bluuebunny/crossref_metadata_2025 huggingface dataset:
Interobserver Agreement of Complete Compression Ultrasound for Clinically Suspected Deep Vein Thrombosis
Authors: Schwarz Thomas , Schmidt Benjamin , Schmidt, Barbara , Schellong Sebastian M.
Published: June 2007

The interobserver variability of compression ultrasound of proximal and distal veins in clinically suspected deep vein thrombosis was assessed. One hundred one symptomatic legs of all patients referred for clinically suspected deep vein thrombosis on 21 consecutive workdays were examined by two investigators independently according to a standardized protocol of complete compression ultrasound (CCUS) with 28 predefined venous segments between groin and ankle. Incompressible vein segments were defined as thrombotic. Cohen's kappa coefficient was used to calculate interobserver variability regarding diagnosis of deep vein thrombosis. Kappa for entire lower extremity was 0.94 (95% CI, 0.87-1). Kappa for proximal veins was 1; for calf veins 0.9 (95% CI, 0.79-1). For the posterior tibial veins and peroneal veins, kappa was 0.84 (95% CI, 0.66-1) and 0.77 (95% CI, 0.59-0.94), respectively. The results show that almost complete interobserver agreement can be achieved in compression ultrasound of both proximal and distal deep veins conducted according to a standardized examination protocol in clinically suspected deep vein thrombosis.
Effects of Extracorporeal Circulation on Thrombin-Antithrombin III and Prothrombin Fragment 1+2 Levels
Authors: Yilmaz Mustafa , Haznedaroglu Ibrahim C. , Kirazli Serafettin , Pasaoglu Ilhan
Published: June 2007

Cardiopulmonary bypass may alter the factors responsible for normal hemostasis by exposing blood to nonendothelial surfaces, for example, extracorporeal circuits. To evaluate the probable effect of extracorporeal circulation on hemostasis, we measured thrombin-antithrombin III complex (TAT) and prothrombin fragment 1+2 (PF 1.2) plasma levels, which are the biologic markers of in vivo coagulation, in 20 patients who underwent coronary artery bypass grafting (CABG). Postoperative PF 1.2 levels were higher in comparison to the preoperative concentrations of the parameter. Preoper ative and postoperative TAT concentrations showed no statistically significant difference. The increment in the PF 1.2 levels in CABG patients might suggest ongoing subclinical hemostatic activation associated with CABG. Further investigations are needed to clarify the exact relationship between increased PF 1.2 levels and thrombotic complications observed in CABG patients. Hemostatis in CABG is still an enigma and remains to be eluciated.
Effects of Recombinant Erythropoietin Therapy on Circulating Endothelial Markers in Hemodialysis Patients
Authors: Borawski Jacek , Mysiwiec Michal
Published: June 2007

Effects of a 4-week course of recombinant human erythropoietin (rHuEpo) therapy on four circulating endothelium-derived cardiovascular risk markers were studied in 20 patients receiving maintenance hemodialysis in relation to surrogates of chronic inflammation, liver function, and arterial blood pressure. Soluble intercellular adhesion molecule-1 (sICAM-1), antigens of plasminogen activator inhibitor-i (PAI-i:Ag) and von Willebrand factor (vWF:Ag), and soluble thrombomodulin (sTM) were determined by immunoenzymatic assays. C-reactive protein; (xi acid-glycoprotein; ax-antitrypsin; immunoglobulin M, A, and G; interleukin-6; lipoprotein(a); fibrinogen; total protein; albumin; total cholesterol; hepatitis B and C markers; liver enzymes; prothrombin time; and phosphorus were measured by routine methods. The rHuEpo treatment resulted in a 25% increase in sICAM-1 (Wilcoxon's p = 0.001), a 50% increase in PAI-i:Ag (p = 0.004), a 15% increase in sTM (p = 0.002), and did not change vWF:Ag levels. The increase in sICAM-1 concentration directly correlated with that of PAI-i:Ag (Spearman's rho = 0.483, p = 0.031). The rHuEpo-induced increases in hemoglobin, platelets, and pre-dialysis diastolic blood pressure levels did not correlate with the increments in the endothelial markers studied. In conclusion, short-term rHuEpo therapy activates vascular endothelium in patients receiving maintenance hemodialysis. This specific effect may influence cardiovascular risk.
Reference Intervals of the Dilute Tissue Thromboplastin Inhibition and Dilute Russell's Viper Venom Tests Revisited
Authors: Gerbutavicius Rolandas , Fareed Jawed , Messmore Harry L. , Iqbal Omer , Hoppensteadt Debra A. , Wehrmacher William H. , Demir Muzaffer , Piccolo Peter , Ahmad Sarfraz , Ma Qing , Griniute Rasa
Published: June 2007

Reference intervals for two well-recognized tests for the lupus anticoagulant were determined using 98 healthy subjects. The purpose of the study was to compare the reference intervals for the dilute tissue thromboplastin inhibition test on this group of healthy subjects calculated by parametric and nonparametric statistical methods, and to compare these results with results obtained on subsets of 20 and 40 randomly selected individuals from the group of 98. The same procedures were followed for the dilute Russell's viper venom test. Results were recorded in seconds of clotting times and in ratios (subject/mean of that set or subset). Statistical analysis revealed Gaussian distribution of the results in the large group as well as in each subset for both tests. The results showed more variation between sets of the dilute tissue thromboplastin inhibition test than of the dilute Russell's viper venom test. Nonparametrically calculated reference intervals were wider than those determined by the parametric method, especially if confidence intervals are provided for both reference limits in a group of 94 controls or in a subset of 40 subjects. The nonparametric technique uses all data for the calculation of reference interval of such sample sizes no matter how widely spread the results are. There was no significant difference between the reference intervals of subsets and the whole group (p > 0.05) calculated by both statistical techniques. Very few outliers were observed among these subjects in both tests.
Plasma Markers of Hypercoagulability in Patients with Serious Infections and Risk of Septic Shock
Authors: Psuja Piotr , Zozulifńska Maria , Turowiecka Zofia , Cieślikowski Waldemar , Vinazzer Helmut , Zawilska Krystyna
Published: June 2007

Hyperthrombinogenesis due to bacterial septicemia may aggravate the risk of irreversible septic shock. In 22 patients with septicemia complicating urinary or alimentary infections, daily assessment of hemostasis was performed throughout 1 week. Standard screening of hemostasis revealed significantly increased mean values of prothrombin time, fibrinogen, and fibrinogen degradation product (FDP) concentration. However, platelet counts, activated partial thromboplastin times (APTI), thrombin times, ethanol gelation tests, and antithrombin activity remained within the normal range. By contrast, except for insignificant changes in protein C activity and activated factor VII content, specific markers of plasma hypercoagulability, that is, thrombin-antithrombin (TAT) complexes, prothrombin activating factor F 1+2, activated factor XII (XIIa), and dimer D were all markedly increased. Pathologic levels of TAT and XIIa were found in 82% and 73% of all plasma samples, respectively. The augmentation of TAT correlated with prolongation of thrombin time and increases in F 1+2 levels. The increase in XIIa correlated with thrombocytopenia, prolongation of APTr, exhaustion of antithrombin, and accumulation of F 1+2 and FDP in the plasma. Moreover, a significant increase in XIIa, stronger positivity of the ethanol gelation test, a greater increase in FDP, and a more pronounced decrease in protein C activity were observed in 8 patients with fatal septic shock. This study suggests the usefulness of TAT and XIIa measurements in the early recognition of plasma hypercoagulation in serious infections.
Acute Effects of Transdermal 17β-Estradiol on Hemostatic Variables after 24-hour Treatment
Authors: Hognert Helena , Ghanoum Bachar , Gustafsson Helena , Milsom Ian , Manhem Karin
Published: June 2007

The aim of this study was to investigate the acute effects of transdermal 17β-estradiol (Estraderm®) on plasma levels of coagulatory and fibrinolytic factors in postmenopausal normotensive and hypertensive women. Eleven normotensive and 13 hypertensive women were included in this placebo-controlled crossover study. In a randomized order each subject was treated with a patch of 100 yig 17β-estradiol or placebo for 24 hours. Serum levels of tissue type plasminogen activator (tPA) activity, plasminogen activator inhibitor I (PAI-1) activity, tPA antigen, PAI-I antigen, FVII, FX, and fibrinogen were assayed after both treatments. There was no significant difference in serum levels of hemostatic variables after treatment with estrogen compared to levels after placebo treatment in either of the groups. Nor was there any measurable difference when comparing hypertensive and normotensive subjects.
Low-Molecular-Weight Heparin in Arterial Reconstructive Surgery: A Double-Blind, Randomized Dose-Finding Trial
Authors: Kujath Peter , Eckmann Christian , Misselwitz Frank
Published: June 2007

Periprocedural and postprocedural anticoagulation during arterial reconstructive surgery (ARS) with intravenous heparin is standard of care. The general use and correct dosage of low-molecular-weight heparin, however, are still under debate. A prospective, randomized, double-blind trial was performed with a parallel group comparison of four dose regimen of a low-molecular-weight heparin, reviparin sodium, in patients undergoing major ARS. Sixty-five patients were randomly allocated to receive twice-daily subcutaneous injections of reviparin, 3500 (group A, n=17), 4200 (group B, n= 16), 5950 (group C, n= 16), and 7000 (group D, n= 16) anti-Xa IU per day. Patients were eligible for the trial if they had angiographically proven peripheral arterial obstructive disease with a planned arterial reconstruction of the infrarenal aorta, iliaca artery, or femoralis artery. Fifty-nine patients completed the trial. The goal was to determine the optimal dose of the low-molecular-weight heparin to achieve a minimum of early vascular events (less than 12%) with a minimum of major bleeding events (less than 10%) during a shortterm follow-up of up to 8 postoperative days. There was no reocclusion in the entire population. Patients randomized into the two lower dose groups (A and B), however, experienced a relatively high incidence of restenosis, whereas patients enrolled in group D, receiving the highest dose of reviparin, experienced an unacceptably high rate of bleeding events (all bleeds, 43%; major bleeding, 14.3%). Thus, the optimal dose of reviparin sodium to be administered in patients undergoing major ARS is half the therapeutic dose:5950 to 6300 anti Xa IU (75-85 anti Xa IU/kg body weight per day). Patients included in group C had no major bleeding event (95% confidence interval, 0% to 6.6%), a significant improvement of the doppler anklebrachial systolic pressure index (difference of 0.46 ± 0.29, P=.017), and a higher rate of responders with regard to the puls status measured at the tibialis posterior arteries (66.7%) compared to groups A and B (46.7% and 54.5%, respectively, P=.086). The efficacy and safety of this dosage regimen in comparison to standard of care should be further substantiated in larger trials.
Changes in Prescription Patterns of Oral Contraceptives in a Northern Italian Province: Relation With Venous Thromboembolism
Authors: Girolami Antonio , Spiezia Luca , Vianello Fabrizio , Girolami Bruno , Fabris Fabrizio
Published: June 2007

Oral contraceptives (OC) are a definite risk for venous thrombosis. It is commonly accepted that they cause a fourfold increased risk of thrombosis compared to non-users. The prescription patterns were evaluated from 1990 to 2000 in a northern Italian province (province of Padua). This province is typical of other northern Italian provinces. As a consequence, it can be safely assumed that the observations gathered may apply to the entire north of Italy. During these years, a sharp increase in the use of OC was noted. Furthermore, around 1995 to 1996, a marked switch toward the use of preparations containing third-generation progestins was noted. During the past few years of the observation period, approximately 80% of women use preparations containing third-generation progestins. During the same period, an increased incidence of episodes of venous thromboembolism (VTE) was noted. The increase in the prevalence of VTE episodes appeared to be proportional to the increased use of OC, regardless of the type of progestin contained in the oral contraceptive preparations.
Value of Thromboelastography in the Assessment of Platelet Function
Authors: Bowbrick Virginia A. , Mikhailidis Dimitri P. , Stansby Gerard
Published: June 2007

Thromboelastography (TEG) is a useful measure of coagulation. Modified TEG (that is with the addition of a GP Ilb/Illa receptor antagonist) has been used to assess the contribution of the fibrinogen-platelet interaction to TEG parameters (in particular the maximum amplitude, MA). Modified TEG was compared with other investigations of platelet function to assess its sensitivity in both normal subjects and in patients with peripheral arterial disease (PAD), a condition associated with activated platelets. Blood was collected from eight healthy subjects and 12 PAD patients. Platelet function was measured by TEG, flow cytometry (using PAC-1, P-selectin, GP Illa and GP lb murine antibodies) and platelet aggregometry (spontaneous and ADP-induced) in the presence and absence of tirofiban (a GP JIb/lla receptor antagonist). TEG showed a statistically significant reduction in MA with tirofiban at 0.4 mg/L and an increase in k (kinetic time; which indicates how fast clot strength is increasing once clotting starts) at 0.2 and 0.4 mg/L of tirofiban in both healthy subjects and PAD patients. Flow cytometry showed a significant decrease in the PAC-1 binding index (at 0.2 mg/b). This finding was compatible with the significant reductions found in spontaneous and ADP-induced platelet aggregation. However, aggregometry and flow cytometry were more sensitive indicators of platelet inhibition than the TEG parameters. TEG does not provide a comprehensive or sensitive reflection of impaired platelet function. If TEG is used as an index of severely impaired platelet function, we recommend that the k parameter should be used as well as MA. TEG should be supplemented by other methods of platelet function assessment wherever possible.
Antiphospholipid Syndrome in Obstetrics
Authors: Heilmann Lothar , Tempelhoff Georg-Friedrich v. , Pollow Kunhard
Published: June 2007

Antiphospholipid syndrome (APLS) in pregnancy is characterized by the presence of autoantibodies in association with recurrent fetal loss and severe complications such as preeclampsia, fetal growth retardation, or placental insufficiency. The most clinically important serologic markers are lupus anticoagulant, anticardiolipin antibodies, and recently anti-beta-2-glycoprotein 1 antibodies. At present, standardization does not exist and a definitive association between specific clinical manifestation and antibody level is not yet known. Experimental data gave evidence that passive transfer of antiphospholipid antibodies result in clinical manifestation of APLS, that is, fetal loss and thrombocytopenia. Treatment with heparin, aspirin, or intravenous immunoglobulins decreased the fetal loss rate. Treatment regimens in human are very difficult to interpret. Evidence from two prospective studies supported treatment with heparin and aspirin to improve pregnancy outcome. The risk of preeclampsia and placental insufficiency was substantial and occurred in 50% of patients. The general failure rate of heparin/aspirin treatment is approximately 30%. In such cases intravenous immunoglobulin in combination with heparin and aspirin has been used to treat APLS.
Global Fibrinolytic Capacity in Colorectal Cancer: A New Clue to Occult Fibrinolysis
Authors: Ozturk Mustafa , Sengul Neriman , Dagli Mehmet , Kosar Ali , Bavbek Nuiket
Published: June 2007

Hemostatic disorders in cancer patients range from asymptomatic laboratory changes to massive thromboembolism or hemorrhage. Routine laboratory tests often fail to identify patients at high risk for hemostatic complications. The postoperative risk of thromboembolic events in colorectal cancer was reported as approximately 2% to 5%. A new diagnostic test was used to assess global fibrinolytic activity, which may detect occult fibrinolysis or disseminated intravascular coagulation in patients with colorectal cancer. Twenty patients with colorectal cancer and 20 healthy control subjects were involved. Using standard silicated fibrin pellets and tissue plasminogen activator, the fibrinolytic capacity of the plasma samples was detected with the amount of D-dimer produced before the reaction was stopped by adding aprotinin to the medium. Mean global fibrinolytic capacity was increased in patients before and after surgery when compared to controls (p=0.002, p=0.001, respectively). In conclusion, a hemostatic imbalance was detected toward primary fibrinolysis in the preoperative period and low-grade disseminated intravascular coagulation postoperatively.
Hypoxia and Altered Platelet Behavior Influence von Willebrand Factor Multimeric Composition in Secondary Pulmonary Hypertension
Authors: Caramurú Lúcia Helena , Soares Rosangela De P. S. , Maeda Nair Yukie , Lopes Antonio Augusto
Published: June 2007

In pulmonary hypertension (PH), defective plasma von Willebrand factor (vWF) lacking the larger multimers with increased concentration of low-molecular-weight fractions (LMW) has been reported, although the mechanisms involved are not completely known. Altered platelet behavior may be involved in this alteration; this hypothesis was investigated in 10 patients with PH associated with chronic hypoxemia and erythrocytosis (age 13 to 51 years, mean pulmonary artery pressure 38 to 98 mmHg). The possible influence of the hematocrit (Hct) and decreased oxygen saturation (SpO2) on vWF abnormalities was examined. Patients were evaluated before and after therapeutic hemodilution. vWF alterations were quantified using the ratio of LMW/total multimers (densitometric analysis of luminographs after Western blotting). Platelet count and activation state (plasma levels of f-thromboglobulin, enzyme-linked immunosorbent assay), the Hct and SpO2 were also assessed before and after hemodilution. Platelet activation and consumption were suggested by increased plasma β-thromboglobulin (p=0.0444) with decreased platelet count (p<0.001). Altered vWF LMW/total ratio correlated significantly with decreased platelet count (p=0.0066) and low SpO2 (p=0.0088). The effects of both variables were independent and additive (p=0.0031, multiple regression). Hemodilution was followed by an increase in platelet count (p=0.0013) associated with improvement of LMW/total ratio (p=0.0079). Residual vWF alterations were associated with persistent hypoxemia and residual platelet activation (plasma β-thromboglobulin still increased). These data suggest a common mechanism for platelet and vWF abnormalities in these chronically hypoxic PH patients. Hypoxia itself may play a role, possibly inducing endothelial release of unprocessed (LMW) vWF molecules.
Differential Effects of DX-9065a, Argatroban, and Synthetic Pentasaccharide on Tissue Thromboplastin Inhibition Test and Dilute Russell's Viper Venom Test
Authors: Gerbutavicius Rolandas , Iqbal Omer , Messmore Harry L. , Wehrmacher William H. , Hoppensteadt Debra A. , Gerbutaviciene Rima , Griniute Rasa , Fareed Jawed
Published: June 2007

New synthetic direct and indirect factor Xa or factor Ila inhibitors are increasingly used for the prevention and treatment of thrombotic disorders, including patients suffering from antiphospholipid syndrome. In this study, the effects of the synthetic direct factor Xa inhibitor DX-9065a, the indirect synthetic heparinomimetic pentasaccharide, and the direct factor IIa inhibitor Argatroban were studied. These two widely used assays for the detection of lupus anticoagulant, namely the tissue thromboplastin inhibition (TTIT) and the dilute Russell viper venom tests (DRVVT) proved useful. The drugs were added to a normal human plasma pool ranging in concentration from 0.04 to 10 Ag/mL. Using the two tests named above, DX-9065a and Argatroban showed a dose-related prolongation of TTIT and DRVVT in the concentration range from 0.04 to 5 Amol/mL, but the pentasaccharide only slightly prolonged the clotting times of these assays even at high concentrations. Argatroban had the more pronounced effect on both tests when compared with DX-9065a (p<0.001). The most responsive assay for DX-9065a up to a concentration of 2.5 Amol/mL was the DRVVT. For Argatroban both TTIT and DRVVT were equally responsive. Patients whose plasma was tested for suspected lupus anticoagulant and who have been given DX-9065a or Argatroban may have false-positive results with the TTIT tests and DRVVT. This effect should be considered during patient management. These results indicate that these assays could be used for the effective quantitation of the direct factor Xa or factor Ila inhibitors when suitable controls are used.
Combination Antiplatelet Therapy in Patients with Peripheral Vascular Bypass Grafts
Authors: Smout Jonathan D. , Mikhailidis Dimitri P. , Shenton Brian K. , Stansby Gerard
Published: June 2007

Peripheral bypass graft occlusion occurs in approximately 25% of cases in the 5 years following surgery; hence, therapies directed at reducing the tendency toward thrombotic occlusion are of clinical importance. This trial was conducted to determine if the addition of clopidogrel to aspirin enhances antiplatelet therapy in patients with infrainguinal bypass grafts. A randomized placebo-controlled study was performed on 20 patients over 3 months following infrainguinal bypass surgery. In addition to their regular aspirin therapy, patients were randomized to receive either clopidogrel (group 1) or placebo (group 2) for 1 week. Platelet activation was measured ex vivo by platelet aggregometry and flow cytometry. In group 1, there was a significant reduction in spontaneous (SP), adenosine diphosphate (ADP), and arachidonic acid (AA)-induced platelet aggregation compared with group 2; SP −17% (CI −33, −0.2 p = 0.048), ADP −39%, (CI −56, −22 p = 0.001), AA −21% (CI −39, −4 p = 0.023). Flow cytometry demonstrated a significant reduction in ADP-induced platelet P-selectin expression and GPIIb/IIIa activation following treatment with clopidogrel but not with placebo. This study demonstrated that the addition of clopidogrel to aspirin reduces platelet activation measured by platelet aggregation and flow cytometry, supporting a long-term trial with clinical endpoints.
The Urine Trans, Trans Muconic Acid Biomarker and Platelet Count in a Sample of Subjects with Benzene Exposure
Authors: Wiwanitkit Viroj , Suwansaksri Jamsai , Soogarun Suphan
Published: June 2007

Benzene exposure is of particular concern because of ongoing exposure to thousands of workers. Prolonged exposure can cause chronic toxicity, especially hematologic disorders. The effects of benzene on red blood cells and white blood cells have been clearly proposed; however, the effect of benzene on platelets has not been studied. The correlation between the level of trans, trans muconic acid (ttMA), a urine metabolite of benzene, and the platelet count of subjects occupationally exposed to benzene was studied. Thirty volunteers who were occupationally exposed to benzene were investigated for both urine ttMA levels and platelet parameters. According to the regression analysis, no significant correlation existed between urine ttMA level and any platelet parameters (p > 0.05). However, although there is no statistical significance, the platelet count and PCT decreased while the urine ttMA increased. In addition, using the upper normal limit ttMA level as the cutoff level, the statistically significant lower platelet count and PCT was observed in the subjects with urine ttMA higher than upper normal limit. This report is the first world report on this topic and the results from this study can provide good basic data for further understanding the effect of benzene exposure on the platelet.
Comparison of Pycnogenol® and Daflon® in Treating Chronic Venous Insufficiency: A Prospective, Controlled Study
Authors: Cesarone M. R. , Belcaro G. , Rohdewald P. , Pellegrini L. , Ledda A. , Vinciguerra G. , Ricci A. , Gizzi G. , Ippolito E. , Fano F. , Dugall M. , Acerbi G. , Cacchio M. , Di Renzo A. , Hosoi M. , Stuard S. , Corsi M.
Published: June 2007

The aim of this study was to investigate the clinical efficacy of oral Pycnogenol® (Horphag Research Ltd., UK) in patients with severe chronic venous insufficiency (CVI) in comparison to the combination of diosmin and hesperidin (Daflon®, Servier, France). A group of 86 patients with severe chronic venous insufficiency (CVI), venous hypertension, ankle swelling) and previous history of venous ulcerations received either oral Pycnogenol (capsules) 150 mg or 300 mg daily for 8 weeks or Daflon, 1000 mg/day. All patients completed the study without dropouts. At the end of the study, microcirculatory results indicated: a progressive decrease of skin flux at rest (RF); a significant decrease in capillary filtration (RAS); an improvement in the symptomatic venous score (ASLS); a reduction in edema; a significant improvement (increase) in pO2 and a decrease in pCO2 in the Pycnogenol group. A significant level of improvement was reached after 4 weeks of treatment in most patients (p < .05) of the Pycnogenol group while clinical improvement was significant only in 6 subjects in the Daflon group. The positive effects of treatment with Pycnogenol after 8 weeks were significantly larger in comparison with the Daflon group. In conclusion, this study confirms the fast clinical efficacy of Pycnogenol in patients with chronic venous insufficiency and venous microangiopathy and its superiority—considering the evaluated parameters—to the combination of diosmin and hesperidin.
Specific Determination of Plasmatic Thrombin Activity
Authors: Stief T. W.
Published: June 2007

Thrombin is the key enzyme of coagulation. Its activity can be determined via fibrinogen øfibrin conversion or via cleavage of a chromogenic substrate. The latter method is easier than the first one, but in plasma it is hampered due to unspecific cleavage of the chromogenic substrate by thrombin-like enzymes of hemostasis, especially those of the contact phase. The concentration of the thrombin substrate (HD-CHG-Ala-Arg-pNA) was optimized, using final substrate concentrations of 0 to 5 mM, a final arginine concentration of 1.13 M, and samples of 10 mIU/mL purified thrombin in 7% human albumin or pooled normal citrated plasma without and with EDTA. Twenty microliters pooled normal citrated plasma (frozen/thawed) or factor II–deficient plasma (lyophilized) were incubated with 10 µL 0% to 0.5% Thromborel S® (100% = 162 ng/mL tissue factor [TF]) in 6% BSA or with 10 µL 0% (physiol. NaCl) to 50% Pathromtin SL®and with 20 µL 25 mM CaCl2. After 0 to 22 minutes (37°C), 20 µL 1.7 M arginine, pH 8.7 were added. Fifteen microliters 0.9 mM HD-CHGAla-Arg-pNA in 2.3 M arginine, pH 8.6, were added and the increase in absorbance (δA) at 405 nm was determined. Thrombin activity was standardized against the 3A measured for 1 IU/mL thrombin in 7% human albumin (8.8 mA/min RT). The optimal final chromogenic substrate concentration to detect thrombin in this assay system is less than 0.6 mM. Higher substrate concentrations in a plasma milieu result in unspecific cleavage of the substrate. Using final concentrations of chromogenic substrate less than 0.4 mM (the approximate Km- value for thrombin) and final concentrations of arginine greater than 800 mM, in factor II–depleted plasma, when activated either by TF or by the contact phase, there is no significant thrombin generation. The circulating thrombin activity measured in EDTA plasma of 39 healthy donors is 100 ± 20% of norm (mean value ± 1 SD; 100% = 5.5 mIU/mL thrombin). This chromogenic assay detects thrombin activity independent of clotting seconds or fibrin mediated turbidity increases. This technique allows to standardize the thrombin activity generated in any biologic system in international thrombin units.
A Pilot Study of the Effects of Vivostat Patient-derived Fibrin Sealant in Reducing Blood Loss in Primary Hip Arthroplasty
Authors: Lassen Michael Rud , Solgaard Søren , Kjersgaard Anne Grete , Olsen Claus , Lind Bjørn , Mittet Karen , Ganes Helle Coff
Published: June 2007

A pilot study evaluated the effectiveness of Vivostat patient-derived fibrin sealant in reducing blood loss in patients who underwent primary hip arthroplasty. Eighty adult patients undergoing elective surgery were randomized to receive either Vivostat sealant or control (no additional hemostatic treatment). Patients allocated Vivostat sealant donated 120 mL of blood, which was then processed perioperatively to produce a fibrin sealant that was applied to the bleeding wound surfaces just before closure. Transfusion requirements, blood loss during surgery, drain volumes, and daily hematocrit and hemoglobin levels were measured. Hospitalization times, adverse events, and postoperative wound complications were also monitored. Blood loss during surgery and wound drainage volume was lower in the Vivostat group than in the control group, although the differences were not significantly different. Transfusion requirements (median, 270 mL of packed red blood cells) and hospitalization times (both median 7 days) were the same for both groups. No adverse events related to the use of Vivostat occurred. There were indications of a possible reduction in the incidence of postoperative wound oozing (15% vs 25%) and hematomas (6% vs 11%) with the use of Vivostat compared with the control group, although differences were not statistically significant. In conclusion, in this pilot study, use of Vivostat patient-derived fibrin in hip arthroplasty was not associated with a significant reduction in blood loss. Further studies, with larger numbers of patients, may be warranted to investigate a possible benefit of Vivostat in reducing postoperative wound complications.
Thromboembolism in Cancer Patients: Pathogenesis and Treatment
Authors: Adess Matthew , Eisner Robert , Nand Sucha , Godwin John , Messmore Harry L. , Wehrmacher William H.
Published: June 2007

In this review we summarize the causes of cancer related thrombosis as well as modern treatment approaches. Malignancy as a risk factor for thromboembolism is becoming increasingly recognized by clinicians caring for these patients. The probability of thrombosis occurring in an individual patient is dependent on several factors, including accompanying medical problems, the type of cancer, the clinical stage, performance status, and the treatment modalities employed. Thrombophilia with a history of thromboembolism is important as well. The overall risk of thrombosis is sevenfold that of noncancer patients. Though much has been learned about the pathogenesis of cancer-related thrombosis, we are in fact just beginning to understand the cross-talk between cancer cells and their related microenvironment, and such investigations are likely to increase our knowledge of cancer-related thrombosis mechanisms. Research in these areas may also suggest new strategies for cancer prevention, metastasis suppression, and new treatments. Drugs used in cancer therapy are increasingly recognized to directly contribute to the thrombotic tendency. Few studies provide data on the optimal management of cancer patients with thrombosis. It has been learned that retreating with the same drug can be very hazardous. In general the approach to prevention of thrombosis is the same as for noncancer patients, recognizing that specific cancer types and stage can place a patient in a high-risk category. Initial coumadin therapy fails in a significant number of patients with cancer. Recognition of the cancer patients at highest risk for coumadin failure is challenging. Low-molecular-weight heparins appear to be more effective in such situations where coumadin is likely to fail or has failed, but these drugs are thought to be costlier. Newer agents such as Factor Xa inhibitors and TF inhibitors are currently under investigation and may be found useful in the management of cancer-related thrombosis.
Control of Edema in Hypertensive Subjects Treated With Calcium Antagonist (Nifedipine) or Angiotensin-Converting Enzyme Inhibitors With Pycnogenol
Authors: Belcaro Gianni , Cesarone Maria Rosaria , Ricci Andrea , Cornelli Umberto , Rodhewald Peter , Ledda Andrea , Di Renzo Andrea , Stuard Stefano , Cacchio Marisa , Vinciguerra Giulia , Gizzi Giuseppe , Pellegrini Luciano , Dugall Mark , Fano Filiberto
Published: June 2007

The presence of edema in different phases and stages of essential hypertension may be due to antihypertensive treatment. Some drugs may cause edema by inducing vasodilatation, increasing the capillary exchange surface and capillary filtration. Pycnogenol has an important anti-edema effect in diabetic microangiopathy and chronic venous insufficiency. This 8-week study evaluated capillary filtration in 2 comparable treatment groups with hypertension treated with a calcium antagonist (nifedipine) or angiotensin-converting enzyme inhibitor to define its efficacy in preventing edema caused by antihypertensives. A significant decrease in filtration was observed in the Pycnogenol groups. Pycnogenol controls this type of edema, it helps to prevent and limit long-term damage in the microcirculation in hypertensive patients, and allows the dose of anti-hypertensive drugs to be reduced in most patients.
Low Frequency of Phlebographic Deep Vein Thrombosis After Laparoscopic Cholecystectomy—A Pilot Study
Authors: Lindberg Fredrik , Björck Martin , Rasmussen Ib , Nyman Rickard , Bergqvist David
Published: June 2007

To investigate the rate of deep vein thrombosis (DVT) after laparoscopic surgery, 50 patients underwent bilateral phlebography 7-11 days after laparoscopic cholecystectomy (LC). All received thromboembolism prophylaxis, either low molecular weight heparin (LMWH) or dextran. Three patients were converted to open cholecystectomy. D-dimer was investigated preoperatively, on day 1 and on the day of phlebography. One asymptomatic DVT was found. One phlebogram was incomplete. Seven phlebograms were not optimal but of sufficient quality to rule out DVT. The frequency of DVT was thus 1 of 49 or 2.0% (95% confidence interval, 0-6.0%). No anticoagulants were prescribed after discharge. No patient developed late thromboembolic complications. D-dimer values increased significantly at day 1 and were further increased at the time of phlebography. The frequency of phlebographical DVTs thus seems to be low despite prophylaxis of questionable efficacy. The D-dimer values, however, suggest that the effects of LC on coagulation/fibrinolysis have a duration of longer than 1 week.
Intravenous DDAVP and Factor VIII-von Willebrand Factor Concentrate for the Treatment and Prophylaxis of Bleedings in Patients With von Willebrand Disease Type 1, 2 and 3
Authors: Michiels Jan Jacques , van Vliet Huub H. D. M. , Berneman Zwi , Gadisseur Alain , van der Planken Marc , Schroyens Wilfried , van der Velden Ann , Budde Ulrich
Published: June 2007

The current standard set of von Willebrand factor (VWF) parameters used to differentiate type 1 from type 2 VWD include bleeding times (BTs), factor VIII coagulant activity (FVIII:C), VWF antigen (VWF:Ag), VWF ristocetine cofactor activity (VWF:RCo), VWF collagen binding activity (VWF:CB), ristocetine induced platelet aggregation (RIPA), and analysis of VWF multimers in low and high resolution agarose gels and the response to DDAVP. The BTs and RIPA are normal in asymptomatic carriers of a mutant VWF allele, in dominant type 1, and in recessive type 2N VWD, and this category has a normal response of VWF parameters to DDAVP. The response of FVIII:C is compromised in type 2N VWD. The BTs and RIPA are usually normal in type Vicenza and mild type 2A VWD, and these two VWD variants show a transiently good response of BT and VWF parameters followed by short in vivo half life times of VWF parameters. The BTS are strongly prolonged and RIPA typically absent in recessive severe type 1 and 3 VWD, in dominant type 2A and in recessive type 2C (very likely also 2D) VWD and consequently associated with low or absent platelet VWF, and no or poor response of VWF parameters to DDAVP. The BTs are prolonged and RIPA increased in dominant type 2B VWD, that is featured by normal platelet VWF and a poor response of BT and functional VWF to DDAVP. The BTs are prolonged and RIPA decreased in dominant type 2A and 2U, that all have low VWF platelet, very low VWF:RCo values as compared to VWF:Ag, and a poor response of functional VWF to DDAVP. VWD type 2M is featured by the presence of all VWF multimers in a low resolution agarose gel, normal or slightly prolonged BT, decreased RIPA, a poor response of VWF:RCo and a good response of FVIII and VWF:CB to DDAVP and therefore clearly in between dominant type 1 and 2U. The existing recommendations for prophylaxis and treatment of bleedings in type 2 VWD patients with FVIII/VWF concentrates are mainly derived from pharmocokinetic studies in type 3 VWD patients. FVIII/VWF concentrates should be characterised by labelling with FVIII:C, VWF:RCo, VWF:CB and VWF multimeric pattern to determine their safety and efficacy in prospective management studies. As the bleeding tendency is moderate in type 2 and severe in type 3 VWD and the FVIII:C levels are near normal in type 2 and very low in type 3 VWD patients. Proper recommendations of FVIII/VWF concentrates using VWF:RCo unit dosing for the prophylaxis and treatment of bleeding episodes are proposed and has to be stratified for the severity of bleeding, the type of surgery either minor or major and for type 2 and type 3 VWD as well.
Role of Hyperhomocystinemia in Retinal Vascular Occlusive Disease
Authors: Sottilotta Gianluca , Oriana Vincenzo , Latella Caterina , Luise Francesca , Piromalli Angela , Ramirez Francesca , Mammi Corrado , Occhiuto Antonio , Lombardo Vincenzo Trapani
Published: June 2007

Elevated plasma homocysteine (Hcy) level is considered a risk factor for vascular diseases. In recent years, many scientific reports have suggested that hyperhomocystinemia may be associated with an increased risk of retinal vascular occlusive disease (RVOD). The prevalence of elevation of homocysteine in patients with a recent retinal vascular occlusion was compared to a health control group in this study. Forty-nine consecutive patients (22 M; 27 F) (age 26-85 years, mean 69) with diagnosis of retinal vascular occlusion were compared with 71 healthy controls. These patients underwent laboratory evaluation for plasma fasting total homocysteine, activated protein C resistance, protein C, protein S, antithrombin III, and antiphospholipid and anticardiolipin antibodies. The G20210 prothrombin gene mutation (FII G20210A) and Factor V Leiden mutation (FVL) were evaluated. None of these enrolled subjects had other prothrombic risk factors. The health control group consisted of healthy subjects from the general population, with no history or clinical evidence of retinal vascular disease, recruited during the same 2-year period. High fasting homocystinemia (higher than 15 μmol/L) was detected in 24/49 subjects (48.9%) ( P < .0005). There was a high prevalence of hyperhomocystinemia: these data suggest an association between RVOD and high fasting homocystinemia. Elevated homocysteine may be an independent risk factor, and its assessment may be important in the investigation, management, and follow-up of patients with RVOD. Further controlled studies are necessary to clarify the exact role of hyperhomocystinemia in RVOD and to evaluate the appropriate therapeutic approach.
Isolation and Characterization of Heparin From Tuna Skins
Authors: Jeske Walter P. , McDonald Meredith K. , Hoppensteadt Debra A. , Bau Elaine C. , Mendes Aline , Dietrich Carl P. , Walenga Jeanine M. , Coyne Erwin
Published: June 2007

This study characterized heparin isolated from tuna skins. Glycosaminoglycans were isolated from tuna skin after digestion using anion exchange resin. Heparin was eluted from the resin by sodium chloride gradient and was further fractionated by acetone fractionation. Anticoagulant activity was determined using the activated partial thromboplastin time and Heptest assays. Potency was determined using amidolytic antifactor IIa and antifactor Xa assays. The presence of heparin in the extracted tuna skin glycosaminoglycans was confirmed using 13C-nuclear magnetic resonance. The activated partial thromboplastin time and Heptest clotting times were doubled at concentrations of about 4 and 1 µg/mL, respectively. The clotting time prolongation and antiprotease activity induced by tuna heparin was readily neutralized by 25 µg/mL protamine sulfate. These results demonstrate that biologically active heparin with properties similar to clinical grade heparin can be derived from tuna skin, a raw material with otherwise relatively little economic value.
Arginine Inhibits Serpins
Authors: Stief Thomas W.
Published: June 2007

Serine protease inactivators (serpins) are important regulators in biochemistry. Often it is necessary to block the serpin action, that is, to stabilize the sample. The guanidine group of arginine is the ligand for the active center pocket of many serine proteases. Arginine or guanidine inhibits serine proteases, and arginine belongs to the reactive P1-P1' center of many serpins. The plasmatic antithrombin, antiplasmin, or anti-C1-esterase activity was determined: A total of 20 µL of pooled normal plasma or 7% human albumin was added to 100 µL of 0—2.67 M arginine, pH 8.6, 10 µL of 26 mIU/mL thrombin in 7% human albumin, and 30 µL of 1.7 mM CHG-Ala-Arg-pNA (37°C). ΔA at 405 nm was determined, by using a microtiter plate reader. Thrombin was substituted by plasmin or C1-esterase, and the chromogenic peptide substrates <Glu-Phe-Lys-pNA or MeOC-Lys(eCBO)-Gly-Arg-pNA, respectively, were used. The IC50 of arginine against plasmatic antithrombin activity is 580 mM; the IC 25 is 440 mM. The IC25 of arginine against plasmatic α 2-antiplasmin or C1-inactivator is 1650 mM. The amidolytic activity of thrombin, plasmin, and C1-esterase is inhibited similarly by arginine: the IC50 for arginine against the amidolytic activity of these proteases is about 400 mM. Arginine at very high concentrations inhibits serpins. This is important, if stabilization of a biological fluid is a prerequisite for valid activities of serine proteases. In addition, these high concentrations of arginine might be a new gentle principle to inhibit pathogens that need serpins for their pathophysiology.
Feedback Controls and Optimal Gain Design of Delayed Periodic Linear Systems
Authors: Sheng Jie , Sun J. Q.
Published: June 2007

In this paper we present an application of a semi-discretization method to the stability analysis of PID feedback controls of linear systems with time delay. The method develops a mapping of the system response in a finite-dimensional state space. Minimization of the largest absolute value of the eigenvalues of the mapping leads to optimal control gains. Numerical examples of both time-invariant and periodic linear systems are presented to demonstrate the method. The tracking control problem of linear systems with time delay is also discussed. We have found that the semi-discretization method provides accurate stability boundaries and performance contours in the parametric space of control gains, and offers an alternative to the classic design approaches of feedback controls.
Robust Stabilization of Uncertain Aircraft Active Systems
Authors: Ibrir Salim , Botez Ruxandra
Published: June 2007

Often, dynamical aircraft systems cannot always be accurate because some approximation assumptions, imprecisions or uncertainties may have been introduced or imposed during the modeling process. Mathematical models of aircraft systems always contain uncertain elements, which model the designer’s lack of knowledge about some parameter values, disturbances and unmodeled dynamics. Using both Lyapunov’s direct method and the linear matrix inequality approach, we develop the controller design procedure, and give a definite feel for stability analysis and robust control for aircraft systems with significant uncertainty. An example of an uncertain thrust vectoring aircraft is studied to illustrate our control design strategy.
Optimal Control of Structural Dynamic Systems in One Space Dimension Using a Maximum Principle
Authors: Sloss J. M. , Sadek I. S. , Bruch J. C. , Adali S.
Published: June 2007

A maximum principle is developed for a class of problems involving the optimal control of a system of linear hyperbolic equations in one space dimension that are not necessarily separable. An index of performance is formulated, which consists of vector functions of the state variable, their first- and second-order space derivatives and first-order time derivative, and a penalty function involving the open-loop control force vector. The solution of the optimal control problem can easily be shown to be unique using convexity arguments. The given maximum principle involves a Hamiltonian, which contains an adjoint vector function as well as an admissible control vector function. The maximum principle can be used to compute the optimal control vector function and is particularly suitable for problems involving the active control of structural elements for vibration suppression. A numerical example is given which studies the active control of a beam under going flexural and torsional vibrations. A comparison of the energies of controlled and uncontrolled beams indicates that the proposed control method is quite effective in damping out the vibrations of structural systems.
The Impact of Interpreters on Parents' Experiences with Ambulatory Care for Their Children
Authors: Morales Leo S. , Elliott Marc , Weech-Maldonado Robert , Hays Ron D.
Published: June 2007

Health plan members who did not need an interpreter in the past 6 months were compared with those who needed one and always, usually, sometimes, or never got one. In multivariate analyses, Hispanic and Asian/Pacific Islanders (API) members who needed interpreters and usually, sometimes, or never used one reported significantly worse (p < .05) provider and office staff communication, access to care, and health plan customer service compared with members who did not need interpreters. Hispanic and API members who needed and always used an interpreter reported similar or significantly better (p < .05) provider and office staff communication, access to care, and health plan customer service than members that did not need interpreters. Use of interpreters reduced White-Hispanic disparities in reports of care by up to 28 percent and White-API disparities by as much as 21 percent. Increasing use of interpreters could reduce racial/ethnic disparities and improve health plan performance.