Introduction: Tissue factor expression on monocytes is implicated in the pathophysiology of sepsis-induced coagulopathy. How tissue factor is expressed by monocyte subsets (classical, intermediate and non-classical) is unknown. Methods: Monocytic tissue factor surface expression was investigated during three conditions. Primary human monocytes and microvascular endothelial cell co-cultures were used for in vitro studies. Volunteers received a bolus of lipopolysaccharide (2 ng/kg) to induce endotoxemia. Patients with sepsis, or controls with critical illness unrelated to sepsis, were recruited from four intensive care units. Results: Contact with endothelium and stimulation with lipopolysaccharide reduced the proportion of intermediate monocytes. Lipopolysaccharide increased tissue factor surface expression on classical and non-classical monocytes. Endotoxemia induced profound, transient monocytopenia, along with activation of coagulation pathways. In the remaining circulating monocytes, tissue factor was up-regulated in intermediate monocytes, though approximately 60 % of individuals (responders) up-regulated tissue factor across all monocyte subsets. In critically ill patients, tissue factor expression on intermediate and non-classical monocytes was significantly higher in patients with established sepsis than among non-septic patients. Upon recovery of sepsis, expression of tissue factor increased significantly in classical monocytes. Conclusion: Tissue factor expression in monocyte subsets varies significantly during health, endotoxemia and sepsis.

AIMS:Stabilization of anticoagulation control is seminal to reducing the risk of adverse effects of vitamin K antagonists. Reliable information on how ageing influences this is lacking. We set out to assess the true age-related changes in anticoagulation control, how gender and patient setting influence this, and the possible implications of these for patient outcomes and management.METHODS:In atrial fibrillation (AF) patients of a unified anticoagulant service monitoring patients in general practice or hospital-based clinics and housebound patients at home, international normalized ratio (INR) and warfarin dose data between 2000 and 2013 were extracted via the DAWN dosing program. Anticoagulation control was assessed by calculating percentage time spent within target INR (TTR).RESULTS:A total of 2094 AF patients [938 (44.8%) in general practice (GP) and 531 (25.4%) in hospital (H)-based clinics and 625 (29.8%) through the domiciliary service (D)] were evaluated. The frequency of warfarin dose changes and INR monitoring events declined until about age 67, then increased as patients got older. The TTR according to age was significantly lower and the probability of having a TTR ≤65% according to age was higher for D than for H and GP, and females had a greater probability of having a TTR ≤65% than age-matched males.CONCLUSION:Identification of factors underlying poorer anticoagulation control in older housebound patients and the introduction of effective modifications to improve the clinical effectiveness of anticoagulation in such patients is needed.

BackgroundDeep vein thrombosis (DVT) is a condition in which a clot forms in the deep veins, most commonly of the leg. It occurs in approximately 1 in 1,000 people. If left untreated, the clot can travel up to the lungs and cause a potentially life-threatening pulmonary embolism (PE). Previously, a DVT was treated with the anticoagulants heparin and vitamin K antagonists. However, two forms of novel oral anticoagulants (NOACs) have been developed: oral direct thrombin inhibitors (DTI) and oral factor Xa inhibitors. The new drugs have characteristics that may be favourable over conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or re-dosing and few known drug interactions. To date, no Cochrane review has measured the effectiveness and safety of these drugs in the treatment of DVT.ObjectivesTo assess the effectiveness of oral DTIs and oral factor Xa inhibitors for the treatment of DVT.Search methodsThe Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched January 2015) and the Cochrane Register of Studies (last searched January 2015). We searched clinical trials databases for details of ongoing or unpublished studies and the reference lists of relevant articles retrieved by electronic searches for additional citations.Selection criteriaWe included randomised controlled trials in which people with a DVT confirmed by standard imaging techniques, were allocated to receive an oral DTI or an oral factor Xa inhibitor for the treatment of DVT.Data collection and analysisTwo review authors (LR, JM) independently extracted the data and assessed the risk of bias in the trials. Any disagreements were resolved by discussion with the third review author (PK). We performed meta-analyses when we considered heterogeneity low. The two primary outcomes were recurrent VTE and PE. Other outcomes included all-cause mortality and major bleeding. We calculated all outcomes using an odds ratio (OR) with a 95% confidence interval (CI).Main resultsWe included 11 randomised controlled trials of 27,945 participants. Three studies tested oral DTIs (two dabigatran and one ximelagatran), while eight tested oral factor Xa inhibitors (four rivaroxaban, two apixaban and two edoxaban). We deemed all included studies to be of high methodological quality and low risk of bias. The quality of the evidence was graded as high as the outcomes were direct and effect estimates were consistent and precise, as reflected in the narrow CIs around the ORs. Meta-analysis of three studies (7596 participants) comparing oral DTIs with standard anticoagulation groups showed no difference in the rate of recurrent VTE (OR 1.09; 95% CI 0.80 to 1.49), recurrent DVT (OR 1.08; 95% CI 0.74 to 1.58), fatal PE (OR 1.00; 95% CI 0.27 to 3.70), non-fatal PE (OR 1.12; 95% CI 0.66 to 1.90) or all-cause mortality (OR 0.82; 95% CI 0.60 to 1.13). However, oral DTIs were associated with reduced bleeding (OR 0.68; 95% CI 0.47 to 0.98). Meta-analysis of eight studies (16,356 participants) comparing oral factor Xa inhibitors with standard anticoagulation demonstrated a similar rate of recurrent VTE between the two treatments (OR 0.89; 95% CI 0.73 to 1.07). Oral factor Xa inhibitors were associated with a lower rate of recurrent DVT (OR 0.75; 95% CI 0.57 to 0.98). However, this was a weak association, heavily dependent on one study. The rate of fatal (OR 1.20; 95% CI 0.71 to 2.03), non-fatal PE (OR 0.94; 95% CI 0.68 to 1.28) and all-cause mortality (OR 0.90; 95% CI 0.65 to 1.23) was similar between the two treatment groups. Oral factor Xa inhibitors were also associated with reduced bleeding (OR 0.57; 95% CI 0.43 to 0.76). None of the included studies measured post-thrombotic syndrome or health-related quality of life.Authors' conclusionsNOACs such as DTIs and factor Xa inhibitors may be an effective and safe alternative to conventional anticoagulation treatment for acute DVT.

BACKGROUNDnovel oral anticoagulants may be particularly cost-effective when INR control (TTR) with warfarin is poor or monitoring difficult.SETTINGthe Newcastle upon Tyne monitoring service, set in hospital or general practice and a domiciliary-based service for housebound patients.OBJECTIVESto examine anticoagulation stability and costs of monitoring.SUBJECTSthree hundred and twenty-six atrial fibrillation patients, 75 years and over, with target INR of two to three, accessing hospital (n = 100), general practice (n = 122) and domiciliary (n = 104) service.METHODSage, co-morbidities, length of warfarin treatment, medications, INR values and dose changes from January to December 2011 were recorded, and costs analysed.RESULTShome-monitored patients had taken warfarin for longer, mean 5.2 years, than hospital (3.7) or general practice (3.1) patients. Age and total number of drugs prescribed chronically were negatively related to TTR. INR measurements and dose changes were negatively associated with the duration of treatment, positively correlated with co-morbidities. The mean TTR was 78% in hospital, 71% in general practice and 68% in domiciliary monitored patients. INR was monitored more often in hospital and domiciliary groups than in general practice and more dose changes occurred in the domiciliary group than in others. Costs of warfarin and monitoring were £128 per patient per year for hospital, £126 for general practice and £222 for domiciliary patients.CONCLUSIONSfurther exploration of the clinical effectiveness of novel anticoagulants in dependent patients is warranted to determine to what extent trial outcomes so far achieved in a fitter elderly population are influenced by the chronic co-morbidities of old age.

AIMS:To compare quantitative point of care (POC) with laboratory d-dimer testing in patients with suspected venous thromboembolism (VTE) presenting to the emergency department. METHODS:A prospective single centre diagnostic study in adults presenting with suspected VTE (pleuritic chest pain or leg swelling) RESULTS:Main outcome measures were the statistical correlation of the two methods. Secondary outcome measures were: test turnaround times, correlation between D-dimer levels, Wells score and final diagnosis. The results showed that there was strong evidence of POC D-dimer being sufficiently accurate to be used as a screening device. The correlation between the two logged assay scores was good. Both logged scores correlated similarly with the Wells score. Once an equivalent cut-off value for POC D-dimer (412 ng/mL) was established, there were only 4 of 100 cases all of which were extremely close to the cut-off. D-dimer turnaround time decreased by 83%. A further recent analysis of laboratory times done in 2013 demonstrates that POC D-dimer results remain 62% quicker. Based on the D-dimer results 27 patients were scanned. The median Wells score in this group was 3.0 (range 2-10) median POC D-dimer levels of 2590 (412-5000) and median lab D-dimer levels of 864 (230-13 000) showing good correlation between D-dimer positive patients and the Wells score. Seven patients had positive scans. There was a significant difference in both logged D-dimer scores between the negative and positive groups indicating that raised D-dimer levels correlate well with final diagnosis. CONCLUSIONS:The POC device was comparable with the laboratory device and was sufficiently accurate to be used as a screening tool in the emergency department setting.

Pulmonary embolism remains a major healthcare burden and some patients still die from this preventable disease, perhaps because of limited knowledge about available treatments for massive pulmonary embolism.1 Systemic thrombolysis has been the mainstay for massive pulmonary embolism. Other options include transcatheter clot removal and locally directed thrombolysis, but their application is …

Introduction: Despite reperfusion therapy for acute myocardial infarction (AMI), heart failure remains a major sequel.Reperfusion leads to further damage, described as ischemiareperfusion-injury (IRI).This contributes up to 50% of the final infarct size.In pre-clinical models nitrite potently protects against IRI in the heart and other organs.Hypothesis: Intravenous (iv) sodium nitrite, administered immediately before opening of the infarctrelated artery, results in significant reduction of IRI in patients with acute ST elevation MI (STEMI).Methods: In this phase II, randomised, placebo-controlled, double-blind, multicentre trial, 220 patients with first acute STEMI and TIMI 0 or 1 flow were randomised in a double-blind fashion to 70micromol iv sodium nitrite or matching placebo over 5 minutes immediately preceding opening of the infarct-related artery.The primary end point was the difference in infarct size between sodium nitrite and placebo groups using cardiovascular magnetic resonance imaging (CMR) at 6-8 days following AMI, adjusted for area at risk (AAR), diabetes status and center.Secondary end points comprised (i) Infarct size (CMR) at six months; (ii) plasma CK and Troponin I measured over 72 hours after injection of the study medication; (iii) Infarct size corrected for AAR measured using T2 weighted CMR; (iv) left ventricular (LV) ejection fraction and LV end systolic volume index measured by CMR at 6-8 days and at six months.Results: Infarct size at 6-8 days by CMR did not differ between nitrite and placebo groups (effect size -0.7% 95%CI -2.2,+0.7;p=0.34).There were no significant differences in the predefined secondary end points.There was no treatment effect in non-diabetics, but in diabetics was -4.5% (95%CI -8.8,-0.2;p=0.041) but the interaction was not significant (p=0.067).Conclusion: Sodium nitrite administered iv immediately prior to reperfusion in patients with acute STEMI did not reduce infarct size.A potential benefit in diabetics warrants further study.Funding, Ethics,

BACKGROUND The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy. METHODS We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation. RESULTS A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR ≥4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001). CONCLUSIONS Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. (Funded by the European Commission Seventh Framework Programme and others; ClinicalTrials.gov number, NCT01119300.).

This chapter describes the common haematological abnormalities seen in rheumatic conditions with special reference to laboratory findings and diagnostic traps. The chapter is organized into sections dealing with red cell abnormalities (and the distinction between anaemia of chronic disease and iron deficiency); white cell abnormalities (neutrophilia and neutropenia); platelets (thrombocytosis, idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura); and finally coagulation abnormalities (lupus anticoagulant).

Pregnant women are at an increased risk of venous thromboembolism (VTE) and the consequences of an acute event in pregnancy can be debilitating, long-lasting or fatal. Screening for risk factors early in pregnancy and the provision of thromboprophylaxis are useful ways of preventing VTE in some women, but even when performed diligently, acute events are likely to remain common for the foreseeable future. It is therefore important for obstetric and non-obstetric clinicians to recognize the symptoms and signs of deep vein thrombosis and pulmonary embolism in pregnancy, to understand how a diagnosis can be reached in an effective yet safe manner and to be aware of the available treatment modalities.