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Biomedical subjects

Marcel Levi

Publications and source records attributed to Marcel Levi.

At least 73 records · Page 4Linked to original sources
PubMed2004

Management of anticoagulant therapy for patients with prosthetic heart valves or atrial fibrillation.

There is a wide array of recommendations for the management of anticoagulant therapy in patients with mechanical heart valves. Especially the optimal intensity of vitamin K antagonists (VKA) is a ongoing matter of debate. On the basis of several studies, recommendations for daily clinical practice can be made. In this review, we discussed the studies and the different guidelines. Guidelines for the prevention of thromboembolic complications in patients with atrial fibrillation are more stringent. VKA with a target INR between 2.0 and 3.0 is more effective in the prevention of stroke than aspirin, especially in the presence of riskfactors for thromboembolism (age above 65, previous thromboembolism, history of hypertension and diabetes, enlarged left atrial diameter and left ventricular dysfunction). In the absence of clinical or echocardiographical riskfactors for thromboembolism, patients may be safely treated with aspirin.

Age Factors↗
PubMed2004

Beyond sepsis: activated protein C and ischemia-reperfusion injury.

OBJECTIVE: To review potential clinical situations beyond sepsis in which activated protein C might be an effective treatment. DATA SOURCE: Published articles between 1970 and 2003 on experimental and clinical studies of activation of both coagulation and inflammation in various disease states. DATA SYNTHESIS AND CONCLUSION: The efficacy of activated protein C in sepsis might rely on the fact that it can modulate both coagulation and inflammation. Therefore, administration of activated protein C could be beneficial in disease states that are also characterized by the simultaneous activation of these systems. Ischemia-reperfusion injury of various organs may represent such a state. Indeed, the involvement of the protein C system has been demonstrated in various experimental studies of ischemia-reperfusion, including studies in renal ischemia-reperfusion syndromes, coronary atherosclerosis and acute coronary syndromes, and intestinal ischemia and reperfusion. In some of these models, activated protein C administration, or other interventions in the protein C system, was shown to be beneficial.

Animals↗
PubMed2004

Inhibition of coagulation and inflammation by activated protein C or antithrombin reduces intestinal ischemia/reperfusion injury in rats.

OBJECTIVE: To examine whether administration of activated protein C or antithrombin reduces local splanchnic derangement of coagulation and inflammation and attenuates intestinal dysfunction and injury following intestinal ischemia/reperfusion. DESIGN: Randomized prospective animal study. SETTING: University research institute. SUBJECTS: Adult male Wistar rats, weighing 300-325 g (n = 72). INTERVENTIONS: Rats were subjected to superior mesenteric artery occlusion consisting of 20 or 40 mins of ischemia and 3 hrs of reperfusion. A randomized intravenous administration of vehicle (0.9% NaCl), heparin, antithrombin, or activated protein C was performed during ischemia, 15 mins before reperfusion. Coagulation and fibrinolysis variables obtained from portal blood were correlated with mucosal fibrin deposition (determined by anti-rat fibrin antibody staining), intestinal function (glucose/water clearance), and intestinal injury (histologic evaluation by Park/Chiu score). MEASUREMENTS AND MAIN RESULTS: Activated protein C- or antithrombin-treated animals demonstrated less ischemia/reperfusion-induced intestinal dysfunction and histologic changes compared with control animals, whereas intravenous administration of heparin only showed less histologic derangement. Activated protein C- or antithrombin-treated animals showed less thrombin generation, fibrin degradation products, and fibrin deposition compared with control animals, as confirmed by histologic examination, whereas heparin administration showed only a limited reduction of portal fibrin degradation product concentrations. Furthermore, activated protein C or antithrombin administration markedly inhibited the inflammatory response, as reflected by reduced interleukin-6 plasma concentrations to baseline values, whereas heparin had no effect. CONCLUSIONS: Administration of activated protein C or antithrombin inhibited local and systemic derangement of coagulation and inflammation following intestinal ischemia/reperfusion, diminished mucosal fibrin deposition, and attenuated ischemia/reperfusion-induced intestinal injury. These observations suggest that activated protein C or antithrombin reduces ischemia/reperfusion-induced intestinal injury, both through their anticoagulant and anti-inflammatory effects.

Animals↗
PubMed2004

Prospective validation of the International Society of Thrombosis and Haemostasis scoring system for disseminated intravascular coagulation.

OBJECTIVES: A diagnosis of disseminated intravascular coagulation (DIC) is hampered by the lack of an accurate diagnostic test. Based on the retrospective analysis of studies in patients with DIC, a scoring system (0-8 points) using simple and readily available routine laboratory tests has been proposed. The aim of this study was to prospectively validate this scoring system and assess its feasibility, sensitivity, and specificity in a consecutive series of intensive care patients. DESIGN: Prospective cohort of intensive care patients. SETTING: Adult intensive care unit in a tertiary academic center. PATIENTS: Consecutive patients with a clinical suspicion of disseminated intravascular coagulation. INTERVENTIONS: Patients were followed during their admission to the intensive care unit, and the DIC score was calculated every 48 hrs and compared with a "gold standard" based on expert opinion. In addition, an activated partial thromboplastin time (aPTT) waveform analysis, which has been reported to be a good predictor for the absence or presence of DIC, was performed. MEASUREMENTS AND MAIN RESULTS: We analyzed 660 samples from 217 consecutive patients. The prevalence of DIC was 34%. There was a strong correlation between an increasing DIC score and 28-day mortality (for each 1-point increment in the DIC score, the odds ratio for mortality was 1.25). The sensitivity of the DIC score was 91% and the specificity 97%. An abnormal aPTT waveform was seen in 32% of patients and correlated well with the presence of DIC (sensitivity 88%, specificity 97%). In 19% of patients, the aPTT waveform-based diagnosis of DIC preceded the diagnosis based on the scoring system. CONCLUSIONS: A diagnosis of DIC based on a simple scoring system, using widely available routine coagulation tests, is sufficiently accurate to make or reject a diagnosis of DIC in intensive care patients with a clinical suspicion of this condition. An aPTT waveform analysis is an interesting and promising tool to assist in the diagnostic management of DIC.

Aged↗
PubMed2004

Recombinant factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers.

We investigated whether the anticoagulant effect of idraparinux, a selective long-acting factor Xa inhibitor, could be neutralized by recombinant factor VIIa (rFVIIa) in healthy male volunteers. We performed a randomized, placebo-controlled trial, comparing idraparinux [7.5 mg subcutaneous (s.c.)] followed at 3 h by rFVIIa [90 microg/kg intravenous (i.v.)] (n = 6), or idraparinux (7.5 mg s.c) followed after 1 week by rFVIIa (90 microg/kg i.v.)(n = 6). rFVIIa, given 3 h after idraparinux, significantly reversed the increased thrombin generation time (TGT), the increased activated partial thromboplastin time (aPTT) and prothrombin time (PT), and the reduced prothrombin fragment 1+2 (F1+2) levels caused by idraparinux, although no clear effect of rFVIIa on the endogenous thrombin potential (ETP) was observed. One week after idraparinux, injection of rFVIIa resulted in a similar relative reduction of the remaining increased aPTT, PT and TGT, with correction to pre-idraparinux values. A clear increase of F1+2 was observed, together with a small increase in ETP. We conclude that rFVIIa has significant effects on the idraparinux-inhibited thrombin generation and clotting parameters. These results suggest that rFVIIa may be useful in serious bleeding complications in idraparinux treated patients.

Adolescent↗
PubMed2004

Enhancement of endogenous fibrinolysis does not reduce local fibrin deposition, but modulates inflammation upon intestinal ischemia and reperfusion.

This study investigated the contribution of endogenous suppression of fibrinolysis and increased fibrin deposition to intestinal dysfunction and injury in a rat model of intestinal ischemia/reperfusion (I/R), as fibrinolytic inhibition may lead to thrombotic obstructions that compromise microcirculation and promote intestinal injury. Circulatory fibrinolysis was enhanced by intravenous administration of recombinant tissue plasminogen activator (rt-PA) or by inhibition of PAI-I by administration of MA-33H1F7. Coagulation and fibrinolysis parameters obtained from portal blood were correlated to fibrin deposition (determined by anti-rat fibrin antibody staining), intestinal function (glucose/water clearance) and intestinal injury (histological evaluation by Park/Chiu score). Enhanced circulatory fibrinolytic activity, as evidenced by increased portal plasma plasminogen activator activity, elevated fibrin degradation products and decreased levels of PAI-I, did not reduce mucosal fibrin deposition and microthrombosis in postischemic intestinal tissue. Furthermore, rt-PA or anti-PAI-I antibody administration did not attenuate I/R-induced intestinal injury or dysfunction, as demonstrated by intestinal histopathology scores of 4.8+/-0.2 and 4.7+/-0.3 (control I/R group 4.7+/-0.2) and glucose clearances of 47+/-6 and 46+/-9 micro L/min g (control I/R group 30+/-8 micro L/min. g) after 40 minutes of intestinal ischemia and 3 hours of reperfusion, respectively. However, both interventions resulted in decreased levels of interleukin-6, which may indicate fibrin-induced modulation of inflammation. Attempts to enhance the fibrinolytic activity (either by rt-PA or by anti-PAI-I administration), indicated by increased portal plasma levels of released FDP, failed to decrease mucosal fibrin deposition and to attenuate intestinal I/R injury. Based on our observations and previous reports, the contribution of suppressed endogenous fibrinolysis to microcirculatory fibrin deposition and I/R-injury may be of limited importance.

Animals↗
PubMed2004

Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activation in healthy volunteers.

The objectives were to investigate whether activation of the extrinsic coagulation cascade by recombinant factor VIIa (rFVIIa) reverses the inhibition of thrombin generation and platelet activation by melagatran, the active form of the oral direct thrombin inhibitor ximelagatran. In a single-blind, randomized, parallel-group study, volunteers (20 per group) received a 5-hour intravenous (i.v.) infusion to achieve steady-state melagatran plasma concentrations of approximately 0.5 micromol/L, with a single i.v. bolus of rFVIIa (90 microg/kg) or placebo at 60 minutes. Prothrombin fragment 1+2, thrombin-anti-thrombin complex, fibrinopeptide A, beta-thromboglobulin, and thrombin-activatable fibrinolysis inhibitor were quantified for venous and shed blood. Activated partial thromboplastin time (APTT), prothrombin time (PT), endogenous thrombin potential, thrombus precursor protein (TpP), and plasmin-alpha(2)-antiplasmin complex concentrations were determined in venous blood. Shed blood volume was measured. Melagatran reduced markers of thrombin generation and platelet activation in shed blood and prolonged APTT. rFVIIa increased FVIIa activity, PT, and TpP in venous blood. All other parameters were unaffected. In conclusion, rFVIIa did not reverse the anticoagulant effects of high constant concentrations of melagatran. However, the potential value of higher, continuous or repeated doses of rFVIIa or its use with lower melagatran concentrations has not been excluded.

Adult↗
PubMed2004

Plantar fat-pad displacement in neuropathic diabetic patients with toe deformity: a magnetic resonance imaging study.

OBJECTIVE: The aim of this study was to quantify the association between claw/hammer toe deformity and changes in submetatarsal head (sub-MTH) fat-pad geometry in diabetic neuropathic feet. RESEARCH DESIGN AND METHODS: Thirteen neuropathic diabetic subjects (mean age 56.2 years) with toe deformity, 13 age- and sex-matched neuropathic diabetic control subjects without deformity, and 13 age- and sex-matched healthy control subjects without deformity were examined. From high-resolution sagittal plane magnetic resonance images of the second and third ray of the foot, toe angle (a measure of deformity), sub-MTH fat-pad thickness, and subphalangeal fat-pad thickness were measured. The ratio of these thicknesses was used to indicate fat-pad displacement. RESULTS: Sub-MTH fat pads were significantly thinner (2.5 +/- 1.3 vs. 6.0 +/- 1.4 mm, P < 0.001) and subphalangeal fat pads significantly thicker (9.1 +/- 1.9 vs. 7.6 +/- 1.2 mm, P < 0.005) in the neuropathic group with deformity compared with neuropathic control subjects. As a result, thickness ratio was substantially smaller in the deformity group: 0.28 +/- 0.14 vs. 0.79 +/- 0.14 in neuropathic control subjects (P < 0.001). A significant correlation of 0.85 was present between toe angle and thickness ratio (P < 0.001). No significant differences were found between neuropathic and healthy control subjects. CONCLUSIONS: This study shows a distal displacement and subsequent thinning of the sub-MTH fat pads in neuropathic diabetic patients with toe deformity and suggests that, as a result, the capacity of the tissue in this region to reduce focal plantar pressure is severely compromised. This condition is likely to increase the risk of plantar ulceration in these patients.

Adipose Tissue↗
PubMed2003

The optimal intensity of vitamin K antagonists in patients with mechanical heart valves: a meta-analysis.

OBJECTIVES: The purpose of this study was to compare two different intensities of vitamin K antagonists (VKA) among patients with mechanical heart valves using meta-analytic techniques. BACKGROUND: Patients with mechanical heart valves are at increased risk for valve thrombosis and systemic embolism, which can be reduced by VKA. The range of optimal intensity of VKA is still a matter of debate. METHODS: A computerized search in the PubMed database was made for relevant articles. A meta-analysis was performed of all eligible studies with data on the incidences of thromboembolic and bleeding complications in patients with mechanical heart valve prostheses during different intensities of VKA therapy. The studies were classified into low-intensity VKA therapy (mean target international normalized ratio [INR] of 3.0 or lower) or high-intensity VKA therapy (mean target INR above 3.0). RESULTS: Thirty-five eligible studies were identified, including in total 23,145 patients, who were studied for 108,792 patient-years. For patients with an aortic valve, high intensity resulted in a lower incidence of thromboembolic events (risk ratio [RR] = 0.73, p < 0.0001); however, the incidence of bleeding was increased (RR = 1.23, p < 0.0001). In the mitral valve group, the incidence rate for thromboembolism was lower in the high-intensity group (RR = 0.74, p < 0.0001), without a significantly increased bleeding incidence (RR = 1.08, p = 0.0524). The total number of thromboembolic and bleeding events was decreased in the high-intensity group compared with low-intensity VKA therapy for both aortic and mitral valve prostheses (RR = 0.94 [p = 0.0067] and 0.84 [p < 0.0001]), respectively. CONCLUSIONS: This meta-analysis shows that both aortic and mitral valves will benefit from a treatment strategy with a target INR higher than 3.0.

Aortic Valve↗
PubMed2003

Infection and inflammation and the coagulation system.

Severe infection and inflammation almost invariably lead to hemostatic abnormalities, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation (DIC). Systemic inflammation results in activation of coagulation, due to tissue factor-mediated thrombin generation, downregulation of physiological anticoagulant mechanisms, and inhibition of fibrinolysis. Pro-inflammatory cytokines play a central role in the differential effects on the coagulation and fibrinolysis pathways. Vice-versa, activation of the coagulation system may importantly affect inflammatory responses by direct and indirect mechanisms. Apart from the general coagulation response to inflammation associated with severe infection, specific infections may cause distinct features, such as hemorrhagic fever or thrombotic microangiopathy. The relevance of the cross-talk between inflammation and coagulation is underlined by the promising results in the treatment of severe systemic infection with modulators of coagulation and inflammation.

Antithrombins↗
PubMed2003

Infections and endothelial cells.

Systemic infection by various pathogens interacts with the endothelium and may result in altered coagulation, vasculitis and atherosclerosis. Endothelium plays a role in the initiation and regulation of both coagulation and fibrinolysis. Exposure of endothelial cells may lead to rapid activation of coagulation via tissue factor (TF) expression and the loss of anticoagulant properties by impairment of antithrombin III, TF pathway inhibitor (TFPI) and the protein C system. Endothelial-derived plasminogen activator inhibitor (PAI) is essential for the regulation of fibrinolysis and impaired endothelial function leads to imbalance in fibrinolysis, resulting in a procoagulant state. The interaction between inflammation and coagulation, soluble adhesion molecules and circulation endothelial cells is important in the pathogenesis of an unbalanced haemostatic system. Rather than being a unidirectional relationship, the interaction between inflammation and coagulation appears to be significant. In the crosstalk, the endothelium is playing a pivotal role.

Acute Disease↗
PubMed2003

The impact on coagulation of an intravenous loading dose in addition to a subcutaneous regimen of low-molecular-weight heparin in the initial treatment of acute coronary syndromes.

OBJECTIVES: We sought to quantify the impact of adding an intravenous loading dose to a subcutaneous regimen of enoxaparin in patients with an acute coronary syndrome (ACS). BACKGROUND: It is unclear whether an intravenous (i.v.) loading dose of enoxaparin should be added to a subcutaneous (s.c.) regimen in patients with ACS. METHODS: Patients admitted with ACS were randomized to i.v.+s.c.(n = 14) or s.c. alone (n = 11) enoxaparin treatment. Coagulation markers were measured at nine time points during the first 24 h of treatment. RESULTS: The i.v.+s.c. therapy immediately resulted in therapeutic anti-Xa levels, which remained significantly higher for 6 h compared with s.c. alone, without reaching excessively high levels. A rapid decrease of plasma prothrombin fragments 1+2 (F(1+2)) levels was observed as soon as 5 min after the i.v. injection (33% lower; p = 0.007), and these levels remained lower up to 2 h after the start of treatment compared with SQ alone. The ex vivo thrombin generation time was maximally prolonged at 5 min post-injection in the i.v.+s.c. group and remained significantly prolonged up to 6 h post-injection compared with s.c. alone. The tissue factor pathway inhibitor plasma activity was immediately increased by 194% with i.v.+s.c., whereas the maximum increase with s.c. alone was 47% at 3 h. CONCLUSIONS: Therapeutic plasma levels of enoxaparin are achieved significantly earlier by an i.v.+s.c. regimen compared with s.c. alone, without leading to unacceptably high levels. As the risk of thrombotic complications is greatest early after admission, the observed differences in antithrombotic effects may translate into a clinical benefit. However, this remains to be established.

Aged↗
PubMed2003

Plasminogen activator inhibitor type-1 deficiency does not influence the outcome of murine pneumococcal pneumonia.

Urokinase-type plasminogen activator (uPA) and its receptor uPAR are components of the fibrinolytic system and are important for an adequate immune response to respiratory tract infection, in part through their role in the migration of inflammatory cells. PA inhibitor-1 (PAI-1) is the predominant inhibitor of soluble and receptor-bound uPA. To determine the role of PAI-1 in host defense against pneumococcal pneumonia, the following studies were performed: (1) Patients with unilateral community-acquired pneumonia demonstrated elevated PAI-1 concentrations together with decreased PA activity in bronchoalveolar lavage fluid (BALF) obtained from the infected, but not from the contralateral, site. (2) Mice with Streptococcus pneumoniae pneumonia displayed elevated PAI-1 protein and mRNA levels in their lungs. (3) PAI-1 gene-deficient mice, however, had an unaltered immune response to pneumococcal pneumonia, as measured by cell recruitment into lungs, bacterial outgrowth, and survival. Furthermore, plasminogen-gene-deficient mice also had an unremarkable defense against pneumococcal pneumonia. These data indicate that pneumonia is associated with inhibition of the fibrinolytic system at the site of the infection secondary to increased production of PAI-1; an intact fibrinolytic response is not required for an adequate host response to respiratory tract infection, however, suggesting that the previously described role of uPA and uPAR are restricted to their function in cell migration.

Adult↗
PubMed2003

Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice.

In the pathogenesis of sepsis and disseminated intravascular coagulation (DIC), dysfunctional anticoagulant pathways are important. The function of the protein C system in DIC is impaired because of low levels of protein C and down-regulation of thrombomodulin. The administration of (activated) protein C results in an improved outcome in experimental and clinical studies of DIC. It is unknown whether congenital deficiencies in the protein C system are associated with more severe DIC. The aim of the present study was to investigate the effect of a heterozygous deficiency of protein C on experimental DIC in mice. Mice with single-allele targeted disruption of the protein C gene (PC+/-) mice and wild-type littermates (PC+/+) were injected with Escherichia coli endotoxin (50 mg/kg) intraperitoneally. PC+/-mice had more severe DIC, as evidenced by a greater decrease in fibrinogen level and a larger drop in platelet count. Histologic examination showed more fibrin deposition in lungs, kidneys, and liver in mice with a heterozygous deficiency of protein C. Interestingly, PC+/- mice had significantly higher levels of proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1beta, indicating an interaction between the protein C system and the inflammatory response. Survival was lower at 12 and 24 hours after endotoxin in the PC+/- mice. These results confirm the important role of the protein C system in the coagulative-inflammatory response on endotoxemia and may suggest that congenital deficiencies in the protein C system are associated with more severe DIC and adverse outcome in sepsis.

Animals↗
PubMed2003

Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomised trial.

BACKGROUND: Recombinant activated factor VII (factor VIIa) has prohaemostatic effects in bleeding patients with coagulation abnormalities. We aimed to test the hypothesis that recombinant factor VIIa could reduce perioperative blood loss in patients with normal coagulation systems. Therefore, we assessed safety and efficacy of this drug in patients undergoing retropubic prostatectomy, which is often associated with major blood loss and need for transfusion. METHODS: In a double-blind, randomised placebo-controlled trial, we recorded blood loss and transfusion requirements in 36 patients undergoing retropubic prostatectomy, who were randomised to receive an intravenous bolus of recombinant factor VIIa (20 microg/kg or 40 microg/kg) or placebo in the early operative phase. FINDINGS: Median perioperative blood loss was 1235 mL (IQR 1025-1407) and 1089 mL (928-1320) in groups given recombinant factor VIIa 20 microg/kg and 40 microg/kg, respectively, compared with 2688 mL (1707-3565) in the placebo group (p=0.001). Seven of twelve placebo-treated patients were transfused, whereas no patients who received 40 microg/kg recombinant factor VIIa needed transfusion. The odds ratio for receiving any blood product in patients treated with recombinant factor VIIa compared with control patients was 0 (95% CI 0.00-0.33) No adverse events arose. INTERPRETATION: An injection of recombinant factor VIIa can reduce perioperative blood loss and eliminate the need for transfusion in patients undergoing major surgery.

Aged↗