PubMed Health⌕ Search

Biomedical subjects

R C Becker

Publications and source records attributed to R C Becker.

At least 37 records · Page 2Linked to original sources
PubMed2000

The scientific basis for combined platelet and thrombin-directed pharmacotherapy in acute coronary syndromes.

There exists incontrovertible scientific evidence that vascular endothelial cell dysfunction and atheromatous plaque disruption are causative pathobiologic events governing the clinical expression of disease in humans with coronary arteriosclerosis. A comprehensive understanding of vascular biology, platelet behavior, and coagulation protein bioamplification sequences forms the scientific basis for pharmacotherapy in acute coronary syndromes (ACS), and identifies the platelet as an attractive target. The three Food and Drug Administration-approved glycoprotein (GP) IIb/IIIa antagonists effectively prevent platelet aggregation. In vitro experiments also showed a dose-dependent decrease in prothrombinase activity and thrombin generation revealing that the GP IIb/IIIa antagonists possess anticoagulant properties as well. Combination pharmacotherapy in ACS is supported by the contribution of platelets and coagulation proteins to coronary artery thrombosis. While unfractionated heparin (UFH) is commonly used conjunctively with GP IIb/IIIa antagonists, several inherent limitations exist, including unpredictable pharmacodynamics, no established therapeutic standards, and the fact that the use of UFH has been associated with platelet activation. Low-molecular-weight heparin preparations offer several potential advantages over UFH: a greater degree of Xa inhibition; more predictable pharmacokinetic profile; the absence of significant platelet activation; and the confirmation of clinical superiority in several large-scale clinical trials. Randomized trials will be required to establish the full clinical impact of combined pharmacotherapy in ACS.

Acute Disease↗
PubMed1999

Management strategies in unstable coronary artery disease--current problems and future directions. The UCAD Council.

Unstable coronary artery disease continues to pose a major challenge to clinicians. The advent of new therapies, such as percutaneous transluminal coronary angioplasty, low-molecular-weight heparins, and glycoprotein IIb/IIIa inhibitors, provides new management options for this indication but also raises new questions with regard to optimal management. Prospective randomized trials with well-defined, long-term outcome measures and a means of identifying which patients will derive most benefit from each treatment, together with a means of rapid and clear dissemination of study results and implications, are required in order to advance the management of unstable coronary artery disease.

Angina, Unstable↗
PubMed1999

A randomized, multicenter trial of weight-adjusted intravenous heparin dose titration and point-of-care coagulation monitoring in hospitalized patients with active thromboembolic disease. Antithrombotic Therapy Consortium Investigators.

BACKGROUND: Therapy with intravenous unfractionated heparin improves clinical outcome in patients with active thromboembolic disease, but achieving and maintaining a therapeutic level of anticoagulation remains a major challenge for clinicians. METHODS: A total of 113 patients requiring heparin for at least 48 hours were randomly assigned at 7 medical centers to either weight-adjusted or non-weight-adjusted dose titration. They were separately assigned to either laboratory-based or point-of-care (bedside) coagulation monitoring. RESULTS: Weight-adjusted heparin dosing yielded a higher mean activated partial thromboplastin time (aPTT) value 6 hours after treatment initiation than non-weight-adjusted dosing (99.9 vs 78.8 seconds; P =.002) and reduced the time required to exceed a minimum threshold (aPTT >45 seconds) of anticoagulation (10.5 vs 8.6 hours; P =.002). Point-of-care coagulation monitoring significantly reduced the time from blood sample acquisition to a heparin infusion adjustment (0.4 vs 1.6 hours; P <.0001) and to reach the therapeutic aPTT range (51 to 80 seconds) (16.1 vs 19.4 hours; P =.24) compared with laboratory monitoring. Although a majority of patients participating in the study surpassed the minimum threshold of anticoagulation within the first 12 hours and reached the target aPTT within 24 hours, maintaining the aPTT within the therapeutic range was relatively uncommon (on average 30% of the overall study period) and did not differ between treatment or monitoring strategies. CONCLUSIONS: Weight-adjusted heparin dosing according to a standardized titration nomogram combined with point-of-care coagulation monitoring using the BMC Coaguchek Plus System represents an effective and widely generalizable strategy for managing patients with thromboembolic disease that fosters the rapid achievement of a desired range of anticoagulation. Additional work is needed, however, to improve on existing patient-specific strategies that can more effectively sustain a therapeutic state of anticoagulation.

Adult↗
PubMed1999

Fatal cardiac rupture among patients treated with thrombolytic agents and adjunctive thrombin antagonists: observations from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction 9 Study.

OBJECTIVES: The purpose of this study was to determine the incidence and demographic characteristics of patients experiencing cardiac rupture after thrombolytic and adjunctive anticoagulant therapy and to identify possible associations between the mechanism of thrombin inhibition (indirect, direct) and the intensity of systemic anticoagulation with its occurrence. BACKGROUND Cardiac rupture is responsible for nearly 15% of all in-hospital deaths among patients with myocardial infarction (MI) given thrombolytic agents. Little is known about specific patient- and treatment-related risk factors. METHODS Patients (n = 3,759) with MI participating in the Thrombolysis and Thrombin Inhibition in Myocardial Infarction 9A and B trials received intravenous thrombolytic therapy, aspirin and either heparin (5,000 U bolus, 1,000 to 1,300 U/h infusion) or hirudin (0.1 to 0.6 mg/kg bolus, 0.1 to 0.2 mg/kg/h infusion) for at least 96 h. A diagnosis of cardiac rupture was made clinically in patients with sudden electromechanical dissociation in the absence of preceding congestive heart failure, slowly progressive hemodynamic compromise or malignant ventricular arrhythmias. RESULTS A total of 65 rupture events (1.7%) were reported-all were fatal, and a majority occurred within 48 h of treatment Patients with cardiac rupture were older, of lower body weight and stature and more likely to be female than those without rupture (all p < 0.001). By multivariable analysis, age >70 years (odds ratio [OR] 3.77; 95% confidence interval [CI] 2.06, 6.91), female gender (OR 2.87; 95% CI 1.44, 5.73) and prior angina (OR 1.82; 95% CI 1.05, 3.16) were independently associated with cardiac rupture. Independent predictors of nonrupture death included age >70 years (OR 3.68; 95% CI 2.53, 5.35) and prior MI (OR 2.14; 95%, CI 1.45, 3.17). There was no association between the type of thrombin inhibition, the intensity of anticoagulation and cardiac rapture. CONCLUSIONS Cardiac rupture following thrombolytic therapy tends to occur in older patients and may explain the disproportionately high mortality rate among women in prior dinical trials. Unlike major hemorrhagic complications, there is no evidence that the intensity of anticoagulation associated with heparin or hirudin administration influences the occurrence of rupture.

Adult↗
PubMed1999

Thrombin generation after the abrupt cessation of intravenous unfractionated heparin among patients with acute coronary syndromes: potential mechanisms for heightened prothrombotic potential.

OBJECTIVES: The purpose of this study was to determine the mechanistic basis for thrombin generation and increased prothrombotic potential after the abrupt cessation of intravenous (i.v.) unfractionated heparin among patients with acute coronary syndromes. BACKGROUND: A "rebound" increase in prothrombotic potential has been observed biochemically and clinically after the abrupt cessation of unfractionated heparin (UFH) among patients with acute coronary syndromes. Although the mechanism is unknown, tissue factor and the extrinsic coagulation cascade, both operative in atherosclerotic vascular disease and arterial thrombosis, are thought to be centrally involved. METHODS: In a single-center, pilot study, 30 patients with either unstable angina or non-ST segment elevation myocardial infarction who had received a continuous i.v. infusion of UFH for 48 h were randomly assigned to: 1) abrupt cessation, 2) i.v. weaning over 12 h or 3) subcutaneous weaning over 12 h. RESULTS: Thrombin generation (prothrombin fragment 1.2) was evident within 1 h of UFH cessation, increased progressively (by nearly two-fold) at 24 h (p = 0.002) and correlated inversely with tissue factor pathway inhibitor concentration (r = -0.61). Thrombin generation was greatest among patients randomized to abrupt cessation (1.6-fold increase at 24 h) and least in those with i.v. weaning. CONCLUSIONS: Thrombin generation after the abrupt cessation of UFH may represent a drug-induced impairment of physiologic vascular thromboresistance in response to locally generated tissue factor. A dosing strategy of abbreviated i.v. weaning attenuates but does not prevent heparin rebound among patients with acute coronary syndromes.

Adult↗
PubMed1999

Ischemic preconditioning may be transferable via whole blood transfusion: preliminary evidence.

This research was designed to test the hypothesis that ischemic preconditioning can be transferred between animals via whole blood transfusion. Preconditioning at a distance refers to the reduction in myocardial infarct size seen when coronary artery occlusion is preceded by brief ischemic episodes of noncardiac tissue. Isolation of the trigger signal responsible for this effect may be useful in the diagnosis and treatment of acute coronary occlusive syndromes. Rabbits were paired by crossmatching blood samples prior to experimentation. Crossmatched pairs were placed into either preconditioned (P) or control sets. Rabbits in the preconditioned sets were further divided into donor (PD) and acceptor (PA) animals. PD animals underwent five episodes of circumflex and renal artery occlusion followed by reperfusion. Before and after each preconditioning episode, a whole blood exchange was performed between PD and PA animals. Alternatively, control rabbits underwent the same surgical procedures and time-sequenced transfusion without preconditioning. All animals then underwent prolonged circumflex occlusion (60 minutes) followed by reperfusion (30 minutes). The area of myocardium at risk (R) was determined by isotope-labeled microsphere injection. Infarct size (I) was determined by NBT staining. The percent infarct within the risk area (I/R) was then compared. The I/R was significantly lower in the PA (14.0% +/- 12.2) and PD (14.3% +/- 11.2) groups as compared with controls (61% +/- 20. 6). There was no significant difference between the tPA and TPD groups. In conclusion, the ischemic preconditioning effect can be transferred to nonpreconditioned animals via whole blood transfusion, suggesting a humoral mechanism for preconditioning at a distance.

Animals↗
PubMed1999

Mucinous cystic neoplasm (mucinous cystadenocarcinoma of low-grade malignant potential) of the pancreas: a clinicopathologic study of 130 cases.

Mucinous cystic neoplasms (MCNs) of the pancreas are uncommon tumors. The classification and biologic potential of these neoplasms remain the subject of controversy. Attempts to classify these tumors in a similar manner to ovarian MCNs remains controversial, as even histologically benign-appearing pancreatic MCNs metastasize and are lethal. One hundred thirty cases of MCNs were identified in the files of the Endocrine Pathology Tumor Registry of the Armed Forces Institute of Pathology from the years 1979 to 1993. The pathologic features, including hematoxylin and eosin staining, histochemistry, immunohistochemistry (IHC), cell cycle analysis, and K-ras oncogene determination were reviewed. These findings were correlated with the clinical follow-up obtained in all cases. There were 130 women, aged 20-95 years (mean age at the outset, 44.6 years). The patients had vague abdominal pain, fullness, or abdominal masses. More than 95% of the tumors were in the pancreatic tail or body and were predominantly multilocular. The tumors ranged in size from 1.5 to 36 cm in greatest dimension, with the average tumor measuring >10 cm. A spectrum of histomorphologic changes were present within the same case and from case to case. A single layer of bland-appearing, sialomucin-producing columnar epithelium lining the cyst wall would abruptly change to a complex papillary architecture, with and without cytologic atypia, and with and without stromal invasion. Ovarian-type stroma was a characteristic and requisite feature. Focal sclerotic hyalinization of the stroma was noted. This ovarian-type stroma reacted with vimentin, smooth muscle actin, progesterone, or estrogen receptors by IHC analysis. There was no specific or unique epithelial IHC. K-ras mutations by sequence analysis were wild type in all 52 cases tested. Ninety percent of patients were alive or had died without evidence of disease (average follow-up 9.5 years), irrespective of histologic appearance; 3.8% were alive with recurrent disease (average 10 years after diagnosis); and 6.2% died of disseminated disease (average 2.5 years from diagnosis). Irrespective of the histologic appearance of the epithelial component, with or without stromal invasion, pancreatic MCNs should all be considered as mucinous cystadenocarcinomas of low-grade malignant potential. Pancreatic MCNs cannot be reliably or reproducibly separated into benign, borderline, or malignant categories.

Adult↗
PubMed1998

The cleaved peptide of the thrombin receptor is a strong platelet agonist.

Thrombin cleaves its G-protein-linked seven-transmembrane domain receptor, thereby releasing a 41-aa peptide and generating a new amino terminus that acts as a tethered ligand for the receptor. Peptides corresponding to the new amino terminal end of the proteolyzed seven-transmembrane domain thrombin receptor [TR42-55, SFLLRNPNDKYEPF, also known as TRAP (thrombin receptor-activating peptide)], previously have been demonstrated to activate the receptor. In this study, we demonstrate that the 41-aa cleaved peptide, TR1-41 (MGPRRLLLVAACFSLCGPLLSARTRARRPESKATNATLDPR) is a strong platelet agonist. TR1-41 induces platelet aggregation. In whole-blood flow cytometric studies, TR1-41 was shown to be more potent than TR42-55 and almost as potent as thrombin, as determined by the degree of increase in: (i) platelet surface expression of P-selectin (reflecting alpha granule secretion); (ii) exposure of the fibrinogen binding site on the glycoprotein (GP) IIb-IIIa complex; and (iii) fibrinogen binding to the activated GPIIb-IIIa complex. As determined by experiments with inhibitors [prostaglandin I2, staurosporine, wortmannin, the endothelium-derived relaxing factor congener S-nitroso-N-acetylcysteine (SNAC), EDTA, EGTA, and genestein], and with Bernard-Soulier or Glanzmann's platelets, we demonstrated that TR1-41-induced platelet activation is: (i) inhibited by cyclic AMP; (ii) mediated by protein kinase C, phosphatidyl inositol-3-kinase, myosin light chain kinase, and intracellular protein tyrosine kinases; (iii) dependent on extracellular calcium; and (iv) independent of the GPIb-IX and GPIIb-IIIa complexes. TR1-41-induced platelet activation was synergistic with TR42-55. In summary, the cleaved peptide of the seven-transmembrane domain TR (TR1-41) is a strong platelet agonist.

Amino Acid Sequence↗
PubMed1998

Effects of prior aspirin and anti-ischemic therapy on outcome of patients with unstable angina. TIMI 7 Investigators. Thrombin Inhibition in Myocardial Ischemia.

Both aspirin and beta-adrenergic blocking drugs have been shown to reduce the risk of death or acute myocardial infarction (AMI) in patients with unstable angina, but their effect during chronic use on the presentation of acute coronary syndromes is less well defined. Calcium antagonists and oral nitrates are also widely prescribed for patients with coronary disease, but their effect on presentation of acute myocardial ischemia is unknown. We retrospectively examined the effects of prior aspirin and anti-ischemic medical therapy on clinical events in 410 patients hospitalized for unstable angina. Ischemic pain occurred at rest for a duration of 5 to 60 minutes. During hospitalization, 97% of patients received aspirin and all received the direct thrombin inhibitor bivalirudin for at least 72 hours. Despite being older and more likely to have risk factors for coronary disease and poor outcome, patients receiving aspirin before admission were less likely to present with non-Q-wave AMI (5% vs 14% in patients not on aspirin, p = 0.004). Prior beta blocker, calcium antagonist, or nitrate administration did not appear to modify presentation as unstable angina or non-Q-wave AMI. In a multivariate model, the combined incidence of death, AMI not present at enrollment, or recurrent angina was best predicted by age (adjusted odds ratio [95% confidence interval] 2.38 [1.14 to 3.98]) and presence of electrocardiographic changes with pain on presentation (adjusted odds ratio 2.83 [1.50 to 5.35]) but was not related to prior or in-hospital medical therapy. Thus, aspirin but not anti-ischemic therapy before hospitalization of patients with unstable angina was associated with a decreased incidence of non-Q-wave AMI on admission.

Adrenergic beta-Antagonists↗
PubMed1998

Early assessment and in-hospital management of patients with acute myocardial infarction at increased risk for adverse outcomes: a nationwide perspective of current clinical practice. The National Registry of Myocardial Infarction (NRMI-2) Participants.

BACKGROUND: Therapeutic decision making in critically ill patients requires both prompt and comprehensive analysis of available information. Data derived from randomized clinical trials provide a powerful tool for risk assessment in the setting of acute myocardial infarction (MI); however, timely and appropriate use of existing therapies and resources are the key determinants of outcome among high-risk patients. METHODS: Demographic, procedural, and outcome data from patients with MI were collected at 1073 U.S. hospitals collaborating in the National Registry of MI (NRMI 2). Patients were classified on hospital arrival as either "low risk" or "high risk" according to a modified Thrombolysis in Myocardial Infarction II Risk Scale based on predetermined demographic, electrocardiographic, and clinical features. RESULTS: Among the 170,143 patients enrolled, 115,222 (67.5%) were classified as low risk and 55,521 (32.5%) as high risk for in-hospital death, recurrent ischemia, recurrent MI, congestive heart failure, and stroke. Using a composite unsatisfactory outcome measure, in-hospital adverse events were had by a greater proportion of patients initially classified as high risk compared with those classified as low risk. By multivariate analysis, age >70 years, prior MI, Killip class >1, anterior site of infarction, and the combination of hypotension and tachycardia were independent predictions of poor outcome in patients with or without ST-segment elevation on the presenting electrocardiogram. High-risk patients with ST-segment elevation were treated with thrombolytics (47.5%) or alternative forms of reperfusion therapy (9.3%) within 62 minutes and 226 minutes of hospital arrival, respectively. High-risk patients offered reperfusion therapy were also more likely to receive aspirin, beta-blockers (intravenous, oral) and angiotensin-converting enzyme inhibitors within 24 hours of infarction (all p < 0.0001), survive their event (8.4% versus 21.4% p < 0.0001), and leave the hospital sooner than those not reperfused. CONCLUSIONS: This large registry experience included more than 150,000 nonselected patients with MI and suggests that high-risk patients can be identified on initial hospital presentation. The current use of reperfusion and adjunctive therapies among high-risk patients is suboptimal and may directly influence outcome. Randomized trials designed to test the impact of specific management strategies on outcome according to initial risk classification are warranted.

Angioplasty, Balloon, Coronary↗
PubMed1998

Use of bedside activated partial thromboplastin time monitor to adjust heparin dosing after thrombolysis for acute myocardial infarction: results of GUSTO-I. Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries.

BACKGROUND: The safety and efficacy of bedside monitors of activated partial thromboplastin time (aPTT) have not been examined in a large population receiving intravenous heparin after thrombolytic treatment for acute myocardial infarction. We compared outcomes among patients monitored with these devices versus standard monitoring methods. METHODS AND RESULTS: Investigators chose the bedside device (n = 1713 patients) or their standard method (n = 26,162) for all aPTT measurements at their sites. Clinical outcomes at 30 days, 1-year mortality rate, and aPTT levels at 6, 12, and 24 hours were compared. Bedside-monitored patients had significantly less moderate/severe bleeding (10% vs 12%, P < .01), fewer transfusions (7% vs 11%, P < .001), and a smaller decrease in hematocrit (5.5% vs 6.7%, P < .001) but significantly more recurrent ischemia (22% vs 20%, P = .01). Fewer bedside-monitored patients had subtherapeutic aPTT levels at 12 and 24 hours. Among patients with subtherapeutic levels at 6 and 12 hours, more bedside-monitored patients had therapeutic levels when next monitored. After adjustment for baseline differences, no significant difference in mortality rate was observed in bedside-monitored patients at 30 days (4.3% vs 4.8%, P = .27) and at 1 year (7.1% vs 7.7%, P = .38). The groups had similar rates of reinfarction, shock, heart failure, and stroke. CONCLUSIONS: This prospective substudy supports the use of bedside monitoring of heparin anticoagulation after thrombolysis.

Aged↗
PubMed1998

Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease.

OBJECTIVES: We sought to examine whether patients with stable coronary artery disease (CAD) have increased platelet reactivity and an enhanced propensity to form monocyte-platelet aggregates. BACKGROUND: Platelet-dependent thrombosis and leukocyte infiltration into the vessel wall are characteristic cellular events seen in atherosclerosis. METHODS: Anticoagulated peripheral venous blood from 19 patients with stable CAD and 19 normal control subjects was incubated with or without various platelet agonists and analyzed by whole blood flow cytometry. RESULTS: Circulating degranulated platelets were increased in patients with CAD compared with control subjects (mean [+/- SEM] percent P-selectin-positive platelets: 2.1 +/- 0.2 vs. 1.5 +/- 0.2, p < 0.01) and were more reactive to stimulation with 1 micromol/liter of adenosine diphosphate (ADP) (28.7 +/- 3.9 vs. 16.1 +/- 2.2, p < 0.01), 1 micromol/liter of ADP/epinephrine (51.4 +/- 4.6 vs. 37.5 +/- 3.8, p < 0.05) or 5 micromol/liter of thrombin receptor agonist peptide (TRAP) (65.7 +/- 6.8 vs. 20.2 +/- 5.1, p < 0.01). Patients with stable CAD also had increased circulating monocyte-platelet aggregates compared with control subjects (percent platelet-positive monocytes: 15.3 +/- 3.0 vs. 6.3 +/- 0.9, p < 0.01). Furthermore, patients with stable CAD formed more monocyte-platelet aggregates than did control subjects when their whole blood was stimulated with 1 micromol/liter of ADP (50.4 +/- 4.5 vs. 28.1 +/- 5.3, p < 0.01), 1 micromol/liter of ADP/epinephrine (60.7 +/- 4.3 vs. 48.0 +/- 4.8, p < 0.05) or 5 micromol/liter of TRAP (67.6 +/- 5.7 vs. 34.3 +/- 7.0, p < 0.01). CONCLUSIONS: Patients with stable CAD have circulating activated platelets, circulating monocyte-platelet aggregates, increased platelet reactivity and an increased propensity to form monocyte-platelet aggregates.

Adenosine Diphosphate↗
PubMed1998

Seasonal distribution of acute myocardial infarction in the second National Registry of Myocardial Infarction.

OBJECTIVES: This observational study sought to determine whether cases of acute myocardial infarction (AMI) reported to the second National Registry of Myocardial Infarction (NRMI-2) varied by season. BACKGROUND: The existence of circadian variation in the onset of AMI is well established. Examination of this periodicity has led to new insights into pathophysiologic triggers of atherosclerotic plaque rupture. Although a seasonal pattern for mortality from AMI has been previously noted, it remains unclear whether the occurrence of AMI also displays a seasonal rhythmicity. Documentation of such a pattern may foster investigation of new pathophysiologic determinants of plaque rupture and intracoronary thrombosis. METHODS: We analyzed the number of cases of AMI reported to NRMI-2 by season during the period July 1, 1994 to July 31, 1996. Data were normalized so that seasonal occurrence of AMI was reported according to a standard 90-day length. RESULTS: A total of 259,891 cases of AMI were analyzed during the study period. Approximately 53% more cases were reported in winter than during the summer. The same seasonal pattern (decreasing occurrence of reported cases from winter to fall to spring to summer) was seen in men and women, in different age groups and in 9 of 10 geographic areas. In-hospital case fatality rates for AMI also followed a seasonal pattern, with a peak of 9% in winter. CONCLUSION: The present results suggest that there is a seasonal pattern in the occurrence of AMIs reported to NRMI-2 that is characterized by a marked peak of cases in the winter months and a nadir in the summer months. This pattern was seen in all subgroups analyzed as well as in different geographic areas. These findings suggest that the chronobiology of seasonal variation in AMI may be affected by variables independent of climate.

Aged↗