Biomedical subjects
Publications and source records attributed to Richard C Becker.
Explore the source record for details and available documents.
BACKGROUND: Temperature variation within human atheromatous plaques, a finding which supports inflammatory cell-mediated thermogenesis, predicts clinical events among patients with coronary artery disease. PURPOSE: Our study was designed to investigate the effect of ambient temperature in vitro on platelet-leukocyte interactions, monocyte tissue factor expression and platelet-dependent thrombin generation. METHODS/RESULTS: Whole blood samples obtained from healthy volunteers were incubated at 37 degrees, 38 degrees and 39 degrees C for three hours. Platelet-leukocyte aggregates, determined by flow cytometry before and after stimulation with lipopolysaccharide (10 ng/ml), increased from 15.0 +/- 2.3% at 37 degrees C to 19.4% at 38 degrees C (22.6% increase; p < 0.01), decreasing to 12.2 +/- 0.9% at 39 degrees C. The responses for individual subpopulations of platelet-lymphocyte, platelet-neutrophil and platelet-monocyte heterotypic aggregates were similar. Monocyte tissue factor expression, quantitated by flow cytometry with CD14 and FITC-labeled anti-human tissue factor antibody stains, increased from 45.2 +/- 3.8% (37 degrees C) to 62.0 +/- 4.3 (38 degrees C), representing a 27.1% rise (p < 0.005). Changes in temperature did not influence the initiation or propagation phases of platelet-dependent thrombin generation. CONCLUSION: A modest increase in ambient temperature increases platelet-leukocyte and monocyte tissue factor expression, providing an additional mechanistic link between atherosclerosis, inflammation and thrombosis. Whether therapies designed to lower vessel wall temperature will provide an antithrombotic effect requires further evaluation.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
BACKGROUND: Tissue factor (TF), a membrane-bound glycoprotein that initiates blood coagulation by allosteric activation of factor (f) VII, is regulated predominantly by tissue factor pathway inhibitor (TFPI). Because vascular endothelial cells synthesize and constitutively secrete TFPI and fXa may directly influence its cellular clearance, we sought to determine the effects of DX-9065a, a direct and selective fXa inhibitor, on TFPI kinetics in culture. METHODS/RESULTS: Human umbilical vein endothelial cells were grown to confluence and incubated with unfractionated heparin (1.0 U/mL), enoxaparin (1.5 U/mL), or DX-9065a at low (10 ng/ml), moderate (30 ng/ml), or high (90 ng/ml) concentrations. Compared to control, increases in TFPI were seen with both unfractionated heparin (182% higher, p < 0.001) and enoxaparin (194% higher, p < 0.001). Low concentration DX-9065a did not increase TFPI levels above control (0.8% higher, p = 0.91). In contrast, moderate and high concentrations produced 124% higher (p < 0.001) and 198% higher (p < 0.001) TFPI concentrations than control, respectively. CONCLUSIONS: DX-9065a increases vascular endothelial cell TFPI concentrations in human tissue culture. Although the mechanism has yet to be established, decreased fXa availability may limit fXa-TFPI complex formation and its subsequent cellular uptake. Whether increased surface TFPI contributes to the overall anticoagulant profile of DX-9065a will require further investigation.
Explore the source record for details and available documents.
Clinical trials and accompanying substudies in patients with acute coronary syndromes (ACS) have over the last several years yielded a wealth of knowledge about the pathophysiology and management of this high-risk condition. The Superior Yield of the New strategy of Enoxaparin, Revascularization, and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial is a large-scale, randomized, controlled trial evaluating the effect of enoxaparin and unfractionated heparin on death and myocardial infarction in high-risk patients presenting with non-ST-segment elevation ACS. The SYNERGY Library has been designed as a coordinated series of investigations with simultaneous data acquisition on the same cohort of approximately 500 SYNERGY patients at 60 centers in North America. Specifically, electrocardiograms, coronary arteriograms, inflammatory markers, coagulation studies, and genetic samples will be collected and processed at core laboratory facilities, and the results will be stored in a central repository. This novel strategy for substudy investigation is unprecedented in cardiovascular clinical trials. The goal is to gain significant understanding about this patient population, discover new principles of pathophysiology, identify novel pharmacologic targets, and streamline further drug development. It is hoped that the SYNERGY Library will serve as a model for future substudy design to maximize academic insight within the framework of a large-scale, multicenter trial.
Explore the source record for details and available documents.
The development of anticoagulants for treating patients with atherothrombotic disorders of the arterial circulatory system has focused, either directly or indirectly, on thrombin - a pleuripotential effector enzyme with prothrombotic and proinflammatory properties. The pivotal role of factor (f) Xa in thrombin generation, coupled with its direct cellular effects and widely recognized limitations of currently available anticoagulants, has led to the development of pharmacologic inhibitors of this important protease. The following review focuses on DX-9065a - first in a class of direct, selective and reversible fXa antagonists - and its potential applications in the management of patients with cardiovascular disease.
This chapter about antithrombotic therapy for coronary artery disease (CAD) is part of the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this chapter are the following: For patients presenting with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS), we recommend immediate and then daily oral aspirin (Grade 1A). For patients with an aspirin allergy, we recommend immediate treatment with clopidogrel, 300-mg bolus po, followed by 75 mg/d indefinitely (Grade 1A). In all NSTE ACS patients in whom diagnostic catheterization will be delayed or when coronary bypass surgery will not occur until > 5 days, we recommend clopidogrel as bolus therapy (300 mg), followed by 75 mg/d for 9 to 12 months in addition to aspirin (Grade 1A). In NSTE ACS patients in whom angiography will take place within 24 h, we suggest beginning clopidogrel after the coronary anatomy has been determined (Grade 2A). For patients who have received clopidogrel and are scheduled for coronary bypass surgery, we recommend discontinuing clopidogrel for 5 days prior to the scheduled surgery (Grade 2A). In moderate- to high-risk patients presenting with NSTE ACS, we recommend either eptifibatide or tirofiban for initial (early) treatment in addition to treatment with aspirin and heparin (Grade 1A). For the acute treatment of NSTE ACS, we recommend low molecular weight heparins over unfractionated heparin (UFH) [Grade 1B] and UFH over no heparin therapy use with antiplatelet therapies (Grade 1A). We recommend against the direct thrombin inhibitors as routine initial antithrombin therapy (Grade 1B). For patients after myocardial infarction, after ACS, and with stable CAD, we recommend aspirin in doses from 75 to 325 mg as initial therapy and in doses of 75 to 162 mg as indefinite therapy (Grade 1A). For patients with contraindications to aspirin, we recommend long-term clopidogrel (Grade 1A). For primary prevention in patients with at least moderate risk for a coronary event, we recommend aspirin, 75 to 162 mg/d, over either no antithrombotic therapy or vitamin K antagonist (VKA) [Grade 2A]; for patients at particularly high risk of events in whom the international normalized ratio (INR) can be monitored without difficulty, we suggest low-dose VKA (target INR, 1.5) [Grade 2A].
Explore the source record for details and available documents.
Explore the source record for details and available documents.
BACKGROUND: The association between the inherited gene mutations of factor V, prothrombin, and homocysteine metabolism and venous thromboembolic events is accepted widely; however, their influence on the arterial circulatory system remains controversial. METHODS: We performed a MEDLINE search to identify published case-control and cohort studies correlating the factor V Leiden, prothrombin (PT) G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T (TT genotype) mutations with myocardial infarction, ischemic stroke, or peripheral vascular disease. Studies were included only when they adhered to specific diagnostic criteria for ischemic events and met the published methodological criteria. Odds ratios (ORs) with accompanying 95% CIs were calculated for each mutation and clinical end points with a random-effects model (DerSimonian and Laird method). RESULTS: The association between inherited gene mutations and arterial ischemic events was modest: factor V Leiden mutation (OR, 1.21; 95% CI, 0.99-1.49), PT G20210A mutation (OR, 1.32; 95% CI, 1.03-1.69), and MTHFR TT mutation (OR, 1.20; 95% CI, 1.02-1.41). Subgroup analyses of younger patients (<55 years old) and of women revealed slightly stronger associations overall. CONCLUSIONS: Genetic abnormalities specific to factor V, prothrombin,and homocysteine metabolism increase the risk for myocardial infarction and ischemic stroke, particularly among younger patients and women. Because the overall association is only modest, screening studies should be limited to carefully selected patient populations. The individual propensity for arterial and venous thrombosis is likely influenced by differing local mechanisms, systemic mechanisms, or both.
Explore the source record for details and available documents.
BACKGROUND: Fibrinolytic therapy represents a widely available and effective treatment modality for ST segment elevation myocardial infarction (MI). Its overall benefit is attenuated by a high incidence of coronary arterial reocclusion. METHODS/RESULTS: Human umbilical vein endothelial cells (HUVEC) were incubated with unfractionated heparin (1.5 U/ml) (to provoke tissue factor pathway inhibitor [TFPI] release) followed by the addition of varying concentrations of alteplase (recombinant tissue plasminogen activator), plasminogen, their combination or plasmin alone. In the presence of 20% TFPI-depleted human plasma, there was a concentration-dependent decrease in TFPI levels following incubation with alteplase (28% reduction at 200 ng/ml; P < 0.01); 37% reduction at 1000 ng/ml (P < 0.001). Similar effects were observed for alteplase combined with plasminogen (P < 0.001), plasmin alone (P < 0.001) and with HUVEC incubated with low concentrations of plasmin (10 ng/ml) prior to heparin exposure. CONCLUSIONS: Plasmin, a non-specific protease, degrades vascular endothelial cell (constitutive) TFPI and heparin-releasable TFPI, attenuating an important pathway of vascular surface thromboresistance and potentially contributing to coronary arterial reocclusion after fibrinolytic therapy.
Atherosclerotic disease is recognized as a chronic inflammatory disorder with intermittent and widely variable phases of cellular proliferation and heightened thrombotic activity. The multi-tiered links between inflammation, atherogenesis and thrombogenesis provide a unique opportunity for research and development of pharmaceuticals which target one or more critical pathobiologic steps (Fig. 1). The purpose of the following review on heparin compounds is to comprehensively examine the multi-cellular, pleuripotential effects of a commonly used anticoagulant drug in the context of normal and disease-altered vascular responses and illustrate possible constructs for avenues of subsequent investigation in the field of atherothrombosis. The overview is divided into five integrated parts; antiinflammatory properties of the normal vessel wall, the relationship between glycosaminoglycans and inflammation, heparin-mediated effects on cellular inflammatory responses, association between molecular weight and antiinflammatory capabilities, and oral heparin compounds for achieving prolonged cell-based inhibition.
Explore the source record for details and available documents.
Explore the source record for details and available documents.