The Anticoagulant and Nonanticoagulant Properties of Heparin

Heparins represent one of the most frequently used pharmacotherapeutics. Discovered around 1926, routine clinical anticoagulant use of heparin was initiated only after the publication of several seminal papers in the early 1970s by the group of Kakkar. It was shown that heparin prevents venous thromboembolism and mortality from pulmonary embolism in patients after surgery. With the subsequent development of low-molecular-weight heparins and synthetic heparin derivatives, a family of related drugs was created that continues to prove its clinical value in thromboprophylaxis and in prevention of clotting in extracorporeal devices. Fundamental and applied research has revealed a complex pharmacodynamic profile of heparins that goes beyond its anticoagulant use. Recognition of the complex multifaceted beneficial effects of heparin underscores its therapeutic potential in various clinical situations. In this review we focus on the anticoagulant and nonanticoagulant activities of heparin and, where possible, discuss the underlying molecular mechanisms that explain the diversity of heparin's biological actions.</p

Decreased endothelial glycocalyx thickness is an early predictor of mortality in sepsis

Microcirculatory alterations play an important role in the early phase of sepsis. Shedding of the endothelial glycocalyx is regarded as a central pathophysiological mechanism causing microvascular dysfunction, contributing to multiple organ failure and death in sepsis. The objective of this study was to investigate whether endothelial glycocalyx thickness at an early stage in septic patients relates to clinical outcome. We measured the perfused boundary region (PBR), which is inversely proportional to glycocalyx thickness, of sublingual microvessels (5-25 mm) using sidestream dark field imaging. The PBR in 21 patients with sepsis was measured within 24 h of admission to the intensive care unit (ICU). In addition, we determined plasma markers of microcirculatory dysfunction and studied their correlation with PBR and mortality. Endothelial glycocalyx thickness in sepsis was significantly lower for non-survivors as compared with survivors, indicated by a higher PBR of 1.97 [1.85, 2.19]mm compared with 1.76 [1.59, 1.97] mm, P = 0.03. Admission PBR was associated with hospital mortality with an area under the curve of 0.778 based on the receiver operating characteristic curve. Furthermore, PBR correlated positively with angiopoietin-2 (rho=0.532, P = 0.03), indicative of impaired barrier function. PBR did not correlate with Acute Physiology and Chronic Health Evaluation IV (APACHE IV), Sequential Organ Failure Assessment score (SOFA score), lactate, syndecan-1, angiopoietin-1 or heparin-binding protein. An increased PBR within the first 24 h after ICU admission is associated with mortality in sepsis. Further research should be aimed at the pathophysiological importance of glycocalyx shedding in the development of multi-organ failure and at therapies attempting to preserve glycocalyx integrity

Variability of Microcirculatory Measurements in Critically Ill Patients

Introduction: Monitoring the microcirculation may be helpful in guiding resuscitation in patients with circulatory shock. Sublingual side-stream dark field imaging cameras allow for noninvasive, bedside evaluation of the microcirculation, although their use in clinical practice has not yet been validated. The GlycoCheck system automatically analyzes images to determine glycocalyx thickness, red blood cell filling percentage, and vessel density. Although GlycoCheck has been used to study microcirculation in critically ill patients, little is known about the reproducibility of measurements in this population. Materials and Methods: A total of 60 critically ill patients were studied. Three consecutive microcirculation measurements were performed with the GlycoCheck system in 40 of these patients by one of two experienced observers. Twenty patients were assessed by both observers. Intra- and interobserver variability were assessed using intraclass correlation coefficients (ICCs). Results: ICCs of single measurements were poor for glycocalyx thickness and good for filling percentage and vessel density. Reproducibility could be substantially increased for all parameters when three consecutive measurements were performed and averaged. Discussion: GlycoCheck can be used to study microcirculation. However, to obtain reliable results three consecutive measurements should be performed and averaged. The variation of the measurements currently hampers the clinical application in individual patients.</p

Transmission EM images after 4 hours of cold (left) or warm ischemia (right).

In cases with warm ischemia, cytoplasmic blebs (arrows) are seen in lumina of proximal tubuli with cytoplasmic blebbing and swelling in peritubular capillaries (surrounded by square). Scale bar represents 5μm. (TIF)</p

Cytotoxicity of extracellular histones to endothelial and kidney epithelial cells.

(A) Endothelial cells (EA.hy926) and porcine kidney epithelial cells (PK-15) were incubated with 5–40 μg/mL histone H3 in serum-free DMEM for 1 hour at 37°C. (B) PK-15 cells were incubated with 10 μg/mL of individual histones H1, H2A, H2B, H3 and H4, or a mixture of these histones (Hmix) under the same conditions as in (A). Cell viability was assessed using flow cytometry with PI and annexin-A5 FITC. Data is shown as the mean + SD. *p (TIF)</p

Fatigue and job stress as predictors for sickness absence during common infections.

Contains fulltext : 47847.pdf (publisher's version ) (Closed access)The objective of this study was to investigate the effect of health and work-related factors as predictors of subsequent sickness absence when experiencing common infections (common cold, flu-like illness, and gastroenteritis). Self-administered questionnaire data were used (baseline n = 12,140). To perform the analysis, employees reporting common infections in the final questionnaire were selected. Employees reporting sickness absence due to common infections were compared with a group who stayed at work during an infection. Multivariate survival analysis revealed no significant effects of job demands, decision latitude, or job strain on absence in workers experiencing common infections. Low levels of commitment (risk [RR] 1.22; confidence interval [CI] 1.03-1.44) and low job satisfaction (RR 1.36; CI 1.13-1.164) increased the chance of being absent during a common cold. Also, having a long-standing disease (RR 1.22; CI 1.05-1.41) and fatigue (RR 1.20; CI 1.05-1.37) increased the chance of being absent during a common infection. Having an executive function decreased the chance of being absent. We conclude that absence during a common cold is partly influenced by motivational factors in work, in contrast to more severe common infections which are more health related. Insight in factors related to absenteeism are important as a start for preventive measures to reduce sickness absence