Aetiology and outcome of massive transfusion in two large London teaching hospitals over a 3-year period (2012-2014).

OBJECTIVES: The objectives of this study were to determine: (i) the incidence of massive transfusion (MT) (defined as transfusion of ≥5 red-blood-cell (RBC) units within 4 h, and/or ≥10 RBC units within 24 h of bleeding) over a 3-year period; (ii) the cause, and mortality rate of patients who received MT (from any cause); and (iii) the risk factors for death. BACKGROUND: MT can occur in different clinical settings, yet little is known about its epidemiology/clinical outcomes. METHODS: Data was extracted using transfusion laboratory information management system (LIMS) and patients' electronic databases. RESULTS: We identified 701 episodes (incidence 1.7 per 1000 admissions [95% confidence interval (CI): 1.6-1.9], belonging to 678 patients (225 females and 453 males, median age 61). Main causes of MT were cardiac surgery (35%), trauma (28%), medical (10%) and vascular surgery (9%). The overall mortality was 32%, and the median number of days spent in hospital was 14 and 2 for those who survived and those who died, respectively. Multivariable analysis showed that cardiac surgery was associated with 56% (95% CI: 9-78%) lower odds of death compared to other surgery, and transfusion of 10-14 RBC and >15 RBC units (compared with 5-9 RBC units) were associated with 2.1 (95% CI: 1.4-3.3) and 9.9 (95% CI: 4.6-21.1) times higher odds of dying, respectively. CONCLUSION: In-hospital morbidity and mortality of MT is high. Future research should focus on unifying the definition of MT, and early identification of the MT markers in order to improve outcomes.

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.

Antenatal screening for pre-eclampsia: evaluation of the NICE and pre-eclampsia community guidelines.

The NICE and PRECOG guidelines are based on systematic reviews of risk factors for pre-eclampsia to identify mothers at risk before 20 weeks' gestation. Cases (64) and controls (112) were classified retrospectively as screen positive or negative as recommended by the two guidelines The NICE guideline had a higher sensitivity rate of 77% (95% CI 65-87%) vs 59% (95% CI 46-71%) but a lower specificity of 54% (95% CI 44-64%) vs 81% (95% CI 73-88%) with the PRECOG guideline. Based on an incidence of pre-eclampsia of 4% the positive predictive values of PRECOG and NICE guidelines were estimated at only 11% and 7%, respectively. The most discriminatory risk factor was history of pre-eclampsia in a previous pregnancy. Neither guideline has a reasonable performance and cannot be recommended for use in clinical practice. Resources should rather be focussed on development of new strategies to identify women at risk of pre-eclampsia.

A case series of interventional radiology in postpartum haemorrhage.

Postpartum haemorrhage (PPH) remains a significant cause of maternal morbidity and mortality in both developed and developing countries. In some instances, PPH can be anticipated and recent improvements in obstetric imaging techniques allow earlier and more reliable diagnosis of abnormalities associated with haemorrhage such as morbid placentation. However, the majority of PPH is unpredicted. Good practice notes published by the Royal College of Obstetricians and Gynaecologists state interventional radiology should be used as emergency intervention in PPH and should be considered when primary management has failed allowing arteries to be embolised to achieve haemostasis. Through collaboration between interventional radiology and maternity, appropriate guidelines need to be developed, on both emergency and elective of interventional radiology in the prevention and management of PPH. As there is mapping for neonatal services, in the future there should be consideration to develop obstetric trauma units. Maternity units which lack facilities for interventional radiology would be able to refer their cases (like placenta accreta) for safe management in units with 24 h interventional radiology services.

Role of interventional radiology in the management of morbidly adherent placenta.

The incidence of morbidly adherent placenta is rising and is directly proportional to the rate of rise of caesarean deliveries. Despite improvement in antenatal diagnosis, by accuracy of ultrasound and MRI techniques, placenta accreta is still associated with a high maternal morbidity rate. Management of pregnancies with a morbidly adherent placenta is extremely challenging and is becoming an increasingly common problem for maternity units globally. The main challenges include controlling the haemorrhage and dissection of the invaded tissues. Traditionally, these cases were managed by caesarean hysterectomy. There has now been a shift towards conservative management of placenta accreta, involving uterine and placental conservation, with the aid of interventional radiology by means of insertion of occluding balloons into appropriate vessels. We describe three cases of morbidly adherent placentas, managed at our unit where meticulous preoperative planning, multidisciplinary approach and the key role of interventional radiology led to a safe outcome for both the mother and the baby.

PathGrid: a service-orientated architecture for microscopy image analysis.

This paper describes 'PathGrid'--an analysis and data integration system, developed initially to meet the demands in the analysis of medical microscopy imaging data. An overview of the current system is given, describing the techniques used in developing the data handling infrastructure and the analysis algorithm development. The use of software created in the context of systems designed for the astronomy domain is noted, specifically infrastructure from the astronomy virtual observatory movement for data discovery, access and workflow management, and astronomical image analysis software adapted for the analysis of high-throughput astronomy imaging surveys. This paper notes the applicability of the techniques from the astronomy domain. The testbed infrastructure deployment is described, emphasizing its speed and ease of use and support. The validity of the analysis techniques is confirmed through the pilot study described here--with the application to a large sample of immunohistochemistry microscopy data obtained in part for assessing the oestrogen receptor status of breast cancers. The analysis showed that the specificity and sensitivity values for the automatic scoring using PathGrid were within the errors of those obtained via a 'gold standard' manual pathologist scoring.

Treatment and secondary prevention of venous thromboembolism in cancer.

Patients with cancer who develop venous thromboembolism (VTE) are at elevated risk for recurrent thrombotic events, even during anticoagulant therapy. The clinical picture is further complicated because these patients are also at increased risk of bleeding while on anticoagulants. In general, there are four key goals of treatment for VTE: preventing fatal pulmonary embolism (PE); reducing short-term morbidities associated with acute leg or lung thrombus; preventing recurrent VTE; and preventing the long-term sequelae of VTE (e.g., post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension). A fifth goal - minimising the risk for bleeding while on anticoagulation - is particularly warranted in patients with cancer. Traditionally, pharmacological treatment of VTE has two phases, with the transition between phases marked by a switch from a rapid-acting, parenterally administered anticoagulant (such as unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or fondaparinux) to an oral vitamin K antagonist (e.g., warfarin). Recent clinical trials of established agents and the advent of new pharmacological options are changing this paradigm. Low-molecular-weight heparin continued for 6 months is more effective than warfarin in the secondary prevention of VTE in cancer patients without increasing the risk of bleeding and is now the preferred treatment option. Given the impact of VTE on short-term and long-term outcomes in patients with cancer, a group of health-care providers based in the United Kingdom gathered in London in 2009 to discuss recent data on cancer-associated thrombosis and to evaluate how these recommendations can be integrated or translated into UK clinical practice. This article, which is the third of four articles covering key topics in cancer thrombosis, focuses on treatment and secondary prevention of VTE in cancer patients.

Circulating markers of arterial thrombosis and late-stage age-related macular degeneration: a case-control study.

PURPOSE: The aim of this study was to examine the relation of late-stage age-related macular degeneration (AMD) with markers of systemic atherothrombosis. METHODS: A hospital-based case-control study of AMD was undertaken in London, UK. Cases of AMD (n=81) and controls (n=77) were group matched for age and sex. Standard protocols were used for colour fundus photography and to classify AMD; physical examination included height, weight, history of or treatment for vascular-related diseases and smoking status. Blood samples were taken for measurement of fibrinogen, factor VIIc (FVIIc), factor VIIIc, prothrombin fragment F1.2 (F1.2), tissue plasminogen activator, and von Willebrand factor. Odds ratios from logistic regression analyses of each atherothrombotic marker with AMD were adjusted for age, sex, and established cardiovascular disease risk factors, including smoking, blood pressure, body mass index, and total cholesterol. RESULTS: After adjustment FVIIc and possibly F1.2 were inversely associated with the risk of AMD; per 1 standard deviation increase in these markers the odds ratio were, respectively, 0.62 (95% confidence interval 0.40, 0.95) and 0.71 (0.46, 1.09). None of the other atherothrombotic risk factors appeared to be related to AMD status. There was weak evidence that aspirin is associated with a lower risk of AMD. CONCLUSIONS: This study does not provide strong evidence of associations between AMD and systematic markers of arterial thrombosis, but the potential effects of FVIIc, and F1.2 are worthy of further investigation.

Platelet activation and endogenous thrombin potential in pre-eclampsia.

INTRODUCTION: Platelets and the coagulation system may be involved in the pathogenesis of pre-eclampsia. We investigated whether platelet and coagulation activation markers, are elevated in pre-eclampsia. MATERIALS/METHODS: Case-control study in which activated platelets, platelet-monocyte/ neutrophil aggregates, platelet microparticles (measured by flow cytometry) and four markers of thrombin generation capacity (endogenous thrombin potential (ETP), peak height, lag time and time to peak) using the Calibrated Automated Thrombogram system were assessed in pregnant women of similar gestational age with (n=46) and without (n=46) pre-eclampsia, and in healthy non-pregnant women (n=42). RESULTS: The percentage of, CD62P+ platelets (p=0.013), CD62P+ platelet microparticles (p=0.029) and platelet-monocyte aggregates (p=0.019) were significantly higher in women with pre-eclampsia than the pregnant controls. Both groups of pregnant women had significantly higher ETP and peak height (p <0.001) than the healthy non pregnant group and the women with pre-eclampsia had significantly higher ETP and peak height (p<0.001) than the normotensive pregnant controls. CONCLUSION: In the most comprehensive laboratory analysis to date, we found evidence of both platelet and coagulation activation in women with pre-eclampsia.

An international multicenter randomized study of computer-assisted oral anticoagulant dosage vs. medical staff dosage.

BACKGROUND: Increased demand for oral anticoagulants is overwhelming facilities worldwide, resulting in increasing use of computer assistance. A multicenter clinical endpoint study has been performed to compare the safety and effectiveness of computer-assisted dosage with dosage by experienced medical staff at the same centers. METHODS: A randomized study of dosage of two commercial computer-assisted dosage programs (PARMA 5 and DAWN AC) vs. manual dosage at 32 centers with an established interest in oral anticoagulation in 13 countries. The aim was to recruit a minimum of 16,000 patient-years randomized to medical staff or computer-assisted dosage. In total, 13,219 patients participated, 6503 patients being randomized to medical staff and 6716 to computer-assisted dosage. The safety and effectiveness of computer-assisted dosage were compared with those of medical staff dosage. RESULTS: In total, 13,052 patients were recruited (18,617 patient-years). International Normalized Ratio (INR) tests numbered 193 890 with manual dosage and 193,424 with computer-assisted dosage. The number of clinical events with computer-assisted dosage was lower (P = 0.1), but in the 3209 patients with deep vein thrombosis/pulmonary embolism, they were reduced by 37 (24%, P = 0.001). Time in target INR range was significantly improved by computer assistance as compared with medical staff dosage at the majority of centers (P < 0.001). CONCLUSIONS: The safety and effectiveness of computer-assisted dosage has been demonstrated using two different marketed programs in comparison with experienced medical staff dosage at the centers with established interest in anticoagulation. Significant prevention of clinical events in patients with deep vein thrombosis/pulmonary embolism and the achievement of target INR in all clinical groups has been observed. The reliability and safety of other marketed computer-assisted dosage programs need to be established.

Impairment of coagulation by commonly used resuscitation fluids in human volunteers.

BACKGROUND: This study compared the effects of two commonly used resuscitation fluids on whole blood coagulation. METHODS: 1000 ml of two resuscitation fluids each (saline and Gelofusine) were given to eight volunteers in a crossover design with a 2-week washout period. The effect on whole blood coagulation was assessed using the Sonoclot analyzer, a conventional coagulation screen and coagulation markers. RESULTS: No significant effect was found on whole blood coagulation by giving saline (time to peak clot increased by a mean of 106 s; (95% confidence interval (CI) -140 to 354), whereas Gelofusine delayed the time to peak by a mean of 845 s (95% CI 435 to 1255). By contrast, there was no change in the conventional coagulation screen with either fluid. CONCLUSION: It was concluded that some resuscitation fluids have an effect on clot formation that is not shown by the conventional coagulation screen, but is disclosed only if the whole coagulation process is studied.

Cumulative risk assessment in unstable angina: clinical, electrocardiographic, autonomic, and biochemical markers.

OBJECTIVES: To determine the incremental value of clinical data, troponin T, ST segment monitoring, and heart rate variability for predicting outcome in patients with non-ST elevation acute coronary syndromes. METHODS: Prospective cohort study of 304 consecutive patients. Baseline clinical and electrocardiographic data were recorded, serial blood samples were obtained for troponin T assay, and 48 hour Holter monitoring was performed for ST segment and heart rate variability analysis. End points were cardiac death and non-fatal myocardial infarction during 12 months' follow up. RESULTS: After 12 months, 7 patients had died and 21 had had non-fatal myocardial infarction. The risk of an event was increased by troponin T > 0.1 microg/l, T wave inversion on the presenting ECG, Holter ST shift, and a decrease in the standard deviation of 5 minute mean RR intervals. Positive predictive values of individual multivariate risk were low; however, analysis of all multivariate risk markers permitted calculation of a cumulative risk score, which increased the positive predictive value to 46.9% while retaining a negative predictive value of 96.9%. CONCLUSION: A cumulative approach to risk stratification in non-ST elevation coronary syndromes successfully identifies a group in whom the risk of cardiac death or non-fatal myocardial infarction approaches 50%.

Genetic determinants of the response to bezafibrate treatment in the lower extremity arterial disease event reduction (LEADER) trial.

Genetic determinants of baseline levels and the fall in plasma triglyceride and fibrinogen levels in response to bezafibrate treatment were examined in 853 men taking part in the lower extremity arterial disease event reduction (LEADER) trial. Three polymorphisms in the peroxisome proliferator activated receptor alpha (PPARalpha) gene were investigated (L162V, G>A in intron 2 and G>C in intron 7), two in the apolipoprotein CIII (APOC3) gene (-482C>T and -455T>C) and one in the beta-fibrinogen (FIBB) gene (-455G>A). The presence of diabetes (n=158) was associated with 15% higher triglyceride levels at baseline compared to non-diabetics (n=654) (P<0.05). Among the diabetic group, carriers of the PPARalpha intron 7 C allele had 20% lower triglyceride levels compared to homozygotes for the common G allele (P<0.05), with a similar (non-significant) trend for the L162V polymorphism, which is in linkage disequilibrium with the intron 7 polymorphism. For the APOC3 gene, carriers of the -482T allele had 13% lower baseline triglyceride levels compared to -482C homozygotes (P<0.02), but no effect was observed with the -455T>C substitution. In the non-diabetic patients, the PPARalpha V162 allele was significantly associated with 9% higher baseline triglyceride levels (P<0.03) and a similar, but non-significant trend was seen for the intron 7 polymorphism. Overall, triglyceride levels fell by 26% with 3 months of bezafibrate treatment, and current smokers showed a poorer response compared to ex/non-smokers (23% fall compared to 28% P=0.03), but none of the genotypes examined had a significant influence on the magnitude of response. Carriers of the -455A polymorphism of the FIBB gene had, as expected, marginally higher baseline fibrinogen levels, 3.43 versus 3.36 g/l (P=0.055), but this polymorphism did not affect response to treatment. Overall, fibrinogen levels fell by 12%, with patients with the highest baseline fibrinogen levels showing the greatest decrease in response to bezafibrate. For both the intron 2 and the L162V polymorphisms of the PPARalpha gene there was a significant interaction (both P<0.01) between genotype and baseline levels of fibrinogen on the response of fibrinogen levels to bezafibrate, such that individuals carrying the rare alleles in the lowest tertile showed essentially no overall decrease compared to a 0.18 g/l fall in homozygotes for the common allele. Thus while these genotypes are a minor determinant of baseline triglyceride and fibrinogen levels, there is little evidence from this study that the magnitude of response to bezafibrate treatment in men with peripheral vascular disease is determined by variation at these loci.

Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease.

The effects of respiratory viral infection on the time course of chronic obstructive pulmonary disease (COPD) exacerbation were examined by monitoring changes in systemic inflammatory markers in stable COPD and at exacerbation. Eighty-three patients with COPD (mean [SD] age, 66.6 [7.1] yr, FEV(1), 1.06 [0.61] L) recorded daily peak expiratory flow rate and any increases in respiratory symptoms. Nasal samples and blood were taken for respiratory virus detection by culture, polymerase chain reaction, and serology, and plasma fibrinogen and serum interleukin-6 (IL-6) were determined at stable baseline and exacerbation. Sixty-four percent of exacerbations were associated with a cold occurring up to 18 d before exacerbation. Seventy-seven viruses (39 [58.2%] rhinoviruses) were detected in 66 (39.2%) of 168 COPD exacerbations in 53 (64%) patients. Viral exacerbations were associated with frequent exacerbators, colds with increased dyspnea, a higher total symptom count at presentation, a longer median symptom recovery period of 13 d, and a tendency toward higher plasma fibrinogen and serum IL-6 levels. Non-respiratory syncytial virus (RSV) respiratory viruses were detected in 11 (16%), and RSV in 16 (23.5%), of 68 stable COPD patients, with RSV detection associated with higher inflammatory marker levels. Respiratory virus infections are associated with more severe and frequent exacerbations, and may cause chronic infection in COPD. Prevention and early treatment of viral infections may lead to a decreased exacerbation frequency and morbidity associated with COPD.

Reversible posterior leukoencephalopathy syndrome following CHOP chemotherapy for diffuse large B-cell lymphoma.

A 63-year-old female with stage IE diffuse large B-cell lymphoma developed reversible posterior leukoencephalopathy syndrome (RPLS) following CHOP chemotherapy, with typical clinical and radiological findings. RPLS is a rare neurological syndrome characterised by visual disturbances, seizures, headaches and altered conscious level which has been associated with malignant hypertension, pre-eclampsia and some drugs, including ciclosporin. It has not been previously reported following CHOP chemotherapy. Alternative treatment should be considered for patients who develop this rare complication.