PubMed Health⌕ Search

Biomedical subjects

W L Chandler

Publications and source records attributed to W L Chandler.

At least 37 records · Page 2Linked to original sources
PubMed1997

Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex: relationship to elevated TPA antigen in patients with high PAI-1 activity levels.

BACKGROUND: To evaluate the effect of plasminogen activator inhibitor type 1 (PAI-1) levels on the clearance of total tissue plasminogen activator (TPA) antigen, we studied the clearance of active TPA and TPA/PAI-1 complex in subjects with low (181+/-109 pmol/L; n=7) and high (1166+/-322 pmol/L; n=4) baseline active PAI-1. METHODS AND RESULTS: A 5-microg/kg bolus of TPA was infused over a 15-second period followed by measurement of TPA activity, TPA antigen, TPA/PAI-1, TPA/C1 inhibitor, PAI-1 activity, and PAI-1 antigen over a 4-hour period. alpha-Phase clearance of total TPA antigen was faster in subjects with low PAI-1 (t(1/2) of 3.5+/-0.7 minutes) versus high PAI-1 (t(1/2) of 5.3+/-0.9 minutes) (P=.006). Clearance of all factors was best fit by a two-compartment pharmacokinetic model based on a computer-simulated human circulatory system. The average hepatic clearance fraction in the two-compartment model was greater for active TPA (89+/-10%, t(1/2) of 2.4+/-0.3 minutes) than for TPA/PAI-1 complex (48+/-17%, t(1/2) of 5.0+/-1.8 minutes) (P=.0006). CONCLUSIONS: Plasma clearance of active TPA was faster than clearance of TPA/PAI-1 complex. High levels of active PAI-1 converted more TPA into TPA/PAI-1 complex, effectively slowing the clearance of total TPA antigen and explaining in part why high levels of PAI-1 activity are associated with increases in total TPA antigen.

Adult↗
PubMed1997

Cerebrospinal fluid creatine kinase BB isoenzyme activity and neurologic prognosis after cardiac arrest.

OBJECTIVE: To assess the relationship between CSF creatine kinase BB isoenzyme activity (CSF CKBB) and neurologic outcome after cardiac arrest in clinical practice. BACKGROUND: CSF CKBB reflects the extent of brain damage following cardiac arrest. METHODS: To help with prognosis, treating physicians ordered CSF CKBB tests on 474 patients over 7.5 years; 351 of these patients had experienced a cardiac arrest. Assays were performed in one laboratory using agarose electrophoresis. By chart review, we determined awakening status for all patients, defined as the patient having comprehensible speech or following commands. RESULTS: CSF CKBB was usually sampled 48 to 72 hours after cardiac arrest and was strongly associated with awakening (p < < 0.001). The median was 4 U/l for 61 patients who awakened and 191 U/l for 290 who never awakened. For those who awakened, 75% of CKBB levels were < 24 U/l, and for those who never awakened, 75% were > 86 U/l. The highest value in a patient who awakened was 204 U/l, a cutoff that yielded a specificity of 100% of never awakening but a sensitivity of forty-eight percent. Only nine patients who awakened had CSF CKBB values greater than 50 U/l, and none regained independence in activities of daily living. Only three unconscious patients were still alive at last contact, with follow-up of 63, 107, and 109 months. Using logistic regression, the probability of never awakening given a CSF CKBB result can be estimated as: 1/(1 + L), where L = e raised to (0.1267 - 0.0211 x CSF CKBB [U/l]). CONCLUSION: CSF CKBB measurement helps to estimate degree of brain damage and thus neurologic prognosis after cardiac arrest. However, results of this retrospective study could reflect in part a self-fulfilling prophecy.

Aged↗
PubMed1997

A comparison of thromboelastography with heparinase or protamine sulfate added in vitro during heparinized cardiopulmonary bypass.

Thromboelastography (TEG) has been used after cardiopulmonary bypass (CPB) to diagnose excessive postoperative hemorrhage. Conventional TEG during CPB is not possible due to the sensitivity of the TEG to even small amounts of heparin, which produces a nondiagnostic tracing. The purpose of this study was to compare heparin neutralization using heparinase or protamine in TEG blood samples obtained during CPB. TEG testing was performed on 48 patients before, during and after CPB. Tissue plasminogen activator activity and antigen were measured on a subset of 32 patients. We found: 1) heparinase neutralized at least 10 IU/ml heparin while 1.6 ug/ml protamine neutralized up to 7 IU/ml heparin, 2) in samples with complete heparin neutralization by both methods, there was no significant difference in the R values, 3) while there was good correlation for other TEG parameters between heparinase and protamine treated samples, heparinase treatment produced shorter K values and higher angle, MA and A60, 4) while fibrinolysis was detected using both methods, heparinase treatment suppressed fibrinolysis in the TEG in both samples from patients and after in vitro addition of tissue plasminogen activator, 5) TEG was not a sensitive indicator of t-PA activity, detecting only 21% of samples with increased t-PA activity during bypass, and 5) heparinase was at least 100 times more expensive than protamine. We conclude that while both heparinase and protamine can be used to neutralize heparin in TEG samples obtained during CPB, protamine neutralization is more sensitive to fibrinolysis and less expensive, but the protamine dose must be carefully selected to match the heparin level used at individual institutions.

Adult↗
PubMed1996

Effects of endurance training on the circadian rhythm of fibrinolysis in men and women.

This randomized study compared the fibrinolytic circadian rhythm of healthy older men and older women (average age 66 +/- 5), before and after 6 months of endurance training versus stretching controls. Compared with men, women at baseline had similar rhythms for tissue plasminogen activator (t-PA) activity and plasminogen activator inhibitor 1 (PAI-1) activity, but lower levels of total t-PA antigen. In men (N = 16), endurance training increased VO2max 15% (P < 0.001), while decreasing PAI-1 activity 37% (P = 0.034) and total t-PA antigen 18% (P = 0.0003) between midnight and 6 a.m., but did not affect t-PA activity. In women (N = 9), endurance training increased VO2max 18% (P = 0.003), and increased t-PA activity 20% (P = 0.027) and total t-PA antigen 55% (P = 0.007) between 10 p.m. and 4 a.m., but had no effect on PAI-1 activity. After endurance training there were no significant differences in the fibrinolytic circadian rhythm of men versus women. Six months of nonaerobic stretching had no effect on VO2max or fibrinolysis in men (N = 11) or women (N = 8). This study indicates that potentially favorable changes occur in fibrinolytic factors after endurance training in older men and older women.

Aged↗
PubMed1995

The circulatory regulation of TPA and UPA secretion, clearance, and inhibition during exercise and during the infusion of isoproterenol and phenylephrine.

BACKGROUND: Exercise to exhaustion and infusions of isoproterenol and phenylephrine were used to study interactions between plasminogen activator regulation and the control of regional blood flow in 10 healthy males. METHODS AND RESULTS: Experimental measurements of cardiac output, heart rate, tissue plasminogen activator (TPA), urokinase plasminogen activator (UPA), plasminogen activator inhibitor (PAI-1), C1-inhibitor, and TPA/C1-inhibitor complex during the infusions and exercise were used to develop a comprehensive fluid-phase model of the circulatory regulation of fibrinolysis. alpha- and beta-adrenergic agonists increased TPA and UPA in plasma by different mechanisms: Phenylephrine decreased hepatic blood flow and thus clearance while isoproterenol stimulated increased secretion of TPA and UPA. Exercise to exhaustion increased TPA and UPA through a combination of increased secretion and decreased clearance. The time course of UPA and TPA release were similar, but the magnitude of their secretion responses differed. In vivo, C1-inhibitor bound to TPA at a rate of 553 mol-1.s-1. C1-inhibitor contributed equally with PAI-1 to TPA inhibition when active PAI-1 levels were low (20 to 50 pmol/L) but was less important when active PAI-1 levels were high. CONCLUSIONS: We conclude that secretion, inhibition, clearance, and regional blood flow effects must all be taken into account when evaluating changes in plasminogen activator levels.

Adrenergic alpha-Agonists↗
PubMed1995

Thromboelastography for the prediction of bleeding after transplant renal biopsy.

The ability of prebiopsy coagulation assays to predict mild postbiopsy bleeding was evaluated in renal transplant patients undergoing renal allograft biopsy (N = 120). The coagulation assays studied included the bleeding time, prothrombin time, partial thromboplastin time, platelet count, and thromboelastograph (TEG). Coagulation results were defined as abnormal if they fell outside the established normal reference range. Bleeding was defined as a drop in the hematocrit equal to or more than 4 points 6 h after the procedure or ultrasound evidence of a new perirenal hematoma. Overall, 21% of patients showed evidence of mild bleeding. Of those who bled, 78% had normal results on all coagulation tests, indicating that most mild bleeding was not associated with coagulation abnormalities. Of the assays tested, only abnormal TEG:angle (P < 0.01) and TEG:k (P < 0.04) values were associated with an increased risk of bleeding. Bleeding times were not predictive of an increased risk of postbiopsy bleeding; five patients had abnormal bleeding times ranging from 10 to 20 min of whom only one bled. All prothrombin time, partial thromboplastin time, and platelet count abnormalities were mild (e.g., no prothrombin times longer than 15 s, no platelet counts below 129,000/microL); none of these assays predicted postbiopsy bleeding. Other clinical characteristics, including patient age, sex, serum creatinine, blood pressure (if less than 160/90 mm Hg), number of biopsy passes, or renal pathology, did not appear to influence bleeding after biopsy. It was concluded that most bleeding after transplant renal biopsy was not associated with coagulation abnormalities and that the TEG was the best assay for detecting mild coagulation abnormalities associated with an increased risk of bleeding.

Biopsy↗
PubMed1995

Individual variations in the fibrinolytic response during and after cardiopulmonary bypass.

The purpose of this study was to determine whether individual patients show different patterns of fibrinolytic response to cardiopulmonary bypass (CPB) and whether preoperative or intraoperative parameters were predictive of these different patterns. Active t-PA, active PAI-1 and total t-PA antigen were measured in plasma samples obtained from 38 subjects, age 32 to 85 (median 69 years), before, during and after CPB. Four patterns of fibrinolytic response were noted: 1) 40% of patients showed the "typical" response, a rapid rise in active and total t-PA during CPB followed postoperatively by elevated PAI-1 and reduced t-PA, 2) 10% showed no change in t-PA or PAI-1 during or after CPB, 3) 24% showed no change in t-PA with an increase in PAI-1 postoperatively, and 4) 26% showed an increase in t-PA during CPB with no change in PAI-1 postoperatively. When present, the t-PA response was rapid, occurring within the first 30 min of CPB and was more common in patients undergoing valve surgery than in coronary artery bypass grafting (p < 0.005). Increased levels of PAI-1 postoperatively were associated with ischemic times greater than 70 min (p = 0.003) but not with the total length of CPB. Age, sex, CPB temperature, total CPB time and preoperative levels of t-PA and PAI-1 were not associated in the intra- or postoperative fibrinolytic response pattern. We conclude that the fibrinolytic response to CPB is heterogeneous. Further studies will be needed to determine whether different response patterns are clinically significant.

Adult↗
PubMed1994

Laboratory evaluation of fibrinolysis in patients with a history of myocardial infarction.

The aims of this study were to determine whether elevated plasminogen activator inhibitor type 1 (PAI-1) activity after myocardial infarction reflects baseline PAI-1 or represents an acute-phase response secondary to the infarction, and to determine how tissue plasminogen activator (t-PA) activity and total t-PA antigen levels in healthy control subjects differ from those in patients after myocardial infarction. Compared with healthy control subjects, patients studied 1-3 months after infarction had elevated levels of PAI-1 activity and fibrinogen but normal levels of C-reactive protein and von Willebrand factor antigen, whereas patients with a noncardiac acute-phase response showed elevation of all four proteins. Elevated PAI-1 activity in the absence of elevations in other acute-phase proteins suggests an intrinsic increase in PAI-1 secretion in the post-myocardial infarction group. In addition, when compared with healthy control subjects, post-myocardial infarction patients had higher levels of total t-PA antigen (bound and free t-PA) but lower t-PA activity and a lower percentage of active t-PA. Overall, survivors of myocardial infarction have reduced t-PA activity and increased PAI-1 activity that is not due to a prolonged acute-phase response.

Acute-Phase Reaction↗
PubMed1993

A kinetic model of the circulatory regulation of tissue plasminogen activator during exercise, epinephrine infusion, and endurance training.

A computer simulation of the circulatory system was used to kinetically model secretion, inhibition, and clearance of tissue plasminogen activator (t-PA) during three different processes that increase active t-PA levels: epinephrine infusion, exercise, and endurance training. Infusion of epinephrine stimulated an increase in t-PA secretion that was proportional to the plasma epinephrine concentration. In addition, epinephrine infusion increased hepatic blood flow and t-PA clearance, thus slowing the increase of plasma t-PA levels. During exercise, t-PA levels increased due both to increased t-PA secretion and to decreased clearance secondary to reduced hepatic blood flow. The increase in t-PA secretion during exercise was directly proportional to the epinephrine concentration in blood with the same ratio of t-PA secretion to epinephrine as found during epinephrine infusion, suggesting that increased plasma epinephrine during exercise was the primary stimulus for t-PA secretion. Lastly, the simulation predicted that 6 months of endurance training produced a decrease in resting plasminogen activator inhibitor type 1 (PAI-1) secretion, resulting in less t-PA inhibition and an overall increase in active t-PA after training. Accurate analysis of the regulation of active t-PA levels in blood required simultaneous modeling of t-PA and PAI-1 secretion, hepatic clearance, and inhibition of t-PA by PAI-1.

Computer Simulation↗
PubMed1992

Adrenergic stimulation of regional plasminogen activator release in rabbits.

The purpose of this study was to determine whether different regions of the rabbit vascular system show variations in the rate of plasminogen activator (PA) secretion. To start, we evaluated the time course, dose response and adrenergic specificity of PA release. Infusion of 1 microgram/kg of epinephrine stimulated a 116 +/- 60% (SD) increase in PA activity that peaked 30 to 60 s after epinephrine administration. Infusion of 1 microgram/kg of norepinephrine, isoproterenol and phenylephrine had no effect on PA activity. Pretreatment with phentolamine, an alpha adrenergic antagonist, blocked the release of PA by epinephrine while pretreatment with the beta blocker propranolol had no effect. This suggests that PA release in the rabbit was mediated by some form of alpha receptor. Significant arterio-venous differences in basal PA activity were found across the pulmonary and splanchnic vascular beds but not the lower extremity/pelvic bed. After stimulation with epinephrine, PA activity increased 46% across the splanchnic bed while no change was seen across the lower extremity/pelvic bed. We conclude that several vascular beds contribute to circulating PA activity in the rabbit, and that these beds secrete PA at different rates under both basal and stimulated conditions.

Animals↗
PubMed1992

Laboratory and clinical aspects of inherited thrombotic disorders.

The laboratory evaluation of patients with recurrent thrombosis is frequently frustrating, with a low diagnostic yield obtained despite extensive testing. The likelihood of reaching a diagnosis in these patients can be increased by considering diagnostic possibilities usually overlooked and by using assays optimal for their detection. This review summarizes clinical and laboratory issues important in inherited thrombotic disease and discusses practical aspects and a strategy for laboratory testing. New information is provided on the fibrinolytic disorders that may be a common cause of recurrent thrombosis.

Homocystinuria↗
PubMed1992

Fibrinolytic response during exercise and epinephrine infusion in the same subjects.

To determine whether exercise-induced increases in tissue plasminogen activator (t-PA) were related to plasma epinephrine concentration during exercise, 14 healthy men (aged 24 to 62 years) were studied during epinephrine infusions (10, 25 and 50 ng/kg per min) and graded supine bicycle exercise, beginning at 33 W and increasing in 33-W increments until exhaustion. Plasma epinephrine, active and total t-PA, active plasminogen activator inhibitor type 1 (PAI-1) and t-PA/PAI-1 complex concentrations were measured at each exercise and infusion level. During epinephrine infusion, active and total t-PA levels increased linearly with the plasma epinephrine concentration (respective slopes [+/- SEM] of 0.062 +/- 0.003 and 0.076 +/- 0.003 pmol/ng epinephrine). During exercise, t-PA levels did not increase until plasma epinephrine levels increased, after which both active and total t-PA levels again increased linearly with the plasma epinephrine concentration, but at twice the rate observed with epinephrine infusion (0.131 +/- 0.005 and 0.147 +/- 0.005 pmol/ng, respectively). The t-PA level in blood was directly proportional to the plasma epinephrine concentration during both exercise and epinephrine infusion, suggesting that epinephrine release during exercise stimulates t-PA secretion. In these healthy subjects, active plasminogen activator inhibitor type 1 and t-PA/PAI-1 complex levels were low (41 +/- 11 and 21 +/- 5 pmol/liter, respectively) and did not change significantly during exercise or epinephrine infusion. It is concluded that approximately 50% of the increase in t-PA during exercise is due to stimulated release of t-PA by epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

A kinetic model of the circulatory regulation of tissue plasminogen activator.

A computer simulation was developed to study the regulation of active tissue plasminogen activator (t-PA) levels in plasma by kinetically modeling t-PA secretion, t-PA inhibition by plasminogen activator inhibitor type 1 (PAI-1), and hepatic clearance of t-PA, PAI-1 and t-PA/PAI-1 complex throughout a simplified human circulatory system. The model indicates that as the active PAI-1 concentration increases, the percent of t-PA in the active form decreases exponentially. Further, the reaction between t-PA and PAI-1 substantially reduces the half-lives of both active factors. By adjusting the t-PA and PAI-1 secretion rates to provide the best fit between simulated and measured circadian variations in t-PA, PAI-1 and complex, the model predicts that the diurnal rhythm in active t-PA levels is principally due to changes in the rate of PAI-1 secretion and not to variations in the t-PA secretion rate. In conclusion, the model predicts that PAI-1 is an important regulator of the concentration, half-life and circadian variation of active t-PA.

Adult↗