Biomedical subjects

Bernd Jilma

Publications and source records attributed to Bernd Jilma.

78 records · Page 5Linked to original sources

PubMed2002

Rapid down modulation of P-selectin glycoprotein ligand-1 (PSGL-1, CD162) by G-CSF in humans.

BACKGROUND: In vitro and animal studies suggest a critical role for P-selectin glycoprotein ligand-1 (PSGL-1) in the regulation of WBC adhesion and neutrophil counts. As WBC activation decreases PSGL-1 expression on WBCs in vitro, the effects of G-CSF on PSGL-1 expression were examined. STUDY DESIGN AND METHODS: Two different G-CSF doses (1 and 5 microg/kg IV) were compared with high-dose dexamethasone (1 mg/kg twice daily) and placebo in a randomized, double-blind, four-way cross-over trial in eight healthy volunteers. Surface expression of WBC adhesion molecules was quantified by flow cytometry. RESULTS: Both G-CSF and dexamethasone led to a delayed down regulation of L-selectin. In contrast, G-CSF rapidly down regulated PSGL-1 expression on neutrophils within 90 minutes, whereas neither dexamethasone nor placebo had an effect. Similarly, incubation of WBCs with clinically relevant G-CSF concentrations (60 microg/L) for 90 minutes down modulated PSGL-1 expression on neutrophils and enhanced CD11b expression, compatible with a direct PSGL-1 down regulation by G-CSF-induced neutrophil activation. Similar to G-CSF, GM-CSF down regulated PSGL-1 in vitro. Both drugs induced shedding of soluble PSGL-1, supporting the concept that proteolytic cleavage is a potential mechanism of PSGL-1 down regulation on neutrophils. CONCLUSION: G-CSF, but not dexamethasone, down regulates PSGL-1 expression on the surface of neutrophils in humans. This could also partly explain the synergistic effects when both drugs are combined for optimal mobilization of neutrophils for clinical granulocyte transfusion programs.

Cell Membrane↗

PubMed2002

Acenocoumarol decreases tissue factor-dependent coagulation during systemic inflammation in humans.

BACKGROUND: Coumarin derivatives are still widely used for prophylaxis of thromboembolic events and therefore represent important comparator substances for new anticoagulants. Measurement of the efficacy of such novel compounds in a human coagulation model with adequate biomarkers could be useful for early-phase clinical drug development. To evaluate the applicability of a well-established model of tissue factor-dependent coagulation for defining anticoagulant potency, we investigated the effects of acenocoumarol in experimental human endotoxemia. METHODS: In a randomized, controlled, 2-by-2 factorial design, healthy volunteers received an infusion of 2 ng/kg endotoxin or placebo after 18 days of pretreatment with acenocoumarol or placebo. Prothrombin fragment 1+2 (F(1+2)), soluble fibrin, and D-dimer were used as markers of thrombin and fibrin formation. RESULTS: As expected, pretreatment with acenocoumarol decreased vitamin K-dependent coagulation factors, but it also decreased spontaneous thrombin formation. Acenocoumarol inhibited endotoxin-induced thrombin generation as measured by F(1+2) levels: endotoxin infusion increased F(1+2) levels 8-fold-from 0.5 to 4.1 nmol/L-in the placebo group, whereas peak F(1+2) levels reached only 1.0 nmol/L in subjects after acenocoumarol pretreatment. This inhibition was also reflected in decreased formation of soluble fibrin and decreased D-dimer levels, showing that depletion of endogenous coagulation factors limits the propagation of nonovert disseminated intravascular coagulation. CONCLUSIONS: Human endotoxemia is a suitable tool for measurement of the efficacy of oral anticoagulants and therefore may become a valuable addition for expeditious pharmacodynamic characterization of lead compounds with anticoagulant potency.

Acenocoumarol↗

PubMed2002

Pharmacodynamics of active site-inhibited factor VIIa in endotoxin-induced coagulation in humans.

BACKGROUND: Inhibition of the tissue factor-factor VIIa pathway attenuated the activation of coagulation and prevented death in a gram-negative bacteremia primate model of sepsis. This lethal animal model suggested that tissue factor also influences inflammatory cascades. METHODS: This trial examined the pharmacodynamic effects of active site-inhibited factor VIIa (FFR-recombinant factor VIIa [rFVIIa]; ASIS) on endotoxin-induced procoagulant, fibrinolytic, and inflammatory responses in healthy humans. A double-blind, randomized, placebo-controlled, parallel-group study was conducted in 12 healthy male volunteers. Subjects received a bolus infusion of 2-ng/kg endotoxin, followed by a bolus infusion of ASIS (400 microg/kg) or placebo 10 minutes later. RESULTS: Endotoxin injection induced inflammation, activation of coagulation, and activation and subsequent inhibition of fibrinolysis. ASIS infusion completely blocked thrombin and fibrin generation, as measured by plasma levels of prothrombin fragment (no increase in the ASIS group, as compared with a 13-fold increase in the placebo group at 4 hours; P <.01), soluble fibrin, and fibrin split product D-dimer. ASIS did not alter endotoxin-induced changes in the fibrinolytic system, cytokine levels, or markers of endothelial (E-selectin, thrombomodulin) or platelet (P-selectin) activation. CONCLUSIONS: In summary, ASIS effectively and selectively attenuates tissue factor-induced thrombin generation. Because ASIS was well tolerated, this study provides seminal data to further characterize its anticoagulant and putative anti-inflammatory effects in critically ill patients.

Adult↗

PubMed2002

Effects of granulocyte colony stimulating factor on retinal leukocyte and erythrocyte flux in the human retina.

PURPOSE: The blue-field entoptic technique was introduced more than 20 years ago to quantify perimacular white blood cell flux. However, a final confirmation that the perceived corpuscles represent leukocytes is still unavailable. METHODS: The study design was randomized, placebo-controlled, and double masked with two parallel groups. Fifteen healthy male subjects received a single dose of granulocyte colony stimulating factor (G-CSF, 300 microg) and 15 other subjects received placebo. The following parameters were assessed at baseline and at 12 minutes and 8 hours after administration: retinal white blood cell flux, with the blue-field entoptic technique; retinal blood velocities, with bidirectional laser Doppler velocimetry; retinal venous diameter determined with a retinal vessel analyzer; and blood pressure and pulse rate determined by automated oscillometry and pulse oxymetry, respectively. RESULTS: After 12 minutes, G-CSF reduced total leukocyte count from 5.5 +/- 1.4 10(9)/L at baseline to 1.9 +/- 0.4 10(9)/L. This was paralleled by a 35% +/- 11% decrease in retinal white blood cell density. After 8 hours G-CSF increased total leukocyte counts to 20.0 +/- 4.4 10(9)/L. Again, this increase in circulating leukocytes was reflected by an increase in retinal white blood cell density (110% +/- 48%). All effects were significant at P < 0.001. By contrast, none of the other hemodynamic parameters was changed by administration of G-CSF. CONCLUSIONS: The results clearly indicate that the blue-field entoptic technique assesses leukocyte movement in the perimacular capillaries of the retina. Moreover, white blood cell density appears to adequately reflect the number of circulating leukocytes within the retinal microvasculature. Hence, an increase in retinal white blood cell density does not necessarily reflect retinal vasodilatation.

Adult↗

PubMed2002

Evaluation of coagulation markers for early diagnosis of acute coronary syndromes in the emergency room.

BACKGROUND: Diagnosis of acute coronary syndromes (ACS) is a major challenge for emergency physicians. Because soluble fibrin (sF) has been suggested as a potential early marker of impending myocardial ischemia, we were interested whether a sF bedside test could help in early identification of patients with ACS in the emergency department. METHODS: We evaluated plasma coagulation markers, including a newly developed sF bedside test, prothrombin fragment (F(1+2)), sF, and D-dimer, in a cross-sectional trial with 184 patients suggestive of ACS. RESULTS: Whereas 76% (13 of 17) of patients with unstable angina pectoris (UAP) had a positive sF bedside test, only 10 of 33 patients (30%) with non-ST-segment-elevation myocardial infarction and 10 of 44 patients (23%) with ST-elevation myocardial infarction tested positive. Three percent of controls (1 of 33) and 11% of patients (6 of 57) with preexisting stable angina had a positive sF bedside test (P <0.001 for noncardiac chest pain vs ACS), yielding an overall specificity of 92% and a sensitivity of 35%. The sensitivity of the established coagulation markers was significantly less to detect ACS (11% for F(1+2), 20% for thrombus precursor protein, and 18% for D-dimer; P <0.02 vs sF bedside test). The sF bedside test presented the earliest objective indicator of impending myocardial damage in the majority (10 of 13) of ACS patients with a normal or nondiagnostic electrocardiogram (ECG). CONCLUSIONS: A sF bedside test offers a specific tool for early identification of patients with ACS in an emergency department setting, although its sensitivity seems sufficient only for the early identification of patients with UAP. A sF bedside test could be useful, particularly in UAP patients with a nondiagnostic ECG.

Acute Disease↗

PubMedDate not supplied

Homozygosity in the single nucleotide polymorphism Ser128Arg in the E-selectin gene associated with recurrent venous thromboembolism.

BACKGROUND: The single nucleotide polymorphism (SNP) Ser128Arg in the E-selectin gene is overrepresented in certain patient populations with atherosclerosis or restenosis. As this SNP enhances tissue factor-triggered coagulation in humans during systemic inflammation, we hypothesized that it may also predispose for the development of recurrent venous thromboembolism (VTE). METHODS: A total of 585 patients were prospectively observed after first VTE for recurrent, objectively documented, symptomatic VTE. Patients with secondary VTE, homozygous factor V Leiden, natural inhibitor deficiencies, lupus anticoagulant, or long-term anticoagulation therapy were excluded. The S128R SNP was genotyped by mutagenically separated polymerase chain reaction. RESULTS: A total of 102 patients (17%) were heterozygous, and 11 were homozygous (2%) for the Ser128Arg mutation. Ninety patients (15%) had recurrent VTE during follow-up. Homozygosity for the Ser128Arg SNP increased the cumulative likelihood, particularly for early recurrent VTE (log rank test, P<.05) and was an independent predictor of recurrent VTE (hazard ratio [HR], 4.1; 95% confidence interval [CI], 1.5-11.4) in a multivariate Cox regression model. In contrast, heterozygosity for the polymorphism was associated with an unaltered HR (HR, 1.1; 95% CI, 0.6-1.9) for recurrent VTE. CONCLUSIONS: Homozygosity for the S128R E-selectin allele appears to increase the risk for recurrent VTE several fold. If these findings are confirmed, this may represent a novel risk factor for recurrent VTE. These results also expand our knowledge on the association of this SNP with thrombotic disorders.

Adult↗