Dual drive mode polydopamine nanomotors for continuous treatment of an inferior vena cava thrombus.

It is of great significance to find effective thrombolytic treatments due to the harm caused by thrombosis to human health. Based on the formation mechanism and complex microenvironment of a thrombus, polydopamine nanomotors (PDANMs) modified by the peptide of Arg-Gly-Asp (RGD) and loaded with urokinase (UK) were designed and prepared. A polydopamine (PDA) substrate has a good photothermal conversion effect. Under near-infrared (NIR) light irradiation, it can not only perform photothermal therapy (PTT) on thrombus, but also provide the driving force of PDANMs. Thrombolytic drug UK was loaded in the mesoporous structure of the PDA substrate and can be released at the thrombus site for drug therapy. The modified RGD can target the thrombus site, moreover, benefiting from the guanidine group of L-arginine in the peptide chain, and RGD can interact with reactive oxygen species (ROS) in the thrombus microenvironment to produce nitric oxide (NO). NO not only propelled the movement of nanomotors, but also promoted the growth of vascular endothelial cells to repair damaged blood vessels. The experimental results show that NIR and NO can provide dual driving sources for the nanosystem to achieve continuous and deep penetration of the drug-loaded nanomotors at the thrombus site, while realizing the photothermal and drug synergistic therapy to enhance the therapeutic effect and promote the growth of vascular endothelium cells. This kind of thrombus treatment strategy based on nanomotor drug delivery systems will provide good technical support for the clinical treatment of inferior vena cava thrombus.

5-HT7 Receptor Restrains 5-HT-induced 5-HT2A Mediated Contraction in the Isolated Abdominal Vena Cava.

ABSTRACT: Although discovered as a vasoconstrictor, 5-hydroxytryptamine (5-HT, serotonin) infused into man and rodent reduces blood pressure. This occurs primarily through activation of 5-HT7 receptors and, at least in part, venodilation. Vascular mechanisms by which this could occur include direct receptor activation leading to vasodilation and/or suppression of contractile 5-HT receptor activation. This study tests the hypothesis that the 5-HT7 receptor restrains activation of the 5-HT2A receptor. A subhypothesis is whether agonist-induced activation-independent of constitutive activity-of the 5-HT7 receptor is necessary for this restraint. The isolated abdominal aorta and vena cava from the normal male Sprague-Dawley rat was our model. Studies used real-time PCR and a pharmacological approach in the isolated tissue bath for measurement of isometric tone. Although 5-HT2A receptor mRNA expression in both aorta and vena cava was significantly larger than that of the 5-HT7 receptor mRNA, the 5-HT7/5-HT2A receptor mRNA ratio was greater in the vena cava (0.30) than in the aorta (0.067). 5-HT7 receptor antagonism by SB266970 and DR 4458 increased maximum contraction to 5-HT in the isolated vein by over 50% versus control. The 5-HT2A receptor agonists TCB-2 and NBOH were more potent in the aorta compared with 5-HT but less efficacious, serving as partial agonists. By contrast, these same three agonists caused no contraction in the vena cava isolated from the same rats up to 10 µM agonist. Antagonism of the 5-HT7 receptor by SB269970 did not increase either the potency or efficacy of TCB-2 or NBOH. These data support that the 5-HT7 receptor itself needs to be stimulated to reduce contraction and suggest there is little constitutive activity of the 5-HT7 receptor in the isolate abdominal vena cava.

Curcumin promotes venous thrombi resolve process in a mouse deep venous thrombosis model via regulating miR-499.

BACKGROUND/AIMS: The morbidity of deep venous thrombosis (DVT) is increasing rapidly and the current therapeutic strategies for DVT are unsatisfactory. Accumulating evidence suggest that venous thrombi resolve (VTR) may provide new insights into DVT therapeutic strategies. The aim of this study was to investigate the role of curcumin in VTR process and try to reveal the potential mechanism. METHODS: Immunofluorescence and HE staining were performed to investigate the therapeutic angiogenesis effect of curcumin in VTR process. Microarray analysis and RT-PCR were performed to examine the expression level of miR-499 in thrombosis after curcumin administration. Cell proliferation, migration and angiogenesis capacity were tested by CCK8 assay, Transwell assay and Tube formation assay, respectively. Dual-luciferase reporter assay (DLR) was used to confirm the connection between miR-499 and paired phosphate and tension homology deleted on chromosome ten (PTEN). RESULTS: We found that curcumin could effectively promote VTR process by activating angiogenesis in thrombus in vivo. The expression of miR-499 exhibited notably downregulated after curcumin administration. The proangiogenic effect of curcumin in HUVECs could be blocked by miR-499 overexpression. In addition, we confirmed that miR-499 directly target to the 3'UTR region of PTEN. CONCLUSION: Curcumin promotes VTR process in DVT through activating therapeutic angiogenesis. Mechanically, curcumin promotes therapeutic angiogenesis by regulating miR-499 mediated PTEN/VEGF/Ang-1 signaling pathway.

von Willebrand Factor Is a Critical Mediator of Deep Vein Thrombosis in a Mouse Model of Diet-Induced Obesity.

OBJECTIVE: Obesity is characterized by chronic low-grade inflammation and consequentially a hypercoagulable state, associating with an increased incidence of venous thromboembolism. Increased VWF (von Willebrand factor) plasma concentration and procoagulant function are independent risk factors for venous thromboembolism and are elevated in obese patients. Here, we explore the pathobiological role of VWF in obesity-associated venous thrombosis using murine models. Approach and Results: We first showed that diet-induced obese mice have increased VWF plasma levels and FVIII (factor VIII) activity compared with littermate controls. Elevated VWF levels appeared to be because of both increased synthesis and impaired clearance. Diet-induced obesity-associated venous thrombosis was assessed using the inferior vena cava-stenosis model of deep vein thrombosis. Diet-induced obese mice developed larger venous thrombi that were rich in VWF, erythrocytes, and leukocytes. Administering a polyclonal anti-VWF antibody or an anti-VWF A1 domain nanobody was protective against obesity-mediated thrombogenicity. Delayed administration (3 hours post-inferior vena cava stenosis) similarly reduced thrombus weight in diet-induced obese mice. CONCLUSIONS: This study demonstrates the critical role of VWF in the complex, thrombo-inflammatory state of obesity. It adds to the growing rationale for targeting VWF-specific interactions in thrombotic disease.

Thrombolytic therapy in preterm infants: Fifteen-year experience.

OBJECTIVE: To report a single-center experience with thrombolytic therapy using recombinant tissue plasminogen activator (rt-PA) in preterm neonates with severe thrombotic events, in terms of thrombus resolution and bleeding complications. STUDY DESIGN: This retrospective study included 21 preterm neonates with severe venous thrombotic events admitted to the neonatal intensive care unit, identified in our pharmacy database from January 2001 to December 2016, and treated with rt-PA until complete or partial clot lysis, no-response or bleeding complications. Our primary outcome was thrombus resolution. RESULTS: Twenty-one preterm neonates were treated with rt-PA for an average of 2.9 cycles. Seventeen patients (80.9%) had superior vena cava thrombosis and superior vena cava syndrome. All patients had a central venous catheter, parenteral nutrition, mechanical ventilation, and sepsis. Fifteen patients (71.4%) were extremely preterm, 11 (52.4%) were extremely low birth weight, and seven (33.3%) were very low birth weight. The patency rate was 85.7%, complete lysis occurred in 11 (52.4%) patients, and partial lysis in seven (33.3%). Minor bleeding occurred in five (23.8%) patients, three patients (14.2%) had clinically relevant nonmajor bleeding events, and major bleeding occurred in six (28%) patients. CONCLUSION: In this study, the rate of thrombus resolution in preterm neonates treated with rt-PA were similar to the percentages reported in children and adolescents, with a high rate of bleeding. Therefore, rt-PA thrombolytic therapy should only be considered as a treatment option for severe life-threatening thrombosis in premature neonates for whom the benefits of the thrombolytic treatment outweigh the risks of bleeding.

Discovery of novel (6S/12aS)-heptachpyridone capable of inhibiting thrombosis in vivo.

The in vitro conversion of (1S,3S)-1-dimethoxylethyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid, (1S,3S)-DCCA, in rat plasma is monitored by HPLC-FT-ICR-MS. We show that the in vitro conversion of (1S,3S)-DCCA in rat plasma for 1 h leads to forming (6S/12aS)-bisdimethoxyethylheptachpyridone, reflecting intermolecular condensation of (1S,3S)-DCCA, and the in vitro conversion of (6S/12aS)-bisdimethoxyethylheptachpyridone in rat plasma for 1 h leads to forming (6S/12aS)-heptachpyridone, reflecting hydrolysis of (6S/12aS)-bisdimethoxyethylheptachpyridone. At a dose of 1.0 µmol/kg (6S/12aS)-heptachpyridone orally inhibits venous thrombosis and arterial thrombosis in vivo. Bleeding time, clotting time and international normalized ratio show that at this dose (6S/12aS)-heptachpyridone has no bleeding risk, does not lengthen clotting time and does not change the exogenous coagulation pathway. We also show that the reactions promoted by rat plasma are easy to practice by chemical synthesis. Thus our findings build a bridge across the in vivo conversion and the application.

Do storage solutions protect endothelial function of arterialized vein graft in an experimental rat model?

BACKGROUND: This study aims to compare the effects of storage solutions commonly used in coronary artery bypass grafting on the vascular reactivity in vein graft interposed in arterial position in syngeneic rats. METHODS: Twenty-seven male Lewis rats were sacrified to sample a vein graft implanted 6 weeks ago into abdominal aorta position. The vein grafts were inferior venae cavae initially pretreated with heparinized saline solution (HS) or autologous heparinized blood (AHB) or our referent solution, GALA. The endothelial functionality, the in situ Reactive Oxygen Species (ROS) levels and the histological characteristics were conducted from segments of arterialized vein graft. RESULTS: At 6 weeks, graft thrombosis occurred respectively in 22% of AHB group, 62.5% in the HS group and 82.5% in the GALA group. In each group, significative intimal hyperplasia was observed. After 6 weeks, an endothelium-remodeling layer associated with an increase of wall thickness was observed in each group. Endothelium-dependent tone was reduced in the vein graft regardless of the group. No difference was observed concerning the ROS in vein graft between the different groups. In distal aortic sections, ROS levels were increased in HS and GALA groups. CONCLUSIONS: Storage solutions used in this experimental model of vein graft implanted in arterial position cause graft injury and a complete disappearance of vascular reactivity. GALA solution did not reduce intimal risk hyperplasia when the vein graft was exposed to arterial flow in a rat model.

Sulodexide Improves Contraction and Decreases Matrix Metalloproteinase-2 and -9 in Veins Under Prolonged Stretch.

High pressure in the lower-limb veins is often associated with chronic venous insufficiency and varicose veins (VVs), making it important to search for the mechanisms and agents that control venous function. We have shown that protracted increases in venous stretch/wall tension reduce vein contraction and augment matrix metalloproteinase (MMP)-2 and -9. Also, MMP-2 and MMP-9 promote venodilation, a hallmark of VVs. Sulodexide (SDX) is a blend of glycosaminoglycans with efficient profibrinolysis and antithrombosis activities, but its actions on vein function and the mechanisms involved are unclear. We tested the hypothesis that SDX enhances venous contractile response by decreasing MMP expression/activity in veins subjected to protracted stretch. Rat inferior vena cava (IVC) rings were treated with SDX (0.001-1 mg/mL) or vehicle, equilibrated under control 0.5-g resting tension or protracted 2-g stretch for 18 hours, and the contractile response to 96-mM KCl and phenylephrine (Phe) in SDX-treated and nontreated veins was recorded. In IVC rings under control 0.5-g resting tension, SDX caused dose-dependent contraction, 96-mM KCl caused marked contraction (176-mg/mg tissue), and Phe caused dose-dependent contraction with a maximum (56-mg/mg tissue) at 10 M. In IVC subjected to protracted 2-g stretch, 96-mM KCl-induced contraction was reduced to 112 mg/mg and maximal Phe-induced contraction was decreased to 23 mg/mg. In IVC subjected to protracted 2-g stretch plus SDX, 96-mM KCl-induced contraction was restored to 228 mg/mg and maximal Phe-induced contraction was improved to 115 mg/mg. Gelatin zymography and Western blots revealed increases in MMP-2 and MMP-9 levels/gelatinolytic activity in veins subjected to protracted 2-g stretch and reversal to control levels in veins subjected to 2-g stretch plus SDX. Thus, SDX improves vein function and augments the contractile response in veins subjected to protracted stretch. The SDX-induced improvement of contraction and restoration of vein function appear to involve decreases in MMP-2 and MMP-9 and may contribute to the benefits of SDX in chronic venous insufficiency and VVs.

Presurgical Pazopanib Improves Surgical Outcomes for Renal Cell Carcinoma With High-level IVC Tumor Thrombosis.

Background/ Aim: We evaluated surgical outcomes following nephrectomy and thrombectomy with and without presurgical treatment with pazopanib in patients with advanced renal cell carcinoma with inferior vena caval tumor thrombosis. MATERIALS AND METHODS: We compared surgical outcomes between patients undergoing presurgical treatment with pazopanib vs. surgery-alone in 19 patients who underwent surgery for advanced renal cell carcinoma with high-level inferior vena caval tumor thrombosis at the Kobe University Hospital. RESULTS: Comparing the presurgical group with the surgery-alone group, respectively, the average operative time was 497 min vs. 627 min (p=0.08); average blood loss was 1,928 ml vs. 7,393 ml (p<0.05); average postoperative hospitalization duration was 15.3 days vs. 21.6 days (p=0.05); and the perioperative complication rate was lower (presurgical: 33% vs. surgery-alone: 50%). CONCLUSION: Presurgical treatment with pazopanib decreased surgical difficulty and improved surgical outcomes for advanced renal cell carcinoma with high-level inferior vena caval tumor thrombosis.

Cardiac Changes in Patients on Long-Term Parenteral Nutrition.

Patients with short bowel syndrome (SBS) on long-term home parenteral nutrition (HPN) chronically receive high fluid volumes directly into the right atrium (RA) through the superior vena cava. We retrospectively evaluated cardiac function measured by routine transthoracic echocardiography (TTE) in a population of 26 SBS patients on long-term HPN and compared their data on echocardiograph-derived right heart structure and function, with those of a control group of 26 patients also bearing a central venous catheter (CVC) for other reasons. Results showed that body weight and BMI were significantly higher in the control group. The echocardiographic estimate of RA pressure was higher in HPN patients than in controls (p = 0.01). An increased estimate of RA pressure indicates the need to consider TTE in the follow-up of long-term HPN patients to detect functional impairment early.

Evaluation of anticoagulant and antiplatelet therapy after iliocaval stenting: Factors associated with stent occlusion.

OBJECTIVE: Iliocaval stenting has gained increased use over recent years for a variety of indications, including May-Thurner syndrome (MTS), post-thrombotic syndrome (PTS), and acute deep vein thrombosis (DVT). METHODS: A retrospective review of 155 patients undergoing iliocaval venous stenting at a large teaching hospital was performed. Clinical and procedural data, mode and duration of anticoagulation or antiplatelet therapy, and outcomes were recorded. RESULTS: Forty-five patients were treated for MTS, 49 for PTS. and 61 for acute DVT. The median follow-up was 19 months (interquartile range, 9-30 months). Primary patency rates were 97.8% in the MTS group, 85.7% in PTS, and 85.2% for the acute DVT group. Stent restenosis or occlusion occurred in one patient with MTS (2.2%), seven patients with PTS (14%), and nine patients with acute DVT (15%). An ipsilateral DVT recurred in 7 patients with PTS (14%) and 15 patients with acute DVT (25%). The stents that occluded had a tendency toward longer length (162.2 vs 125.2 mm; P = NS) and extension into the common femoral vein (18.8 vs 5.3%; P = NS). The patent stent group had statistically larger nominal diameter stents (P = .013). The duration of anticoagulation did not seem to be a significant factor in stent patency. CONCLUSIONS: Stent diameter has a significant influence on iliocaval stent patency rates.

Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome.

Potentiation of neutrophil extracellular trap (NET) release is one mechanism by which antiphospholipid antibodies (aPL Abs) effect thrombotic events in patients with antiphospholipid syndrome (APS). Surface adenosine receptors trigger cyclic AMP (cAMP) formation in neutrophils, and this mechanism has been proposed to regulate NETosis in some contexts. Here we report that selective agonism of the adenosine A2A receptor (CGS21680) suppresses aPL Ab-mediated NETosis in protein kinase A-dependent fashion. CGS21680 also reduces thrombosis in the inferior vena cavae of both control mice and mice administered aPL Abs. The antithrombotic medication dipyridamole is known to potentiate adenosine signaling by increasing extracellular concentrations of adenosine and interfering with the breakdown of cAMP. Like CGS21680, dipyridamole suppresses aPL Ab-mediated NETosis via the adenosine A2A receptor and mitigates venous thrombosis in mice. In summary, these data suggest an anti-inflammatory therapeutic paradigm in APS, which may extend to thrombotic disease in the general population.

Neoadjuvant Sunitinib Decreases Inferior Vena Caval Thrombus Size and Is Associated With Improved Oncologic Outcomes: A Multicenter Comparative Analysis.

BACKGROUND: We analyzed outcomes of neoadjuvant sunitinib in patients with renal-cell carcinoma (RCC) and inferior vena caval (IVC) tumor and compared outcomes to patients who did not undergo neoadjuvant therapy before surgery. PATIENTS AND METHODS: We performed a multicenter retrospective comparison of RCC patients with IVC tumor who underwent neoadjuvant sunitinib before surgery versus those who did not. Response to sunitinib was defined by Response Evaluation Criteria in Solid Tumors (RECIST). Primary outcome was cancer-specific survival. Secondary outcomes included overall survival. Multivariate analysis was performed to identify risk factors associated with primary and secondary outcomes. Kaplan-Meier analysis compared survival in neoadjuvant and primary surgery groups. RESULTS: Data of 53 patients were analyzed (19 neoadjuvant sunitinib, 34 primary surgery; median follow-up, 58 months). Eighteen (9 in each group, P = .143) had metastatic RCC. There was no difference in IVC tumor level between the 2 groups (P = .76). After neoadjuvant sunitinib, median primary tumor decreased size from 8.1 to 6.8 cm, and IVC tumor decreased by 1.3 cm. IVC tumor level decreased in 8 (42.1%) of 19 and was stable in 10 (52.6%) of 19; 5 (26.3%) of 19 experienced partial response. Similar proportions of patients underwent robot-assisted or minimally invasive approaches (P = .351), and no differences were noted in complications (P = .194). Multivariate analysis showed neoadjuvant sunitinib was associated with improved cancer-specific survival (odds ratio = 3.28; P = .021). Kaplan-Meier analysis demonstrated significantly longer median cancer-specific survival (72 vs. 38 months, P = .023) for neoadjuvant sunitinib. CONCLUSION: Neoadjuvant sunitinib was associated with a reduction in primary tumor and thrombus size as well as improved survival. Further investigation is needed to determine the utility of neoadjuvant sunitinib in RCC with IVC tumor.

Deep Vein Thrombosis is Modulated by Inflammation Regulated via Sirtuin 1/NF-κB Signalling Pathway in a Rat Model.

BACKGROUND: Inflammation plays an important role in thrombus formation, and Sirtuin 1 (SIRT1) negatively regulates inflammation via deacetylating nuclear factor-kappa B. However, the relationship between SIRT1-regulated inflammation and deep vein thrombosis (DVT) is still unknown. OBJECTIVE: The aim of this study was to investigate whether SIRT1 plays a critical role in inferior vena cava (IVC) stenosis-induced DVT. MATERIALS AND METHODS: Thrombus weight and histopathologic analysis of IVC were evaluated at different time points after IVC stenosis in rats. Serum levels of inflammatory cytokines and protein expressions of SIRT1, acetylated p65 (Ace-p65), phosphorylated p65 (p-p65) and tissue factor (TF) in thrombosed IVC were assessed. Besides, the effects of resveratrol (RES, a SIRT1 agonist) and EX527 (a selective SIRT1 inhibitor) on DVT were evaluated. RESULTS: Thrombus weight was increased from 1 to 3 days after IVC stenosis, and then was decreased afterwards. Leukocytes infiltration appeared and serum levels of cytokines were significantly increased in rats of IVC stenosis. SIRT1 protein expression was significantly down-regulated at 1 hour and 1 day after stenosis, while p-p65, Ace-p65 and TF protein expressions appeared a contrary trend. RES reduced thrombus weight, leukocytes infiltration, levels of tumour necrosis factor-α and interleukin-1ß and protein expressions of Ace-p65 and TF as well. Moreover, RES significantly increased the protein and messenger ribonucleic acid expressions of SIRT1, while EX527 abolished the protective effects of RES. CONCLUSION: SIRT1 activation attenuated IVC stenosis-induced DVT via anti-inflammation in rats. Therefore, SIRT1 may be a potential therapeutic target that could ameliorate DVT.

Endothelial progenitor cell-derived exosomes, loaded with miR-126, promoted deep vein thrombosis resolution and recanalization.

BACKGROUND: Deep vein thrombosis (DVT) is caused by blood clotting in the deep veins. Thrombosis resolution and recanalization can be accelerated by endothelial progenitor cells. In this report, we investigated the effects of miR-126-loaded EPC-derived exosomes (miR-126-Exo) on EPCs function and venous thrombus resolution. METHODS: In vitro promotional effect of miR-126-Exo on the migration and tube incorporation ability of EPCs was investigated via transwell assay and tube formation assay. In addition, a mouse venous thrombosis model was constructed and treated with miR-126-Exo to clarify the therapeutic effect of miR-126-Exo by histological analysis. Lastly, this study predicted a target gene of miR-126 using target prediction algorithms and confirmed it by luciferase activity assay, RT-qPCR, and Western blot. RESULTS: Transwell assay and tube formation assay indicated that miR-126-Exo could enhance the migration and tube incorporation ability of EPCs. Moreover, in vivo study manifested enhanced thrombus organization and recanalization after miR-126-Exo treatment. Meanwhile, we identified that Protocadherin 7 as a target gene of miR-126. CONCLUSIONS: To sum up, our results demonstrated that EPC-derived exosomes loaded with miR-126 significantly promoted thrombus resolution in an animal model of venous thrombosis, indicating exosomes as a promising potential vehicle carrying therapeutic molecules for DVT therapy.

Antiplatelet Therapy is Associated with Stent Patency After Iliocaval Venous Stenting.

PURPOSE: To examine the effectiveness of antithrombotic medications to prevent venous stent malfunction for iliocaval occlusive disease. MATERIALS AND METHODS: A retrospective analysis was performed on 62 patients who underwent technically successful endovascular iliocaval stent placement between May 2008 and April 2017. Clinical records were reviewed for demographic information, procedure details, post-stenting antithrombotic prophylaxis and stent patency on follow-up. Stent malfunction was defined as > 50% stenosis or occlusion at follow-up. Risk factors for stent malfunction were assessed with univariable and multiple Cox proportional hazard models. RESULTS: The median follow-up period was 11.6 months (range 0.1-76.4). Overall primary and secondary cumulative patency rates at 12 months were 70.0% and 92.4%, respectively. After stent placement, 97% of patients received anticoagulation with warfarin, enoxaparin or a factor Xa inhibitor. In addition, 61% received antiplatelet prophylaxis with aspirin, clopidogrel or a combination. In multiple Cox regression analysis, post-stenting antiplatelet use remained significantly associated with primary stent patency (HR = 0.28, P = 0.022). CONCLUSION: After iliocaval venous stenting, stent patency was best predicted by concomitant antiplatelet and anticoagulation therapy rather than anticoagulation alone. This novel finding warrants further research underlying mechanisms leading to venous stent thrombosis, and has implications for optimal medical management after venous stenting.

Presurgical pazopanib for renal cell carcinoma with inferior vena caval thrombus: a single-institution study.

The aim of this study was to investigate the clinical benefit of presurgical therapy with pazopanib in renal cell carcinoma (RCC) patients with a tumor thrombus extending to a high level in the vena cava. A retrospective review was performed for seven consecutive patients with RCC and tumor thrombus involving the vena cava above the hepatic vein (level 3-4, Mayo Clinic classification) treated with pazopanib without initial cytoreductive nephrectomy at our institution. The effect of pazopanib was assessed in terms of the primary site response, thrombus diameter, and height (before and after treatment) on computed tomography or MRI. The tumor thrombus level before the induction of pazopanib was 3 in one patient and 4 in the remaining six patients. After pazopanib, shrinkage of the primary site and thrombus diameter and length were observed in all patients except one (with a rhabdoid tumor). The mean decreases of primary tumor diameter, tumor thrombus diameter, and length were 14, 9, and 31 mm, respectively. The tumor thrombus level decreased in three (43%) patients and remained stable in the remaining patient. Our findings suggest that presurgical treatment with pazopanib may shrink the tumor thrombus and decrease the surgical invasiveness in RCC patients with a high-level tumor thrombus.

Distinct Pathogenesis of Pancreatic Cancer Microvesicle-Associated Venous Thrombosis Identifies New Antithrombotic Targets In Vivo.

OBJECTIVE: Cancer patients are at high risk of developing deep venous thrombosis (DVT) and venous thromboembolism, a leading cause of mortality in this population. However, it is largely unclear how malignant tumors drive the prothrombotic cascade culminating in DVT. APPROACH AND RESULTS: Here, we addressed the pathophysiology of malignant DVT compared with nonmalignant DVT and focused on the role of tumor microvesicles as potential targets to prevent cancer-associated DVT. We show that microvesicles released by pancreatic adenocarcinoma cells (pancreatic tumor-derived microvesicles [pcMV]) boost thrombus formation in a model of flow restriction of the mouse vena cava. This depends on the synergistic activation of coagulation by pcMV and host tissue factor. Unlike nonmalignant DVT, which is initiated and propagated by innate immune cells, thrombosis triggered by pcMV was largely independent of myeloid leukocytes or platelets. Instead, we identified externalization of the phospholipid phosphatidylethanolamine as a major mechanism controlling the prothrombotic activity of pcMV. Disrupting phosphatidylethanolamine-dependent activation of factor X suppressed pcMV-induced DVT without causing changes in hemostasis. CONCLUSIONS: Together, we show here that the pathophysiology of pcMV-associated experimental DVT differs markedly from innate immune cell-promoted nonmalignant DVT and is therefore amenable to distinct antithrombotic strategies. Targeting phosphatidylethanolamine on tumor microvesicles could be a new strategy for prevention of cancer-associated DVT without causing bleeding complications.

Comparison of sonographic inferior vena cava and aorta indexes during fluid administered in children.

OBJECTIVES: This prospective, observational study evaluated changes in ultrasound measurements of the inferior vena caval index (IVCI), the aorta diameter/IVC diameter index (Ao/IVCD), and the aorta area/IVC area index (Ao/IVCA) during fluid administration in children requiring intravenous fluid administration. METHODS: Children who presented to the pediatric emergency department with symptoms of dehydration were enrolled between May 2015 and February 2016. The maximum diameter of the aorta, from inner wall to inner wall, and the long and short axis diameters of IVC were measured using a convex array transducer in the transverse view. Subsequently, we measured the diameter of the IVC at the subxiphoid area during inspiration and expiration in longitudinal view. We calculated IVCI, Ao/IVCD, and Ao/IVCA during administration of 10ml/kg and 20ml/kg normal saline boluses. RESULTS: IVCI and Ao/IVCA significantly changed immediately after administration of initial 10ml/kg of NS. Ao/IVCA showed significant change during the additional administration of 10ml/kg (total 20ml/kg) normal saline boluses (1.43, IQR 1.12-1.86 vs. 1.08, IQR 0.87-1.45, p value<0.001). No significant changes were observed for IVCI and Ao/IVCD. Ao/IVCA was significantly correlated with the volume of fluid administered. The coefficient between initial and administration of the 10ml/kg normal saline bolus was -0.396 (p value=0.010), and that between the 10ml/kg and 20ml/kg normal saline boluses was -0.316 (p value=0.038). CONCLUSIONS: Ao/IVCA showed better correlations with the volume of fluid administered than IVCI and Ao/IVCA. Ao/IVCA might be a promising index for assessing the effects of fluid administration.