Prognostic value of platelet-derived growth factor in patients with severe sepsis.

Primary Objective: Platelet-derived growth factor-BB (PDGF-BB) has been shown to promote the structural integrity of the vessel wall and to increase wound healing capacity. Aim of the present study was to determine the role of PDGF-BB in the context of outcome of septic patients. Furthermore, the effect of treatment with recombinant human activated protein C (rhAPC) on plasma levels of PDGF-BB in severe sepsis was evaluated as well as the in vitro effect of rhAPC on PDGF-BB-release from human endothelial cells (HUVEC).

Epidemiology of sepsis in Germany: results from a national prospective multicenter study.

Objective: To determine the prevalence and mortality of ICU patients with severe sepsis in Germany, with consideration of hospital size.

Design: Prospective, observational, cross-sectional 1-day point-prevalence study.

Setting: 454 ICUs from a representative nationwide sample of 310 hospitals stratified by size.

Matrix-metalloproteinases and their inhibitors are elevated in severe sepsis: prognostic value of TIMP-1 in severe sepsis.

The enzyme group of matrix metalloproteinases (MMPs) and their inhibitors, so-called tissue inhibitors of matrix-metalloproteinases (TIMPs), are crucial mediators responsible for wound repair after parenchymal damage. Little is known about the role of MMPs and TIMPs in severe sepsis. The aim of the present study was therefore to investigate their levels in patients with severe sepsis and to examine their association with prognosis.

Recombinant human activated protein C upregulates the release of soluble fractalkine from human endothelial cells.

Fractalkine is a unique endothelial cell-derived chemokine that functions both as a chemoattractant and as an adhesion molecule. Recent findings suggest that fractalkine plays an important role in inflammatory diseases by modulating leucocyte endothelial cell interactions. A modulating effect on the immune system in severe sepsis has been suggested for recombinant human activated protein C (rhAPC).

[Mechanisms of action of recombinant human activated Protein C].

Human activated protein C (APC) is a serineprotease and one of the most important physiological inhibitors of the coagulation system. Apart from anticoagulative effects, profibrinolytic and anti-inflammatory modes of action have been reported for APC. The administration of recombinant human activated protein C (rhAPC), drotrecogin alfa (activated), Xigris, to patients with severe sepsis and sepsis-induced multi-organ failure reduced mortality in large clinical trials.

Increased plasma levels of NT-proANP and NT-proBNP as markers of cardiac dysfunction in septic patients.

The family of natriuretic peptides comprises several structurally related 22-53-amino acid peptides, such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which are vasoactive peptides with vasodilator and diuretic properties and play an important role in cardiovascular homeostasis. The salutary cardiovascular effects of natriuretic peptides suggest that ANP and BNP may have a pathophysiological significance in the cardiac dysfunction of septic patients. We determined plasma levels of the stable N-terminal prohormone forms of ANP (NT-proANP) and BNP (NT-proBNP) as well as troponin I (TNI) as a marker of myocardial cell injury by ELISA methods in 19 septic patients and 19 healthy controls at day one of severe sepsis.

Prognostic value of plasma N-terminal pro-brain natriuretic peptide in patients with severe sepsis.

Background: Increased plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have been identified as predictors of cardiac dysfunction and prognosis in congestive heart failure and ischemic heart disease. In severe sepsis patients, however, no information is available yet about the prognostic value of natriuretic peptides. Therefore, the aim of the present study was to determine the role of the N-terminal prohormone forms of ANP (NT-proANP) and BNP (NT-proBNP) in the context of outcome of septic patients.

Recombinant human activated protein C upregulates cyclooxygenase-2 expression in endothelial cells via binding to endothelial cell protein C receptor and activation of protease-activated receptor-1.

Prostacyclin (PGI(2)) has beneficial cytoprotective properties, is a potent inhibitor of platelet aggregation and has been reported to improve microcirculatory blood flow during sepsis. The formation of PGI(2) in response to proinflammatory cytokines is catalysed by the inducible cyclooxygenase (COX) isoform COX-2. Recombinant human activated protein C (rhAPC, drotrecogin alfa (activated)) was shown to have multiple biological activities in vitro and to promote resolution of organ dysfunction in septic patients.

Time course of systemic markers of inflammation in patients presenting with acute coronary syndromes.

Inflammation within coronary plaques may cause an acute coronary syndrome by promoting rupture and erosion. It was the aim of this study to examine whether markers of inflammation derive from a cardiac or extracardiac source and how their levels develop over time. Blood samples were taken from patients with acute coronary syndromes (ACS) with proven atherosclerotic lesion(s) of the left coronary artery (n=13) and from control patients without coronary artery disease (n=13).

N-terminal pro-atrial natriuretic peptide as a biochemical marker of long-term interventional success after radiofrequency catheter ablation of paroxysmal supraventricular tachyarrhythmias.

Radiofrequency (RF) catheter ablation has been shown to be highly effective in the treatment of supraventricular tachycardias. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (B-type natriuretic peptide; BNP) are secreted by the heart mainly in response to myocardial stretch induced by volume load. The aim of the present study was to determine the time course of the N-terminal prohormone forms of ANP (NT-proANP) and BNP (NT-proBNP) in patients undergoing radiofrequency (RF) catheter ablation for paroxysmal supraventricular tachycardias.

Markers of myocardial damage, tissue healing, and inflammation after radiofrequency catheter ablation of atrial tachyarrhythmias.

Introduction: Radiofrequency ablation produces a localized endomyocardial necrosis that may result in release of biochemical markers reflecting myocardial cell damage, inflammation, and tissue reparation. The aim of this study was to determine the extent of rise and time course of markers of inflammation and tissue reparation in patients undergoing radiofrequency catheter ablation.

Methods And Results: Serial blood samples were taken from patients with AV nodal reentrant tachycardia (n = 5), Wolff-Parkinson-White syndrome (n = 3), and atrial flutter (n = 5) undergoing radiofrequency ablation.

Activated protein C inhibits the release of macrophage inflammatory protein-1-alpha from THP-1 cells and from human monocytes.

Several lines of evidence have implicated activated protein C (APC) to be an endogenous inhibitor of the inflammatory septic cascade. APC may exhibit direct anti-inflammatory properties, independent of its antithrombotic effects. Chemokines influence the interaction of monocytes at the endothelium during infection and sepsis and are involved in the molecular events leading to an adverse and lethal outcome of sepsis.

Anti-hirudin antibodies alter pharmacokinetics and pharmacodynamics of recombinant hirudin.

Recombinant hirudin (r-hirudin) is a potent direct thrombin inhibitor with immunogenic properties. Anti-hirudin antibodies (aHAb) are detected in up to 74% of patients treated with r-hirudin for more than 5 days. aHAb may alter the pharmacokinetics and pharmacodynamics of r-hirudin.

Stabilization of monocyte chemoattractant protein-1-mRNA by activated protein C.

The activated protein C (APC) pathway has been suggested to be a common link between coagulation and inflammation. APC may function to restore hemostasis via modulation of cytokine expression. We investigated the effect of APC on the endothelial expression of monocyte chemoattractant protein-1 (MCP-1), a chemokine that is controlled by the activation of central proinflammatory transcription factors, such as nuclear factor-kappa B (NF-kappaB).

Biological relevance of anti-recombinant hirudin antibodies--results from in vitro and in vivo studies.

This article provides an overview of the clinically relevant characteristics of antibodies directed toward recombinant (r) hirudin, with emphasis on the different ways in which these antibodies may influence pharmacokinetics and pharmacodynamics of r-hirudin. A high incidence of anti-hirudin antibody (AHAb) formation, mainly of the immunoglobulin G (IgG) subclass, was reported in up to 74% of patients treated with r-hirudin for more than 5 days. Like other drug-induced antibodies, AHAb may be responsible for accumulation or neutralization of the drug.

Bioequivalence of subcutaneous and intravenous body-weight-independent high-dose low-molecular-weight heparin Certoparin on anti-Xa, Heptest, and tissue factor pathway inhibitor activity in volunteers.

The objective of the study was to demonstrate the bioequivalence of subcutaneously (s.c.) and intravenously (i.

Cutaneous reactions to anticoagulants. Recognition and management.

Anticoagulant-induced skin reactions appear as allergic or necrotic responses to vitamin K antagonists or heparins. Cutaneous allergy has been reported with danaparoid sodium and flush reactions have been seen with hirudins. The pathogenesis of the reactions differs between drugs.

Effects of a heparin-binding protein on blood coagulation and platelet function.

The objective of this study was to characterize the heparin-binding properties of a protein secreted by mouse myeloma cells. The characterization was performed using clinical assays, such as heparin activity assays and heparin-induced thrombocytopenia (HIT) platelet activation assays. The tests were performed in the presence of heparin, low-molecular-weight heparins (LMWH), or heparinoids and either heparin-binding protein (HBP) or saline to determine whether the HBP affects the activity of heparins.

Laboratory diagnosis of heparin-induced thrombocytopenia type II after clearance of platelet factor 4/heparin complex.

Laboratory confirmation of heparin-induced thrombocytopenia (HIT) is limited by assay sensitivity. We investigated whether laboratory confirmation can be improved after antigen clearance by determining free antibody and combining the results of antigenic and biologic assays. Blood samples were collected over 5 to 6 weeks in 14 HIT patients.

Improved laboratory confirmation of heparin-induced thrombocytopenia type II. Time course of antibodies and combination of antigen and biologic assays.

We studied whether laboratory confirmation of heparin-induced thrombocytopenia (HIT) can be improved after antigen clearance by determining free antibody and combining the results of an antigenic and a biologic assay. Blood samples taken over 40 days in 14 patients with HIT with thromboembolism underwent fluorescence-linked immunofiltration and the carbon 14-serotonin release assays. Of the 14 patients, 11 showed positive results in both assays at day 1 after stopping heparin.

A new therapeutic option by subcutaneous recombinant hirudin in patients with heparin-induced thrombocytopenia type II: a pilot study.

We prospectively studied 15 patients suffering from acute heparin-induced thrombocytopenia (HIT) type II with and without thromboembolic events and 4 patients with anamnestically known HIT type II recurrently requiring thromboprophylaxis in order to develop new therapeutic strategies by subcutaneous recombinant hirudin administration. Patients with acute venous or arterial thromboembolism were treated with aPTT-controlled intravenous (mean: 19.3 days) followed by subcutaneous r-hirudin (mean: 22.

Quantitative determination of PEG-hirudin in human plasma using a competitive enzyme-linked immunosorbent assay.

Polyethylene glycol (PEG) coupled r-hirudin mutein is determined by biological methods-the coagulation system. In the present study, a competitive enzyme-linked immunosorbent assay (ELISA) is described that permits the measurement of PEG r-hirudin. The ELISA system adopts a rabbit IgG antibody to quantitatively detect PEG-hirudin in human plasma.

[Prevention of thrombosis with subcutaneous recombinant hirudin in heparin-induced thrombocytopenia type II. A pilot study].

Background: Heparin-induced thrombocytopenia (HIT) type II is a severe complication of heparin therapy with a high incidence of thromboembolic events.

Aim: The aim of this prospective study was to evaluate efficacy and safety of prophylaxis of thromboembolism with subcutaneous r-hirudin (25 mg twice daily) in patients with HIT type II.

Patients And Methods: From 01/06/1997 until 01/08/1999, 19 patients were prospectively included into the study.