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Biomedical subjects

W L Chandler

Publications and source records attributed to W L Chandler.

At least 19 recordsLinked to original sources
PubMed2001

Comparison of the lipoprotein, carbohydrate, and hemostatic effects of phasic oral contraceptives containing desogestrel or levonorgestrel.

Desogestrel (DSG) is a less-androgenic progestogen than levonorgestrel (LNG). This difference in androgenicity may be responsible for observed differences in metabolic effects between oral contraceptive (OC) formulations containing almost equivalent estrogen doses but with either DSG or LNG as a progestogen. To test the hypothesis, a prospective 9-month randomized comparison of plasma lipids, glucose, insulin, hemostasis, and sex hormone binding globulin (SHBG) was conducted in 66 healthy women using phasic formulations of OCs containing either DSG (DSG-OC) or LNG (LNG-OC). The study results showed that SHBG increased 3-fold with DSG-OC and 2-fold with LNG-OC. DSG-OC increased HDL-C, HDL(2)-C and HDL(3)-C; LDL-C decreased transiently. LNG-OC decreased HDL(2)-C and increased HDL(3)-C; HDL-C was unchanged and LDL-C decreased transiently. Both formulations increased VLDL-C and triglycerides, more with DSG-OC, but apolipoprotein B levels increased equally. Apo A-I and A-II increased more with DSG-OC than with LNG-OC. Neither formulation altered Lp(a) or fasting glucose and insulin levels. Postprandially, both formulations decreased glucose and increased insulin responses, but to an equivalent degree. Both OCs slightly enhanced procoagulant and profibrinolytic parameters to the same extent except for internally compensating decreases in Factor V and protein S with DSG-OC. In summary, at almost equivalent estrogen doses, a phasic OC containing DSG compared with LNG has a less androgenic effect on lipoproteins and SHBG, similar effects on hemostatic parameters with lower protein S and factor V activity and equivalent effects on carbohydrate metabolism. The lipoprotein, SHBG, and protein S and factor V differences are likely due to the lesser androgenicity of DSG allowing for a greater expression of the dose of estrogen.

Adult↗
PubMed2001

Activation, aggregation and adhesion of platelets exposed to high-intensity focused ultrasound.

Using platelet-rich plasma, we investigated the effect of 1.1-MHz continuous wave high-intensity focused ultrasound (HIFU) on platelet activation, aggregation and adhesion to a collagen-coated surface. Platelets were exposed for durations of 10-500 s at spatial average intensities of up to 4860 W/cm(2). To avoid heating effects, the average temperature in the HIFU tank was maintained at 33.8 +/- 4.0 degrees C during platelet experiments. Flow cytometry, laser aggregometry, environmental scanning electron microscopy and passive cavitation detection were used to observe and to quantify platelet activation, aggregation, adhesion to a collagen-coated surface and associated cavitation. It was determined that HIFU can activate platelets, stimulate them to aggregate and promote their adherence to a collagen-coated surface. In principle, HIFU can stimulate primary, or platelet-related, hemostasis. Cavitation was monitored by a passive cavitation detector during aggregation trials and was quantified to provide a relative measure of the amount of cavitation that occurred in each aggregation trial. Regression analysis shows a weak correlation (r(2) = 0.11) between aggregation and ultrasound intensity, but a substantial correlation (r(2) = 0.76) between aggregation and cavitation occurrence.

Flow Cytometry↗
PubMed2001

Factor XIIIA and clot strength after cardiopulmonary bypass.

Reduced factor XIIIA levels and decreased clot strength have been associated with increased bleeding after cardiopulmonary bypass (CPB). The purpose of this study was to evaluate the relationship between hemostatic factors, including factor XIIIA, and clot strength before, during and after CPB. Factor XIIIA antigen, platelet counts, fibrinogen, factor V activity, tissue plasminogen activator and clot strength (by thromboelastograph) were measured at baseline, after 45 min of CPB, at the end of CPB and 4 h post-operatively in 34 patients. Baseline factor XIIIA antigen was 5.2 +/- 1.4 mg/l. On average, factor XIIIA levels dropped to 64% and clot strength to 77% of baseline values after 45 min on CPB and remained below baseline during the immediate post-operative period. Clot strength was significantly correlated (r = 0.81) with platelet count and fibrinogen but not plasma factor XIIIA levels. Addition of 10 mg/l recombinant factor XIII[a2] significantly increased clot strength. Postoperative bleeding at 2 h was inversely correlated with platelet count, factor XIIIA antigen and clot strength measured at the end of CPB. Maintenance of adequate platelet counts and factor XIIIA levels at the end of CPB may play a role in maintaining clot strength and reducing blood loss.

Adult↗
PubMed2001

Thrombogenic alleles, Escherichia coli O157:H7 infections, and hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) of childhood most commonly follows gastrointestinal infection with Escherichia coli O157:H7. This pathogen elaborates Shiga toxins that are believed to cause microvascular injury and to trigger a thrombogenic response. The exact mechanisms leading to variable disease manifestations are unknown. Allelic variation in genes encoding selected coagulation factors and inhibitors of fibrinolysis were examined to determine whether or not a causal relationship exists between hypercoagulability and the development of HUS. No correlation between the thrombogenic factor V (G1691A), factor II (G20210A), methylenetetrahydrofolate reductase (C677T), or the plasminogen activator inhibitor (PAI)-1 promotor (4G/5G) genotypes and the risk of infection with E. coli O157:H7, or the risk of development of HUS among infected patients, was found. Serum PAI-1 levels did not correlate with the PAI-1 genotype. We conclude that the alleles studied are not major risk factors for the acquisition of E. coli O157:H7 infection, or of E. coli O157:H7-related HUS.

Alleles↗
PubMed2001

von Willebrand factor and von Willebrand factor-cleaving metalloprotease activity in Escherichia coli O157:H7-associated hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) usually occurs after infection with Shiga toxin-producing bacteria. Thrombotic thrombocytopenic purpura, a disorder with similar clinical manifestations, is associated with deficient activity of a circulating metalloprotease that cleaves von Willebrand factor at the Tyr842-Met843 peptide bond in a shear stress-dependent manner. We analyzed von Willebrand factor-cleaving metalloprotease activity and the status of von Willebrand factor in 16 children who developed HUS after Escherichia coli O157:H7 infection and in 29 infected children who did not develop this complication. Von Willebrand factor-cleaving metalloprotease activity was normal in all subjects, but von Willebrand factor size was decreased in the plasma of each of 16 patients with HUS. The decrease in circulating von Willebrand factor size correlated with the severity of thrombocytopenia and was proportional to an increase in von Willebrand factor proteolytic fragments in plasma. Immunohistochemical studies of the kidneys in four additional patients who died of HUS demonstrated glomerular thrombi in three patients, and arterial and arteriolar thrombi in one patient. The glomerular thrombi contained fibrin but little or no von Willebrand factor. A decrease in large von Willebrand factor multimers, presumably caused by enhanced proteolysis from abnormal shear stress in the microcirculation, is common in HUS.

ADAM Proteins↗
PubMed2000

A second-generation blood substitute (Perfluorodichlorooctane emulsion) generates spurious elevations in platelet counts from automated hematology analyzers.

UNLABELLED: Perfluorocarbon emulsions (PFEs) appear as platelets in automated cell counters, which may affect samples from thrombocytopenic patients (less than 100,000/microL). Therefore, we mixed clinically relevant concentrations of perfluorodichlorooctane (Oxyfluor(R); Hemagen, Inc., St. Louis, MO) in vitro with whole blood samples ranging from 0 to 150,000 platelets/microL and compared a new counter that uses optical platelet recognition (Abbott CellDyn 3200; Santa Clara, CA) with conventional electroimpedance-based counters (Abbott CellDyn 3500 and CellDyn 1700). We found that emulsion particles appear as small-sized platelets either in diluent or in blood. The emulsion results in a reproducible overestimate of the platelet counts, of greater importance as PFE concentration increases, and as the actual platelet count of the blood samples decreases. The new optical technology yields smaller overestimates but, even at low PFE concentrations, gives an unacceptable relative error at platelet counts near the transfusion thresholds recommended by the American Society of Anesthesiologists guidelines for blood component therapy. Unexpected interference in the leukocyte and erythrocyte channels is also reported. Experimental limitations preclude extrapolation of these findings to other automated cell counters, because differences in technology or software may affect their capacity to separate PFE particles from platelets. IMPLICATIONS: Perfluorocarbons are being investigated under conditions in which thrombocytopenia is likely to occur. In this in vitro study, we demonstrate significant overestimates in platelet counts from automated cell counters at clinically relevant perfluorocarbon concentrations in thrombocytopenic blood samples.

Blood Substitutes↗
PubMed2000

Measurement of different forms of tissue plasminogen activator in plasma.

BACKGROUND: We evaluated assays to measure both total tissue plasminogen activator (tPA) and the three principle forms of tPA in plasma: active tPA, tPA complexed with plasminogen activator inhibitor type 1 (PAI-1), and tPA complexed with C1-inhibitor. METHODS: Active tPA was measured by use of an indirect amidolytic assay and immunofunctional assays. tPA/PAI-1, tPA/C1-inhibitor, and total tPA antigen were measured by use of microtiter plates coated with anti-tPA antibodies and, respectively, anti-PAI-1, anti-C1-inhibitor, and anti-tPA antibodies conjugated to peroxidase. RESULTS: The immunofunctional tPA assay detected 1 U/L (0.001 U/mL) tPA and recovered 108% +/- 12% of active tPA added to samples containing high (mean, 60 000 IU/L) PAI-1 activities vs a detection limit of 10 U/L (0.01 U/mL) and 13% +/- 25% recovery for the indirect amidolytic tPA activity assay. For measurement of tPA/PAI-1 complex, polyclonal anti-PAI-1 conjugates recovered 112% +/- 20% of the expected tPA/PAI-1 vs recovery of only 38% +/- 16% when monoclonal anti-PAI-1 conjugates were used. Of three methods tested, two total tPA antigen assays correlated well (r(2) = 0.85) and showed recoveries near 100%, whereas the third method showed lower correlations, higher intercepts, and falsely high recovery. A single anti-tPA capture antibody that performed the best in the individual assay evaluations was used to measure the different forms of tPA in 22 samples with a range of tPA and PAI-1 values. The sum of the molar concentrations of active tPA, tPA/PAI-1, and tPA/C1-inhibitor using the optimized methods was equal to 94% +/- 7% of measured total tPA. CONCLUSION: Optimized assays based on a single anti-tPA capture antibody can be used to accurately measure the major forms of tPA in plasma.

Cardiopulmonary Bypass↗
PubMed2000

A kinetic model of the circulatory regulation of tissue plasminogen activator during orthotopic liver transplantation.

To better understand the regulation of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) during liver transplantation, we used a computer model of the human circulatory system to simultaneously evaluate the effect of t-PA secretion, t-PA inhibition by PAI-1, hepatic clearance of t-PA, blood loss, transfusion and hemodynamics on t-PA and PAI-1 levels during liver transplantation in three patients that differed in severity of liver disease, blood loss and anhepatic changes in t-PA. Higher preoperative t-PA levels were primarily related to underlying liver disease and reduced hepatic clearance. During the anhepatic stage, when hepatic t-PA clearance was eliminated: (1) the expected rise in t-PA was modulated by the extent of bleeding, which acted as an alternate t-PA clearance mechanism; and (2) the ratio of t-PA:PAI-1 was increased due both to lower t-PA clearance and reduced PAI-1 secretion. Recirculation of the new liver was associated with renewed clearance of t-PA, an acute phase increase in PAI-1 and a drop in the t-PA:PAI-1 ratio. Understanding fibrinolytic regulation required simultaneous analysis of t-PA secretion, inhibition and clearance. Anhepatic t-PA levels could be predicted based on preoperative liver function and surgical blood loss, which acted as an alternate t-PA clearance mechanism.

Aged↗
PubMed1999

Cerebrospinal fluid creatine kinase-BB isoenzyme activity and outcome after subarachnoid hemorrhage.

BACKGROUND: The brain is rich in creatine kinase-BB isoenzyme activity (CK-BB), which is not normally present in cerebrospinal fluid (CSF). Results of previous studies have shown that CK-BB can be detected in the CSF of patients with aneurysmal subarachnoid hemorrhage (SAH), but whether CK-BB levels correlate with patients' neurologic outcomes is unknown. OBJECTIVE: To evaluate the relationship between CSF CK-BB level and outcome after SAH. DESIGN: Prospective observational cohort. SETTING: University-affiliated tertiary care center. PATIENTS: Convenience sample of 30 patients seen for cerebral aneurysm clipping. INTERVENTIONS: We sampled and assayed CSF for CK isoenzymes a median of 3 days after SAH in 27 patients, and at the time of unruptured aneurysm clipping in 3 patients. MAIN OUTCOME MEASURES: Without knowledge of CK results, we assigned the Glasgow Outcome Scale score early (approximately 1 week) and late (approximately 2 months) after surgery. RESULTS: Higher CSF CK-BB levels were associated with higher Hunt and Hess grades at hospital admission (Spearman rank correlation, p = 0.69; P<.001), lower Glasgow Coma Scale scores at hospital admission (p = -0.72; P<.001), and worse early outcomes on the Glasgow Outcome Scale (p = -0.64; P<.001). For patients with a favorable early outcome (Glasgow Outcome Scale score, 3-5), all CK-BB levels were less than 40 U/L. With a cutoff value of 40 U/L, CK-BB had a sensitivity of 70% and a specificity of 100% for predicting unfavorable early outcome (Glasgow Outcome Scale score, 1-2). Having a CK-BB level greater than 40 U/L increased the chance of an unfavorable early outcome, from 33% (previous probability) to 100%, whereas a CK-BB level of 40 U/L or less decreased it to 13%. Similar findings were obtained when considering late outcomes. CONCLUSION: The level of CSF CK-BB may help predict neurologic outcome after SAH.

Adult↗
PubMed1999

Effect of high-intensity focused ultrasound on whole blood with and without microbubble contrast agent.

Using human whole blood samples with and without contrast agent (CA), we evaluated the effect of exposures to focused, continuous wave (CW) 1.1-MHz ultrasound for durations of 10 ms to 1 s at spatial average intensities of 560 to 2360 W/cm2. Cavitation was monitored with a passive cavitation detector and hemolysis was determined with spectroscopy. In whole blood alone, no significant cavitation, heating or hemolysis was detected at any exposure condition. Conversely, cavitation and hemolysis, but not heating, were detected in whole blood with CA. A CA concentration as low as 0.28 microL CA per mL whole blood at an intensity of 2360 W/cm2 for 1 s resulted in measurable cavitation and a 6-fold increase in hemolysis compared to shams. Cavitation and hemolysis increased proportional to the concentration of CA and duration of exposure. In samples containing 4.2 microL CA per mL whole blood exposed for 1 s, a threshold was seen at 1750 W/cm2 where cavitation and hemolysis increased 10-fold compared to exposures at lower intensities. HIFU exposure of whole blood containing CA leads to significant hemolysis in vitro and may lead to clinically significant hemolysis in vivo.

Albumins↗
PubMed1999

Venous thrombus stability during acute phase of therapy.

The purpose of this study was to use serial venous duplex scans to document the status of deep venous thrombi during the early phase of therapy for acute, deep-vein thrombosis (DVT). A total of 71 consecutive participants treated for a first episode of acute DVT were monitored for new venous thrombosis using serial venous duplex scans. An average of 4.6 duplex scans were performed per patient (range, three to seven) during the 3-week study period. The cumulative incidence of contiguous/non-contiguous extension of the DVT at 3 weeks was 26% (95% CI = 14% to 38%). Nine of the 15 (60%) occurrences were asymptomatic. None of the classical risk factors for DVT was significantly associated with the development of new thrombi. The fraction of time during which the level of anticoagulation was considered 'adequate' (international normalized ratio > or =2.0 and/or heparin concentration > or =0.2 IU/ml) was inversely associated with the risk of extension/new thrombi (p = 0.01, Cox proportional hazards analysis). It was concluded that: (1) the frequency of contiguous/non-contiguous extension of venous thrombosis detectable during the first 3 weeks of therapy was higher than previously reported; (2) the majority of the occurrences were asymptomatic; and (3) the risk of developing this complication was inversely associated with the level of anticoagulation achieved.

Adult↗
PubMed1998

Heparin-coated bypass circuits (Carmeda) suppress the release of tissue plasminogen activator during normothermic coronary artery bypass graft surgery.

OBJECTIVES: To study fibrinolysis in a homogeneous first-time coronary artery bypass surgery (CABG) population in whom heparin-coated circuits were used. DESIGN: A prospective, blinded, randomized, placebo-controlled study. SETTING: A university hospital, tertiary care, intraoperative and postoperative intensive care unit. PARTICIPANTS: Twenty-one adult elective primary CABG patients. INTERVENTIONS: Randomized circuit-type centrifugal pump, membrane oxygenator, rigid cardiotomy reservoir, either placebo (n = 10) or heparin-coated (n = 11) (Carmeda; Medtronic Inc., Anaheim, CA). MEASUREMENTS AND MAIN RESULTS: Blood samples were analyzed for tissue plasminogen activator (TPA) activity, TPA antigen, plasminogen activator inhibitor-1 (PAI-1) activity, prothrombin complex F1.2, and antithrombin III (AT-III) at the following times: before cardiopulmonary bypass (CPB), during CPB (30 and 60 minutes), post-CPB, and day 1 postsurgery. TPA activity and antigen increased fivefold in the placebo group during CPB, whereas it did not even double in the heparin-coated group. PAI-1, F1.2, and AT-III were not different between groups. CONCLUSIONS: Heparin-coated CPB circuits reduced TPA release in this homogeneous CABG population with routine heparin/protamine management.

Adult↗
PubMed1998

A second-generation blood substitute (perfluorodichlorooctane emulsion) does not activate complement during an ex vivo circulation model of bypass.

OBJECTIVES: To examine whether a second-generation perfluorocarbon (PFC) blood substitute added to the cardiopulmonary bypass (CPB) prime influences complement production. DESIGN: A prospective, randomized, single-blinded, ex vivo model. SETTING: A university hospital, laboratory, and clinics. PARTICIPANTS: Ten healthy adult consented volunteer blood donors (five men, five women). INTERVENTIONS: Ex vivo closed-loop extracorporeal circuit including membrane oxygenator, tubing, and filter primed with crystalloid or crystalloid plus PFC was circulated for 1 hour with the addition of 500 mL of heparinized fresh human whole blood. MEASUREMENTS AND MAIN RESULTS: Laboratory specimens were drawn from the circuit at 10-minute intervals for 1 hour and measured for complement (C3a, Bb fragment) concentrations, blood gases, fibrinogen concentration, platelet count, and hematocrit. In the PFC group, C3a and Bb fragments were equal to or less than those in the group that received crystalloid alone. CONCLUSION: The second-generation PFC added to the prime of a CPB circuit does not independently increase complement production.

Adolescent↗
PubMed1998

False negative factor V Leiden assay following allogeneic stem cell transplant.

We report a case where a phenotypic test (an activity assay for activated protein C resistance) correctly indicated that the patient had an abnormality, whereas the initial genetic test (a PCR-based DNA assay used to detect the mutation in the FV gene) incorrectly indicated that the patient did not. The apparent false negative result of the DNA-based test was due to the use of peripheral blood leucocytes for DNA analysis. The patient had undergone a stem cell transplant several months before, and the leucocytes in her blood were derived from the stem cell donor, which lacked the FV defect.

Blood Protein Disorders↗
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↗