Direct puncture versus contralateral femoral artery approach for catheter-directed thrombolysis of occluded infra-inguinal arterial bypass grafts.

AIM: To compare the safety, effectiveness, and clinical outcome of percutaneous direct puncture approach versus contralateral femoral native vessel approach for catheter-directed thrombolysis of occluded infra-inguinal bypass grafts. MATERIALS AND METHODS: A retrospective analysis was performed comprising a cohort of patients who underwent catheter-directed thrombolysis procedures of occluded infra-inguinal bypass grafts between January 2013 and January 2022, with a follow-up period until June 2022. This included 55 procedures via the native vessel approach and 18 procedures via the direct puncture approach. Primary outcomes were technical success and procedural safety; secondary outcomes included re-intervention rate, limb salvage, and mortality as assessed by log-rank testing and Kaplan-Meier curves. RESULTS: There were no differences between the two groups with regard to patient demographics, except for the number of previous vascular procedures (n=6.83 ± 3.07 direct approach versus n=4.96 ± 2.79 native vessel approach, p=0.025). Thrombolysis was comparably successful in both groups (n=13/18; 72% direct approach versus n=42/55; 76%, p=0.723). There were no differences in the duration of thrombolysis administration. The rate of adverse events was slightly lower in the direct approach group, but without significance (p=0.092). There were no adverse events related to the puncture site in the direct approach group. No differences were found between the time-to-event values for re-occlusion, re-intervention, amputation, or mortality respectively (p=0.662; p=0.520; p=0.816; p=0.462). CONCLUSION: The direct puncture approach seems to be a safe and efficient approach for catheter-directed thrombolysis procedures in infra-inguinal occluded bypass grafts, with clinical outcomes comparable to the native vessel approach.

Patients with Lemierre syndrome have a high risk of new thromboembolic complications, clinical sequelae and death: an analysis of 712 cases.

BACKGROUND: Lemierre syndrome is characterized by head/neck vein thrombosis and septic embolism usually complicating an acute oropharyngeal bacterial infection in adolescents and young adults. We described the course of Lemierre syndrome in the contemporary era. METHODS: In our individual-level analysis of 712 patients (2000-2017), we included cases described as Lemierre syndrome if these criteria were met: (i) primary site of bacterial infection in the head/neck; (ii) objectively confirmed local thrombotic complications or septic embolism. The study outcomes were new or recurrent venous thromboembolism or peripheral septic lesions, major bleeding, all-cause death and clinical sequelae. RESULTS: The median age was 21 (Q1-Q3: 17-33) years, and 295 (41%) were female. At diagnosis, acute thrombosis of head/neck veins was detected in 597 (84%) patients, septic embolism in 582 (82%) and both in 468 (80%). After diagnosis and during in-hospital follow-up, new venous thromboembolism occurred in 34 (5.2%, 95% CI 3.8-7.2%) patients, new peripheral septic lesions became evident in 76 (11.7%; 9.4-14.3%). The rate of either was lower in patients who received anticoagulation (OR: 0.59; 0.36-0.94), higher in those with initial intracranial involvement (OR: 2.35; 1.45-3.80). Major bleeding occurred in 19 patients (2.9%; 1.9-4.5%), and 26 died (4.0%; 2.7-5.8%). Clinical sequelae were reported in 65 (10.4%, 8.2-13.0%) individuals, often consisting of cranial nerve palsy (n = 24) and orthopaedic limitations (n = 19). CONCLUSIONS: Patients with Lemierre syndrome were characterized by a substantial risk of new thromboembolic complications and death. This risk was higher in the presence of initial intracranial involvement. One-tenth of survivors suffered major clinical sequelae.

A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study.

BACKGROUND: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. METHODS: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. DISCUSSION: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. TRIAL REGISTRATION: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

D-dimer levels and risk of recurrence following provoked venous thromboembolism: findings from the RIETE registry.

BACKGROUND: Patients with venous thromboembolism (VTE) secondary to transient risk factors may develop VTE recurrences after discontinuing anticoagulation. Identifying at-risk patients could help to guide the duration of therapy. METHODS: We used the RIETE database to assess the prognostic value of d-dimer testing after discontinuing anticoagulation to identify patients at increased risk for recurrences. Transient risk factors were classified as major (postoperative) or minor (pregnancy, oestrogen use, immobilization or recent travel). RESULTS: In December 2018, 1655 VTE patients with transient risk factors (major 460, minor 1195) underwent d-dimer measurements after discontinuing anticoagulation. Amongst patients with major risk factors, the recurrence rate was 5.74 (95% CI: 3.19-9.57) events per 100 patient-years in those with raised d-dimer levels and 2.68 (95% CI: 1.45-4.56) in those with normal levels. Amongst patients with minor risk factors, the rates were 7.79 (95% CI: 5.71-10.4) and 3.34 (95% CI: 2.39-4.53), respectively. Patients with major risk factors and raised d-dimer levels (n = 171) had a nonsignificantly higher rate of recurrences (hazard ratio [HR]: 2.14; 95% CI: 0.96-4.79) than those with normal levels. Patients with minor risk factors and raised d-dimer levels (n = 382) had a higher rate of recurrences (HR: 2.34; 95% CI: 1.51-3.63) than those with normal levels. On multivariate analysis, raised d-dimers (HR: 1.74; 95% CI: 1.09-2.77) were associated with an increased risk for recurrences in patients with minor risk factors, not in those with major risk factors. CONCLUSIONS: Patients with raised d-dimer levels after discontinuing anticoagulant therapy for VTE provoked by a minor transient risk factor were at an increased risk for recurrences.

Edoxaban for treatment of venous thromboembolism in patient groups with different types of cancer: Results from the Hokusai VTE Cancer study.

BACKGROUND: The safety and efficacy of edoxaban and dalteparin is unclear for several cancer groups. METHODS: We evaluated the occurrence of the primary outcome in large cancer groups. The primary outcome was the composite of recurrent VTE or major bleeding over 12 months. RESULTS: In patients with gastrointestinal cancer, the primary outcome occurred in 19.4% patients given edoxaban and in 15.0% given dalteparin (risk difference [RD], 4.4%; 95%-CI, -4.1% to 12.8%). The corresponding rates for edoxaban and dalteparin were 10.4% and 10.7% for lung cancer (RD, -0.3%; 95%-CI, -10.0% to 9.5%), 13.6% and 12.5% for urogenital cancer (RD, 1.1; 95%-CI, -10.1-12.4), 3.1% and 11.7% for breast cancer (RD, -8.6; 95%-CI, -19.3-2.2), 8.9% and 10.9% for hematological malignancies (RD, -2.0; 95%-CI, -13.1-9.1), and 10.4% and 17.4% for gynecological cancer (RD, -7.0; 95%-CI, -19.8-5.7). In the subgroup of gastrointestinal cancer, edoxaban was associated with a 3.5% lower absolute risk of recurrent VTE and a 7.9% higher risk of major bleeding. CONCLUSION: Edoxaban has a similar risk-benefit ratio to dalteparin in most cancer groups. In those with gastrointestinal cancer, the lower risk of recurrent VTE and the advantages of oral therapy need to be balanced against the increased risk of major bleeding.

Tranexamic acid to reduce bleeding after dental extraction in patients treated with non-vitamin K oral anticoagulants: design and rationale of the EXTRACT-NOAC trial.

Bleeding after dental extraction in patients treated with non-vitamin K oral anticoagulants (NOAC) may lead to unplanned reinterventions and interruption of anticoagulation, thereby exposing patients to a risk of thromboembolism. We have designed a study (EXTRACT-NOAC) to investigate whether tranexamic acid (TXA) mouthwash decreases bleeding after extraction in such patients. The study is a randomised, double-blind, placebo-controlled trial. We plan to randomise 236 patients listed for dental extraction and treated with NOAC to 10% TXA mouthwash or placebo. Patients are instructed to use the mouthwash before the dental extraction, and three times a day for three days thereafter. The primary outcome is oral bleeding. Secondary outcomes include type of bleeding, procedural bleeding score, number of reinterventions after oral bleeding, and number of interruptions in NOAC treatment. Any bleeding from sources other than the mouth, and thrombotic events, are recorded as safety outcomes. Patients are followed-up for seven days. This study will provide evidence to guide the management of patients taking NOAC who need teeth extracted.

Acute non-cirrhotic portal vein thrombosis : review.

A 35-year-old man with a medical history of myocardial infarction, presenting with fever, general malaise and vague abdominal discomfort, was diagnosed with a portomesenteric venous thrombosis and acute cytomegalovirus (CMV) infection. Thrombophilia screening resulted in detection of heterozygosity for factor II G20210A gene mutation. Low molecular weight heparin in therapeutic dose was started, followed by disappearance of thrombus on imaging CT two months after diagnosis. The multifactorial origin of portal thrombosis and the importance of awareness of the link between CMV infection and an increased risk of thrombosis is emphasized with this case and review of the literature. Identifying CMV infection as a trigger for thrombosis can help to avoid extended anticoagulation. Acute non-cirrhotic PVT is a rare but probably underestimated condition as symptoms may be discrete or non-specific. The origin of portal thrombosis is frequently multifactorial. Recent literature has emphasized the increasing prevalence of CMV-induced PVT in immunocompetent patients. The multifactorial origin of portal thrombosis and the importance of awareness of the link between CMV infection and an increased risk of thrombosis is emphasized with this review of the literature and included case. Identifying CMV infection as a trigger for thrombosis can help to avoid extended anticoagulation.

The adsorption of dabigatran is as efficient as addition of idarucizumab to neutralize the drug in routine coagulation assays.

INTRODUCTION: The direct thrombin inhibitor dabigatran interferes with thrombophilia screening and with the diagnosis of hemostasis disorders that develop during treatment with the anticoagulant. In vitro addition of idarucizumab, a humanized antibody fragment that binds dabigatran, to plasma samples containing dabigatran fully neutralizes the drug. This study was carried out to determine whether binding of dabigatran on selected insoluble commercial adsorbent material, DOAC-STOPR , was as efficient as idarucizumab to neutralize the anticoagulant activity of the drug in vitro. METHODS: Coagulation assays sensitive to dabigatran were carried out with patient and control plasma samples spiked with dabigatran and supplemented with idarucizumab or incubated with adsorbent material. RESULTS: In samples containing upto 10 000 ng/mL dabigatran, the adsorption procedure was at least as efficient as the addition of idarucizumab to neutralize the activity of the anticoagulant drug. Neither the adsorption procedure nor the addition of idarucizumab did impair routine coagulation assays carried out with plasma devoid of dabigatran, such as the activated partial thromboplastin time, prothrombin time, fibrinogen Clauss, and the thrombophilia screening assays used to detect antiphospholipid antibodies or activated protein C resistance. In addition, the adsorption procedure did not interfere with the detection of lupus anticoagulant samples. CONCLUSIONS: Adsorption of dabigatran in plasma samples containing the drug neutralizes its activity as efficiently as the addition of idarucizumab. This method allows the evaluation of thrombophilia markers without interruption of anticoagulation therapy or the detection of hemostasis disorders in patients treated with the drug.

Age-adjusted D-dimer to rule out deep vein thrombosis: findings from the PALLADIO algorithm.

Essentials The accuracy of the age-adjusted D-dimer in suspected venous thromboembolism is still debated. We assessed the performance of age-adjusted D-dimer combined with the PALLADIO algorithm. The age-adjusted threshold can reduce the need for imaging tests compared to the fixed cut-off. The safety of this approach should be confirmed in large management studies. SUMMARY: Background Age-adjusted D-dimer has been proposed to increase specificity for the diagnosis of venous thromboembolism (VTE). However, the accuracy of this threshold has been recently questioned. Objectives To assess the diagnostic performance of age-adjusted D-dimer combined with clinical pretest probability (PTP) in patients with suspected deep vein thrombosis (DVT). Methods PALLADIO (NCT01412242) was a multicenter management study that validated a new diagnostic algorithm, incorporating PTP, D-dimer (using the manufacturer's cut-off) and limited or extended compression ultrasonography (CUS) in outpatients with clinically suspected DVT. Patients with unlikely PTP and negative D-dimer had DVT ruled out without further testing (group 1); patients with likely PTP or positive D-dimer underwent limited CUS (group 2); patients with likely PTP and positive D-dimer underwent extended CUS (group 3). Patients with DVT ruled out at baseline had a 3-month follow-up. In this post-hoc analysis we evaluated age-adjusted D-dimer cut-off (defined as age times 10 µg L-1 , or age times 5 µg L-1 for D-dimers with a lower manufacturer's cut-off, in patients > 50 years). Results In total, 1162 patients were enrolled. At initial visit, DVT was detected in 4.0% of patients in group 2 and 53.0% in group 3. The age-adjusted D-dimer, compared with the fixed cut-off, resulted in 5.1% (95% CI, 4.0-6.5%) reduction of CUS. The incidence of symptomatic VTE during follow-up was: 0.24% (95% CI, 0.04-1.37) in group 1; 1.12% (95% CI, 0.44-2.85) in group 2; and 1.89% (95% CI, 0.64-5.40) in group 3. Conclusions The PALLADIO algorithm using age-adjusted D-dimer slightly decreased the number of required imaging tests, but this approach should be confirmed in large management studies.

Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians.

Click to hear Dr Baglin's perspective on the role of the laboratory in treatment with new oral anticoagulants SUMMARY: One of the key benefits of the direct oral anticoagulants (DOACs) is that they do not require routine laboratory monitoring. Nevertheless, assessment of DOAC exposure and anticoagulant effects may become useful in various clinical scenarios. The five approved DOACs (apixaban, betrixaban, dabigatran etexilate, edoxaban and rivaroxaban) have different characteristics impacting assay selection and the interpretation of results. This article provides an updated overview on (i) which test to use (and their advantages and limitations), (ii) when to assay DOAC levels, (iii) how to interpret the results relating to bleeding risk, emergency situations and perioperative management, and (iv) what is the impact of DOACs on routine and specialized coagulation assays. Assays for anti-Xa or anti-IIa activity are the preferred methods when quantitative information is useful, although the situations in which to test for DOAC levels are still debated. Different reagent sensitivities and variabilities in laboratory calibrations impact assay results. International calibration standards for all specific tests for each DOAC are needed to reduce the inter-laboratory variability and allow inter-study comparisons. The impact of the DOACs on hemostasis testing may cause false-positive or false-negative results; however, these can be minimized by using specific assays and collecting blood samples at trough concentrations. Finally, prospective clinical trials are needed to validate the safety and efficacy of proposed laboratory thresholds in relation to clinical decisions. We offer recommendations on the tests to use for measuring DOACs and practical guidance on laboratory testing to help patient management and avoid diagnostic errors.

An open conformation of ADAMTS-13 is a hallmark of acute acquired thrombotic thrombocytopenic purpura.

Essentials Conformational changes in ADAMTS-13 are part of its mode-of-action. The murine anti-ADAMTS-13 antibody 1C4 discriminates between folded and open ADAMTS-13. ADAMTS-13 conformation is open in acute acquired thrombotic thrombocytopenic purpura (TTP). Our study forms an important basis to fully elucidate the pathophysiology of TTP. SUMMARY: Background Acquired thrombotic thrombocytopenic purpura (aTTP) is an autoimmune disorder characterized by absent ADAMTS-13 activity and the presence of anti-ADAMTS-13 autoantibodies. Recently, it was shown that ADAMTS-13 adopts a folded or an open conformation. Objectives As conformational changes in self-antigens play a role in the pathophysiology of different autoimmune diseases, we hypothesized that the conformation of ADAMTS-13 changes during acute aTTP. Methods Antibodies recognizing cryptic epitopes in the spacer domain were generated. Next, the conformation of ADAMTS-13 in 40 healthy donors (HDs), 99 aTTP patients (63 in the acute phase versus 36 in remission), 12 hemolytic-uremic syndrome (HUS) patients and 63 sepsis patients was determined with ELISA. Results The antibody 1C4 recognizes a cryptic epitope in ADAMTS-13. Therefore, we were able to discriminate between a folded and an open ADAMTS-13 conformation. We showed that ADAMTS-13 in HDs does not bind to 1C4, indicating that ADAMTS-13 circulates in a folded conformation. Similar results were obtained for HUS and sepsis patients. In contrast, ADAMTS-13 of acute aTTP patients bound to 1C4 in 92% of the cases, whereas, in most cases, this binding was abolished during remission, showing that the conformation of ADAMTS-13 is open during an acute aTTP episode. Conclusions Our study shows that, besides absent ADAMTS-13 activity and the presence of anti-ADAMTS-13 autoantibodies, an open ADAMTS-13 conformation is also a hallmark of acute aTTP. Demonstrating this altered ADAMTS-13 conformation in acute aTTP will help to further unravel the pathophysiology of aTTP and lead to improved therapy and diagnosis.

Staphylococcus aureus, master manipulator of the human hemostatic system.

The coagulation system does not only offer protection against bleeding, but also aids in our defense against invading microorganisms. The hemostatic system and innate immunity are strongly entangled, which explains why so many infections are complicated by either bleeding or thrombosis. Staphylococcus aureus (S. aureus), currently the most deadly infectious agent in the developed world, causes devastating intravascular infections such as sepsis and infective endocarditis. During these infections S. aureus comes in close contact with the host hemostatic system and proves to be a master in manipulating coagulation. The coagulases of S. aureus directly induce coagulation by activating prothrombin. S. aureus also manipulates fibrinolysis by triggering plasminogen activation via staphylokinase. Furthermore, S. aureus binds and activates platelets and interacts with key coagulation proteins such as fibrin(ogen), fibronectin and von Willebrand factor. By manipulating the coagulation system S. aureus gains a significant advantage over the host defense mechanisms. Studying the interplay between S. aureus and the hemostatic system can therefore lead to new innovative therapies for battling S. aureus infections.

Clumping factor A, von Willebrand factor-binding protein and von Willebrand factor anchor Staphylococcus aureus to the vessel wall.

Essentials Staphylococcus aureus (S. aureus) binds to endothelium via von Willebrand factor (VWF). Secreted VWF-binding protein (vWbp) mediates S. aureus adhesion to VWF under shear stress. vWbp interacts with VWF and the Sortase A-dependent surface protein Clumping factor A (ClfA). VWF-vWbp-ClfA anchor S. aureus to vascular endothelium under shear stress. SUMMARY: Objective When establishing endovascular infections, Staphylococcus aureus (S. aureus) overcomes shear forces of flowing blood by binding to von Willebrand factor (VWF). Staphylococcal VWF-binding protein (vWbp) interacts with VWF, but it is unknown how this secreted protein binds to the bacterial cell wall. We hypothesized that vWbp interacts with a staphylococcal surface protein, mediating the adhesion of S. aureus to VWF and vascular endothelium under shear stress. Methods We studied the binding of S. aureus to vWbp, VWF and endothelial cells in a micro-parallel flow chamber using various mutants deficient in Sortase A (SrtA) and SrtA-dependent surface proteins, and Lactococcus lactis expressing single staphylococcal surface proteins. In vivo adhesion of bacteria was evaluated in the murine mesenteric circulation using real-time intravital vascular microscopy. Results vWbp bridges the bacterial cell wall and VWF, allowing shear-resistant binding of S. aureus to inflamed or damaged endothelium. Absence of SrtA and Clumping factor A (ClfA) reduced adhesion of S. aureus to vWbp, VWF and activated endothelial cells. ADAMTS-13 and an anti-VWF A1 domain antibody, when combined, reduced S. aureus adhesion to activated endothelial cells by 90%. Selective overexpression of ClfA in the membrane of Lactococcus lactis enabled these bacteria to bind to VWF and activated endothelial cells but only in the presence of vWbp. Absence of ClfA abolished bacterial adhesion to the activated murine vessel wall. Conclusions vWbp interacts with VWF and with the SrtA-dependent staphylococcal surface protein ClfA. The complex formed by VWF, secreted vWbp and bacterial ClfA anchors S. aureus to vascular endothelium under shear stress.

Improving the diagnostic management of upper extremity deep vein thrombosis.

Essentials The Constans score and D-dimer can rule out upper extremity deep vein thrombosis without imaging. We evaluated the performance of an extended Constans score and an age-adjusted D-dimer threshold. The extended Constans score did not increase the efficiency compared to the original score. Age-adjusted D-dimer testing safely increased the efficiency by 4%, but this needs validation. SUMMARY: Background Among patients with clinically suspected upper extremity deep vein thrombosis (UEDVT), a clinical decision rule based on the Constans score combined with D-dimer testing can safely rule out the diagnosis without imaging in approximately one-fifth of patients. Objectives To evaluate the performance of the original Constans score, an extended Constans score and an age-adjusted D-dimer positivity threshold. Methods Data of 406 patients with suspected UEDVT previously enrolled in a multinational diagnostic management study were used. The discriminatory performance, calibration and diagnostic accuracy of the Constans score were evaluated. The Constans score was extended by selecting clinical variables that may have incremental value in detecting UEDVT, conditional on the original Constans score items. The performance of the Constans rule was evaluated in combination with fixed and age-adjusted D-dimer thresholds. Results The original Constans score showed good discriminatory performance (c-statistic, 0.81; 95% confidence interval [CI], 0.76-0.85). An extended Constans score with five additional clinical items improved discriminatory performance and calibration, but this did not translate into a higher efficiency in avoiding imaging tests. Compared with a fixed threshold, age-adjusted D-dimer testing increased the proportion of patients for whom imaging and anticoagulation could be withheld from 21% to 25% (gain, 3.7%; 95% CI, 2.3-6.0%). Conclusions The Constans score has good discriminatory performance in the diagnosis of UEDVT. Age-adjusted D-dimer testing is likely to safely increase the efficiency of the diagnostic algorithm, but this approach needs prospective validation.

Inhibition of major integrin αV ß3 reduces Staphylococcus aureus attachment to sheared human endothelial cells.

Essentials Staphylococcus aureus (S. aureus) binds and impairs function of vascular endothelial cells (EC). We investigated the molecular signals triggered by S. aureus adhesion to EC. Inhibition of the EC integrin αVß3 reduces S. aureus binding and rescues EC function. αVß3 blockade represents an attractive target to treat S. aureus bloodborne infections. SUMMARY: Background Vascular endothelial dysfunction with associated edema and organ failure is one of the hallmarks of sepsis. Although a large number of microorganisms can cause sepsis, Staphylococcus aureus (S. aureus) is one of the primary etiologic agents. Currently, there are no approved specific treatments for sepsis, and the initial management bundle is therefore focused on cardiorespiratory resuscitation and mitigation of the immediate threat of uncontrolled infection. The continuous emergence of antibiotic-resistant strains of bacteria necessitates the development of new therapeutic approaches for this disease. Objective To identify the molecular mechanisms leading to endothelial dysfunction as a result of S. aureus binding. METHODS: Binding of wild type and Clumping factor A (ClfA) deficient S. aureus Newman to the endothelium was measured in vitro and in the mesenteric circulation of C57Bl/6 mice. The effects of the αV ß3 blocker-cilengitide-on bacterial binding, endothelial VE-cadherin expression, apoptosis, proliferation and permeability were assessed. Results The major S. aureus cell wall protein ClfA bound to endothelial cell αV ß3 in the presence of fibrinogen. This interaction resulted in disturbances in barrier function mediated by VE-cadherin in endothelial cell monolayers, and ultimately cell death by apoptosis. With a low concentration of cilengitide, ClfA binding to αV ß3 was significantly inhibited both in vitro and in vivo. Moreover, preventing S. aureus from attaching to αV ß3 resulted in a significant reduction in endothelial dysfunction following infection. Conclusion Inhibition of S. aureus ClfA binding to endothelial cell αV ß3 by cilengitide prevents endothelial dysfunction.

Current management strategies and long-term clinical outcomes of upper extremity venous thrombosis.

UNLABELLED: Essentials Few data exist on outcome of upper extremity deep and superficial vein thrombosis (UEDVT and UESVT). We followed 102 and 55 patients with UEDVT or UESVT, respectively, for a median of 3.5 years. Risk of recurrent venous thromboembolism was low in both diseases, and the mortality high. Postthrombotic symptoms were infrequent and cancer patients had a higher risk of recurrent VTE. SUMMARY: Background There is scant information on the optimal management and clinical outcome of deep and superficial vein thrombosis of the upper extremity (UEDVT and UESVT). Objectives To explore treatment strategies and the incidence of recurrent venous thromboembolism (VTE), mortality, postthrombotic symptoms, and bleeding in patients with UEDVT and UESVT and to assess the prognosis of cancer patients with UEDVT. Patients/methods Follow-up of patients with UEDVT or UESVT, who were enrolled previously in a diagnostic management study. Results We followed 102 and 55 patients with UEDVT and UESVT, respectively, both for a median of 3.5 years. Anticoagulant treatment was started in 100 patients with UEDVT (98%) and in 40 (73%) with UESVT. Nine patients with UEDVT (9%) developed recurrent VTE, 26 (26%) died, 6 (8%) of 72 patients had moderate postthrombotic symptoms, and 5 (5%) experienced major bleeding. One patient with UESVT had a recurrent VTE, 18 (33%) died, none had moderate postthrombotic symptoms, and none had major bleeding. Of the cancer patients with UEDVT, 18% had recurrent VTE vs. 7.5% in non-cancer patients (adjusted hazard ratio 2.2, 95%CI 0.6-8.2). The survival rate was 50% in cancer patients with UEDVT vs. 60% in those without (adjusted HR 0.8, 95%CI 0.4-1.4). Conclusions The risk of recurrent VTE was low in patients with UEDVT, and negligible for UESVT. Mortality was high for both diseases. Postthrombotic symptoms were infrequent and mild. Anticoagulant therapy of UEDVT carried a substantial risk of major bleeding. Cancer patients had a significant risk of recurrent VTE.