses and lipiodol deposition in PVTT in predicting prognosis was analysed in subgroup patients with stable disease (SD) after TACE. RESULTS: Of the 379 patients, 264 (69.7%) had negative and 115 (30.3%) had positive lipiodol deposition in PVTT after TACE. Multivariate analysis identified positive lipiodol deposition in PVTT as an independent prognostic factor for favourable OS (p = 0.001). The median OS and PFS of negative and positive lipiodol deposition groups were 4.70 vs. 8.97 months (p = 0.001) and 3.1 months vs. 5.8 months (p < 0.001). In subgroup patients, the median OS and PFS of negative and positive lipiodol deposition groups were 4.7 months vs. 10.5 months (p < 0.001) and 3.5 months vs. 7.0 months (p < 0.001), respectively. CONCLUSIONS: The patients with positive lipiodol deposition in PVTT had a longer OS than those with negative lipiodol deposition. Furthermore, the positive lipiodol deposition in PVTT can further differentiate HCC patients with favourable prognosis from SD patients. KEY POINTS: • Lipiodol deposition in PVTT is a prognostic indicator for HCC patients after TACE treatment. • Positive lipiodol deposition in PVTT is associated with a better prognosis.

Phenprocoumon based anticoagulation is an underestimated factor in the pathogenesis of calciphylaxis.

BACKGROUND: Calciphylaxis is a life threatening complication in renal patients. Of great importance is the identification of concomitant factors for calciphylaxis. Due to the variability of clinical presentation the evaluation of such factors may be obscured when calciphylaxis diagnosis is based just on clinical features. We aimed to characterize associated factors only in patients with calciphylaxis proven by histomorphological parameters in addition to clinical presentation. METHODS: In a single center retrospective study we analyzed 15 patients in an 8 year period from 2008 to 2016. Only patients with clinical features and histomorphological proof of calciphylaxis were included. Criteria for histological diagnosis of calciphylaxis were intimal hyperplasia, micro thrombi or von Kossa stain positive media calcification. RESULTS: The mean age of patients was 64.8 years. Nine patients (60%) were female; 12 (80%) were obese with a Body-Mass-Index (BMI) > 30 kg/m2; 3 (20%) had no renal disease; 12 (80%) had CKD 4 or 5 and 10 (66.7%) had end-stage renal disease (ESRD). One-year mortality in the entire cohort was 73.3%. With respect to medication history, the majority of patients (n = 13 (86.7%)) received vitamin K antagonists (VKA); 10 (66.7%) were treated with vitamin D; 6 (40%) had oral calcium supplementation; 5 (33.3%) had been treated with corticosteroids; 12 (80%) were on proton pump inhibitors (PPI); 13 (86.7%) patients had a clinical proven hyperparathyroidism. Ten (66.7%) patients presented with hypoalbuminemia at diagnosis. CONCLUSIONS: The evaluation of biopsy proven calciphylaxis demonstrates that especially treatment with vitamin K antagonists and liver dysfunction are most important concomitant factors in development of calciphylaxis. As progression and development of calciphylaxis are chronic rather than acute processes, early use of DOACs instead of VKA might be beneficial and reduce the incidence of calciphylaxis.

[Basic research of fibrosis on atherosclerotic plaque stability and related drug application].

In the background of the high incidence and high mortality of cardiovascular diseases,atherosclerosis is the main pathological feature of cardiovascular diseases and the core pathological basis for disease progression. In the evolution of atherosclerotic plaques,the rupture of unstable plaques,plaque shedding and formation of thrombosis are the most dangerous parts. In this process,the formation of plaque fibrosis is the core mechanism regulating plaque stability. Additionally,fibrosis reflects dynamic changes in the inflammatory processes and pathological changes. In view of the inflammation regulation and fibrosis regulation,this paper clarified the process of atherosclerotic plaque,explained the roles of relevant inflammatory cells and cytokines in plaque stability,and summed up drug researches related with stable plaque in recent years. In the future,improving the fibrosis will be a new idea for stabilizing plaque in atherosclerosis drug development.

LongShengZhi Capsule reduces carrageenan-induced thrombosis by reducing activation of platelets and endothelial cells.

Formation of thrombosis is associated with activation of platelets and endothelial cells. The effect of LongShengZhi Capsule (LSZ), a traditional Chinese medicine used for treatment of vascular diseases, on thrombosis was investigated in this study. BALB/c mice were induced thrombosis by injection of carrageenan while receiving pre or simultaneous LSZ treatment. We also compared the therapeutic effects of LSZ and clopidogrel on formed thrombi. LSZ inhibited carrageenan-induced thrombi in mouse tissue vessels. In addition, LSZ but not clopidogrel reduced formed thrombi with a short time window. The reduction of thrombi by LSZ was associated with reduced serum P-selectin, reduced expression of TNF-α and P-selectin and activated matrix metalloproteinase 2 expression in tissues. In vitro, LSZ decreased thrombin-induced human platelet clot retraction which was associated with inactivation of AKT and ERK1/2. LSZ also reduced adhesion of platelets or THP-1 monocytes to human umbilical vein endothelial cells (HUVECs) induced by oxidized low-density lipoprotein or lipopolysaccharide. The anti-adherent actions of LSZ was attributed to reduction of oxidative stress, expression of platelet receptors (P2Y12, PAR4 and CD36) and AKT activity in platelets. LSZ also reduced adhesion molecules or tissue factor but activated tissue factor pathway inhibitor expression in HUVECs. Taken together, our study demonstrates the antithrombotic properties of LSZ by reducing activation of platelets and endothelial cells, and suggests its potential application in clinics.

Osteopontin Attenuates Secondary Neurodegeneration in the Thalamus after Experimental Stroke.

Cortical cerebral ischemia elicits neuroinflammation as well as secondary neuronal degeneration in remote areas. Locally distinct and specific secondary neurodegeneration affecting thalamic nuclei connected to cortical areas highlights such processes. Osteopontin (OPN) is a cytokine-like glycoprotein that is excreted in high amounts after cerebral ischemia and exerts various immunomodulatory functions. We here examined putative protective effects of OPN in secondary thalamic degeneration. We subjected male Wistar rats to photothrombosis and subsequently injected OPN or placebo intracerebroventricularly. Immunohistochemical and fluorescence staining was used to detect the extent of neuronal degeneration and microglia activation. Ex vivo autoradiography with radiotracers available for human in vivo PET studies, i.e., CIS-4-[18F]Fluor-D-Proline (D-cis-[18F]FPRO), and [6-3H]thymidine ([3H]thymidine), confirmed degeneration and proliferation, respectively. We found secondary neurodegeneration in the thalamus characterized by microglial activation and neuronal loss. Neuronal loss was restricted to areas of microglial infiltration. Treatment with OPN significantly decreased neurodegeneration, inflammation and microglial proliferation. Microglia displayed morphological signs of activation without expressing markers of M1 or M2 polarization. D-CIS-[18F]FPRO-uptake mirrored attenuated degeneration in OPN-treated animals. Notably, [3H]thymidine and BrdU-staining revealed increased stem cell proliferation after treatment with OPN. The data suggest that OPN is able to ameliorate secondary neurodegeneration in thalamic nuclei. These effects can be visualized by radiotracers D-CIS-[18F]FPRO and [3H]thymidine, opening new vistas for translational studies. Graphical Abstract Intracerebroventricular injection of osteopontin attenuates thalamic degeneration after cortical ischemia (pink area). Disruption of thalamocortical connections (blue) and degeneration of thalamic nuclei (encircled) leads to microglia activation. Osteopontin protects from both neurodegeneration and microglia activation as assessed by histological analysis and autoradiograpic studies.

Meropenem-Vaborbactam as Salvage Therapy for Ceftazidime-Avibactam-Resistant Klebsiella pneumoniae Bacteremia and Abscess in a Liver Transplant Recipient.

We report a case of a 24-year-old liver transplant recipient who developed hepatic artery thrombosis and graft failure, which was complicated by subphrenic abscess and persistent Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae bacteremia. Ceftazidime-avibactam treatment led to emergence of resistance, and alternative combination therapy failed due to persistent infection and toxicity. The infection resolved after initiation of meropenem-vaborbactam, which created a bridge to retransplantation. Treatment-emergent ceftazidime-avibactam resistance is increasingly recognized, suggesting a role for meropenem-vaborbactam.

Regulation of platelet function and thrombosis by omega-3 and omega-6 polyunsaturated fatty acids.

Thrombosis is the most common underlying pathology responsible for morbidity and mortality in cardiovascular disease (CVD). Platelet adhesion, activation, and aggregation play central roles in hemostasis; however, the same process may also cause thrombosis and vessel occlusion at the site of ruptured atherosclerotic lesions leading to heart attack and stroke. ω-3 and ω-6 polyunsaturated fatty acids (PUFAs) are an essential component of the platelet phospholipid membrane and play a major role in many aspects of platelet function. Dietary supplementation of ω-3 and ω-6 PUFAs has long been used to slow the progression of CVD and to prevent acute cardiovascular events. Despite this, the role of ω-3 and ω-6 PUFAs and their oxylipin metabolites in platelet function remains controversial due to the lack in our understanding of the mechanistic regulation controlling platelet reactivity in vitro and substantial evidence for PUFA regulation of thrombotic events in vivo. In this review, we will outline the role of platelet physiology in hemostasis and the effect of ω-3 and ω-6 PUFAs on platelet function, with special emphasis on in vivo effects on hemostasis and thrombosis due to the role of PUFAs and their bioactive lipids in circulation. Further, recent mechanistic insights and evidence for cardio-protective effects of PUFAs and their bioactive lipids will be discussed.

Anti-annexin A5 antibodies and 25-hydroxy-cholecalciferol in female patients with primary antiphospholipid syndrome.

Vascular antiphospholipid syndrome (VAPS) and obstetric (OAPS) are different entities because some patients only develop thrombosis (without recurrent pregnancy losses) and vice versa. Only two articles have reported that low 25-hydroxy-cholecalciferol (vitamin D3, VD3) levels were not correlated with the presence of conventional antiphospholipid antibodies (aPL Abs: anticardiolipin (aCL), anti-beta2glycoprotein I (aß2gpI), and lupus anticoagulant (LA)), but no article analyzed the association of VD3 and anti-annexin A5 (aanxA5) Abs. The aim of our study was to investigate the association between VD3, multiple positivity of conventional aPL and aanxA5 Abs levels only in female OAPS vs. VAPS. Our study included 62 consecutive female PAPS patients. Concentrations of Abs were measured by ELISA, while VD3 levels were determined by immunochemiluminescence. Only 10/62 (16.13%) had sufficient (≥ 30 ng/ml) VD3 levels, while 48/62 (77.42%) and 4/62 (6.45%) had insufficiency and VD3 deficiency, respectively. Statistically significant VD3 deficiency was noticed in VAPS (vs. OAPS, P = 0.013). A negative correlation between VD3 levels and the age of patients was noticed (r = - 0.493, P = 0.032) only in VAPS subgroup. Multiple positivity of aPL and aanxA5 Abs was not associated with VD3 deficiency. Newly emerging aPL Abs, such as aanxA5 Abs, or their combinations with classical aPL Abs are not associated with VD3 deficiency in neither OAPS nor VAPS patients. Due to its immunomodulatory roles in B-Ly homeostasis, supplementation with VD3 should be considered in APS, at least in subgroup with severe form of the disease, i.e., VAPS.

NaoXinTong Capsule Inhibits Carrageenan-Induced Thrombosis in Mice.

Formation of thrombosis is mainly associated with dysfunctions of endothelial cells. NaoXinTong capsule (NXT), a traditional Chinese medicine, has been demonstrated multiple protective effects on vascular systems. However, it is unknown the effect of NXT on thrombosis. In this study, we determined whether NXT can inhibit carrageenan-induced thrombosis and the underlying mechanisms. Two days after carrageenan injection, severe thrombi were found in blood vessels of mouse tail and liver. By contrast, thrombi were substantially reduced by NXT treatment, and the reduction was associated with reduced serum tumor necrosis factor α and P-selectin levels. In vitro, NXT reduced lipopolysaccharide-activated adhesion of THP-1 monocytes to human umbilical vein endothelial cells (HUVECs) by inhibiting expression of adhesion molecules and interleukin 6, and reducing production of mitochondrial superoxide that is related to activation of antioxidant enzymes expression. NXT also reduced oxidized low-density lipoprotein-activated adhesion of platelets to HUVECs. In addition, NXT protected HUVECs against clopidogrel-induced cell death by inhibiting expression of tumor necrosis factor-like cytokine 1A and activating expression of vascular endothelial growth factor α. Taken together, our study indicates the potential application of NXT in antithrombosis by multiple antithrombotic functions.