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Background: Portal vein thrombosis (PVT) is a serious complication of liver cirrhosis (LC) and is closely related to gut homeostasis. The study aimed to investigate the composition of gut microbiota and its putative role in PVT development in LC., Methods: 33 patients with LC admitted between January 2022 and December 2022 were enrolled in this study. Based on imaging findings, they were categorized into LC without PVT ( n  = 21) and LC with PVT ( n  = 12) groups. Fecal samples were collected from each participant and underwent 16S rDNA sequencing., Results: D-Dimer and platelet elevations were the main clinical features of LC with PVT. The alpha and beta diversity of the gut microbiota in LC with PVT group was found to be significantly higher compared to the control group. The structure of the gut microbiota was significantly different between the two groups. Based on LEfSe data, the genera Akkermansia , Eubacterium hallii group, Fusicatenibacter , and Anaerostipes were enriched in the LC with PVT, while Enterococcus, Weissella, Bacteroides, and Subdoligranulum were enriched in those of the LC subjects. Changes in microbiota structure result in significant differences in gut microbiota metabolism between the two groups. Altered levels of the microbiota genera were shown to be correlated with coagulation factor parameters. In animal experiments, the addition of Bacteroides reversed the CCl 4 -induced PVT., Conclusion: Liver cirrhosis with PVT led to a disorder in the gut microbiota, which was characterized by an increase in pathogenic bacteria and a decrease in beneficial bacteria. Furthermore, modulating the gut microbiota, especially Bacteroides , may be a promising therapeutic approach to reduce the progression of PVT in LC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huang, Zhang, Yi, Lei, Ma, Huang, Yang, Li and Zhang.)

Abstract Acquired hemophilia A (AHA) is a rare acquired bleeding disorder caused by autoantibodies against autologous factor VIII (FVIII). It is a disease that most commonly affects the elderly, but it has been described in children and during the post-partum period. It is idiopathic in 50% of cases and is associated with autoimmune disease, malignancy, pregnancy, infection or certain medications in the other 50%. The diagnosis should be suspected in patients with an isolated prolonged aPPT without previous personal or familial bleeding history. Treating the bleeding and eradication of the inhibitor is the mainstay of treatment. The first line of treatment for acute bleeding is the use of bypassing agents. The most commonly used method for eradicating the inhibitor is immunosuppression, namely corticosteroids alone or in combination with cyclophosphamide. This review summarises current knowledge and reviews management options and guidelines. [ABSTRACT FROM AUTHOR]

Background: Argininemia is an autosomal recessive urea cycle disorder (UCD). Unlike other UCD, hyperammonemia is rarely seen. Patients usually present in childhood with neurological symptoms. Uncommon presentations like neonatal cholestasis or cirrhosis have been reported. Although transient elevations of liver transaminases and coagulopathy have been reported during hyperammonemia episodes, a permanent coagulopathy has never been reported. Methods: In this retrospective study, coagulation disturbances are examined in 6 argininemia patients. All of the patients were routinely followed up for hepatic involvement due to argininemia. Laboratory results, including liver transaminases, albumin, prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), and clotting factor levels, were assessed in all of the patients. Results: All of the patients had a prolonged PT and an increased INR, while none of the patients had a prolonged aPTT. Five patients had slightly elevated liver transaminases. A liver biopsy was performed in 1 patient but neither cirrhosis nor cholestasis was documented. Five of the 6 patients had low factor VII and factor IX levels, while other clotting factors were normal. Conclusions: Argininemia patients should be investigated for coagulation disorders even if there is no apparent liver dysfunction or major bleeding symptoms. [ABSTRACT FROM AUTHOR]

Objective: To assess the reliability and validity of six patient‐reported outcomes (PRO) instruments for evaluating health‐related quality of life in adults with mild‐severe hemophilia B and caregivers of children with hemophilia B, including affected women/girls. Methods: Adults with hemophilia B and caregivers completed separate online surveys containing several PRO instruments, which were administered to adult participants only (EQ‐5D‐5L, Brief Pain Inventory v2 Short Form, Hemophilia Activities List, and International Physical Activities Questionnaire), both adults and caregivers (Patient Health Questionnaire [PHQ‐9]), or caregivers only (Generalized Anxiety Disorder 7‐Item [GAD‐7] scale). Construct validity and item‐total correlation were assessed using Pearson product‐moment correlation, internal consistency was assessed using Cronbach's alpha coefficient, and known‐group validity was assessed by comparisons to self‐reported characteristics based on the Kruskal‐Wallis test. Results: Patient‐reported outcomes instruments generally showed satisfactory reliability for adults (n = 299) and caregivers (n = 150). In adults, PRO instruments generally showed high construct validity. Most PRO instruments showed expected significant differences among known groups for adults and caregivers. PHQ‐9 and GAD‐7 did not show significant differences among caregiver age groups. Conclusions: Patient‐reported outcomes instruments administered in B‐HERO‐S demonstrated reliability and validity in the broader population of adults with hemophilia B and caregivers when including all severities and genders. [ABSTRACT FROM AUTHOR]

People with haemophilia (PWH) experience acute pain during joint bleeds and might develop chronic pain due to joint degeneration. However, there is a lack of standardized measures to comprehensively assess pain in PWH. This study aimed to develop a multidimensional questionnaire for haemophilia-related pain, the Multidimensional Haemophilia Pain Questionnaire (MHPQ), and to present initial validation data among adults.The questionnaire distinguishes between acute/chronic pain and queries about pain locations, duration, frequency, triggering factors, intensity, interference, strategies, specialists for pain management and satisfaction with treatment. An initial version was tested with 16 patients to ensure item comprehensibility and face validity. The final version was answered by 104 adults, with 82 (78.8%) reporting haemophilia-related pain in the previous year (mean age = 43.17; SD = 13.00). The non-response analysis revealed good item acceptability. Exploratory and confirmatory factor analysis (EFA/CFA), reliability (internal consistency, test-retest, inter-item and item-total correlations) and convergent validity were analysed for the intensity and interference dimensions of the questionnaire. A combined EFA with these two constructs supported a 2-factor structure distinguishing intensity (α = 0.88) from interference items (α = 0.91). CFA was tested for the interference dimension, demonstrating suitability for this sample. Item-total correlations were >0.30 on both dimensions and most inter-item correlations were <0.70. Test-retest reliability (n = 42) was good for intensity (r = 0.88) and interference (r = 0.73), and convergent validity was confirmed for most hypotheses (r>0.30).This questionnaire is a comprehensible tool, achieving a thorough assessment of relevant pain dimensions. The MHPQ can help guide treatment recommendations by highlighting relevant topics and contributing to more effective, integrated treatments. [ABSTRACT FROM AUTHOR]

Background: We evaluated optimal duration of dual antiplatelet therapy (DAPT) after second-generation drug-eluting stent (DES) implantation in acute coronary syndrome (ACS). Material and methods: From pooled analysis of three randomized clinical trials (EXCELLENT, IVUS-XPL, RESET), a total of 2,216 patient with ACS undergoing second-generation DES implantation were selected. Each study randomized patients to a short-duration DAPT arm (n = 1119; ≤6 months) or a standard-duration DAPT arm (n = 1097; ≥12 months). Two-thirds of patients were male, and their mean age was 63 years. Mean DAPT durations were 164 ±76 and 359 ±68 days, respectively. The primary endpoint was composite of cardiac death, myocardial infarction, stent thrombosis, stroke or major bleeding during the first 12 months after implantation, analyzed according to the intention-to-treat population. Results: Demographic characteristics were balanced between groups. Mean DAPT duration was 164 and 359 days, respectively. Primary endpoint occurred in 22 patients with short-DAPT and 21 patients with standard-DAPT (2.0% versus 1.9%; hazard ratio [HR] 1.03; 95% confidence interval [CI] 0.56–1.86; p = 0.94). Landmark analysis after six-months, no significant difference in primary endpoint between short and standard duration DAPT (1.0% versus 0.8%; HR 1.22; 95% CI 0.51–2.95; p = 0.66). Conclusions: Short-duration DAPT (≤6 months) demonstrated a similar incidence of net adverse cardiovascular and clinical events at 12 months after second-generation DES in ACS compared with standard duration DAPT (≥12 months). Clinical trial registration: EXCELLENT (ClinicalTrials.gov, ), RESET (ClinicalTrials.gov, ), IVUS-XPL (ClinicalTrials.gov, ) [ABSTRACT FROM AUTHOR]

Purpose: Fibrin clot is essential for post-operative abdominal adhesion formation. Fucoidans, sulfated polysaccharides, inhibit fibrin clot formation. In addition, they inhibit inflammation and fibrosis, which also play important roles in adhesion formation. The purpose of this study was to evaluate fucoidans’ potential for inhibiting post-operative abdominal adhesions and measure their effects on systemic coagulation parameters when administered intraperitoneally (IP). Methods and materials: Female Sprague Dawley rats were studied. A 2.5x2.5cm full thickness segment of abdominal wall was excised. The skin edges were approximated. This model induces extensive adhesions and allows objective quantitation. Three fucoidans were evaluated- Sigma Fucoidan Crude (SFC), Fucus vesiculosis 95% (Sigma) and, Peridan. One protocol involved continuous infusion into the abdomen from a subcutaneous osmotic pump. Alternatively, boluses of the solutions were injected IP at the end of the operation. Rats were sacrificed a week later. Adhesion extent was scored. Systemic coagulation effects of fucoidans were also evaluated. INR and aPTT were measured following IP injection of the fucoidan solutions and after 7 days of continuous infusion. Results: Animals given a continuous infusion of either SFC or Peridan yielded adhesion reduction of 80 to 90% from control. Bolus Peridan had no discernable influence on adhesion formation, but a single bolus of SFC caused significant adhesion reductions. Peridan resulted in prompt aPTT elevations which fell to nearly normal by 5 hours. The maximum peak value after SFC injection was seen in 15 hours. The maximal INR elevations were around 2. Measurement of INR and aPTT after a week of continuous infusion of either Peridan or SFC, were always in the normal control range. The third agent, Sigma, frequently yielded intraperitoneal infection found at autopsy. Conclusions: These findings indicate that selected fucoidans infused intraperitoneally for a week after abdominal operations reduce adhesion extent by up to 90%. [ABSTRACT FROM AUTHOR]

Background: Antiphospholipid syndrome is associated with endothelial dysfunction, which leads to thrombosis and early atheroma. Given that hydroxychloroquine has anti-thrombotic properties in lupus, we hypothesized that it could reduce endothelial dysfunction in an animal model of antiphospholipid syndrome. We evaluated the effect of hydroxychloroquine in preventing endothelial dysfunction in a mouse model of antiphospholipid syndrome. Methods: Antiphospholipid syndrome was induced by an injection of monoclonal anti-beta-2-GPI antibodies. Vascular reactivity was evaluated in mesenteric resistance arteries isolated from mice 3 weeks (APL3W) after receiving a single injection of anti-beta-2-GPI antibodies and after 3 weeks of daily oral hydroxychloroquine treatment (HCQ3W) compared to control mice (CT3W). We evaluated endothelial dysfunction by measuring acetylcholine-mediated vasodilation. A pharmacological approach was used to evaluate NO synthase uncoupling (tetrahydrobiopterin) and the generation of reactive oxygen species (Tempol). Results: Impaired acetylcholine-mediated dilation was evidenced in mice 3 weeks after anti-beta-2-GPI antibodies injection compared to CT3W, by reduced maximal dilation (p<0.0001) and sensitivity (pKd) (p = 0.01) to acetylcholine. Hydroxychloroquine improved acetylcholine-dependent dilation, on pKd (p = 0.02) but not maximal capacity compared to untreated mice. The addition of tetrahydrobiopterin (p = 0.02) and/or Tempol (p = 0.0008) improved acetylcholine-mediated dilation in APL3W but not in HCQ3W. Conclusions: We demonstrated that endothelial dysfunction in mouse resistance arteries persisted at 3 weeks after a single injection of monoclonal anti-beta-2-GPI antibodies, and that hydroxychloroquine improved endothelium-dependent dilation at 3 weeks, through improvement of NO synthase coupling and oxidative stress reduction. [ABSTRACT FROM AUTHOR]

Thrombotic manifestations are a hallmark of many auto-immune diseases (AID), specially of warm autoimmune hemolytic anemia (wAIHA), as 15 to 33% of adults with wAIHA experience venous thromboembolic events (VTE). However, beyond the presence of positive antiphospholipid antibodies and splenectomy, risk factors for developing a VTE during wAIHA have not been clearly identified. The aim of this retrospective study was to characterize VTEs during wAIHA and to identify risk factors for VTE. Forty-eight patients with wAIHA were included, among whom 26 (54%) had secondary wAIHA. Eleven (23%) patients presented at least one VTE, that occurred during an active phase of the disease for 10/11 patients (90%). The frequency of VTE was not different between primary and secondary AIHA (23.7 vs. 19.2%; p = 0.5). The Padua prediction score based on traditional risk factors was not different between patients with and without VTE. On multivariate analysis, total bilirubin ≥ 40 μmol/L [odds ratio (OR) = 7.4; p = 0.02] and leucocyte count above 7x109/L (OR = 15.7; p = 0.02) were significantly associated with a higher risk of thrombosis. Antiphospholipid antibodies were screened in 9 out the 11 patients who presented a VTE and were negative. Thus, the frequency of VTE is high (23%) during wAIHA and VTE preferentially occur within the first weeks of diagnosis. As no clinically relevant predictive factors of VTE could be identified, the systematic use of a prophylactic anticoagulation should be recommended in case of active hemolysis and its maintenance after hospital discharge should be considered. The benefit of a systematic screening for VTE and its procedure remain to be determined. [ABSTRACT FROM AUTHOR]

Background and objectives: The effect of oral contraceptive (OC) usage on coagulation has been studied worldwide. However, no such studies have been conducted in Saudi Arabia on Saudi women using OCs. The aim of this study was to investigate the effects of OC-induced changes of thrombin generation (TG) in the absence and presence of activated protein C (APC) or thrombomodulin (TM) in Saudi women. Methods: A total of 115 adult women, 47 on oral contraception (OC users) and 68 controls (not using OCs) were recruited from the obstetrics-gynecology outpatient clinic in Saudi Arabia. OCs that were used in this study include the following: Marvelon, Gynera, Cerrazetem, Yasmine, Microlut, Gracial and Diane. The plasma calibrated automated thrombinography (CAT) was used to determine TG which was expressed as endogenous thrombin potential (ETP; nM/min), lag time (min), peak (nM) and time-to-peak (ttpeak; min). In the presence of TM or APC, TG parameters were expressed relative to the parameters in the absence of TM or APC. Results and conclusion: As in other populations, our study demonstrated that OC usage induced prothrombotic changes in plasma of Saudi women, including resistance to the inhibitory actions of TM and APC. More specifically, OC usage in our population predominantly influenced TG and APC/TM sensitivity in overweight and obese individuals, a finding that needs confirmation in large cohort studies. The effects of APC and TM on TG parameters showed a positive association, and the correlation coefficients were higher in OC users for both ETP and peak values. [ABSTRACT FROM AUTHOR]

We aimed to investigate the incidence of bleeding-related adverse events (AEs) among patients with disseminated intravascular coagulation (DIC) receiving recombinant thrombomodulin (rTM) and those receiving other DIC treatments, the incidence by type of surgery, and the incidence when either blood transfusion or a hemostatic procedure was administered to treat DIC. In this cohort study, data were obtained from a large medical database (22 centers in Japan). The primary endpoint was the incidence rate of bleeding-related AEs by type of surgery. The secondary endpoint was the incidence rate of bleeding-related AEs based on whether blood transfusion or a hemostatic procedure was administered after the day of DIC treatment. In total, 4234 propensity score-matched patients were included in the main analysis (2117 patients each in the rTM and non-rTM groups). In the rTM and non-rTM groups, respectively, the incidence of bleeding-related AEs was 18.8% and 24.8% (p <0.001; risk ratio [RR] 0.757, 95% confidence interval [CI] 0.674–0.849), among patients requiring any type of surgery; 15.0% and 19.5% (p = 0.0001; RR 0.769, 95% CI 0.673–0.879) in patients requiring blood transfusion or a hemostatic procedure after the day of DIC treatment; 10.2% and 11.6% (p = 0.4470; RR 0.879, 95% CI 0.630–1.226) in patients undergoing hepatic, biliary, or pancreatic surgery; 24.3% and 25.4% (p = 0.6439; RR 0.955, 95% CI 0.786–1.160) in patients undergoing gastrointestinal surgeries; and 18.5% and 30.1% (p = 0.0001; RR 0.614, 95% CI 0.481–0.782) in patients undergoing cardiac or cardiovascular surgery. Our findings suggest that rTM treatment for Japanese postsurgical patients who develop DIC was associated with significantly fewer bleeding-related AEs compared with those receiving other DIC treatments. [ABSTRACT FROM AUTHOR]

Objective: Data concerning the effect of current smoking on solely new-generation drug-eluting stents (DES) are limited. We investigated the impact of current smoking on 2-year clinical outcomes between durable-polymer (DP)-coated DES (zotarolimus-eluting [ZES] and everolimus eluting [EES]) and biodegradable-polymer (BP)-coated biolimus-eluting stent (BES) in acute myocardial infarction (AMI) patients after successful percutaneous coronary intervention (PCI). Methods: Finally, a total of 8357 AMI patients with current smoking underwent successful PCI with new-generation DES (ZES, EES, and BES) were enrolled and divided into three groups as ZES (n = 3199), EES (n = 3987), and BES group (n = 1171). The primary endpoint was the occurrence of major adverse cardiac events (MACE) defined as all-cause death (cardiac death [CD] or non-cardiac death), recurrent AMI (re-MI), any revascularization (target lesion revascularization [TLR], target vessel revascularization [TVR], and non-TVR). The secondary endpoint was the incidence of definite or probable stent thrombosis (ST). Results: The 2-year adjusted hazard ratio (HR) of MACE for ZES vs. EES (1.055; 95% confidence interval [CI], 0.843–1.321; p = 0.638), ZES vs. BES (HR, 0.885; 95% CI, 0.626–1.251; p = 0.488), EES vs. BES (HR, 0.889; 95% CI, 0.633–1.250; p = 0.499), and ZES/EES vs. BES (HR, 0.891; 95% CI, 0.648–1.126; p = 0.480) were similar. The occurrence of ST after adjustment were also comparable. In addition, the 2-year adjusted HR for all-cause death, CD, re-MI, TLR, TVR, and non-TVR were not different. Conclusions: In this study, DP-DES and BP-DES showed comparable safety and efficacy during 2-year follow-up periods. Therefore, DP-DES or BP-DES are equally acceptable in AMI patients with current smoking undergoing PCI. [ABSTRACT FROM AUTHOR]

Background: Small randomized controlled studies and meta-analyses have shown that thrombolysis, especially catheter-directed thrombolysis, can reduce the incidence of post-thrombotic syndrome (PTS). However, the recent ATTRACT trial did not demonstrate the same effects. Given this confusing situation, we performed an updated meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of thrombolysis, especially catheter-directed thrombolysis, on the outcomes of deep venous thrombosis (DVT). Methods: We searched PubMed, Embase, and the Cochrane Library for relevant studies comparing thrombolysis in combination with anticoagulation and with anticoagulation alone. The primary endpoint was PTS during the longest follow-up period. The safety endpoint was the incidence of major bleeding events. We also evaluated the outcomes of catheter-directed thrombolysis as a subgroup analysis. Results: Six RCTs, including 1418 patients with DVT, were included in our meta-analysis. Thrombolysis in combination with anticoagulation did not reduce PTS (RR: 0.90, [0.80–1.01], P = 0.19) and increased major bleeding (RR: 2.07, [1.12–3.81], P = 0.02). However, trial sequential analysis (TSA) showed that more patients are needed to support the conclusion that thrombolysis in combination with anticoagulation increased major bleeding. Catheter-directed thrombolysis did not reduce the incidence of PTS (RR: 0.88, [0.68–1.13], P = 0.31) and did increase the incidence of major bleeding events (RR: 1.89, [1.00–3.59], P = 0.05). Conclusion: Thrombolysis, including catheter-directed thrombolysis, did not reduce the incidence of PTS and increased the incidence of major bleeding. However, the results were not supported by TSA and sensitivity analysis, so more relevant studies are needed. [ABSTRACT FROM AUTHOR]

Although the Factor V Leiden (FVL) gene variant is the most prevalent genetic risk factor for venous thrombosis, only 10% of FVL carriers will experience such an event in their lifetime. To identify potential FVL modifier genes contributing to this incomplete penetrance, we took advantage of a perinatal synthetic lethal thrombosis phenotype in mice homozygous for FVL (F5L/L) and haploinsufficient for tissue factor pathway inhibitor (Tfpi+/-) to perform a sensitized dominant ENU mutagenesis screen. Linkage analysis conducted in the 3 largest pedigrees generated from the surviving F5L/L Tfpi+/- mice (‘rescues’) using ENU-induced coding variants as genetic markers was unsuccessful in identifying major suppressor loci. Whole exome sequencing was applied to DNA from 107 rescue mice to identify candidate genes enriched for ENU mutations. A total of 3,481 potentially deleterious candidate ENU variants were identified in 2,984 genes. After correcting for gene size and multiple testing, Arl6ip5 was identified as the most enriched gene, though not reaching genome-wide significance. Evaluation of CRISPR/Cas9 induced loss of function in the top 6 genes failed to demonstrate a clear rescue phenotype. However, a maternally inherited (not ENU-induced) de novo mutation (Plcb4R335Q) exhibited significant co-segregation with the rescue phenotype (p = 0.003) in the corresponding pedigree. Thrombosis suppression by heterozygous Plcb4 loss of function was confirmed through analysis of an independent, CRISPR/Cas9-induced Plcb4 mutation (p = 0.01). [ABSTRACT FROM AUTHOR]

Aim: Free fatty acids refer to the fatty acids that are not bound to triglyceride structure in the structure of fat and are in free form. Free fatty acids, which are more susceptible to oxidation than other components of the fat, have some adverse effects on both the product and health. The aim of this study was to explain the effects of the elevated level of plasma free fatty acid on health. Method: The articles published in the last 15 years were examined with "free fatty acid" keyword by utilizing Science Direct, PubMed and Google Scholar databases and Turkish and international journals in the field of health sciences. Results/Conclusion: An increase in the level of circulating free fatty acids causes defects in the phosphorylation and the structure of insulin receptor substrates (IRS), and glucose transport. As a result, the use of insulin-mediated glucose is reduced and endogenous glucose production by gluconeogenesis is increased. In addition, the elevated level of free fatty acid causes the increase in the release of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-a), monocyte chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6), vascular cell adhesion molecule-1 (VCAM- 1), and intercellular adhesion molecule-1 (ICAM-1), thereby increases the risk of inflammation and atherosclerosis. Free fatty acids, which have proarrhythmic activity causing cardiomyocyte ion channel defects, threaten cardiovascular health by causing defects in myocardial and endothelial dysfunctions and nitric oxide production. As a result, the elevated level of plasma free fatty acid is associated with the increased risk of hypertension, insulin resistance, diabetes, metabolic syndrome, dyslipidemia, coagulation disorders and the increased risk of atherosclerotic vascular disease. Indeed, many studies indicated that the levels of plasma free fatty acid are higher in obese individuals with diabetes, metabolic syndrome, and individuals with coronary failure and acute coronary syndromes than healthy ones. [ABSTRACT FROM AUTHOR]

Background: Previous results regarding the prevalence of Factor V Leiden (FVL) in patients with cerebral venous thrombosis (CVT) varied remarkably. Therefore, we performed a meta-analysis to evaluate the potential association between FVL and CVT. Methods: The PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched for relevant case-control studies. The data were pooled for analysis of the association between FVL and CVT with a random-effects model. Subgroup and sensitivity analyses were performed to evaluate the robustness of the results. Publication bias was assessed by funnel plot and the Egger’s test. Results: A total of 39 case-control studies including 1807 cases of CVT and 7699 control cases were included. FVL was more common in patients with CVT (195/1822) than in controls(369/7795), [odds ratio(OR) = 2.70, 95% confidence interval(CI) 2.16–3.38, P < 0.00001]. Results of subgroup analyses indicated that the association between FVL and CVT varied according to geographic regions. The associations between FVL and CVT were significant in studies from Germany (OR = 2.42, 95%CI 1.70–3.45, P < 0.00001), Brazil(OR = 2.82, 95%CI 1.24–6.42, P = 0.01), France (OR = 5.44, 95%CI 1.35–21.92, P = 0.02), Iran (OR = 6.61, 95%CI 1.83–23.93, P = 0.004), and Tunisia (OR = 6.54, 95%CI 2.89–14.82, P < 0.00001), but not in those from Italy (OR = 1.49, 95%CI 0.59–3.78, P = 0.40) or the US (OR = 2.37, 95%CI 0.59–9.42, P = 0.22). Conclusion: FVL may be more common in patients with CVT. However, the association between FVL and CVT varied depending on the geographic origin of the studies. [ABSTRACT FROM AUTHOR]

Background: Use of everolimus-eluting stents (EES) has proven to be clinically effective and safe in patients with ST-segment elevation myocardial infarction but it remains unclear whether it is cost-effective compared to bare-metal stents (BMS) in the long-term. We sought to assess the cost-effectiveness of EES versus BMS based on the 5-year results of the EXAMINATION trial, from a Spanish health service perspective. Methods: Decision analysis of the use of EES versus BMS was based on the patient-level clinical outcome data of the EXAMINATION trial. The analysis adopted a lifelong time horizon, assuming that long-term survival was independent of the initial treatment strategy after the end of follow-up. Life-expectancy, health-state utility scores and unit costs were extracted from published literature and publicly available sources. Non-parametric bootstrapping was combined with probabilistic sensitivity analysis to co-assess the impact of patient-level variation and parameter uncertainty. The main outcomes were total costs and quality-adjusted life-years. The incremental cost-effectiveness ratio was expressed as cost per quality-adjusted life-years gained. Costs and effects were discounted at 3%. Results: The model predicted an average survival time in patients receiving EES and BMS of 10.52 and 10.38 undiscounted years, respectively. Over the life-long time horizon, the EES strategy was €430 more costly than BMS (€8,305 vs. €7,874), but went along with incremental gains of 0.10 quality-adjusted life-years. This resulted in an average incremental cost-effectiveness ratio over all simulations of €3,948 per quality-adjusted life-years gained and was below a willingness-to-pay threshold of €25,000 per quality-adjusted life-years gained in 86.9% of simulation runs. Conclusions: Despite higher total costs relative to BMS, EES appeared to be a cost-effective therapy for ST-segment elevation myocardial infarction patients due to their incremental effectiveness. Predicted incremental cost-effectiveness ratios were below generally acceptable threshold values. [ABSTRACT FROM AUTHOR]

Objectives: This matched-cohort retrospective study investigated the long-term (9-year) safety and efficacy outcomes of patients with ST-segment elevation myocardial infarction (STEMI) and primary percutaneous coronary intervention (pPCI) with Genous (n = 102) versus TAXUS Liberté (n = 101) stents in 2006–2008. Background: In the era of off-label use of drug-eluting stents for pPCI in patients with STEMI, the use of first-generation Genous stents (endothelial progenitor cell capture stents that have a passive coating and accelerate re-endothelialization) was proposed. Methods: The primary endpoint was 9-year major adverse cardiac and cerebrovascular events (MACCE), including all-cause death, re-infarction, target vessel revascularization (TVR), and stroke. The secondary endpoints were the separate primary endpoint events at pre-defined time-points (in-hospital, 6 months, and yearly) and stent thrombosis. Time-dependent 9-year composite MACCE, all-cause death, and TVR were compared using Kaplan-Meier estimates and multivariate Cox regression models. Results: Propensity score analysis confirmed the comparability of the groups. Patients in the Genous and TAXUS groups had 7 and 1 acute definitive stent thrombosis events, respectively (p<0.001). There was a trend towards higher in-hospital MACCE in the Genous group (10.8%) versus the TAXUS group (4.0%). Kaplan-Meier analysis showed that 9-year MACCE was significantly worse in the Genous than in the TAXUS group. The in-hospital, 6-month, 1-year, and 9-year mortality rates were 7.8%, 8.8%, 9.8%, and 23.5% in the Genous group and 2.0%, 3.0%, 4.0%, and 16.8% in the TAXUS group. Conclusions: Higher peri-procedural, in-hospital, and short-term mortality led to worse outcomes for first-generation Genous stents versus TAXUS Liberté stents for pPCI in STEMI. TAXUS Liberté stents had more favorable 9-year clinical outcomes. [ABSTRACT FROM AUTHOR]

This prospective observational study was designed to analyze platelet functions across time in 50 patients scheduled for liver transplantation (LT) secondary to decompensated cirrhosis or hepatocellular carcinoma. Platelet functions were assessed before LT (pre-LT), one week (D7) and 1 month (D28) after LT. Platelet count significantly increased from pre-LT time to day 28 as well as circulating CD34+hematopoietic stem cells. To avoid any influence of platelet count on assays, platelet function was evaluated on platelet-rich-plasma adjusted to pre-LT platelet count. Although platelet secretion potential did not differ between time-points, as evaluated by the expression of CD62P upon strong activation, platelet aggregation in response to various agonists significantly increased along time, however with no concomitant increase of circulating markers of platelet activation: platelet microvesicles, platelet-leukocyte complexes, soluble CD40L and soluble CD62P. In the multivariate analysis, hepatic function was associated with platelet count and function. A lower platelet aggregation recovery was correlated with Child C score. History of thrombosis or bleeding was associated with respective higher or lower values of platelet aggregation. This longitudinal analysis of platelet functions in LT patients showed an improvement of platelet functions along time together with platelet count increase, with no evidence of platelet hyperactivation at any time-point. [ABSTRACT FROM AUTHOR]

Living donor kidneys with two arteries can be revascularized using various techniques depending on anatomy. We hypothesized that the revascularization technique could impact long-term outcomes. We retrospectively analyzed 1714 living donor renal transplants at our institution between 1999 and 2015. Three hundred and eleven kidneys had dual arteries, and these were categorized into 5 groups; end-to-side (n = 18), inferior epigastric artery (n = 21), direct anastomosis (n = 65), side-to-side (n = 126) and ligated (n = 81). We then compared the outcomes with that of a control group (single artery, n = 1403) using Kaplan-Meier and Cox regression analyses. Cox regression was adjusted by age, sex and race/ethnicity of donor and recipient, side of kidney, transplant period and recipient surgeon. Compared to the control group, the end-to-side group had increased all-cause graft loss (10 years: 77.2% vs 24.5%, adjusted hazard ratio [aHR] 3.02, 95% confidence interval [CI] 1.30–7.03, p = 0.010) and death-censored graft loss (10 years: 82.0% vs 55.9%, aHR 4.17, 95% CI 1.63–10.68, p = 0.003), whereas the other groups did not. Our study shows that 10-year overall survival and death-censored graft survival were significantly worse for end-to-side arterial reconstruction than for other techniques. Alternative techniques to the end-to-side method should be used for accessory arteries that require revascularization. [ABSTRACT FROM AUTHOR]

Background: Liver is considered to be one of the synthetic organs regarding coagulation factors. Patients with liver disease undergo a rebalanced state, where a procoagulant state is also established along with an anticoagulant state. The risk of thrombosis is as common as the risk of bleeding. Aims and objectives: The following discussion will highlight the importance of rebalanced system and will explain the role of common coagulation tests in patient with advanced liver disease. This discussion will also emphasize the limitation of common coagulation tests and will describe an approach to such patients in clinical settings. Material and Methods: A narrative literature review utilizing PubMed and OVID as databases was carried out in August 2018. Keywords used were: "Advanced liver disease", "Coagulation disorders", "Thrombosis and embolism" and "Coagulopathy of liver diseases". This literature search was confined only to studies performed on human beings and published in English language only. [ABSTRACT FROM AUTHOR]

The KBI (kissing balloon inflation) technique is considered the default strategy for the two-stent approach in real world practice. Studies comparing KBI and No-KBI in patients undergoing the one-stent approach have reported conflicting results. The meta-analysis was performed to compare the clinical outcomes of the KBI strategy and the No-KBI strategy for coronary bifurcation lesions in the one-stent approach. Five randomized studies were included, and a total of 1264 patients were involved in the meta-analysis. The primary outcome was cardiac death. The secondary end points were stent thrombosis, MI (myocardial infarction), target lesion revascularization (TLR), target vessel revascularization (TVR), and main vessel and side branch restenosis. Compared with the No-KBI strategy, the KBI strategy was associated with a significant reduction in side branch restenosis (OR: 0.44, 95% CI: 0.30–0.64, p<0.001). A high risk of main vessel restenosis was found in the KBI group (OR: 2.96, 95% CI: 1.74–5.01, p<0.001). There were no significant differences in rates of cardiac death (OR: 1.89, 95% CI: 0.60–5.95, p = 0.28), stent thrombosis (OR: 0.98, 95% CI: 0.19–4.94, p = 0.98), MI (OR: 0.68, 95% CI: 0.33–1.44, p = 0.30), TLR (OR 1.14, 95% CI 0.68–1.90, p = 0.62), or TVR (OR 1.27, 95% CI 0.75–2.16, p = 0.38). Compared with the No-KBI strategy, the KBI strategy reduced the incidence of side branch restenosis and increased the risk of main branch restenosis in the one-stent approach. However, the clinical outcomes were similar between the KBI and No-KBI groups. [ABSTRACT FROM AUTHOR]

Background: The optimal antithrombotic therapy for atrial fibrillation (AF) patients undergoing coronary stenting is unknown. The present meta-analysis sought to investigate the efficacy and safety of triple therapy (TT; warfarin, clopidogrel and aspirin) vs dual antiplatelet therapy (DAPT; clopidogrel plus aspirin) in those patients. Methods: PubMed and Cochrane Library were searched for studies enrolling AF patients undergoing coronary stenting on TT and DAPT up to September 2016, and fourteen studies were included. Efficacy outcomes included ischemic stroke, stent thrombosis, major adverse cardiovascular event (MACE), all-cause mortality and myocardial infarction (MI); safety outcome was major bleeding. We conducted meta-analysis and used odds ratio (OR) with 95% confidence intervals (CI) to compare TT and DAPT. Meta-regression, sensitivity and subgroup analysis were taken to investigate the source of heterogeneity in the outcome of major bleeding. Results: 14 eligible observational studies with 11,697 subjects were identified. Compared with DAPT, TT had decreased the risk of ischemic stroke [OR = 0.74, 95% CI (0.59, 0.93), P = 0.009] and stent thrombosis [OR = 0.40, 95% CI (0.18, 0.93), P = 0.033]. While, there was an increased risk of major bleeding [OR = 1.55, 95% CI (1.16, 2.09), P = 0.004] associated with TT. The risk of MACE, all-cause mortality and MI had no significant statistical difference between TT and DAPT. Furthermore, the results of univariate and multivariate meta-regression analysis implicated that there were no obvious correlations between certain baseline characteristics (age, gender, race, hypertension, study design) and risk of major bleeding. Also of major bleeding, the findings of sensitivity analysis were generally robust, and a prespecified subgroup analysis of race demonstrated that the source of heterogeneity might attribute to Asian studies mostly. Conclusions: TT reduced the risk of ischemic stroke and stent thrombosis with an acceptable major bleeding risk compared with DAPT, and TT was considered as a valid alternative in AF patients undergoing coronary stenting. Further prospective randomized trials are needed to ensure the reliability of these data and find the optimal therapeutic strategy in this setting of patients. [ABSTRACT FROM AUTHOR]

Isolated traumatic brain injury (TBI) is often associated with abnormalities in coagulation parameters. Prehospital fluids exceeding 2,000 ml may be associated with coagulation disorders in patients with TBI. The aim of this study was to investigate the incidence of coagulation disorders, to establish its relation to the outcome, and to establish a correlation between prehospital fluid infusion and development of coagulation disorders. The study included 82 patients with isolated brain injury. Coagulation parameters were determined using the values of prothrombin time (PT), activated partial thromboplastin time (APPT) and platelet count. We also analyzed a correlation between prehospital administered fluid and the occurrence of coagulopathy. Pearson’s correlation analysis showed that in terms of survival, there was no significant difference between the groups (group A OR 37 CI 0.11-1,27; group B OR 0,48 CI 0,16-1,49; group C OR 0,69, CI 0,24-1,98), but it also indicated that prehospital fluid administered in a larger amount was in a negative correlation with the treatment outcome (-0,240). The results of our studies have confirmed the correlation of coagulation abnormalities with the lethal outcome in patients with TBI. Administration of more than 1,500 ml of fluid is associated with more frequent occurrence of coagulation disorders and with poor outcome. [ABSTRACT FROM AUTHOR]

Over the past decade, veno-venous extracorporeal membrane oxygenation (vvECMO) has been increasingly utilized in respiratory failure in patients. This study presents our institution´s experience focusing on the life span of ECMO systems reflecting the performance of a particular system. A retrospective review of our ECMO database identified 461 adult patients undergoing vvECMO (2010–2017). Patients that required more than one system and survived the first exchange >24 hours (n = 139) were included. Life span until the first exchange and exchange criteria were analyzed for all systems (PLS, Cardiohelp HLS-set, both Maquet Cardiopulmonary, Rastatt, Germany; Deltastream/Hilite7000LT, iLA-activve, Xenios/NovaLung, Heilbronn, Germany; ECC.O5, LivaNova, Mirandola, Italy). At our ECMO center, the frequency of a system exchange was 30%. The median (IQR) life span was 9 (6–12) days. There was no difference regarding the different systems (p = 0.145 and p = 0.108, respectively). However, the Deltastream systems were exchanged more frequently due to elective technical complications (e. g. worsened gas transfer, development of coagulation disorder, increased bleedings complications) compared to the other exchanged systems (p = 0.013). In summary, the used ECMO systems are safe and effective for acute respiratory failure. There is no evidence for the usage of a specific system. Only the increased predictability of an imminent exchange preferred the usage of a Deltastream system. However, the decision to use a particular system should not depend solely on the possible criteria for an exchange. [ABSTRACT FROM AUTHOR]

Background: Cancer and factor V Leiden mutation are both risk factors for venous thromboembolism (VTE). Cancer critically increases the thrombotic risk whereas Factor V Leiden is the most common pro-thrombotic mutation. The impact of the factor V Leiden on the risk of VTE in cancer patients remains uncertain. Objective: To assess the impact of factor V Leiden mutation in cancer-associated thrombosis. Methods: The EDITH hospital-based case-control study enrolled 182 patients with cancer and VTE as well as 182 control patients with cancer, matched for gender, age and cancer location, between 2000 and 2012, in the University Hospital of Brest. All cases and controls were genotyped for the factor V Leiden mutation and interviewed with a standardized questionnaire. Results: Twenty one of 182 (11.5%) patients with cancer-associated thrombosis carried the factor V Leiden mutation and 4 of 182 (2.2%) controls with cancer but no venous thrombosis. In multivariate analysis including cancer stage and family history of VTE, cancer patients with factor V Leiden mutation had a seven-fold increased risk of venous thromboembolism (adjusted odds ratio [OR], 7.04; 95% CI, 2.01–24.63). Conclusion: The pro-thrombotic Factor V Leiden mutation was found to be an independent additional risk factor for venous thromboembolism in cancer patients and might therefore be considered in the individual thrombotic risk assessment. [ABSTRACT FROM AUTHOR]

Background: Several specialty societies participate in the Choosing Wisely (CW) campaign in an attempt to reduce waste in health care spending. We surveyed internal medicine (IM) residents with an objective of classifying knowledge of and confidence in using the American Society of Hematology (ASH) CW principles in hemostasis, thrombosis, and non-malignant hematology. Methods: Multi-institutional study of IM residents at 5 academic training programs in the United States. A 10-question, case-based multiple choice test, with each question accompanied by a 5-point Likert-scale confidence assessment, was distributed electronically. Responses were summarized with frequencies and percentages or medians and ranges, as appropriate. Two sample t-tests or Wilcoxon rank-sum tests were used to compare confidence and knowledge scores. Results: Of 892 IM residents, 174 (19.5%) responded to all questions. Overall, residents answered a median of 7 of 10 questions correctly (range 2–10) and median resident confidence in their responses was 3.1 (on a 5-point scale). Correct responses were significantly associated with higher confidence for all but one question. Having a hematology rotation experience was significantly associated with more correct responses and with higher confidence (p = 0.001 and p<0.001, respectively). Conclusions: IM residents at several academic hospitals have variable knowledge of ASH-CW guidelines in thrombosis and hemostasis/non-malignant hematology. Residents who have done hematology rotations, particularly a hematology consult rotation, were more likely to answer questions correctly and to be more confident that their answers were correct. Adequate clinical exposure and training in cost-effective care is essential to train clinicians who are cost-conscious in any specialty. [ABSTRACT FROM AUTHOR]

Background: Bioresorbable Vascular Scaffolds (BVS) were introduced to overcome some of the limitations of drug-eluting stent (DES) for PCI. Data regarding the clinical outcomes of the BVS versus DES beyond 2 years are emerging. Objective: To study mid-term outcomes. Methods: We searched online databases (PubMed/Medline, Embase, CENTRAL), several websites, meeting presentations and scientific session abstracts until August 8th, 2017 for studies comparing Absorb BVS with second-generation DES. The primary outcome was target lesion failure (TLF). Secondary outcomes were all-cause mortality, myocardial infarction, target lesion revascularization (TLR) and definite/probable device thrombosis. Odds ratios (ORs) with 95% confidence intervals (CIs) were derived using a random effects model. Results: Ten studies, seven randomized controlled trials and three propensity-matched observational studies, with a total of 7320 patients (BVS n = 4007; DES n = 3313) and a median follow-up duration of 30.5 months, were included. Risk of TLF was increased for BVS-treated patients (OR 1.34 [95% CI: 1.12–1.60], p = 0.001, I2 = 0%). This was also the case for all myocardial infarction (1.58 [95% CI: 1.27–1.96], p<0.001, I2 = 0%), TLR (1.48 [95% CI: 1.19–1.85], p<0.001, I2 = 0%) and definite/probable device thrombosis (of 2.82 (95% CI: 1.86–3.89], p<0.001 and I2 = 40.3%). This did not result in a difference in all-cause mortality (0.78 [95% CI: 0.58–1.04], p = 0.09, I2 = 0%). OR for very late (>1 year) device thrombosis was 6.10 [95% CI: 1.40–26.65], p = 0.02). Conclusion: At mid-term follow-up, BVS was associated with an increased risk of TLF, MI, TLR and definite/probable device thrombosis, but this did not result in an increased risk of all-cause mortality. [ABSTRACT FROM AUTHOR]

Rift Valley fever virus is an arbovirus that affects both livestock and humans throughout Africa and in the Middle East. Despite its endemicity throughout Africa, it is a rare event to identify an infected individual during the acute phase of the disease and an even rarer event to collect serial blood samples from the affected patient. Severely affected patients can present with hemorrhagic manifestations of disease. In this study we identified three Ugandan men with RVFV disease that was accompanied by hemorrhagic manifestations. Serial blood samples from these men were analyzed for a series of biomarkers specific for various aspects of human pathophysiology including inflammation, endothelial function and coagulopathy. There were significant differences between biomarker levels in controls and cases both early during the illness and after clearance of viremia. Positive correlation of viral load with markers of inflammation (IP-10, CRP, Eotaxin, MCP-2 and Granzyme B), markers of fibrinolysis (tPA and D-dimer), and markers of endothelial function (sICAM-1) were all noted. However, and perhaps most interesting given the fact that these individuals exhibited hemorrhagic manifestations of disease, was the finding of a negative correlation between viral load and P-selectin, ADAMTS13, and fibrinogen all of which are associated with coagulation pathways occurring on the endothelial surface. [ABSTRACT FROM AUTHOR]

Objective: We sought to evaluate the effect of antiplatelet therapy in addition to conventional immunosuppressive therapy for lupus nephritis (LN) patients positive for antiphospholipid antibodies (aPL) without definite antiphospholipid syndrome (APS). Methods: Patients with biopsy-proven LN class III or IV were retrospectively evaluated. We selected patients positive for anticardiolipin antibody (aCL) or lupus anticoagulant (LA) who did not meet the criteria for a diagnosis of APS. The patients were divided into two subgroups according to whether antiplatelet therapy was received. The cumulative complete renal response (CR) rate, relapse-free rate, and change in estimated glomerular filtration rate (eGFR) over 3 years after induction therapy were calculated. Results: We identified 17 patients who received antiplatelet therapy and 21 who did not. Baseline clinicopathological characteristics and immunosuppressive therapy did not show a significant difference between the two groups except for a higher incidence of LN class IV in the treatment group (p = 0.03). There was no difference in cumulative CR rate, relapse-free rate, or eGFR change between these subgroups. However, when data on LA-positive patients were assessed, an improvement in eGFR was found (p = 0.04) in patients receiving antiplatelet treatment. Conclusion: Addition of anti-platelet therapy was associated with an improvement of eGFR in LA-positive patients with LN class III or IV. [ABSTRACT FROM AUTHOR]

The major challenge in the diagnosis of disseminated intravascular coagulation (DIC) comes from the lack of specific biomarkers, leading to developing composite scoring systems. DIC scores are simple and rapidly applicable. However, optimal fibrin-related markers and their cut-off values remain to be defined, requiring optimization for use. The aim of this study is to optimize the use of DIC-related parameters through machine learning (ML)-approach. Further, we evaluated whether this approach could provide a diagnostic value in DIC diagnosis. For this, 46 DIC-related parameters were investigated for both clinical findings and laboratory results. We retrospectively reviewed 656 DIC-suspected cases at an initial order for full DIC profile and labeled their evaluation results (Set 1; DIC, n = 228; non-DIC, n = 428). Several ML algorithms were tested, and an artificial neural network (ANN) model was established via independent training and testing using 32 selected parameters. This model was externally validated from a different hospital with 217 DIC-suspected cases (Set 2; DIC, n = 80; non-DIC, n = 137). The ANN model represented higher AUC values than the three scoring systems in both set 1 (ANN 0.981; ISTH 0.945; JMHW 0.943; and JAAM 0.928) and set 2 (AUC ANN 0.968; ISTH 0.946). Additionally, the relative importance of the 32 parameters was evaluated. Most parameters had contextual importance, however, their importance in ML-approach was different from the traditional scoring system. Our study demonstrates that ML could optimize the use of clinical parameters with robustness for DIC diagnosis. We believe that this approach could play a supportive role in physicians’ medical decision by integrated into electrical health record system. Further prospective validation is required to assess the clinical consequence of ML-approach and their clinical benefit. [ABSTRACT FROM AUTHOR]

Currently, nanosecond pulsed electric fields (nsPEFs) with short pulse duration and non-thermal effects have various potential applications in medicine and biology, especially in tumor ablation. Additionally, there are a few investigations on its proliferative effects in the normal cell. Clinically, proliferation of endothelial cells can perhaps accelerate the stent endothelialization and reduce the risk of acute thrombosis. To explore the feasibility using nsPEFs to induce proliferation of endothelial cells, in this study, porcine iliac endothelial (PIEC) cell line was cultured and tested by CCK-8 assay after nsPEFs treatment. The results reflected that nsPEFs with low field strength (100ns, 5 kV/cm, 10 pulses) had a significant proliferative effect with an increase in the PIEC cell growth of 16% after a 48 hour’ post-treatment. To further understand the mechanism of cell proliferation, intracellular Ca2+ concentration was measured through fluo-4 AM and reactive oxygen species assay was applied to estimate the level of intracellular reactive oxygen species (ROS). Finally, the total nitric oxide assay for NO production in the cultured medium was evaluated. An enhanced concentration of intracellular Ca2+ and ROS were observed, while the concentration of extracellular NO also increased after nsPEFs treatment. Such experimental results demonstrated that nsPEFs with appropriate pulse parameters could effectively enhance cell proliferation on PIEC cells, and the cell proliferation associated strongly with the changes of intracellular Ca2+ concertation, ROS and NO production induced by nsPEFs treatment. This in vitro preliminary study indicates that as a novel physical doping, the nsPEFs have potential in stimulating endothelial cells to accelerate stent endothelialization. [ABSTRACT FROM AUTHOR]

The study focuses the dose administration of dabigatran to avoid the deaths due to hemorrhagic complications and thromboembolic stroke in clinics worldwide. To target the issue, a novel emerging acoustic technology, namely ''Quartz Crystal Microbalance with Dissipation'' (QCM-D) has been applied, while the acoustic assays namely ''activated Partial Thromboplastin Time'' (aPTT) and ''Prothrombinase complex-induced Clotting Test'' (PiCT) have been compared with the standard methods in parallel. Both techniques have been applied to 300 samples, including 220 plasma samples of patients suffering coagulation disorders and 80 plasma samples of non-patients. In comparison, the coagulation times of the acoustic aPTT and PiCT yielded an excellent correlation with the standard methods with in analytical standard deviation limits. Finally, the acoustic aPTT assay is the ''gold standard'' for a dose administration of the new oral anticoagulant, where the Δf/ΔΓ ratio of the acoustic assay demonstrates that dabigatran with FEIBA 50 combination could be a safe remedy to avoid the deaths in clinics. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the relationship between placental pathological findings and physiological development during the neonate and infantile periods. Study participants were 258 infants from singleton pregnancies enrolled in the Hamamatsu Birth Cohort for Mothers and Children (HBC Study) whose placentas were stored in our pathological division. They were followed up from birth to 18 months of age. Physiological development (body weight and the ponderal index [PI]) was assessed at 0, 1, 4, 6, 10, 14, and 18 months. Placental blocks were prepared by random sampling and eleven pathological findings were assessed, as follows: ‘Accelerated villous maturation’, ‘Decidual vasculopathy’, ‘Thrombosis or Intramural fibrin deposition’, ‘Avascular villi’, ‘Delayed villous maturation’, ‘Maternal inflammatory response’, ‘Fetal inflammatory response’, ‘Villitis of unknown etiology (VUE)’, ‘Deciduitis’, ‘Maternal vascular malperfusion’, and ‘Fetal vascular malperfusion’. Mixed model analysis with the use of the xtmixed command by the generic statistical software, Stata version 13.1., identified ‘Accelerated villous maturation’ and ‘Maternal vascular malperfusion’ as significant predictors of a lower body weight and ‘Deciduitis’ as a significant predictor of a small PI, throughout the first 18 months of life. In conclusion, the present study is the first to demonstrate that some pathological findings of the placenta are associated with changes in infantile physical development during the initial 18 months of life in the Japanese population. [ABSTRACT FROM AUTHOR]

Purpura fulminans is a deadly complication of Neisseria meningitidis infections due to extensive thrombosis of microvessels. Although a Disseminated Intra-vascular Coagulation syndrome (DIC) is frequently observed during Gram negative sepsis, it is rarely associated with extensive thrombosis like those observed during meningococcemia, suggesting that the meningococcus induces a specific dysregulation of coagulation. Another specific feature of N. meningitidis pathogenesis is its ability to colonize microvessels endothelial cells via type IV pili. Importantly, endothelial cells are key in controlling the coagulation cascade through the activation of the potent anticoagulant Protein C (PC) thanks to two endothelial cell receptors among which the Endothelial Protein C Receptor (EPCR). Considering that congenital or acquired deficiencies of PC are associated with purpura fulminans, we hypothesized that a defect in the activation of PC following meningococcal adhesion to microvessels is responsible for the thrombotic events observed during meningococcemia. Here we showed that the adhesion of N. meningitidis on endothelial cells results in a rapid and intense decrease of EPCR expression by inducing its cleavage in a process know as shedding. Using siRNA experiments and CRISPR/Cas9 genome edition we identified ADAM10 (A Disintegrin And Metalloproteinase-10) as the protease responsible for this shedding. Surprisingly, ADAM17, the only EPCR sheddase described so far, was not involved in this process. Finally, we showed that this ADAM10-mediated shedding of EPCR induced by the meningococcal interaction with endothelial cells was responsible for an impaired activation of Protein C. This work unveils for the first time a direct link between meningococcal adhesion to endothelial cells and a severe dysregulation of coagulation, and potentially identifies new therapeutic targets for meningococcal purpura fulminans. [ABSTRACT FROM AUTHOR]

Objectives: The clinical significance of the laboratory-based phenomenon of clopidogrel hypo-responsiveness and platelet reactivity associated with acute myocardial infarction, despite chronic clopidogrel therapy, is largely unknown. We aimed to determine platelet reactivity and clinical and angiographic features in 29 consecutive patients sustaining an acute myocardial infarction despite chronic (≥1 month) clopidogrel therapy. Methods: Platelet reactivity was determined on admission using conventional aggregometry. All patients underwent coronary angiography within 24 hours of admission. Patients were matched with clopidogrel-naïve acute myocardial infarction patients. Clopidogrel-naïve patients received a 600 mg clopidogrel loading dose and 75 mg/day thereafter. Results: Of the 29 study patients, 19 (66%) presented with ST-elevation myocardial infarction, and in 25% the infarction was related to angiographically-proved definite stent thrombosis. Two-thirds of these patients were poor responders to clopidogrel (adenosine diphosphate-induced platelet aggregation >50%) and dual antiplatelet poor responsiveness was found in 57% in the chronic clopidogrel therapy group. Compared with clopidogrel-naïve patients, chronic clopidogrel therapy patients were more likely to demonstrate clopidogrel poor responsiveness (66% versus 38%, p = 0.02), to be diabetic (52% versus 33%, p = 0.1) and to have multi-vessel coronary disease (79% versus 55%, p = 0.03). Conclusions: Patients sustaining acute coronary syndrome despite chronic clopidogrel therapy are more likely to exhibit inadequate platelet inhibition with clopidogrel. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Pain, functional impairment, anxiety, and depression associated with joint disease may affect health‐related quality of life (HRQoL) in people with hemophilia. Objective: To report detailed patient‐reported outcomes (PRO) assessments related to HRQoL in participants in the Pain, Functional Impairment, and Quality of Life (P‐FiQ) study. Methods: Pain and HRQoL were assessed via PRO instruments in US adult males with hemophilia A or B and a history of joint pain or bleeding. PRO instruments included EQ‐5D‐5L with visual analog scale, Brief Pain Inventory v2 Short Form, SF‐36v2, and Hemophilia Activities List. Instrument domain and item responses were described. Results: Responses were collected from 381 adult males with a median age of 34 years. Pain was observed across instruments and affected daily activities and quality of life. Respondents reported functional impairment that limited the kind of work and activities they participated in, with activities involving the lower extremities being most affected. A high prevalence of mental health disorders was identified across instruments. Conclusions: Pain and HRQoL were evaluated using multiple PRO instruments, which vary in timescales of assessment and levels of detail. More consistent clinical assessments and patient dialog regarding pain and aspects of HRQoL may help drive improved outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Pain and functional impairment associated with joint disease are major problems for people with hemophilia, and impact on health‐related quality of life (HRQoL) may vary across groups defined by demographic and treatment‐related characteristics. Objective: To evaluate differences in overall HRQoL, pain, function, and joint status between P‐FiQ study subgroups. Methods: Adult males with hemophilia and a history of joint pain/bleeding completed a pain history and the patient‐reported outcome instruments EQ‐5D‐5L, Brief Pain Inventory v2 Short Form (BPI), International Physical Activity Questionnaire (IPAQ), and Hemophilia Activities List (HAL); optionally, joint status was assessed (Hemophilia Joint Health Score v2.1 [HJHS]). Scores were analyzed between subgroups across sets of participant characteristics. Results: A total of 381 adult males with hemophilia were enrolled, with median age of 34 years. Worse scores on EQ‐5D‐5L index, BPI pain severity/interference, HAL overall score, and HJHS were generally associated with being college educated, unemployment, self‐reporting both acute and chronic pain, and self‐reporting anxiety/depression. Conclusions: Measures of joint status and HRQoL were consistently lower in participants who had higher educational levels, were unemployed, self‐reported having both acute and chronic pain, and self‐reported having anxiety/depression. A greater understanding of the association of these factors with disease outcomes may improve individualized patient management. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Levels of pain and dysfunction appear to differ among people with hemophilia despite similar levels of joint disease. Objective: To determine patient characteristics that influence pain and function independent of joint status. Methods: US adults with hemophilia completed a survey that included information on clinical characteristics, demographics, and patient‐reported outcome instruments assessing pain (Brief Pain Inventory v2 Short Form [BPI]), functional impairment (Hemophilia Activities List [HAL]), and health status (EQ‐5D‐5L). Additionally, physiotherapists optionally completed a clinical joint evaluation (Hemophilia Joint Health Score [HJHS]). Associations were examined using simple and multiple regression models. Results: Of 381 adults enrolled, 240 had complete HJHS scores (median age, 32 years). After controlling for HJHS and opiate use, anxiety/anxiolytic use was significantly associated with worse pain severity and interference scores. After controlling for HJHS, the most significant predictors of functional impairment were older age, unemployment, more severe hemophilia, and greater pain. EQ‐5D‐5L pain/discomfort was associated with worse outcomes on most HAL scores. Conclusion: Unemployment, anxiety, and depression were each associated with both greater pain and functional disability after controlling for joint status. Continued attention to pain and psychosocial issues will be important in improving clinical care and research efforts in the hemophilia population. [ABSTRACT FROM AUTHOR]

Background: Patients with spinal cord injury (SCI) are at risk of thrombosis and bleeding. Data on the risks during rehabilitation are inconsistent, and thromboprophylactic strategies are heterogeneous. We aimed to evaluate the thrombotic risk and bleeding events of SCI patients during rehabilitation. Methods: We retrospectively collected hospital record data of 263 consecutive SCI patients admitted at a rehabilitation clinic. 78 patients with acute venous thromboembolism (VTE) at the primary center, without acute trauma or lower extremity paresis, less than one month rehabilitation, or reasons for long-term therapeutic anticoagulation, were excluded. All patients received pharmacologic thromboprophylaxis throughout rehabilitation. Primary endpoint was objectively diagnosed VTE; secondary endpoint was bleeding. Results: Of 185 patients, 162 (88%) were men; mean age was 47.8 years. 94 patients were tetraplegic, 91 paraplegic. During a mean (±SD) time of 5.1±2.1 months, VTE was diagnosed in 8 patients. After excluding five patients with VTE detected within 2 days after admission, the probability of developing VTE after 6 months of rehabilitation was 2% (95% CI 0–4.4%). Only high D-Dimer upon admission was associated with risk of VTE (adjusted HR 2.3, 95% CI 1.4–4.1). Of 24 bleedings, 14 (64%) occurred at the heparin injection site. Two patients had major bleeding and five had clinically relevant non major bleeding. Conclusion: SCI patients are at risk of VTE and bleeding during rehabilitation. Strategies need to be developed to identify these patients in order to initiate adequate anticoagulation. Direct oral anticoagulants, which have a favourable risk-benefit profile and are convenient, should be explored. [ABSTRACT FROM AUTHOR]

Background: Venous thromboembolism (VTE) is a major cause of morbidity and mortality in elderly patients. Extracellular DNA is a pro-inflammatory and pro-thrombotic mediator in vitro and in animal models. Levels of circulating extracellular DNA (ceDNA) are increased in VTE patients, but the association of ceDNA with VTE extent and clinical outcome is poorly understood. Objectives: We analyzed the association of ceDNA with the extent of VTE, categorized as distal and proximal deep vein thrombosis and pulmonary embolism, and with the clinical outcomes VTE recurrence and mortality. Methods: We quantified ceDNA by a fluorescent probe, as well as circulating nucleosomes and neutrophil extracellular traps (NETs) by ELISA in plasma from 611 patients aged ≥ 65 years with acute VTE of a prospective cohort study (SWITCO65+). Results: Levels of ceDNA and nucleosomes, but not NETs, correlated with VTE extent. Infectious comorbidities independently increased ceDNA levels in VTE. CeDNA strongly correlated with C-reactive protein and leukocytosis, suggesting an association of ceDNA with inflammation in VTE patients. CeDNA furthermore predicted PE-related and all-cause mortality, but not VTE recurrence, during a 3-year follow-up. Conclusions: Our study suggests that ceDNA levels in VTE patients reflect the degree of inflammation and may serve as a biomarker to stratify VTE patients at risk for mortality. [ABSTRACT FROM AUTHOR]

Receiver operating characteristic (ROC) analysis is widely used to describe the discriminatory power of a diagnostic test to differentiate between populations having or not having a specific disease, using a dichotomous threshold. In this way, positive and negative likelihood ratios (LR+ and LR-) can be calculated to be used in Bayes’ way of estimating disease probabilities. Similarly, LRs can be calculated for certain ranges of test results. However, since many diagnostic tests are of quantitative nature, it would be desirable to estimate LRs for each quantitative result. These LRs are equal to the slope of the tangent to the ROC curve at the corresponding point. Since the exact distribution of test results in diseased and non-diseased people is often not known, the calculation of such LRs for quantitative test results is not straightforward. Here, a simple distribution-independent method is described to reach this goal using Bézier curves that are defined by tangents to a curve. The use of such a method would help in standardizing quantitative test results, which are not always comparable between different test providers, by reporting them as LRs for a specific diagnosis, in addition to, or instead of, quantities such as mg/L or nmol/L, or even indices or units. [ABSTRACT FROM AUTHOR]

Introduction: We investigated whether thrombus length measured in Computed Tomography Angiography (CTA) is predictive of the success rate of intravenous thrombolysis (IVT) in acute basilar occlusion and whether recanalization can be achieved by additional mechanical endovascular thrombectomy. Methods: In 51 patients with acute basilar thrombosis thrombus length was measured on CTA images before intravenous thrombolysis (IVT) with rt-PA was started. After 114 minutes on average success of IVT was evaluated either by CTA or DSA. Patients with persistent basilar occlusion and no major brainstem infarction on CT underwent endovascular recanalization. Results: 87% of patients had no recanalization of basilar artery after IVT alone. The average thrombus length was 15 mm in patients with persistent basilar occlusion after IVT and 7 mm in patients with recanalization after IVT. Thrombi longer than 13 mm did not resolve after IVT alone and 80% of thrombi shorter than 13 mm did not resolve either. 41 patients were transferred to endovascular recanalization; endovascular therapy was performed successfully in 90% (37 / 41). Conclusions: Recanalization rates in acute basilar occlusion after IVT alone are low and dependent on thrombus length. Additional mechanical endovascular thrombectomy showed to be a very successful recanalization therapy. [ABSTRACT FROM AUTHOR]

Background: Transfusion therapy is associated with increased morbidity, mortality and costs. Conventional coagulation tests (CCT) are weak bleeding predictors, poorly reflecting coagulation in vivo. Thromboelastometry (ROTEM) provides early identification of coagulation disorders and can guide transfusion therapy by goals, reducing blood components transfusion. Objective: The aim of this study is to describe coagulation profile of critically ill patients using ROTEM and evaluate the association between CCT and thromboelastometry. Methods: This is a retrospective, observational study conducted in medical-surgical intensive care unit (ICU). Adult patients (≥18 years) admitted to ICU between November 2012 and December 2014, in whom ROTEM analyses were performed for bleeding management were included in this study. The first ROTEM and CCT after ICU admission were recorded simultaneously. Additionally, we collected data on blood components transfusion and hemostatic agents immediately after laboratory tests results. Results: The study included 531 patients. Most ROTEM tests showed normal coagulation profile [INTEM (54.8%), EXTEM (54.1%) and FIBTEM (53.3%)] with divergent results in relation to CCT: low platelet count (51.8% in INTEM and 55.9% in EXTEM); prolonged aPTT (69.9% in INTEM and 63.7% in EXTEM) and higher INR (23.8% in INTEM and 27.4% in EXTEM). However 16,7% of patients with normocoagulability in ROTEM received platelet concentrates and 10% fresh frozen plasma. Conclusion: The predominant ROTEM profile observed in this sample of critically ill patients was normal. In contrast, CCT suggested coagulopathy leading to a possibly unnecessary allogenic blood component transfusion. ROTEM test may avoid inappropriate allogeneic blood products transfusion in these patients. [ABSTRACT FROM AUTHOR]

Background & aims: Prophylactic injections of factor VIII reduce the incidence of bleeds and slow the development of joint damage in people with hemophilia. The aim of this study was to identify optimal person-specific prophylaxis regimens for children with hemophilia A. Methods: Analytic and numerical methods were used to identify prophylaxis regimens which maximize the time for which plasma factor VIII concentrations exceed a threshold, maximize the lowest plasma factor VIII concentrations, and minimize risk of bleeds. Results: It was demonstrated analytically that, for any injection schedule, the regimen that maximizes the lowest factor VIII concentration involves sharing doses between injections so that all of the trough concentrations in a prophylaxis cycle are equal. Numerical methods were used to identify optimal prophylaxis schedules and explore the trade-offs between efficacy and acceptability of different prophylaxis regimens. The prophylaxis regimen which minimizes risk of bleeds depends on the person’s pattern of physical activity and may differ greatly from prophylaxis regimens that optimize pharmacokinetic parameters. Prophylaxis regimens which minimize risk of bleeds also differ from prophylaxis regimens that are typically prescribed. Predictions about which regimen is optimal are sensitive to estimates of the effects on risk of bleeds of factor VIII concentration and physical activity. Conclusion: The methods described here can be used to identify optimal, person-specific prophylaxis regimens for children with hemophilia A. [ABSTRACT FROM AUTHOR]

Introduction: The pathogenesis of thrombocytopenia in patients with sepsis is not fully understood. The aims of this study were to investigate changes in thrombopoietic activity over time by using absolute immature platelet counts (AIPC) and to examine the impact of platelet production on thrombocytopenia and mortality in patients with sepsis. Methods: This retrospective observational study included adult patients with sepsis admitted to the intensive care unit at a university hospital. Two hundred five consecutive sepsis patients were stratified into four groups according to nadir platelet count: severe (nadir ≤40×103/μL), moderate (41–80×103/μL), or mild thrombocytopenia (81–120×103/μL), or normal-increased platelet count (>120×103/μL). The development of thrombocytopenia was assessed during the first week; mortality was assessed at day 28. Result: Of the 205 patients included, 61 (29.8%) developed severe thrombocytopenia. On admission, AIPC did not differ among the four groups. In patients with severe thrombocytopenia, AIPC decreased significantly from days 2 to 7, but remained within or above the normal range in the other three groups (overall group comparison, P<0.0001). Multivariate analysis including coagulation biomarkers revealed that AIPC was independently associated with the development of severe thrombocytopenia (day 3 AIPC, odds ratio 0.49 [95% confidence interval (CI) 0.35–0.66], P<0.0001; day 5 AIPC, 0.59 [95% CI 0.45–0.75], P<0.0001). AIPC was a significant predictor of 28-day mortality in Cox hazard models adjusted for Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores (day 3 AIPC, hazard ratio 0.70 [95% CI 0.52–0.89], P = 0.0029; day 5 AIPC, 0.68 [95% CI 0.49–0.87], P = 0.0012). Conclusions: Thrombopoietic activity was generally maintained in the acute phase of sepsis. However, a decrease in AIPC after admission was independently associated with the development of severe thrombocytopenia and mortality, suggesting the importance of suppressed thrombopoiesis in the pathophysiology of sepsis-induced thrombocytopenia. [ABSTRACT FROM AUTHOR]

Background: While oral anticoagulants (OACs) are highly effective for ischemic stroke prevention in atrial fibrillation, intracerebral hemorrhage (ICH) remains the most feared complication of OAC. Clinical controversy remains regarding OAC resumption and its timing for ICH survivors with atrial fibrillation because the balance between risks and benefits has not been investigated in randomized trials. Aims/Hypothesis: To survey the practice of stroke neurologists, thrombosis experts and neurosurgeons on OAC re-initiation following OAC-associated ICH. Methods: An online survey was distributed to members of the International Society for Thrombosis and Haemostasis, Canadian Stroke Consortium, NAVIGATE-ESUS trial investigators (Clinicatrials.gov identifier NCT02313909) and American Association of Neurological Surgeons. Demographic factors and 11 clinical scenarios were included. Results: Two hundred twenty-eight participants from 38 countries completed the survey. Majority of participants were affiliated with academic centers, and >20% managed more than 15 OAC-associated ICH patients/year. Proportion of respondents suggesting OAC anticoagulant resumption varied from 30% (for cerebral amyloid angiopathy) to 98% (for traumatic ICH). Within this group, there was wide distribution in response for timing of resumption: 21.4% preferred to re-start OACs after 1–3 weeks of incident ICH, while 25.3% opted to start after 1–3 months. Neurosurgery respondents preferred earlier OAC resumption compared to stroke neurologists or thrombosis experts in 5 scenarios (p<0.05 by Kendall’s tau). Conclusions: Wide variations in current practice exist among management of OAC-associated ICH, with decisions influenced by patient- and provider-related factors. As these variations likely reflect the lack of high quality evidence, randomized trials are direly needed in this population. [ABSTRACT FROM AUTHOR]