Emily K. Rimmer

The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis.

Objective:To evaluate the efficacy and safety of heparin in patients with sepsis, septic shock, or disseminated intravascular coagulation associated with infection. Design:Systematic review and metaanalysis. Data Sources:Randomized controlled trials from MEDLINE, EMBASE, CENTRAL, Global Health, Scopus, Web of Science, the International Clinical Trials Registry Platform (inception to April 2014), conference proceedings, and reference lists of relevant articles. Study Selection and Data Extraction:Two reviewers independently identified and extracted trial-level data from randomized trials investigating unfractionated or low molecular heparin administered to patients with sepsis, severe sepsis, septic shock, or disseminated intravascular coagulation associated with infection. Internal validity was assessed in duplicate using the Risk of Bias tool. The strength of evidence was assessed in duplicate using Grading of Recommendations Assessment, Development, and Evaluation methodology. Our primary outcome was mortality. Safety outcomes included hemorrhage, transfusion, and thrombocytopenia. Measurements and Main Results:We included nine trials enrolling 2,637 patients. Eight trials were of unclear risk of bias and one was classified as having low risk of bias. In trials comparing heparin to placebo or usual care, the risk ratio for death associated with heparin was 0.88 (95% CI, 0.77–1.00; I2 = 0%; 2,477 patients; six trials; moderate strength of evidence). In trials comparing heparin to other anticoagulants, the risk ratio for death was 1.30 (95% CI, 0.78–2.18; I2 = 0%; 160 patients; three trials; low strength of evidence). In trials comparing heparin to placebo or usual care, major hemorrhage was not statistically significantly increased (risk ratio, 0.79; 95% CI, 0.53–1.17; I2 = 0%; 2,392 patients; three trials). In one small trial of heparin compared with other anticoagulants, the risk of major hemorrhage was significantly increased (2.14; 95% CI, 1.07–4.30; 48 patients). Important secondary and safety outcomes, including minor bleeding, were sparsely reported. Conclusions:Heparin in patients with sepsis, septic shock, and disseminated intravascular coagulation associated with infection may be associated with decreased mortality; however, the overall impact remains uncertain. Safety outcomes have been underreported and require further study. Increased major bleeding with heparin administration cannot be excluded. Large rigorous randomized trials are needed to evaluate more carefully the efficacy and safety of heparin in patients with sepsis, severe sepsis, and septic shock.

Activated protein C and septic shock: a propensity-matched cohort study*.

Background:Septic shock is a highly inflammatory and procoagulant state associated with significant mortality. In a single randomized controlled trial, recombinant human activated protein C (drotrecogin alfa) reduced mortality in patients with severe sepsis at high risk of death. Further clinical trials, including a recently completed trial in patients with septic shock, failed to reproduce these results. Objective:To evaluate the effectiveness of recombinant human activated protein C on mortality in a cohort of patients with septic shock and to explore possible reasons for inconsistent results in previous studies. Design:Retrospective, 2:1 propensity-matched, multicenter cohort study. Setting:Twenty-nine academic and community intensive care units in three countries. Patients:Seven thousand three hundred ninety-two adult patients diagnosed with septic shock, of which 349 received recombinant human activated protein C within 48 hrs of intensive care unit admission between 1997 and 2007. Measurements and Main Results:Our primary outcomes were mortality over 30 days and mortality stratified by Acute Physiology and Chronic Health Evaluation II quartile. Using a propensity-matched Cox proportional hazard model, we observed a 6.1% absolute reduction in 30-day mortality associated with the use of recombinant human activated protein C (108/311 [34.7%] vs. 254/622 [40.8%], hazard ratio 0.72, 95% confidence interval 0.52–1.00, p = .05) and noted consistent reductions in mortality among Acute Physiology and Chronic Health Evaluation II quartiles. A time to event analysis showed that the time to appropriate antimicrobials after documented hypotension decreased for each year of study (p = .003), a finding that was congruent with a decrease in annual mortality over the study period (odds ratio 0.96 per year [95% confidence interval 0.93–0.99], p = .003). Conclusions:In this retrospective, propensity-matched, multicenter cohort study of patients with septic shock, early use of recombinant human activated protein C was associated with reduced mortality. Improvements in general quality of care such as speed of antimicrobial delivery leading to decreasing mortality of patients with septic shock may have contributed to the null results of the recently completed trial of recombinant human activated protein C in patients with septic shock.

Coronary artery bypass surgery in a patient with Haemophilia A: a case report

laboratory because of improved precision, specificity and speed of assay [3]. However, it is important that laboratories recognize the limitations of their assay of choice including the interference from a number of substance including icterus, lipaemia and certain antibodies. The Siemens and Werfen VWF:Ag both use polyclonal rabbit anti-human VWF antibodies. The BC VWF:RCo, Werfen VWF:RCo and manual assay do not contain any antibodies whereas mouse monoclonal antibodies are present in the Innovance VWF Ac and Werfen VWF Act reagents. The chemiluminescent VWF:RCo does contains mouse monoclonal antibodies but includes a blocking agent for HAMA up to 1 lg mL . The Werfen VWF Act assay also contains a blocking agent against HAMA, but it is likely that the level in our patient swamps this agent. Acquired Von Willebrand Syndrome with a bleeding diathesis is a rare disorder [8], however, AVWS in the absence of bleeding appears to be more prevalent, particularly in patients secondary to lymphoor myelo-proliferative or cardiovascular diseases [9]. At present it is unknown how many humans develop anti-animal antibodies that interfere with assays employed in coagulation laboratories. The results presented in this report clearly demonstrate that some automated VWF activity assays may misdiagnose patients with AVWS and VWD. When using these VWF activity assays, which do not include ristocetin and platelets, in the initial diagnosis of acquired haemophilia and VWS, it is imperative that a VWF antigen should be tested at the same time. Where a discrepancy between a low VWF:Ag and higher VWF activity is found then an alternative, ristocetin-based assay, should be performed to exclude an erroneously high result and monitor subsequent replacement therapy.

Efficacy of iron supplementation on fatigue and physical capacity in non-anaemic iron-deficient adults: a systematic review of randomised controlled trials

Objective Iron supplementation in iron-deficiency anaemia is standard practice, but the benefits of iron supplementation in iron-deficient non-anaemic (IDNA) individuals remains controversial. Our objective is to identify the effects of iron therapy on fatigue and physical capacity in IDNA adults. Design Systematic review and meta-analysis of randomised controlled trials (RCTs). Setting Primary care. Participants Adults (≥18 years) who were iron deficient but non-anaemic. Interventions Oral, intramuscular or intravenous iron supplementation; all therapy doses, frequencies and durations were included. Comparators Placebo or active therapy. Results We identified RCTs in Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health, SportDiscus and CAB Abstracts from inception to 31 October 2016. We searched the WHO’s International Clinical Trials Registry Platform for relevant ongoing trials and performed forward searches of included trials and relevant reviews in Web of Science. We assessed internal validity of included trials using the Cochrane Risk of Bias tool and the external validity using the Grading of Recommendations Assessment, Development and Evaluation methodology. From 11 580 citations, we included 18 unique trials and 2 companion papers enrolling 1170 patients. Using a Mantel-Haenszel random-effects model, iron supplementation was associated with reduced self-reported fatigue (standardised mean difference (SMD) −0.38; 95% CI −0.52 to −0.23; I2 0%; 4 trials; 714 participants) but was not associated with differences in objective measures of physical capacity, including maximal oxygen consumption (SMD 0.11; 95% CI −0.15 to 0.37; I2 0%; 9 trials; 235 participants) and timed methods of exercise testing. Iron supplementation significantly increased serum haemoglobin concentration (MD 4.01 g/L; 95% CI 1.22 to 6.81; I2 48%; 12 trials; 298 participants) and serum ferritin (MD 9.23 µmol/L; 95% CI 6.48 to 11.97; I2 58%; 14 trials; 616 participants). Conclusion In IDNA adults, iron supplementation is associated with reduced subjective measures of fatigue but not with objective improvements in physical capacity. Given the global prevalence of both iron deficiency and fatigue, patients and practitioners could consider consumption of iron-rich foods or iron supplementation to improve symptoms of fatigue in the absence of documented anaemia. PROSPERO registration number CRD42014007085.

Bleeding by the numbers: The utility and the limitations of bleeding scores, bleeding prediction tools, and bleeding case definitions

A patients history of bleeding, whether spontaneous or in response to challenges, provides important information about both the likelihood of that patient having a biochemically-defined hemostatic defect, and that patients risk of future bleeding. Other variables including age, comorbidities and medications influence these probabilities. Scoring systems have been devised in an effort to make the estimates quantitative in specific populations. An example of a bleeding score is the MCMDM1-VWD questionnaire, which was developed to predict the likelihood of a patient having von Willebrand disease. It sums standardized details of the bleeding history, weighted by severity. The HAS-BLED score typifies bleeding prediction tools, developed to predict bleeding during anticoagulant therapy. Although prior bleeding is one item in this score, other comorbidities like hypertension or a history of stroke count for more. A third and related concept is that of bleeding case definitions, which are critical to standardize the reporting of outcomes in trials of antithrombotic agents, and which have entrenched the recognition of different severities of bleeding. We advocate that future efforts should blend some of these features. Information about comorbidities and medication use could refine the interpretation of bleeding events in a bleeding score. So could the introduction of a denominator reflecting the number and duration of challenges to which the patient has been exposed when bleeding might have been expected. More detailed information about the type, frequency and severity of prior bleeding could improve the prognostic power of bleeding prediction tools. More detailed history-based scores might ultimately supersede biochemical testing in many cases.

Discordant von Willebrand factor (VWF) activity in patients with VWF p.Gly1324Ser confirmed in vitro

8. Calvez T, Chambost H, d’Oiron R, et al. Analyses of the FranceCoag cohort support immunogenicity differences among one plasmaderived and two recombinant factor VIII brands in boys with severe hemophilia A. Haematologica. 2018;103:179-189. 9. Peyvandi F, Mannucci PM, Garagiola I, et al. A Randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med. 2016;374:2054-2064. 10. Peyvandi F, Mannucci PM, Palla R, Rosendaal FR. SIPPET: methodology, analysis and generalizability. Haemophilia. 2017;23:353-361. 11. van den Berg HM, Pipe S, Ljung R. Plasma products do not solve the inhibitor problem. Haemophilia. 2017;23:346-347. 12. Fischer K, Blatny J. Do the SIPPET study results apply to the patients I treat? Haemophilia. 2017;23:348-349. 13. Iorio A. Research and policy implications of a recently published controlled study in previously untreated haemophilia patients at high risk of inhibitor development. Haemophilia. 2017;23:350-352.