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Biomedical subjects

Harry R Büller

Publications and source records attributed to Harry R Büller.

At least 19 recordsLinked to original sources
PubMed2006

Effects on coagulation and fibrinolysis induced by influenza in mice with a reduced capacity to generate activated protein C and a deficiency in plasminogen activator inhibitor type 1.

Influenza infections increase the risk of diseases associated with a prothrombotic state, such as venous thrombosis and atherothrombotic diseases. However, it is unclear whether influenza leads to a prothrombotic state in vivo. To determine whether influenza activates coagulation, we measured coagulation and fibrinolysis in influenza-infected C57BL/6 mice. We found that influenza increased thrombin generation, fibrin deposition, and fibrinolysis. In addition, we used various anti- and prothrombotic models to study pathways involved in the influenza-induced prothrombotic state. A reduced capacity to generate activated protein C in TM(pro/pro) mice increased thrombin generation and fibrinolysis, whereas treatment with heparin decreased thrombin generation in influenza-infected C57Bl/6 mice. Thrombin generation was not changed in hyperfibrinolytic mice, deficient in plasminogen activator inhibitor type-1 (PAI-1(-/-)); however, increased fibrin degradation was seen. Treatment with tranexamic acid reduced fibrinolysis, but thrombin generation was unchanged. We conclude that influenza infection generates thrombin, increased by reduced levels of protein C and decreased by heparin. The fibrinolytic system appears not to be important for thrombin generation. These findings suggest that influenza leads to a prothrombotic state by coagulation activation. Heparin treatment reduces the influenza induced prothrombotic state.

Animals↗
PubMed2006

Combined utility of brain natriuretic peptide and cardiac troponin T may improve rapid triage and risk stratification in normotensive patients with pulmonary embolism.

BACKGROUND: Evaluation of the combined utility of brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) for risk stratification in normotensive patients with acute pulmonary embolism. The changing patterns of BNP and cTnT levels during the initial management of pulmonary embolism and their correlation with clinical outcome were the focus of this study. METHODS: BNP and cTnT levels were measured in 28 consecutive normotensive on admission patients (age 53+/-18 years) with acute pulmonary embolism. Twenty-seven healthy age-matched volunteers served as controls (age 42+/-12 years). Blood samples from all patients were obtained during the first hour of presentation. Follow-up blood samples were acquired after 90 days. RESULTS: Six patients (2%) had increased BNP (59+/-30 pmol/L) and cTnT (0.044+/-0.025 ng/mL) and RV dysfunction as diagnosed by echocardiography. Two of these patients died during follow-up as a consequence of RV failure due to pulmonary embolism. Eight patients (29%) had increased BNP (40.6+/-32.6 pmol/L) and normal cTnT at presentation. In four of these patients BNP levels remained increased after treatment (46.9+/-21.0 pmol/L). During follow-up these patients were diagnosed with chronic PE and RV pressure overload (RVSP>40 mm Hg). Fourteen patients (50%) with confirmed pulmonary embolism had normal BNP and cTnT levels at presentation, which remained normal during follow-up. These 14 patients were in good clinical condition during follow-up. CONCLUSIONS: Combined use of BNP and cTnT may be useful in risk stratification of normotensive patients with acute pulmonary embolism. Patients with increased BNP and cTnT are at risk for adverse outcome. Future studies in larger numbers of patients are needed to confirm the usefulness of biomarkers in the clinical management of individual patients.

Adult↗
PubMed2006

Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography.

CONTEXT: Previous studies have evaluated the safety of relatively complex combinations of clinical decision rules and diagnostic tests in patients with suspected pulmonary embolism. OBJECTIVE: To assess the clinical effectiveness of a simplified algorithm using a dichotomized clinical decision rule, D-dimer testing, and computed tomography (CT) in patients with suspected pulmonary embolism. DESIGN, SETTING, AND PATIENTS: Prospective cohort study of consecutive patients with clinically suspected acute pulmonary embolism, conducted in 12 centers in the Netherlands from November 2002 through December 2004. The study population of 3306 patients included 82% outpatients and 57% women. INTERVENTIONS: Patients were categorized as "pulmonary embolism unlikely" or "pulmonary embolism likely" using a dichotomized version of the Wells clinical decision rule. Patients classified as unlikely had D-dimer testing, and pulmonary embolism was considered excluded if the D-dimer test result was normal. All other patients underwent CT, and pulmonary embolism was considered present or excluded based on the results. Anticoagulants were withheld from patients classified as excluded, and all patients were followed up for 3 months. MAIN OUTCOME MEASURE: Symptomatic or fatal venous thromboembolism (VTE) during 3-month follow-up. RESULTS: Pulmonary embolism was classified as unlikely in 2206 patients (66.7%). The combination of pulmonary embolism unlikely and a normal D-dimer test result occurred in 1057 patients (32.0%), of whom 1028 were not treated with anticoagulants; subsequent nonfatal VTE occurred in 5 patients (0.5% [95% confidence interval {CI}, 0.2%-1.1%]). Computed tomography showed pulmonary embolism in 674 patients (20.4%). Computed tomography excluded pulmonary embolism in 1505 patients, of whom 1436 patients were not treated with anticoagulants; in these patients the 3-month incidence of VTE was 1.3% (95% CI, 0.7%-2.0%). Pulmonary embolism was considered a possible cause of death in 7 patients after a negative CT scan (0.5% [95% CI, 0.2%-1.0%]). The algorithm was completed and allowed a management decision in 97.9% of patients. CONCLUSIONS: A diagnostic management strategy using a simple clinical decision rule, D-dimer testing, and CT is effective in the evaluation and management of patients with clinically suspected pulmonary embolism. Its use is associated with low risk for subsequent fatal and nonfatal VTE.

Adult↗
PubMed2006

Low incidence of deep vein thrombosis after knee arthroscopy without thromboprophylaxis: a prospective cohort study of 335 patients.

BACKGROUND: There is little data on the risk of deep vein thrombosis after knee arthroscopy. PATIENTS AND METHODS: We performed a prospective cohort study to establish the incidence of venous thrombo-embolic (VTE) complications after knee arthroscopy in daycare, as detected by bilateral complete compression ultrasonography (CCUS) at day 14 (11-17) postoperatively. 335 patients completed bilateral extended ultrasound. No thromboprophylaxis was given. RESULTS: 19 (5.7%; 95% CI: 3.5%-8.7%) showed VTE on CCUS, of whom 2 were symptomatic. 1 patient developed a non-fatal pulmonary embolus during the 8-week follow-up period. There was no difference in immobilization characteristics between the patients who developed postoperative DVT and those who did not; nor could other risk factors be identified. INTERPRETATION: Since the incidence of VTE is low and a specific high-risk group for the development of VTE could not be identified, it seems justified to withhold routine pharmacological thromboprophylaxis after arthroscopy of the knee in a daycare setting.

Adult↗
PubMed2006

Endotoxaemia induces resistance to activated protein C in healthy humans.

Systemic inflammation activates the tissue factor/factor VIIa complex (TF/FVIIa), leading to a procoagulant state, which may be enhanced by impairment of physiological anticoagulant pathways, such as the protein C system. Besides impaired protein C activation, resistance to activated protein C (APC) may occur. We studied the effect of endotoxemia on APC resistance, analysed its determinants and evaluated the effect of TF/FVIIa inhibition on endotoxin-induced APC resistance. Sixteen healthy male volunteers participated in the study, eight receiving endotoxin alone and eight receiving the combination of endotoxin and recombinant Nematode Anticoagulant Protein c2 (rNAPc2), a potent inhibitor of TF/FVIIa. Parameters of coagulation were subsequently studied. The sensitivity to APC was determined by two tests: a test based on the endogenous thrombin potential and a test based on the activated partial thromboplastin time. In response to endotoxemia, both tests detected a transient APC resistance that was predominantly mediated by an increase in factor VIII and was not influenced by TF/FVIIa inhibition. In vitro tests confirmed that an increase in factor VIII induced APC resistance, as measured by both tests. This finding suggests that APC resistance might play a role in the procoagulant state occurring during human endotoxemia.

Activated Protein C Resistance↗
PubMed2006

Symptomatic peripheral arterial disease: the value of a validated questionnaire and a clinical decision rule.

BACKGROUND: If a validated questionnaire, when applied to patients reporting with symptoms of intermittent claudication, could adequately discriminate between those with and without peripheral arterial disease, GPs could avoid the diagnostic measurement of the ankle brachial index. AIM: To investigate the Edinburgh Claudication Questionnaire (ECQ) in general practice and to develop a clinical decision rule based on risk factors to enable GPs to easily assess the likelihood of peripheral arterial disease. DESIGN OF STUDY: An observational study. SETTING: General practice in The Netherlands. METHOD: This observational study included patients of > or =55 years visiting their GP for symptoms suggestive of intermittent claudication or with one risk factor. The ECQ and the ankle brachial index were performed. The prevalence of peripheral arterial disease, defined as an ankle brachial index <0.9, was related to risk factors using logistic regression analyses, on which a clinical decision rule was developed and related to the presence of peripheral arterial disease. RESULTS: Of the 4790 included patients visiting their GP with symptoms suggestive of intermittent claudication, 4527 were eligible for analyses. The prevalence of peripheral arterial disease in this group was 48.3%. The sensitivity of the ECQ was only 56.2%. The prevalence of peripheral arterial disease in a clinical decision rule that included age, male sex, smoking, hypertension, hypercholesterolemia, and a positive ECQ, increased from 14% in the lowest to 76% in the highest category. CONCLUSION: This study indicates that the ECQ alone has an inadequate diagnostic value in detecting patients with peripheral arterial disease. The ankle brachial index should be performed to diagnose peripheral arterial disease in patients with complaints suggestive of intermittent claudication, although our clinical decision rule could help to differentiate between extremely high and lower prevalence of peripheral arterial disease.

Aged↗
PubMed2005

A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk.

BACKGROUND: A C1173T polymorphism in intron 1 of the VKORC1 gene has been claimed to determine the interindividual variability in the response to vitamin K antagonist therapy (VKA), but it is unknown whether it also influences bleeding risk. We aimed to confirm the relationship between C1173T status and phenprocoumon or acenocoumarol use, and to examine the risk of severe bleeding for the various genotypes. METHODS AND FINDINGS: We studied this in a case-control study of 110 patients who bled during VKA therapy and 220 control patients free of bleeding under the same therapy. To achieve the same target INR, CT genotype and TT genotype control patients required less phenprocoumon (CC genotype 2.9 mg/d [95% confidence interval (CI): 2.6-3.2], CT genotype 2.6 mg/d [95% CI: 2.1-3.1], TT genotype 1.4 mg/d [95 % CI: 1.1-1.7]) or acenocoumarol (CC genotype 3.2 mg/d [95% CI: 2.9-3.5], CT genotype 2.3 mg/d [95% CI: 2.1-2.5], TT genotype 1.7 mg/d [95% CI: 1.3-2.1]) than CC genotype control patients. Compared with CC genotype individuals, carriers of at least one T allele had an increased risk of bleeding in the phenprocoumon users (crude odds ratio = 2.6, 95% CI: 1.2-5.7), but not in acenocoumarol users (crude odds ratio = 1.2, 95% CI: 0.6-2.3). CONCLUSION: These findings encourage taking further steps towards the evaluation of the use of VKORC1 genetic testing for bleeding prevention in individuals who receive VKA therapy.

Acenocoumarol↗
PubMed2005

Risk of thromboembolism and bleeding after general surgery in patients with atrial fibrillation.

We provide insight into the risk of perioperative thromboembolism and bleeding in patients who have atrial fibrillation, use anticoagulants, and undergo a surgical procedure. Ninety-four patients underwent 121 noncardiac operations during a mean follow-up of 29 months. There was a 3.6-fold increased risk for all bleeding complications within 1 month after surgery compared with the control period (95% confidence interval 1.05 to 12.0). No thromboembolic event occurred in the first month after surgery compared with 11 events in the remaining period (0.4% per month).

Aged↗
PubMed2005

Cerebral white matter lesions predict both ischemic strokes and myocardial infarctions in patients with established atherosclerotic disease.

BACKGROUND: Cerebral white matter lesions (WML) are regarded as manifestations of small vessel disease, but have also been associated with large vessel atherosclerosis. We investigated whether WML have a predictive value for future ischemic events. METHODS AND RESULTS: Two-hundred-thirty patients with proven atherosclerotic disease, recent ischemic stroke (IS, n=70), recent myocardial infarction (MI, n=71), or peripheral arterial disease (PAD, n=89) were included. The presence of periventricular lesions (PVL) and deep white matter lesions (DWML) on MRI at entry and ischemic events during follow-up were registered. During follow-up with a mean duration of 3.5+/-1.4 years 22 patients had a MI, 21 patients suffered an IS and 2 patients died suddenly. The frequency of ischemic events during follow-up was higher among patients with PVL than in those without PVL (IS: 18% versus 5%, p=0.001; MI: 15% versus 7%, p=0.03; any ischemic event: 36% versus 11%, p<0.001). DWML was associated only with the combined outcome any ischemic event (p=0.04). In multivariate regression analysis the presence of PVL was independently associated with IS (HR 3.2 (95%CI 1.3-8.4) and MI (HR 3.4 (95%CI 1.4-8.0)). CONCLUSION: We observed an association between WML, especially PVL, and future ischemic strokes and myocardial infarctions in patients with established atherosclerotic disease.

Aged↗
PubMed2005

Recombinant human activated protein C resets thrombin generation in patients with severe sepsis - a case control study.

INTRODUCTION: Recombinant human activated protein C (rhAPC) is the first drug for which a reduction of mortality in severe sepsis has been demonstrated. However, the mechanism by which this reduction in mortality is achieved is still not clearly defined. The aim of the present study was to evaluate the dynamics of the anticoagulant, anti-inflammatory and pro-fibrinolytic action of rhAPC in patients with severe sepsis, by comparing rhAPC-treated patients with case controls. METHODS: In this prospectively designed multicenter case control study, 12 patients who were participating in the ENHANCE study, an open-label study of rhAPC in severe sepsis, were treated intravenously with rhAPC at a constant rate of 24 microg/kg/h for a total of 96 h. Twelve controls with severe sepsis matching the inclusion criteria received standard therapy. The treatment was started within 48 h after the onset of organ failure. Blood samples were taken before the start of the infusion and at 4, 8, 24, 48, 96 and 168 h, for determination of parameters of coagulation and inflammation. RESULTS: Sepsis-induced thrombin generation as measured by thrombin-antithrombin complexes and prothrombin fragment F1+2, was reset by rhAPC within the first 8 h of infusion. The administration of rhAPC did not influence parameters of fibrinolysis and inflammation. There was no difference in outcome or occurrence of serious adverse events between the treatment group and the control group. CONCLUSION: Sepsis-induced thrombin generation in severely septic patients is reset by rhAPC within the first 8 h of infusion without influencing parameters of fibrinolysis and inflammation.

Analysis of Variance↗
PubMed2005

Combined training of GPs and practice-assistants on peripheral arterial disease: positive effects after six months.

OBJECTIVES: To improve the use of the ankle-brachial index (ABI) measurement, and management of patients with peripheral arterial disease (PAD) a combined training, targeting GPs and practice assistants (PAs) was developed. To measure the effect of the combined training on the management of patients with PAD, a cross-sectional study was performed. METHODS: Fifty consecutive patients referred by GPs to a vascular surgery out-patient clinic were analysed. Six months after the training an additional fifty patients were included. In all patients the ABI measurement, risk factor management, and treatment as performed by the GP, prior to referral, were analysed. RESULTS: The measurement of the ABI significantly increased from 10% before the training to 53% after the training (GPs with training: 83%, GPs without training: 35%; P: 0.001). The referral of patients with actual PAD significantly increased from 32% before the training to 70% after the training (GPs with training: 83%, GPs without training: 59%; P: 0.05). The presence and treatment of risk factors did not differ between the groups. CONCLUSIONS: Within the limitations of a before and after study the combined training of GPs and PAs appears to be an effective method to increase ABI measurements and significantly improve adequate diagnostics.

Aged↗
PubMed2005

The effect of low molecular weight heparin on survival in patients with advanced malignancy.

PURPOSE: Studies in cancer patients with venous thromboembolism suggested that low molecular weight heparin may prolong survival. In a double-blind study, we evaluated the effect of low molecular weight heparin on survival in patients with advanced malignancy without venous thromboembolism. METHODS: Patients with metastasized or locally advanced solid tumors were randomly assigned to receive a 6-week course of subcutaneous nadroparin or placebo. The primary efficacy analysis was based on time from random assignment to death. The primary safety outcome was major bleeding. RESULTS: In total, 148 patients were allocated to nadroparin and 154 patients were allocated to placebo. Mean follow-up was 1 year. In the intention-to-treat analysis the overall hazard ratio of mortality was 0.75 (95% CI, 0.59 to 0.96) with a median survival of 8.0 months in the nadroparin recipients versus 6.6 months in the placebo group. After adjustment for potential confounders, the treatment effect remained statistically significant. Major bleeding occurred in five (3%) of nadroparin-treated patients and in one (1%) of the placebo recipients (P = .12). In the a priori specified subgroup of patients with a life expectancy of 6 months or more at enrollment, the hazard ratio was 0.64 (95% CI, 0.45 to 0.90) with a median survival of 15.4 and 9.4 months, respectively. For patients with a shorter life expectancy, the hazard ratio was 0.88 (95% CI, 0.62 to 1.25). CONCLUSION: A brief course of subcutaneous low molecular weight heparin favorably influences the survival in patients with advanced malignancy and deserves additional clinical evaluation.

Adult↗