Evaluating the Impact of Cardiopulmonary Bypass Priming Fluids on Bleeding After Pediatric Cardiac Surgery: A Systematic Review and Meta-Analysis.

OBJECTIVES: Cardiopulmonary bypass (CPB) predisposes young children to coagulopathy. The authors evaluated possible effects of CPB priming fluids on perioperative bleeding in pediatric cardiac surgery. DESIGN: Meta-analysis and systematic review of previously published studies. SETTING: Each study was conducted in a surgical center or intensive care unit. PARTICIPANTS: Studies investigating patients <18 years without underlying hematologic disorders were included. INTERVENTIONS: The authors evaluated randomized controlled trials (RCTs) published between 1980 and 2020 on MEDLINE, EMBASE, PubMed, and CENTRAL databases. The primary outcome was postoperative bleeding; secondary endpoints included blood product transfusion, mortality, and safety. MEASUREMENTS AND MAIN RESULTS: Twenty eligible RCTs were analyzed, with a total of 1,550 patients and a median of 66 patients per study (range 20-200). The most frequently assessed intervention was adding fresh frozen plasma (FFP) to the prime (8/20), followed by albumin (5/20), artificial colloids (5/20), and blood-based priming solutions (3/20). Ten studies with 771 patients evaluated blood loss at 24 hours in mL/kg and were included in a meta-analysis. Most of them investigated the addition of FFP to the priming fluid (7/10). No significant difference was found between intervention and control groups, with a mean difference of -0.13 (-2.61 to 2.34), p = 0.92, I2 = 69%. Further study endpoints were described but their reporting was too heterogeneous to be quantitatively analyzed. CONCLUSIONS: This systematic review of current evidence did not show an effect of different CPB priming solutions on 24-hour blood loss. The analysis was limited by heterogeneity within the dataset regarding population, type of intervention, dosing, and the chosen comparator, compromising any conclusions.

Oral semaglutide versus injectable glucagon-like peptide-1 receptor agonists: a cost of control analysis.

Aims: The efficacy and safety of oral semaglutide, the first glucagon-like peptide-1 (GLP-1) receptor agonist developed for oral administration for the treatment of type 2 diabetes, was evaluated in the PIONEER clinical trial program, and a recently published network meta-analysis allowed comparison with further injectable GLP-1 receptor agonists. The present study aimed to assess the short-term cost- effectiveness of oral semaglutide 14 mg versus subcutaneous once-weekly dulaglutide 1.5 mg, once-weekly exenatide 2 mg, twice-daily exenatide 10 µg, once-daily liraglutide 1.8 mg, once-daily lixisenatide 20 µg, and once-weekly semaglutide 1 mg, in terms of the cost per patient achieving glycated hemoglobin (HbA1c) targets (cost of control).Materials and methods: Cost of control was calculated by dividing the annual treatment costs associated with an intervention by the proportion of patients achieving the treatment target with an intervention, with outcomes calculated for targets of HbA1c ≤6.5% and HbA1c <7.0% for all included GLP-1 receptor agonists. Annual treatment costs were accounted in 2019 United States dollars (USD), based on 2019 wholesale acquisition cost.Results: For the treatment target of HbA1c ≤6.5%, once-weekly semaglutide 1 mg and oral semaglutide 14 mg were associated with the lowest costs of control, at USD 15,430 and USD 17,383 per patient achieving target, respectively. Similarly, the cost of control was lowest with once-weekly semaglutide 1 mg at USD 12,627 per patient achieving target, followed by oral semaglutide 14 mg at USD 13,493 per patient achieving target for the target of HbA1c <7.0%. All other interventions were associated with higher cost of control values for both targets.Conclusions: Oral semaglutide 14 mg is likely to be cost-effective versus dulaglutide, exenatide (once weekly and twice daily), liraglutide, and lixisenatide in terms of bringing people with type 2 diabetes to glycemic control targets of HbA1c ≤6.5% and HbA1c <7.0% in the US.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) as a therapeutic target in psoriasis: randomized, controlled investigation using namilumab, a specific human anti-GM-CSF monoclonal antibody.

BACKGROUND: The relevance of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the management of psoriasis has not been studied previously. GM-CSF is important in the initiation and maintenance of chronic inflammatory processes. OBJECTIVES: To investigate the clinical use of GM-CSF neutralization by evaluating the efficacy and safety of namilumab (AMG203), a monoclonal antibody GM-CSF inhibitor, in patients with moderate-to-severe plaque psoriasis. METHODS: A phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group, dose-finding, proof-of-concept study (NEPTUNE) was conducted. Four doses of namilumab (20, 50, 80 and 150 mg, via subcutaneous injection) were compared with placebo. Assessment of the primary end point - the proportion of patients achieving ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75 treatment response) - was performed at week 12. Exploratory investigation at the tissue level was conducted in a subset of the overall study population. The trial was registered with the number NCT02129777. RESULTS: In total, 122 patients were enrolled and 106 (86·9%) completed the double-blind treatment; 16 (13·1%) prematurely discontinued study medication. Serum concentration-time profiles were as expected for subcutaneous delivery of an IgG1 monoclonal antibody, and exposure increased proportionally with dose elevation. The number of patients showing PASI 75 treatment response at week 12 was low in all groups; no significant difference was recorded in this end point between placebo and any namilumab group. Similar outcomes were recorded for other clinical study end points. Moreover, no significant treatment-related changes from baseline were observed in laboratory investigations of cell types or subpopulations, or cytokines relevant to inflammatory pathways in psoriasis. CONCLUSIONS: GM-CSF blockade is not critical for suppression of key inflammatory pathways underlying psoriasis.

Evaluating the short-term cost-effectiveness of liraglutide versus lixisenatide in patients with type 2 diabetes in the United States.

AIMS: Bringing patients with type 2 diabetes to recommended glycated hemoglobin (HbA1c) treatment targets can reduce the risk of developing diabetes-related complications. The aim of the present analysis was to evaluate the short-term cost-effectiveness of once-daily liraglutide 1.8 mg vs once-daily lixisenatide 20 µg as an add-on to metformin for treatment of type 2 diabetes in the US by assessing the cost per patient achieving HbA1c-focused and composite treatment targets. MATERIALS AND METHODS: Percentages of patients achieving recommended targets were obtained from the LIRA-LIXI trial, which compared the efficacy and safety of once-daily liraglutide 1.8 mg and once-daily lixisenatide 20 µg as an add-on to metformin in patients with type 2 diabetes failing to achieve glycemic control with metformin. Annual costs were estimated from a healthcare payer perspective. An economic model was developed to evaluate the annual cost per patient achieving target (cost of control) with liraglutide 1.8 mg vs lixisenatide 20 µg for five end-points. RESULTS: Annual treatment costs were higher with liraglutide 1.8 mg than lixisenatide 20 µg, but this was offset by greater clinical efficacy, and the cost of control was lower with liraglutide 1.8 mg than lixisenatide 20 µg for all five end-points. The annual cost of control was USD 3,850, USD 11,404, USD 3,807, USD 4,299, and USD 6,901 lower for liraglutide 1.8 mg than lixisenatide 20 µg for targets of HbA1c < 7.0%, HbA1c ≤ 6.5%, HbA1c < 7.0% and no weight gain, HbA1c < 7.0% with no weight gain and no confirmed hypoglycemia, and HbA1c < 7.0% with no weight gain and systolic blood pressure <140 mmHg, respectively. CONCLUSIONS: Once-daily liraglutide 1.8 mg was associated with greater clinical efficacy than once-daily lixisenatide 20 µg, which resulted in a lower annual cost of control for HbA1c-focused and composite treatment targets.

Graduated Compression Stockings as an Adjunct to Low Dose Low Molecular Weight Heparin in Venous Thromboembolism Prevention in Surgery: A Multicentre Randomised Controlled Trial.

BACKGROUND: The evidence base upon which current global venous thromboembolism (VTE) prevention recommendations have been made is not optimal. The cost of purchasing and applying graduated compression stockings (GCS) in surgical patients is considerable and has been estimated at £63.1 million per year in England alone. OBJECTIVE: The aim was to determine whether low dose low molecular weight heparin (LMWH) alone is non-inferior to a combination of GCS and low dose LMWH for the prevention of VTE. METHODS: The randomised controlled Graduated compression as an Adjunct to Pharmacoprophylaxis in Surgery (GAPS) Trial (ISRCTN 13911492) will randomise adult elective surgical patients identified as being at moderate and high risk of VTE to receive either the current "standard" combined thromboprophylactic LMWH with GCS mechanical thromboprophylaxis, or thromboprophylactic LMWH pharmacoprophylaxis alone. To show non-inferiority (3.5% non-inferiority margin) for the primary endpoint of all VTE within 90 days, 2236 patients are required. Recruitment will be from seven UK centres. Secondary outcomes include quality of life, compliance with stockings and LMWH, overall mortality, and GCS or LMWH related complications (including bleeding). Recruitment commenced in April 2016 with the seven UK centres coming "on-line" in a staggered fashion. Recruitment will be over a total of 18 months. The GAPS trial is funded by the National Institute for Health Research Health Technology Assessment in the UK (14/140/61).

Risk of symptomatic venous thromboembolism following emergency appendicectomy in adults.

BACKGROUND: Appendicectomy is the commonest intra-abdominal emergency surgical procedure, and little is known regarding the magnitude and timing of the risk of venous thromboembolism (VTE) after surgery. This study aimed to determine absolute and relative rates of symptomatic VTE following emergency appendicectomy. METHODS: A cohort study was undertaken using linked primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care data of patients who had undergone emergency appendicectomy from 2001 to 2011. Crude rates and adjusted incidence rate ratios (IRRs) for VTE were calculated using Poisson regression, compared with baseline risk in the year before appendicectomy. RESULTS: A total of 13 441 patients were identified, of whom 56 (0·4 per cent) had a VTE in the first year after surgery. The absolute rate of VTE was highest during the in-hospital period, with a rate of 91·29 per 1000 person-years, which was greatest in those with a length of stay of 7 days or more (267·12 per 1000 person-years). This risk remained high after discharge, with a 19·1- and 6·6-fold increased risk of VTE in the first and second months respectively after discharge, compared with the year before appendicectomy (adjusted IRR: month 1, 19·09 (95 per cent c.i. 9·56 to 38·12); month 2, 6·56 (2·62 to 16·44)). CONCLUSION: The risk of symptomatic VTE following appendicectomy is relatively high during the in-hospital admission and remains increased after discharge. Trials of extended thromboprophylaxis are warranted in patients at particularly high risk.

A critical appraisal of point-of-care coagulation testing in critically ill patients.

Derangement of the coagulation system is a common phenomenon in critically ill patients, who may present with severe bleeding and/or conditions associated with a prothrombotic state. Monitoring of this coagulopathy can be performed with conventional coagulation assays; however, point-of-care tests have become increasingly attractive, because not only do they yield a more rapid result than clinical laboratory testing, but they may also provide a more complete picture of the condition of the hemostatic system. There are many potential areas of study and applications of point-of-care hemostatic testing in critical care, including patients who present with massive blood loss, patients with a hypercoagulable state (such as in disseminated intravascular coagulation), and monitoring of antiplatelet treatment for acute arterial thrombosis, mostly acute coronary syndromes. However, the limitations of near-patient hemostatic testing has not been fully appreciated, and are discussed here. The currently available evidence indicates that point-of-care tests may be applied to guide appropriate blood product transfusion and the use of hemostatic agents to correct the hemostatic defect or to ameliorate antithrombotic treatment. Disappointingly, however, only in cardiac surgery is there adequate evidence to show that application of near-patient thromboelastography leads to an improvement in clinically relevant outcomes, such as reductions in bleeding-related morbidity and mortality, and cost-effectiveness. More research is required to validate the utility and cost-effectiveness of near-patient hemostatic testing in other areas, especially in traumatic bleeding and postpartum hemorrhage.

Variation in the risk of venous thromboembolism following colectomy.

BACKGROUND: Guidelines recommend extended thromboprophylaxis following colectomy for malignant disease, but not for non-malignant disease. The aim of this study was to determine absolute and relative rates of venous thromboembolism (VTE) following colectomy by indication, admission type and time after surgery. METHODS: A cohort study of patients undergoing colectomy in England was undertaken using linked primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care data (2001-2011). Crude rates and adjusted hazard ratios (HRs) were calculated for the risk of first VTE following colectomy using Cox regression analysis. RESULTS: Some 12,388 patients were identified; 312 (2·5 per cent) developed VTE after surgery, giving a rate of 29·59 (95 per cent c.i. 26·48 to 33·06) per 1000 person-years in the first year after surgery. Overall rates were 2·2-fold higher (adjusted HR 2·23, 95 per cent c.i. 1·76 to 2·50) for emergency compared with elective admissions (39·44 versus 25·78 per 1000 person-years respectively). Rates of VTE were 2·8-fold higher in patients with malignant disease versus those with non-malignant disease (adjusted HR 2·84, 2·04 to 3·94). The rate of VTE was highest in the first month after emergency surgery, and declined from 121·68 per 1000 person-years in the first month to 25·65 per 1000 person-years during the rest of the follow-up interval. Crude rates of VTE were similar for malignant and non-malignant disease (114·76 versus 120·98 per 1000 person-years respectively) during the first month after emergency surgery. CONCLUSION: Patients undergoing emergency colectomy for non-malignant disease have a similar risk of VTE as patients with malignant disease in the first month after surgery.

The current place of tranexamic acid in the management of bleeding.

There has been an explosion of interest in the ability of tranexamic acid to reduce morbidity and mortality in surgical and traumatic bleeding. Tranexamic acid has been shown to reduce mortality due to traumatic bleeding by a third, without apparent safety issues. It is now clearly established that intravenous tranexamic acid reduces blood loss in patients with surgical bleeding and the need for transfusion. It can also be used topically to reduce bleeding. Its use is being explored further in large pragmatic trials in traumatic head injury, postpartum haemorrhage and in upper gastro-intestinal haemorrhage. There are few side effects from the use of tranexamic acid except when administered in high dose where neurological events have been noted, possibly relating to tranexamic acid interfering with cerebral GABA and glycine receptors. However, clinical studies suggest that there is no increased efficacy in using a higher dose, and that a dose of 1 g intravenously in an adult patient has maximal efficacy, which is not increased by higher doses. The CRASH-2 trauma trial clearly showed no increase in thrombotic events after its use in trauma, indeed there was a significant reduction in myocardial infarction. However, trials of tranexamic acid in surgery have failed to adequately study its effects on the risk of postoperative venous and possible reduction in arterial thrombo-embolism, and this needs to be the subject of future research.

Esophagectomy for failed endoscopic therapy in patients with high-grade dysplasia or intramucosal carcinoma.

Endoscopic therapy (ablation +/- endoscopic resection) for high-grade dysplasia and/or intramucosal carcinoma (IMC) of the esophagus has demonstrated promising results. However, there is a concern that a curable, local disease may progress to systemic disease with repeated endotherapy. We performed a retrospective review of patients who underwent esophagectomy after endotherapy at three tertiary care esophageal centers from 2006 to 2012. Our objective was to document the clinical and pathologic outcomes of patients who undergo esophagectomy after failed endotherapy. Fifteen patients underwent esophagectomy after a mean of 13 months and 4.1 sessions of endotherapy for progression of disease (53%), failure to clear disease (33%), or recurrence (13%). Initially, all had Barrett's, 73% had ≥3-cm segments, 93% had a nodule or ulcer, and 91% had multifocal disease upon presentation. High-grade dysplasia was present at index endoscopy in 80% and IMC in 33%, and some patients had both. Final pathology at esophagectomy was T0 (13%), T1a (60%), T1b (20%), and T2 (7%). Positive lymph nodes were found in 20%: one patient was T2N1 and two were T1bN1. Patients with T1b, T2, or N1 disease had more IMC on index endoscopy (75% vs. 18%) and more endotherapy sessions (median 6.5 vs. 3). There have been no recurrences a mean of 20 months after esophagectomy. Clinical outcomes were comparable to other series, but submucosal invasion (27%) and node-positive disease (20%) were encountered in some patients who initially presented with a locally curable disease and eventually required esophagectomy after failed endotherapy. An initial pathology of IMC or failure to clear disease after three treatments should raise concern for loco-regional progression and prompt earlier consideration of esophagectomy.

Diabetes and gout: efficacy and safety of febuxostat and allopurinol.

AIM: Assess influences of demographics and co-morbidities of gout patients with or without diabetes on safety and efficacy of urate-lowering agents. METHODS: Post-hoc analysis of 312 diabetic and 1957 non-diabetic gout patients [baseline serum urate levels (sUA) ≥8.0 mg/dl] enrolled in a 6-month randomized controlled trial comparing urate-lowering efficacy (ULE) and safety of daily xanthine oxidase inhibitors (XOIs) febuxostat (40 mg or 80 mg) and allopurinol (200 mg or 300 mg). We compared baseline demographic, gout and co-morbid characteristics, ULE, and safety of XOI treatment in diabetic and non-diabetic gout patients. ULE was measured by the proportion of diabetic and non-diabetic patients in each treatment group achieving final visit sUA < 6.0 mg/dl. Safety was monitored throughout the trial. RESULTS: Diabetic gout patients were older, more frequently female, and had longer gout duration. Co-morbidities were more frequent among diabetic patients: cardiovascular disease; impaired renal function; hyperlipidemia; and obesity (body mass index >30 kg/m²) (p < 0.001 for all comparisons). Febuxostat 80 mg ULE exceeded that of febuxostat 40 mg or allopurinol (p < 0.050) at all levels of renal function, achieving sUA goal range in the majority of diabetic and non-diabetic patients. Diabetics and non-diabetics reported self-limiting diarrhoea and URIs as the most common adverse events. CONCLUSIONS: Despite higher co-morbidity rates in diabetic patients, febuxostat and allopurinol were safe in both groups at the doses tested. Febuxostat 80 mg achieved sUA <6.0 mg/dl more often than febuxostat 40 mg or allopurinol at commonly prescribed doses.

Evaluating the clinical and economic burden of healthcare-associated infections during hospitalization for surgery in France.

Over 4 million patients suffer nosocomial infections annually in the European Union. This study aimed to estimate the healthcare burden associated with healthcare-associated infections (HAIs) following surgery in France, and explore the potential impact of infection control strategies and interventions on the clinical and economic burden of disease. Data on the frequency of HAIs were gathered from the 2010 Programme de Médicalisation des Systèmes d'Information (PMSI), and cost data were taken from the 2009 Echelle Nationale de Coûts à Méthodologie Commune (ENCC). It was estimated that 3% of surgical procedures performed in 2010 in France resulted in infection, resulting in an annual cost of €57 892 715. Patients experiencing a HAI had a significantly increased mortality risk (4.15-fold) and an increased length of hospital stay (threefold). Scenario analysis in which HAI incidence following surgery was reduced by 8% (based on a study of the effectiveness of triclosan-coated sutures), suggested that, annually, 20 205 hospital days and €4 588 519 could be saved. Analyses of 20% and 30% reductions in incidence (based on an estimate of the number of preventable nosocomial infections) suggested that annual savings of €11 548 057 and €17 334 696, respectively, could be made. New infection control interventions which reduce HAI incidence during hospitalization for surgery have the potential to provide valuable cost savings to healthcare providers.

The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients.

BACKGROUND: Among trauma patients who survive to reach hospital, exsanguination is a common cause of death. A widely practicable treatment that reduces blood loss after trauma could prevent thousands of premature deaths each year. The CRASH-2 trial aimed to determine the effect of the early administration of tranexamic acid on death and transfusion requirement in bleeding trauma patients. In addition, the effort of tranexamic acid on the risk of vascular occlusive events was assessed. OBJECTIVE: Tranexamic acid (TXA) reduces bleeding in patients undergoing elective surgery. We assessed the effects and cost-effectiveness of the early administration of a short course of TXA on death, vascular occlusive events and the receipt of blood transfusion in trauma patients. DESIGN: Randomised placebo-controlled trial and economic evaluation. Randomisation was balanced by centre, with an allocation sequence based on a block size of eight, generated with a computer random number generator. Both participants and study staff (site investigators and trial co-ordinating centre staff) were masked to treatment allocation. All analyses were by intention to treat. A Markov model was used to assess cost-effectiveness. The health outcome was the number of life-years (LYs) gained. Cost data were obtained from hospitals, the World Health Organization database and UK reference costs. Cost-effectiveness was measured in international dollars ($) per LY. Deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results to model assumptions. SETTING: Two hundred and seventy-four hospitals in 40 countries. PARTICIPANTS: Adult trauma patients (n = 20,211) with, or at risk of, significant bleeding who were within 8 hours of injury. INTERVENTIONS: Tranexamic acid (loading dose 1 g over 10 minutes then infusion of 1 g over 8 hours) or matching placebo. MAIN OUTCOME MEASURES: The primary outcome was death in hospital within 4 weeks of injury, and was described with the following categories: bleeding, vascular occlusion (myocardial infarction, stroke and pulmonary embolism), multiorgan failure, head injury and other. RESULTS: Patients were allocated to TXA (n = 10,096) and to placebo (n = 10,115), of whom 10,060 and 10,067 patients, respectively, were analysed. All-cause mortality at 28 days was significantly reduced by TXA [1463 patients (14.5%) in the TXA group vs 1613 patients (16.0%) in the placebo group; relative risk (RR) 0.91; 95% confidence interval (CI) 0.85 to 0.97; p = 0.0035]. The risk of death due to bleeding was significantly reduced [489 patients (4.9%) died in the TXA group vs 574 patients (5.7%) in the placebo group; RR 0.85; 95% CI 0.76 to 0.96; p = 0.0077]. We recorded strong evidence that the effect of TXA on death due to bleeding varied according to the time from injury to treatment (test for interaction p < 0.0001). Early treatment (≤ 1 hour from injury) significantly reduced the risk of death due to bleeding [198 out of 3747 patients (5.3%) died in the TXA group vs 286 out of 3704 patients (7.7%) in the placebo group; RR 0.68; 95% CI 0.57 to 0.82; p < 0.0001]. Treatment given between 1 and 3 hours also reduced the risk of death due to bleeding [147 out of 3037 patients (4.8%) died in the TXA group vs 184 out of 2996 patients (6.1%) in the placebo group; RR 0.79; 95% CI 0.64 to 0.97; p = 0.03]. Treatment given after 3 hours seemed to increase the risk of death due to bleeding [144 out of 3272 patients (4.4%) died in the TXA group vs 103 out of 3362 patients (3.1%) in the placebo group; RR 1.44; 95% CI1.12 to 1.84; p = 0.004]. We recorded no evidence that the effect of TXA on death due to bleeding varied by systolic blood pressure, Glasgow Coma Scale score or type of injury. Administering TXA to bleeding trauma patients within 3 hours of injury saved an estimated 755 LYs per 1000 trauma patients in the UK. The cost of giving TXA to 1000 patients was estimated at $30,830. The incremental cost of giving TXA compared with not giving TXA was $48,002. The incremental cost per LY gained of administering TXA was $64. CONCLUSIONS: Early administration of TXA safely reduced the risk of death in bleeding trauma patients and is highly cost-effective. Treatment beyond 3 hours of injury is unlikely to be effective. Future work [the Clinical Randomisation of an Antifibrinolytic in Significant Head injury-3 (CRASH-3) trial] will evaluate the effectiveness and safety of TXA in the treatments of isolated traumatic brain injury (http://crash3.lshtm.ac.uk/). TRIAL REGISTRATION: Current Controlled Trials ISRCTN86750102, ClinicalTrials.gov NCT00375258 and South African Clinical Trial Register DOH-27-0607-1919. FUNDING: The project was funded by the Bupa Foundation, the J P Moulton Charitable Foundation and the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 10. See HTA programme website for further project information.

The coagulopathy and thrombotic risk associated with L-asparaginase treatment in adults with acute lymphoblastic leukaemia.

The dramatic improvements seen in the outcome of paediatric patients with acute lymphoblastic leukaemia (ALL) have led to increasing incorporation of L-asparaginase (L-Asp) in adult treatment protocols. However, its use is associated with a disruption in the physiological balance between haemostatic and anticoagulant pathways, with the predominant clinical manifestation being thrombosis. Although L-Asp therapy is known to be associated with an acquired deficiency of antithrombin (AT), the concurrent depletion of fibrinogen and other haemostatic proteins means that the precise mechanism of thrombosis remains to be defined. In vitro coagulation assays are often prolonged but thrombosis rather than haemorrhage is the primary concern. Management of thrombotic events in these patients is based around agents that rely on AT for their anticoagulant effect, even though it is usually depleted. There is currently only limited evidence supporting the use of AT concentrates in either primary prevention or management following an established event. Evidence-based guidelines for prevention and management strategies are lacking.

Plasminogen receptors and their role in the pathogenesis of inflammatory, autoimmune and malignant disease.

Plasminogen is the proenzyme of plasmin, the key protease of the fibrinolytic system, but its role is not limited to fibrinolysis regulation. Plasminogen binds not only to fibrin, but also to different receptors on cell surfaces, including the heterotetrameric complex Annexin A2-S100A10, enolase-1, histone H2B and the plasminogen receptor Plg-R(KT) . These receptors localize plasmin generation to the cell surface and provide a broad spectrum of reactions including proteolytic activity, cell migration and recruitment as well as signaling pathway activation. These plasminogen-binding proteins are involved in both physiologic and pathologic processes such as inflammation, thrombosis and cancer. Thus, plasminogen is at the center of a complex tightly controlled and regulated system where plasminogen-binding proteins have a crucial role, suggesting new therapeutic and diagnostic strategies. This review will discuss currently available information on plasminogen receptors, particularly their mechanisms of action and their roles in inflammatory, autoimmune and malignant disease.

The incidence and magnitude of fibrinolytic activation in trauma patients.

BACKGROUND: Trauma is a global disease, with over 2.5 million deaths annually from hemorrhage and coagulopathy. Overt hyperfibrinolysis is rare in trauma, and is associated with massive fatal injuries. Paradoxically, clinical trials suggest a much broader indication for antifibrinolytics. OBJECTIVE: To determine the incidence and magnitude of fibrinolytic activation in trauma patients and its relationship to clot lysis as measured by thromboelastometry. METHODS: A prospective cohort study of 303 consecutive trauma patients admitted between January 2007 and June 2009 was performed. Blood was drawn on arrival for thromboelastometry (TEM) and coagulation assays. Follow-up was until hospital discharge or death. TEM hyperfibrinolysis was defined as maximum clot lysis of > 15%. Fibrinolytic activation (FA) was determined according to plasmin-antiplasmin (PAP) complex and D-dimer levels. Data were collected on demographics, mechanism, severity of injury, and baseline vital signs. The primary outcome measure was 28-day mortality. The secondary outcome measures were 28-day ventilator-free days and 24-h transfusion requirement. RESULTS: Only 5% of patients had severe fibrinolysis on TEM, but 57% of patients had evidence of 'moderate' fibrinolysis, with PAP complex levels elevated to over twice normal (> 1500 µg L(-1)) without lysis on TEM. TEM detected clot lysis only when PAP complex levels were increased to 30 times normal (P < 0.001) and antiplasmin levels were < 75% of normal. Patients with FA had increased 28-day mortality as compared with those with no FA (12% vs. 1%, P < 0.001), fewer ventilator-free days, and longer hospital stay. CONCLUSIONS: FA occurs in the majority of trauma patients, and the magnitude of FA correlates with poor clinical outcome. This was not detected by conventional TEM, which is an insensitive measure of endogenous fibrinolytic activity.

Management strategies for acute proximal deep vein thrombosis: a Delphi consensus.

OBJECTIVES: Deep vein thrombosis (DVT) is a leading cause of cardiovascular disease. We tested the hypothesis that there is a consensus regarding the treatment of acute DVT among clinicians experienced in DVT management. METHOD: A Delphi consensus approach was used to gather expert opinion regarding attitudes towards the treatment of acute proximal DVT and management of specific cases. Strength of preference for various treatment strategies across a number of case scenarios was quantified. Univariate and multivariate analyses were performed to quantify the influence of various factors on treatment modality selected. RESULTS: Respondents strongly agreed that DVT was a significant health problem and that further research was a priority. A multidisciplinary team approach with access to various treatment strategies was encouraged. Pregnancy and recent surgery independently predicted preference for medical treatment, whereas proximal DVT and May-Thurner syndrome were associated with interventional strategies. CONCLUSION: Acute proximal DVT is a significant health problem for which a variety of treatments are available. This study demonstrates that no consensus exists as to the optimum strategy for certain patient groups. Trends in opinion based on local experience and case-series exist, but the results of ongoing randomized trials will ultimately inform best practice.