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Biomedical subjects

Marcel Levi

Publications and source records attributed to Marcel Levi.

At least 55 records · Page 3Linked to original sources
PubMed2005

Disseminated intravascular coagulation: What's new?

Disseminated intravascular coagulation (DIC) is a syndrome characterized by a systemic activation of coagulation leading to the intravascular deposition of fibrin in the (micro) vasculature and the simultaneous consumption of coagulation factors and platelets. The occurrence of microvascular thrombosis as a consequence of DIC is underscored by pathological, experimental and clinical findings, demonstrating a link between DIC and organ dysfunction. Pathogenetic pathways that play a role in the development of DIC include tissue factor-dependent activation of coagulation, defective physiological anticoagulant pathways (such as the antithrombin system and the protein C system), and impaired fibrinolysis, caused by elevated levels of plasminogen activator inhibitor type 1. Novel therapeutic strategies are based on current insights into the pathogenesis of DIC, and include anticoagulant strategies (eg, directed at tissue factor) and strategies to restore physiological anticoagulant pathways (such as activated protein C concentrate).

Animals↗
PubMed2005

New antithrombotics in the treatment of thromboembolic disease.

New insights into the in vivo function of the coagulation system have resulted in the development of new antithrombotic agents with a more specific point of impact and more reliable pharmacological properties. Inhibition of coagulation can be achieved by specific thrombin inhibitors (e.g. melagatran), agents specifically targeted at factor Xa (e.g. pentasaccharides), and by tissue factor/factor VIIa blockers (e.g. recombinant NAPc2). In some situations, these agents are more effective and safer than the antithrombotics currently used. However, the major difference may be that the newer generation of antithrombotics does not require repeated laboratory control and dose adjustment to obtain a stable level of anticoagulation; therefore, they are more suitable for application in clinical practice. In this overview, we will briefly discuss the various new compounds that have recently become available or that will be introduced into clinical medicine in the near future and their relative efficacy and safety in comparison to currently used antithrombotic agents.

Journal Article↗
PubMed2005

Elevated plantar pressures in neuropathic diabetic patients with claw/hammer toe deformity.

Elevated plantar foot pressures during gait in diabetic patients with neuropathy have been suggested to result, among other factors, from the distal displacement of sub-metatarsal head (MTH) fat-pad cushions caused by to claw/hammer toe deformity. The purpose of this study was to quantitatively assess these associations. Thirteen neuropathic diabetic subjects with claw/hammer toe deformity, and 13 age- and gender-matched neuropathic diabetic controls without deformity, were examined. Dynamic barefoot plantar pressures were measured with an EMED pressure platform. Peak pressure and force-time integral for each of 11 foot regions were calculated. Degree of toe deformity and the ratio of sub-MTH to sub-phalangeal fat-pad thickness (indicating fat-pad displacement) were measured from sagittal plane magnetic resonance images of the foot. Peak pressures at the MTHs were significantly higher in the patients with toe deformity (mean 626 (SD 260)kPa) when compared with controls (mean 363 (SD 115) kPa, P<0.005). MTH peak pressure was significantly correlated with degree of toe deformity (r=-0.74) and with fat-pad displacement (r=-0.71) (P<0.001). The ratio of force-time integral in the toes and the MTHs (toe-loading index) was significantly lower in the group with deformity. These results show that claw/hammer toe deformity is associated with a distal-to-proximal transfer of load in the forefoot and elevated plantar pressures at the MTHs in neuropathic diabetic patients. Distal displacement of the plantar fat pad is suggested to be the underlying mechanism in this association. These conditions increase the risk for plantar ulceration in these patients.

Diabetic Foot↗
PubMed2005

Struggle for implementation of new strategies in intensive care medicine: anticoagulation, insulin, and lower tidal volumes.

The management of intensive care patients have changed dramatically in the last years: from merely supportive care, it has moved to evidence-based strategies that have been demonstrated to reduce mortality of the severely ill patients. Clinical research have brought numerous positive clinical trials offering intensive care physicians specific therapies to improve outcome of intensive care patients. Among them were the trials that tested the infusion of activated protein C in patients with severe sepsis, tight glycemic control in surgical intensive care patients, and use of lung protective mechanical ventilation by using small tidal volumes in patients with acute lung injury. Although results of these trials were sufficiently strong to, at least, consider implementation of these strategies in critical care medicine, published and yet unpublished reports show that there is significant struggle with implementation of these therapies. This manuscript focuses on the potential reasons that underlie this problem.

Anticoagulants↗
PubMed2005

Two-way interactions between inflammation and coagulation.

Activation of inflammatory and coagulation pathways is important in the pathogenesis of vascular disease. There is ample evidence that extensive cross-talk between these two systems exists, whereby inflammation not only leads to activation of coagulation, but coagulation also markedly affects inflammatory activity. The main interfaces linking coagulation and inflammation are the tissue factor pathway, thrombin, the protein C system and the fibrinolytic (or plasminogen-plasmin) system. Proinflammatory cytokines and chemokines can affect all these coagulation mechanisms, and vice versa, activated coagulation proteases and physiological anticoagulants or components of the plasminogen-plasmin system can modulate inflammation by specific cell receptors. The intricate relationship between inflammation and coagulation may not only be relevant for vascular thrombotic disease but also has major consequences in the pathogenesis of microvascular failure and subsequent multiple organ failure in the setting of severe infection. This review focuses on the present understanding of the bidirectional relationship between inflammation and coagulation.

Antigens↗
PubMed2005

Platelets in sepsis.

Platelets are circulating blood cells that will normally not interact with the intact vessel wall but that may swiftly respond to vascular disruption by adhering to subendothelial structures, followed by interaction with each other, thereby forming a platelet aggregate. The activated platelet (phospholipid) membrane may form a suitable surface on which further coagulation activation may occur. These processes are part of the first line of defence of the body against bleeding but may also contribute to pathological thrombus formation in vascular disease, such as thrombus formation on top of a ruptured atherosclerotic plaque. In case of systemic inflammatory syndromes, such as the response to sepsis, disseminated intravascular platelet activation may occur, which will contribute to microvascular failure and thereby play a role in the development of organ dysfunction. In addition, in this situation platelets may be directly involved in the inflammatory response by releasing inflammatory mediators and growth factors.

Blood Coagulation↗
PubMed2005

Dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with mortality and organ failure.

OBJECTIVE: To determine whether changes in coagulation biomarkers during the first day of severe sepsis correlate with progression from single to multiple organ failure and subsequent death. DESIGN: Analysis of secondary endpoints in a prospective, randomized, placebo-controlled, multinational clinical trial (PROWESS). SETTING: The study involved 164 medical centers. PATIENTS: A total of 840 patients who met criteria for severe sepsis and were randomized to receive placebo plus supportive care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Coagulation biomarkers, prothrombin time, antithrombin activity, and D-dimer and protein C levels were measured, and Sequential Organ Failure Assessment was performed daily. Multiple logistic regression analysis identified baseline antithrombin activity <54% and changes in prothrombin time, D-dimer, and antithrombin activity during the first calendar day after the onset of the first sepsis-induced organ dysfunction (i.e., the first day of severe sepsis, day 1) as predictive of 28-day mortality (p < or = .01). A composite coagulopathy score was determined using points for predetermined levels of change from baseline to day 1. The composite coagulopathy score correlated with progression from single to multiple organ failure (p = .0007), time to resolution of organ failure (p = .0004), and 28-day mortality (p < .0001). Combining the composite coagulopathy score with the Acute Physiology and Chronic Health Evaluation (APACHE) II score improved ability to identify patients who would progress to multiple organ failure (area under receiver operating characteristic curve 0.61 APACHE II vs. 0.65 APACHE II + composite coagulopathy score) and who would die (area under receiver operating characteristic curve 0.69 APACHE II vs. 0.74 APACHE II + composite coagulopathy score). CONCLUSIONS: Continuation or worsening of coagulopathy during the first day of severe sepsis was associated with increased development of new organ failure and 28-day mortality. These results further suggest that coagulation abnormalities contribute to organ failure and death.

APACHE↗
PubMed2005

Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review.

BACKGROUND: Recombinant activated factor VII (factor VIIa) is a prohemostatic agent that can be used for patients with complicated coagulation disorders. Recombinant factor VIIa is, however, increasingly used for several other indications, including patients with a preexistent normal coagulation system but who experience serious bleeding, for example, after major surgery or trauma. DATA SOURCE: We performed a systematic review of all published and unpublished clinical studies using MEDLINE (1966-2004) and all other sources available to assess the available evidence on the efficacy and safety of recombinant factor VIIa in patients with or without coagulation disorders. STUDY SELECTION: We found 483 articles related to the pharmacologic use of recombinant factor VIIa, including 28 clinical trials, 124 case series, and 176 case reports, which were all considered for this review. DATA SYNTHESIS: Recombinant factor VIIa is an effective and relatively potent prohemostatic agent in approximately 90% of patients with hemophilia and inhibiting antibodies and other types of complex coagulation disorders. The application of recombinant factor VIIa in other patients who experience severe bleeding is promising, and although sound evidence from controlled clinical trials is only scarcely available so far, forthcoming trials are likely to provide more substantiation for this use. Recombinant factor VIIa appears to be relatively safe with a 1-2% incidence of thrombotic complications based on published trials. CONCLUSIONS: More randomized controlled clinical trials are required to assess the efficacy and safety of recombinant factor VIIa for patients without a preexistent coagulation disorder and with severe bleeding. In the meantime, off-label use of recombinant factor VIIa may be considered in patients with life-threatening bleeding.

Acute Disease↗
PubMed2005

Platelets.

Explore the source record for details and available documents.

Animals↗
PubMed2005

Activation of coagulation and inhibition of fibrinolysis in the lung after inhalation of lipopolysaccharide by healthy volunteers.

Pneumonia is frequently associated with changes in coagulation and fibrinolysis in the bronchoalveolar space. To determine the effect of lipopolysaccharide (LPS) on the hemostatic balance in the human lung, six healthy subjects inhaled nebulized LPS or saline in a randomized cross-over study and bronchoalveolar lavage fluid was obtained six hours thereafter. LPS induced soluble tissue factor and thrombin-antithrombin complexes and inhibited plasminogen activator activity in BALF. Additionally plasminogen activator inhibitor type 1 production was upregulated after LPS inhalation. LPS also elicited local activation of neutrophils (release of elastase, myeloperoxidase and bactericidal/permeability increasing protein) and secretion of interleukin (IL)-6 and IL-8. Inhalation of LPS by healthy humans reproduces major features of the procoagulant response to inflammatory and infectious lung diseases and may be used as a novel model to evaluate pathogenetic mechanisms and new interventions.

Administration, Inhalation↗
PubMed2004

Inhibition of the tissue factor/factor VIIa pathway does not influence the inflammatory or antibacterial response to abdominal sepsis induced by Escherichia coli in mice.

BACKGROUND: Anticoagulants have gained increasing attention for the treatment of sepsis. Inhibition of the tissue factor (TF)/factor (F) VIIa pathway has been shown to attenuate the activation of coagulation and to prevent death in a primate model of sepsis caused by gram-negative bacteria. METHODS: To determine the role of the TF/FVIIa complex in the host response to peritonitis, mice received an intraperitoneal injection of live Escherichia coli with or without concurrent treatment with recombinant nematode anticoagulant protein c2 (rNAPc2), a selective inhibitor of the TF/FVIIa pathway. RESULTS: Peritonitis was associated with an increase in the expression of TF at the tissue level and activation of coagulation, as reflected by elevated levels of thrombin-antithrombin complexes and by increased fibrin(ogen) deposition in the liver and lungs. rNAPc2 strongly attenuated this procoagulant response but did not influence the inflammatory response (histopathology, leukocyte recruitment to the peritoneal cavity, and cytokine and chemokine levels). Moreover, rNAPc2 did not alter bacterial outgrowth locally or dissemination of the infection, and survival was not different between rNAPc2-treated mice and control mice. CONCLUSIONS: These data suggest that TF/FVIIa activity contributes to the activation of coagulation during E. coli peritonitis but does not play a role in the inflammatory response or antibacterial host defense.

Animals↗
PubMed2004

Coagulation in sepsis: all bugs bite equally.

Sepsis almost invariably leads to hemostatic abnormalities, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation. There is compelling evidence from clinical and experimental studies that disseminated intravascular coagulation is involved in the pathogenesis of microvascular dysfunction and contributes to organ failure. Data from the PROWESS phase III clinical trial of recombinant activated protein C in patients with severe sepsis confirm this notion and demonstrate that the vast majority of patients with severe sepsis have increased markers for systemic coagulation activation, decreased physiological anticoagulant proteins and depressed fibrinolysis. There is no correlation between the type of microorganism that has caused the infection and the presence or severity of the coagulation disorder.

Biomarkers↗
PubMed2004

Inhibition of plasmin activity by tranexamic acid does not influence inflammatory pathways during human endotoxemia.

OBJECTIVE: Plasmin activates several proinflammatory pathways at the cellular level in vitro. Lipopolysaccharide (LPS) administration to healthy humans results in a rapid generation of plasmin activity, accompanied by activation of a number of inflammatory systems. METHODS AND RESULTS: To determine the role of early plasmin activity in LPS-induced inflammation in vivo, 16 healthy males received an intravenous bolus injection with LPS (from Escherichia coli, 4 ng/kg) directly preceded by a 30-minute intravenous infusion of tranexamic acid (2 g, n=8), a plasmin activation inhibitor, or placebo (n=8). LPS injection induced marked increases in the plasma levels of D-dimer and plasmin-alpha2-antiplasmin complexes, indicative of plasmin activation and generation, respectively, which were strongly attenuated by tranexamic acid (both P<0.01 versus placebo). However, tranexamic acid did not influence LPS-induced coagulation activation, granulocytosis, neutrophil activation (expression of CD11b, CD66b, and L-selectin) or degranulation (plasma concentrations of elastase-alpha1-antitrypsin and bactericidal permeability-increasing protein), endothelial cell activation (plasma levels of von Willebrand factor and soluble E-selectin), or cytokine release. CONCLUSIONS: These data argue against a role of early plasmin generation in the subsequent activation of other inflammatory pathways during human endotoxemia.

Adult↗
PubMed2004

Recombinant factor VIIa as an antidote for anticoagulant treatment.

Increasing knowledge on the function of the hemostatic system in vivo and limitations of currently available anticoagulant agents have led to the development of a new generation of anticoagulants. These new agents have a greater specificity towards activated coagulation pathways and factors and are presently being evaluated in clinical studies. The new generation anticoagulants include specific inhibitors of factor IIa (melagatran), factor Xa (pentasaccharides), and agents that interfere with tissue factor (TF) activity. A limitation of this new class of anticoagulants may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs. Recombinant factor VIIa (rFVIIa) is a potent prohemostatic agent and may represent an interesting option for consideration when an antidote is required. Indeed, rFVIIa has proven to be efficacious in the reversal of anticoagulant treatment with vitamin K antagonists. Studies in healthy subjects have also revealed that rFVIIa administration corrects coagulation time and can induce thrombin generation during anticoagulation with pentasaccharides or TF-inhibiting therapy. These results indicate that rFVIIa infusion results in a prohemostatic response in vivo in patients receiving treatment with factor Xa- or TF-specific anticoagulants. This suggests that rFVIIa may be a good candidate as an antidote for new anticoagulants in cases of (severe) bleeding or in patients scheduled for emergency surgery.

Anticoagulants↗
PubMed2004

New treatment strategies for disseminated intravascular coagulation based on current understanding of the pathophysiology.

A variety of clinical conditions may cause systemic activation of coagulation, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation (DIC). DIC consists of a widespread systemic activation of coagulation, resulting in diffuse fibrin deposition in small and midsize vessels. There is compelling evidence from clinical and experimental studies that DIC is involved in the pathogenesis of microvascular dysfunction and contributes to organ failure. In addition, the massive and ongoing activation of coagulation, may result in depletion of platelets and coagulation factors, which may cause bleeding. Recent understanding of important pathogenetic mechanisms that may lead to DIC has resulted in novel preventive and therapeutic approaches to patients with sepsis and a derangement of coagulation. Thrombin generation proceeds via the (extrinsic) tissue factor/factor VIIa route and simultaneously occurring depression of inhibitory mechanisms, such as antithrombin III and the protein C system. Also, impaired fibrin degradation, due to high circulating levels of the fibrinolytic inhibitor plasminogen activator inhibitor, type 1 (PAI-1), contributes to enhanced intravascular fibrin deposition. Interestingly, an extensive cross-talk between activation of inflammation and coagulation exists, where inflammatory mediators (such as cytokines) not only activate the coagulation system, but vice versa activated coagulation proteases and protease inhibitors may modulate inflammation through specific cell receptors. Supportive strategies aimed at the inhibition of coagulation activation may theoretically be justified and have been found beneficial in experimental and initial clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways, for example by means of the administration of recombinant human activated protein C.

Anticoagulants↗