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Biomedical subjects

Marcel Levi

Publications and source records attributed to Marcel Levi.

At least 91 records · Page 5Linked to original sources
PubMed2003

Prevention and treatment of bleeding by pro-hemostatic treatment strategies.

Pro-hemostatic therapy may achieve an improvement of hemostasis, by amelioration of primary hemostasis, stimulation of fibrin formation or inhibition of fibrinolysis. Pro-hemostatic interventions appear to be effective in reducing peri-operative blood loss and reducing transfusion requirements in specific situations and may be helpful adjuncts in the management of severe spontaneous and post-operative bleeding. The risk of a higher incidence of thrombotic complications associated with the use of pro-hemostatic therapy is unknown but seems not to be very high in clinical practice. There is a need for more systematic and adequately controlled clinical observations to better establish the efficacy and safety of pro-hemostatic interventions.

Antifibrinolytic Agents↗
PubMed2003

Local intravascular coagulation and fibrin deposition on intestinal ischemia-reperfusion in rats.

BACKGROUND: This study investigates intravascular coagulation and thrombotic obstruction in the splanchnic vasculature after intestinal ischemia in relation to epithelial integrity and function. METHODS: Intestinal ischemia was induced in rats by superior mesenteric artery occlusion for 20 or 40 minutes. Intestinal injury was assessed by histologic analysis, biochemical markers, and functional studies. During reperfusion, portal and systemic blood samples were collected to analyze activation of coagulation and fibrinolysis. RESULTS: Superior mesenteric artery occlusion resulted in mild to moderate intestinal injury. Twenty and 40 minutes of ischemia and 3 hours of reperfusion resulted in local intestinal thrombin generation and conversion of fibrinogen to fibrin, reflected by 3- and 4-fold increases in thrombin-antithrombin complex levels and a 3-fold elevation of fibrin degradation products (D-dimer), respectively. During reperfusion, after a short-lasting initial activation of local fibrinolysis, plasminogen activator activity was suppressed, as indicated by an approximately 4-fold increase in portal plasma levels of the plasminogen activator inhibitor. D-dimer levels showed that activation of coagulation and depression of fibrinolysis resulted in fibrin formation, which was confirmed to be intravascular fibrin deposition by histologic examination. CONCLUSIONS: Intestinal ischemia-reperfusion results in local intravascular coagulation and fibrin deposition.

Animals↗
PubMed2003

Bronchoalveolar coagulation and fibrinolysis in endotoxemia and pneumonia.

OBJECTIVES: To review the involvement of coagulation and fibrinolysis in the pathogenesis of acute lung injury during severe infection. To review the cross-talk between coagulation and inflammation that may affect this response. DATA SOURCES: Published articles on experimental and clinical studies of coagulation and fibrinolysis during infection, inflammation, acute lung injury, and evolving acute respiratory distress syndrome. CONCLUSIONS: Fibrin deposition is an important feature of pulmonary infection or severe inflammation. The mechanisms that contribute to this fibrin deposition are bronchoalveolar tissue factor-mediated thrombin generation and localized depression of urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. These effects on pulmonary coagulation and fibrinolysis are regulated by various proinflammatory cytokines. Rather than being a unidirectional relationship, the interaction between inflammation and coagulation involves significant cross-talk. Coagulation and fibrinolytic proteins may have an additional role beyond fibrin turnover and inflammation, e.g., in mechanisms mediating cell recruitment and migration.

Bronchoalveolar Lavage Fluid↗
PubMed2003

Activation of coagulation by administration of recombinant factor VIIa elicits interleukin 6 (IL-6) and IL-8 release in healthy human subjects.

The activation of coagulation has been shown to contribute to proinflammatory responses in animal and in vitro experiments. Here we report that the activation of coagulation in healthy human subjects by the administration of recombinant factor VIIa also elicits a small but significant increase in the concentrations of interleukin 6 (IL-6) and IL-8 in plasma. This increase was absent when the subjects were pretreated with recombinant nematode anticoagulant protein c2, the inhibitor of tissue factor-factor VIIa.

Blood Coagulation↗
PubMed2003

Anticoagulant therapy for acute lung injury or pneumonia.

Pulmonary changes in thrombin formation in patients with acute lung injury or pneumonia are remarkably similar to systemic changes in coagulation observed in septic patients. Since anticoagulant therapy has proven to be successful in the treatment of patients with sepsis, the same therapeutic strategy may benefit patients with acute lung injury or pneumonia. Based on the fact that inflammation not only leads to dysregulation of the coagulation system, but vice versa, activation of coagulation amplifies inflammatory processes as well, it can be questioned whether the advantage of anticoagulant therapy is solely related to its influence on disturbed thrombin formation. In this paper we will discuss local changes in the haemostatic balance during acute lung injury, both in pre-clinical and clinical studies. Until now, pre-clinical studies have demonstrated that interventions aimed at correction of coagulation abnormalities may form an important strategy in patients with acute lung injury in the future. Pre-clinical studies on use of anticoagulants during pneumonia are presently performed and data are underway.

Animals↗
PubMed2003

Cancer and thrombosis.

Cancer is frequently complicated by thrombosis, which may even be the first sign of an unrecognized cancer. There are several risk factors for cancer-associated thrombosis, such as type of malignancy, the presence of metastatic disease, and the use of chemotherapy. In most patients with cancer, a procoagulant state can be identified, ranging from subclinical laboratory abnormalities to full-blown disseminated intravascular coagulation. A specific entity is the occurrence of thrombotic microangiopathy that is specifically related to (high-dose) chemotherapy and radiotherapy. The pathogenetic pathways that play a role in the cancer-associated coagulopathy have been identified in recent years.

Anticoagulants↗
PubMed2002

Effects of IC14, an anti-CD14 antibody, on coagulation and fibrinolysis during low-grade endotoxemia in humans.

To determine the role of CD14 in lipopolysaccharide (LPS)-induced effects on coagulation and fibrinolysis in humans, 16 healthy subjects received an intravenous injection of LPS preceded by intravenous IC14, a recombinant chimeric monoclonal antibody against human CD14, or placebo. LPS-induced coagulation activation (tissue-factor mRNA in whole blood cells and plasma concentrations of F1+2) was not influenced by IC14, whereas the antibody reduced the increase in thrombin-antithrombin complexes and soluble fibrin. LPS injection also was associated with an early activation of fibrinolysis (plasma concentrations of tissue-type plasminogen activator and plasmin-alpha(2)-antiplasmin complexes), followed by an inhibitory response (plasminogen activator inhibitor type 1), which were attenuated by IC14. Furthermore, LPS reduced thrombin-activatable fibrinolysis-inhibitor antigen levels and increased soluble thrombomodulin levels, which were not influenced by IC14. These results suggest that different hemostatic responses during endotoxemia may proceed via CD14-dependent and -independent pathways.

Adult↗
PubMed2002

Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers.

BACKGROUND: The novel anticoagulant fondaparinux proved to be effective and safe in the postoperative prevention of venous thrombosis. Current phase III trials with this synthetic selective factor Xa inhibitor focus on its use in the treatment of patients with venous and arterial thrombosis. As with any anticoagulant therapy, there is a risk of bleeding complications; hence, a strategy to reverse the effects of fondaparinux is desirable. The aim of this study was to investigate whether recombinant factor VIIa (rFVIIa) could neutralize the anticoagulant effects of subcutaneously administered fondaparinux. METHODS AND RESULTS: In a randomized, placebo-controlled design, 16 healthy male subjects received either a single subcutaneous dose of fondaparinux (10 mg) and a single intravenous bolus of rFVIIa (90 microg/kg; n=8), fondaparinux and placebo (n=4), or placebo and rFVIIa (n=4). Fondaparinux (or placebo) was administered 2 hours before rFVIIa (or placebo). Injection of rFVIIa after fondaparinux normalized the prolonged activated partial thromboplastin and prothrombin times and reversed the decrease in prothrombin activation fragments 1+2 (F(1+2)), as observed with fondaparinux alone. Thrombin-generation time and endogenous thrombin potential, which were inhibited by fondaparinux, normalized up to 6 hours after rFVIIa injection. CONCLUSIONS: rFVIIa is capable of normalizing coagulation times and thrombin generation during fondaparinux treatment. The duration of this effect ranged from 2 to 6 hours after rFVIIa injection. These results suggest that rFVIIa may be useful to reverse the anticoagulant effect of fondaparinux in case of serious bleeding complications or need for acute surgery during treatment with fondaparinux.

Adolescent↗
PubMed2002

Urokinase receptor is necessary for adequate host defense against pneumococcal pneumonia.

Cell recruitment is a multistep process regulated by cytokines, chemokines, and growth factors. Previous work has indicated that the urokinase plasminogen activator receptor (uPAR) may also play a role in this mechanism, presumably by an interaction with the beta(2) integrin CD11b/CD18. Indeed, an essential role of uPAR in neutrophil recruitment during pulmonary infection has been demonstrated for beta(2) integrin-dependent respiratory pathogens. We investigated the role of uPAR and urokinase plasminogen activator (uPA) during pneumonia caused by a beta(2) integrin-independent respiratory pathogen, Streptococcus pneumoniae. uPAR-deficient (uPAR(-/-)), uPA-deficient (uPA(-/-)), and wild-type (Wt) mice were intranasally inoculated with 10(5) CFU S. pneumoniae. uPAR(-/-) mice showed reduced granulocyte accumulation in alveoli and lungs when compared with Wt mice, which was associated with more S. pneumoniae CFU in lungs, enhanced dissemination of the infection, and a reduced survival. In contrast, uPA(-/-) mice showed enhanced host defense, with more neutrophil influx and less pneumococci in the lungs compared with Wt mice. These data suggest that uPAR is necessary for adequate recruitment of neutrophils into the alveoli and lungs during pneumonia caused by S. pneumoniae, a pathogen eliciting a beta(2) integrin-independent inflammatory response. This function is even more pronounced when uPAR is unoccupied by uPA.

Animals↗
PubMed2002

Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors.

PURPOSE: To investigate the feasibility and pharmacokinetics of the combination cisplatin, gemcitabine, and SU5416. PATIENTS AND METHODS: Patients received cisplatin 80 mg/m(2) on day 1, gemcitabine 1,250 mg/m(2) on days 1 and 8, repeated every 3 weeks, and SU5416 (85 and 145 mg/m(2)) intravenously twice weekly. Pharmacokinetics of all three agents, side effects, and antitumor response were investigated in patients with solid tumors amenable to therapy with cisplatin/gemcitabine. RESULTS: In the first cohort of three patients entered at the 85 mg/m(2) dose, no dose-limiting toxicities were observed. In the next cohort (145 mg/m(2)), three patients developed a thromboembolic event. After entry was restricted to patients with low thromboembolic risk, three additional patients enrolled at 145 mg/m(2) developed a thromboembolic event. The dose was then reduced to 85 mg/m(2) in all patients still on the study, and three additional patients were entered on this dose level. In 19 treated patients, eight patients developed nine thromboembolic events (three transient ischemic attacks, two cerebrovascular accidents, and four deep venous thromboses). The most common toxicities observed were those previously reported for SU5416 alone (headache and phlebitis) and for this chemotherapy regimen (nausea, thrombocytopenia, and leucopenia). No significant pharmacologic interaction among the three drugs was observed. Response rates were similar to those expected in the patient population selected for this study. Analysis of variables of the coagulation cascade and of vessel wall activation was performed in three patients and showed significant increases in thrombin generation and endothelial cell perturbation in a treatment cycle-dependent manner. CONCLUSION: The incidence of thromboembolic events, possibly related to the particular regimen tested in this study, discourages further investigation of this regimen.

Adult↗
PubMed2002

Bioavailability of subcutaneous low-molecular-weight heparin to patients on vasopressors.

Venous thromboembolism is a frequent complication in patients admitted to intensive care units (ICU), despite prophylactic treatment with subcutaneous low-molecular-weight (LMW) heparin. We postulated that poor efficacy of subcutaneous heparin might be due to administration of vasopressors, which could cause impaired peripheral circulation and inadequate systemic bioavailability of the anticoagulant. We compared concentrations of factor Xa activity in three groups of 15 patients: individuals in ICU who had and had not received vasopressors, and general surgery patients. Those who received vasopressors had lower plasma concentrations of factor-Xa activity than patients in ICU not on vasopressors and postoperative controls. Patients in ICU who take vasopressors could need higher doses of LMW heparin, or a different mode of administration of the drug, to attain adequate thrombosis prophylaxis.

Anticoagulants↗
PubMed2002

Rebound thrombin generation after heparin therapy in unstable angina. A randomized comparison between unfractionated and low-molecular-weight heparin.

OBJECTIVES: This study compared rebound coagulation in patients with acute coronary syndrome patients after discontinuation of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). BACKGROUND: Up to a quarter of patients hospitalized for unstable angina experience recurrent ischemia after discontinuation of UFH or LMWH therapy, which may be the result of rebound coagulation activation and subsequent thrombosis. It is unknown whether UFH and LMWH differ in this respect. METHODS: We randomized 71 patients admitted with unstable angina to intravenous UFH or subcutaneous LMWH (dalteparin) and measured plasma markers of coagulation before, during, and after treatment. RESULTS: A complete series of measurements was obtained in 59 patients. Plasma prothrombin fragment 1+2 (F(1+2)) levels decreased in both groups during treatment. After loss of therapeutic plasma drug levels, F(1+2) increased (within 3 h) to a maximum level at 12 to 24 h that was higher than before or during treatment in both groups (p < 0.0001). In both groups, F(1+2) levels remained higher than pretreatment up to 24 h after discontinuation. Similarly, thrombin-antithrombin (TAT) levels exceeded treatment and pretreatment levels, at a slower rate after dalteparin than after UFH. However, after dalteparin a higher peak value of TAT was observed. CONCLUSIONS: Rebound coagulation activation occurs within hours after discontinuation of both UFH and dalteparin. With both drugs, thrombin generation is significantly greater after treatment than before or during treatment. A longer duration or weaning of treatment, or continuation with another anticoagulant treatment, may reduce rebound coagulation activation and ischemic events.

Angina, Unstable↗
PubMed2002

Tissue factor and coronary artery disease.

Plaque disruption with superimposed thrombosis is the main cause of acute coronary events such as acute myocardial infarction and unstable angina. Among other factors, tissue factor seems to play an important role determining plaque thrombogenicity. Tissue factor is a potent initiator of the coagulation cascade situated within the vessel wall and is highly exposed to the blood after plaque rupture. Several mediators involved in the process of atherosclerotic plaque formation are capable of inducing tissue factor expression in cells such as monocytes, macrophages and endothelial cells, which under normal conditions do not express tissue factor or to a limited extent only. The increased expression of tissue factor is not limited to the plaque but is also found in circulating monocytes in patients with acute coronary syndromes. In addition, studies have shown an important contribution of tissue factor in the pathogenesis of thrombosis and restenosis after balloon angioplasty. Recent basic studies focus on the therapeutic inhibition of tissue factor. Specific and non-specific inhibitors of tissue factor or the tissue factor/factor VIIa complex have been developed or identified, and have been tested in experimental studies. Clinical studies are currently being initiated. In this review, we present the current knowledge on the role of tissue factor in atherosclerosis, arterial intervention and potential pharmacological approaches, with focus on acute coronary syndromes.

Acute Disease↗
PubMed2002

The diagnosis of disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) is a syndrome characterized by systemic intravascular activation of coagulation, leading to widespread deposition of fibrin in the circulation. In recent years, the pathogenetic pathways leading to DIC have been largely identified, which could result in more precise diagnostic tests for this disorder. However, the clinical and laboratory diagnosis of DIC may remain difficult, since routinely available tests do not specifically assess ongoing thrombin generation. Molecular markers for activation of coagulation and fibrinogen to fibrin conversion are highly sensitive but also disappointedly aspecific for the diagnosis of DIC. Moreover, these tests are often not available in most settings for daily clinical care. A combination of widely available tests, however, may be helpful in making the diagnosis of DIC, according to a recently developed algorithm.

Algorithms↗
PubMed2002

Time course of platelet counts in critically ill patients.

BACKGROUND: Although thrombocytopenia in the intensive care unit (ICU) is associated with a poorer outcome, the precise relationship between the time course of platelet counts and the mortality rate has not been well defined. OBJECTIVE: To describe the time course of the platelet count in relation to the mortality rate in critically ill patients. DESIGN: Substudy of a prospective, multicenter, observational cohort analysis. SETTING: Forty ICUs in 16 countries from Europe, America, and Australia. PATIENTS: Data were collected from all ICU admissions in a 1-month period, excluding patients younger than 12 yrs old and those who stayed in the ICU for <48 hrs after uncomplicated surgery. A total of 1,449 critically ill patients were enrolled, including 257 who stayed in the ICU for >2 wks. INTERVENTIONS: None. MEASUREMENTS: Platelet counts were collected daily throughout the ICU stay, together with other measures of organ dysfunction. Thrombocytopenia was defined as a platelet count of <150 x 103/mm3. A relative increase in platelet count was defined as a 25% increase above the admission value, together with an absolute platelet count of > or =150 x 103/mm3. MAIN RESULTS: For the entire population, the platelet count was lower in the 313 nonsurvivors than in the 1,131 survivors throughout the ICU course. Of the 257 patients who stayed in the ICU for >2 wks, 187 (64%) survived. The platelet count decreased significantly in the first days after admission to reach a nadir on day 4 in both survivors and nonsurvivors. In the survivors, the platelet count returned to the admission value by the end of the first week and continued to rise to become significantly greater than the admission value by day 9. In the nonsurvivors, the platelet count also returned to the admission value after 1 wk, but there was no subsequent increase in platelet count. A total of 138 (54%) patients had thrombocytopenia on day 4, and these patients had a greater mortality rate than the other patients (33% vs. 16%; p <.05). On day 14, 51 (20%) patients had thrombocytopenia, and these patients had a greater mortality rate than the other patients (66% vs. 16%; p <.05). Thrombocytopenia was less common on day 14 than on day 4 (20% vs. 54%; p <.05), but the mortality rate was greater in the thrombocytopenic patients on day 14 than those who were thrombocytopenic on day 4 (66% vs. 33%; p <.05). The ICU mortality rate of nonthrombocytopenic patients on day 14 was also significantly lower in patients with, than without, a relative increase in platelet count on day 14 (11% vs. 30%; p <.05). CONCLUSION: Platelet count changes in the critically ill have a biphasic pattern that is different in survivors and nonsurvivors. Late thrombocytopenia is more predictive of death than early thrombocytopenia. A relative increase in platelet count after thrombocytopenia was present in survivors but not in nonsurvivors. Although a single measured platelet count is of little value for predicting outcome, changes in platelet count over time are related to patient outcome.

Adolescent↗
PubMed2002

Endothelium: interface between coagulation and inflammation.

OBJECTIVE: To review the involvement of endothelial cells in the pathogenesis of coagulation abnormalities during severe infection, the differential role of proinflammatory cytokines in these mechanisms, and the cross talk between coagulation and inflammation. DATA SOURCES: Published articles on experimental studies of coagulation activation during inflammation and clinical studies of patients with sepsis and associated hemostatic abnormalities. DATA SYNTHESIS AND CONCLUSION: The endothelium plays a central role in all major pathways involved in the pathogenesis of the hemostatic derangement observed during severe inflammation (i.e., initiation and regulation of thrombin generation and inhibition of fibrinolysis). Rather than being a unidirectional relationship, the interaction between inflammation and coagulation involves significant cross talk in which the endothelium seems to play a pivotal role.

Animals↗