bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kinetic Study of Factor X During Oral Anticoagulation with Acenocoumarol: Potential Value for the Initiation of Treatment
Authors: Aiach M , Fiessinger J-N , Capron L , Nussas C , Housset E , Leclerc M 
Published: July 2018

SummaryWe measured prothrombin time and coagulation factors (F) VII and X in 19 patients under heparin treatment receiving acenocoumarol (3 mg per day) without a loading dose. Blood samples were obtained on the 1st (D0), 2nd (D1), 3d (D2), 5th (D4), 7th (D6) and 9th (D8) days of treatment. In 7 patients (group A) acenocoumarol dosage had to be reduced at D2, D4, or D6, based on a prothrombin time smaller than 25% of normal. In the remaining 12 patients (group B), FVII and prothrombin time followed a double exponential decline. Conversely, the FX decrease could be fitted to a single exponential pattern. The slope of the linear relation, loge (FX) = b - a (D), calculated from measurements made at D0, D1, and D2, allowed us to predict the FX level at D8 by simple extrapolation, and, consequently, to estimate as early as D2 whether a change of acenocoumarol dosage would have been required. In group A this extrapolation always announced a dangerously low FX concentration at Dg that justified the preventive reduction of acenocoumarol dosage. We conclude that FX can be a valuable guide in the initiation of an oral anticoagulant treatment.
The Stability of Factor IX Concentrate During Storage
Authors: Suomela H , Vahtera Elina 
Published: July 2018

SummaryA storage study of factor IX concentrate was performed on 35 randomly selected batches that had been prepared between 1976 and 1980. Vacuum stability, dissolution time, F IX procoagulant activity, NAPTT, and thrombin generation were measured immediately after the manufacturing process and compared in this study with the results obtained from the spare samples analysed in 1981. No significant changes during storage at cold room temperature for up to 5 years were established. The product can thus be considered to be stable for 5 years at + 4° C.
Rapid Isolation of High Molecular Weight Urokinase from Native Human Urine
Authors: Huber Kurt , Kirchheimer Johannes , Binder Bernd R 
Published: July 2018

SummaryUrokinase (UK) could be purified to apparent homogeneity starting from crude urine by sequential adsorption and elution of the enzyme to gelatine-Sepharose and agmatine-Sepharose followed by gel filtration on Sephadex G-150. The purified product exhibited characteristics of the high molecular weight urokinase (HMW-UK) but did contain two distinct entities, one of which exhibited a two chain structure as reported for the HMW-UK while the other one exhibited an apparent single chain structure. The purification described is rapid and simple and results in an enzyme with probably no major alterations. Yields are high enough to obtain purified enzymes for characterization of UK from individual donors.
Sequential Treatment of Deep Leg Vein Thrombosis with Porcine Plasmin and Low Dose Streptokinase
Authors: Marbet G A , Eichlisberger R , Duckert F , de Silva M A , Biland L , Widmer L K , Ritz R , Schmitt H E 
Published: July 2018

SummarySequential treatment of deep leg vein thrombosis with porcine plasmin and low dose streptokinase (10,000-20,000 U/h) produces strong systemic fibrinolysis as demonstrated by the sustained decrease of euglobulin lysis time, of thromboplastin time values in percent, fibrinogen and factor V levels. There is a statistically significant negative correlation between thrombolytic results and euglobulin lysis time. Treatment periods below 3 days are unlikely to give satisfactory results. Occluded vein segments with an apparent median age of 4 days including thrombi older than 10 days (20% of cases) are cleared with an average chance of 50%. Complete dissolution of all thrombi proximal to the crural veins has been demonstrated in 47/114 = 41.2%, some thrombolytic effect in 31/114 = 27.2% and treatment failure in 36/114 = 31.6%. The data favour laboratory monitoring of thrombolytic therapy.
A Unique Pathway for the Plasma Elimination of α2-Antiplasmin-Protease Complexes in Mice
Authors: Gonias S L , Fuchs H E , Pizzo S V 
Published: July 2018

SummaryRadiolabeled α2-antiplasmin cleared slowly from the circulation of mice. Complex formation with either plasmin or trypsin resulted in a significant increase in the plasma elimination rate of the protease inhibitor. Approximately 20 min and 14 min were required for 50% of the injected α2-antiplasmin-plasmin and α2-antiplasmin-trypsin to clear from the circulation, respectively. Significant competition was observed when radiolabeled α2-antiplasmin-plasmin was cleared in the presence of a large molar excess of unlabeled α2-antiplasmin-plasmin. α1-Antitrypsin-trypsin failed to compete with radiolabeled α2-antiplasmin-plasmin even when present at 2000 fold molar excess. Organ distribution studies localized the major site of α2-antiplasmin-plasmin clearance in the liver. Microscopic autoradiography data suggested that the cell responsible for the clearance pathway was the hepatocyte.
Decreased Levels of Histidine-Rich Glycoprotein (HRG) and Increased Levels of Free Plasminogen in Women on Oral Contraceptives Low in Estrogen
Authors: Jespersen Jørgen , Kluft Cornelis 
Published: July 2018

SummaryDeterminations by immunologic methods of histidine-rich glycoprotein (HRG) and plasminogen, were made in plasma samples collected during one normal or hormone induced cycle in 15 young, normal women and in 11 women using oral contraceptives with 30 μg ethinyl estradiol and 150 μg levo-norgestrel. The hormone group showed an increase in plasminogen level to about 150% of normal, while the concentration of HRG was decreased to about 75% of normal. This resulted in a considerable relative increase in the concentration of free plasminogen in the hormone group (calculated from the equilibrium: HRG·plasminogen ⇌ HRG + plasminogen, using KD = 1.0 μM), representing a doubling of that in the normal group. Hence, more plasminogen is available for binding to fibrin and activation in the hormone group.
In Vivo Photoactivation of Caged-Thrombin
Authors: Arroyo Jorge G , Jones Paul B , Porter Ned A , Hatchell Diane L 
Published: July 2018

SummaryAberrant ocular neovascularization is a major cause of blindness in the world. Abnormal blood vessels in the eye may produce corneal opacification, corneal transplant rejection, neovascular glaucoma, vitreous hemorrhage, traction retinal detachment, and subretinal scars from choroidal neovascular membranes (1-5). Light-induced clotting of blood within these abnormal vessels could provide a novel method for the ablation of deleterious neovascularization. Thrombin is a serine proteinase that participates in the final stages of the coagulation cascade. An inhibitor of thrombin, p-Amidinophenyl-(E)-4-diethyl- amino-2-hydroxy-α-methylcinnamate hydrochloride, MeCINN (1), covalently attaches to the active site serine hydroxyl, inhibiting or caging, the enzyme. Photolysis of the caged-thrombin in vitro causes a trans-cis isomerization of MeCINN which leads to regeneration of active enzyme and cleaving of fibrinogen into fibrin (6). Using a rabbit model of corneal neovascularization, we found that light at 366 nm safely and effectively photoactivates intravenous caged-thrombin and produces localized thrombosis in vivo. These results suggest that intra- vascular photoactivation of caged-thrombin could be used to occlude abnormal blood vessels in the human eye.
Comparison of the Effects of Different Low Molecular Weight Heparins on the Hemostatic System Activation In Vivo in Man
Authors: Wolzt Michael , Eder Michaela , Weltermann Ansgar , Entlicher Jesusa , Eichler Hans-Georg , Kyrle Paul A 
Published: July 2018

SummaryIn a double-blind, randomized, cross-over study the effects of single subcutaneous doses of 120 anti-Xa units/kg body wt. of three different low molecular weight heparin (LMWH) preparations were investigated in 15 healthy subjects by determination of thrombin-antithrombin El complex (TAT), prothrombin fragment 1.2 (fl.2), and β-thromboglobin (β-TG) in shed blood and in venous blood.Certoparin, dalteparin, and enoxaparin significantly inhibited coagulation activation marker formation in shed blood. The substantial inhibition of TAT and fl.2 formation was slightly more pronounced in response to certoparin. β-TG was decreased following certoparin and enoxaparin, but not following dalteparin. However, no difference between groups was detectable. A small but consistent decrease of fl.2 formation in venous blood was noted for all LMWHs and dalteparin and enoxaparin, but not certoparin, inhibited TAT formation. Only a minor impact of the three LMWH preparations was noted on β-TG plasma concentrations.Our data indicate that the studied LMWH preparations have a major impact on blood clotting in the activated state and inhibit in vivothe hemostatic system to a comparable extent.
Sympathoadrenal Activation and Muscarinic Receptor Stimulation Induce Acute Release of Tissue-Type Plasminogen Activator but not von Willebrand Factor across the Human Forearm
Authors: Jern Christina , Selin Lena , Tengborn Lilian , Jern Sverker 
Published: July 2018

SummaryWe have previously shown that both mental stress and administration of the muscarinic receptor agonist methacholine induce an acute release of tissue-type plasminogen activator (t-PA) across the human forearm. There are data indicating that the regulated acute release of t-PA from the endothelium is closely interrelated with release of von Willebrand factor (vWF). The aim of the present study was to simultaneously determine basal and stimulated in vivo release rates of t-PA and vWF in an intact human muscle vascular bed. Eighteen healthy young males were studied at rest and during 10 min of mental stress (forced arithmetic). A subsample of ten subjects also received a stepwise i.a. infusion of methacholine (0.1-0.8-4.0 |xg/min). Forearm blood flow was determined by venous occlusion plethysmography and interconverted to forearm plasma flow (FPF) using individual hematocrits. Net release/uptake rates of t-PA and vWF were calculated as the product of the arteriovenous concentration gradient and FPF. At rest there was a net release of both t-PA antigen and activity. In contrast, there was no significant local net release of vWF antigen across the forearm. Net release rates of t-PA roughly doubled in response to the stress test (0.4 to 0.8 and 0.2 to 0.5 ng X min-1X 100 ml-1for t-PA antigen and activity, respectively, p <0.05 for both). Local administration of methacholine induced a more than 10-fold increase in the net release rates of t-PA (0.6 to 9.6 and 0.3 to 6.6 ng X min-1X 100 ml-1at the highest dose step for antigen and activity respectively, p <0.01 for both). In contrast, neither mental stress nor local administration of methacholine induced a significant net release of vWF antigen across the forearm. The results demonstrate that the processes of acute release of t-PA and vWF are not necessarily linked in vivo in man.
Effect of a New Monoclonal Anti-Glycoprotein IX Antibody, KMP-9, on High Shear-Induced Platelet Aggregation
Authors: Miyake Tetsuya , Nomura Shosaku , Komiyama Yutaka , Miyazaki Yasuhiko , Kagawa Hideo , Masuda Midori , Takahashi Hakuo , Fujimura Yoshihiro , Ikeda Yasuo , Fukuhara Shirou 
Published: July 2018

SummaryHuman platelet glycoprotein Ib/IX complex acts as a receptor for von Willebrand factor. It is widely accepted that glycoprotein lb is the essential receptor component, but the role of glycoprotein IX is still unclear. We produced a new monoclonal anti-glycoprotein IX antibody (KMP-9) by the hybridoma technique using platelets from a patient with Glanzmann’s thrombasthenia. The epitope of KMP-9 was localized to the C-terminal 8 kD fragment of glycoprotein IX using ELISA analysis of polyethylene-pin-synthesized peptides, as well as Western blot analysis of platelets after digestion with N-glycosidase and Staphylococcus aureus V8 protease. KMP-9 partially inhibited high shear stress-induced platelet aggregation, but had no effect on aggregation induced by ristocetin or low shear stress. Its inhibitory effect on high shear stress-induced aggregation was weaker than that of antiglycoprotein lb or anti-glycoprotein Ilb/IIIa monoclonal antibodies. A 21-mer synthetic peptide (glycoprotein IX L110-G130) inhibited the binding of KMP-9 to platelets. It also competively inhibited the suppression of high shear stress-induced platelet aggregation by KMP-9, but had no direct effect on this aggregation. KMP-9 may be useful to clarify the physiological role of GPIX.
Observations on the Development of Mural Thrombi in Chronic Experimental Aneurysms in Sheep
Authors: Stehbens W E 
Published: July 2018

SummaryObservations were made on mural thrombi in experimental venous pouch aneurysms in sheep. Thrombi associated with mural tears and dissection consisted predominantly of laminated fibrin masking the earlier platelet deposition and infiltrating the wall to some extent. Thrombus growth was associated with platelet masses of Zahn and secondary fibrin deposition. Intervening spaces contained a variable quantity of coagulated plasma, fibrin mesh, leucocytes, disintegrating red cells and platelets rather than red thrombus as often suggested. Periodic deposition of platelet masses with surface rippling, the whorling patterns of laminated fibrin and mechanical disruption of red cells indicated the importance of haemodynamics. Coarse macroscopic lamination of mural thrombi was attributed in part to recurrent dissections between the wall and the mural thrombus and of the thrombus itself. These accounted for growth of thrombus with expansion of the wall and interference with organization of the thrombus. The model has proved suitable for the study of thrombogenesis and thrombus behaviour in aneurysms.
Effect of Changes in Liver Blood Flow on the Pharmacokinetics of Saruplase in Patients with Acute Myocardial Infarction
Authors: van Griensven Jean M T , Koster Rudolph W , Hopkins Gwynn R , Beier Horst , Günzler Wolfgang A , Kroon Ria , Schoemaker Rik C , Cohen Adam F 
Published: July 2018

SummaryBackground: The recombinant unglycosylated single chain urokinase-type plasminogen activator saruplase is cleared for a large part by the liver. A large interindividual variation in saruplase concentration is found in acute myocardial infarction (AMI) patients. The variable cardiac performance after an infarct may induce differences in liver blood flow that could explain the concentration diversity. This study was performed to investigate the relation between hepatic blood flow and the pharmacokinetic and pharmacodynamic properties of saruplase.Methods and Results: Thirteen AMI patients were enroled in this open label study. Patients received a bolus injection of 20 mg saruplase followed by a one-hour infusion of 60 mg saruplase. Concurrently 36 mg intravenous indocyanine green (ICG) was given over 1 h to measure hepatic blood flow. Blood samples were taken at regular time intervals to measure plasma levels of urokinase-type plasminogen activator (u-PA) antigen and activity, the two-chain form (tcu-PA) activity, indocyanine green, fibrinogen, fibrin and fibrin degradation products, α2-antiplasmin and thrombin antithrombin III complex. A correlation was seen between the clearance of ICG and both those of u-PA antigen (r = 0.62; p <0.05) and u-PA activity (r = 0.57; p <0.05). A negative correlation was seen between the area under the curve of tcu-PA activity and the areas under the effect curves of both fibrinogen and α2-antiplas-min (r = -0.84; p <0.01 and r = -0.65; p <0.05).Conclusions: Liver blood flow is an important determinant of the clearance of u-PA antigen and activity and reduction of flow in patients with heart failure will lead to an increase in plasma concentrations. High plasma concentrations of tcu-PA activity lead to increased systemic fibrinogenolysis. These results may be used to optimize saruplase treatment in patients with impaired cardiac function or after co-medication with drugs that affect liver blood flow.
Release of the Thrombin Receptor (PAR-1) N-terminus from the Surface of Human Platelets Activated by Thrombin
Authors: Ramachandran Ram , Klufas Alexandra S , Molino Marina , Ahuja Menaka , Hoxie James A , Brass Lowrence F 
Published: July 2018

SummaryPlatelet activation by thrombin is at least partially mediated by a G-protein-coupled receptor whose extended N-terminus is cleaved by thrombin. Theoretically, this should release a small fragment containing the original receptor N-terminus. However, the fate of this fragment is unknown, as is its biological role, if any. To begin to examine these issues, we have prepared monoclonal anti-receptor antibodies whose epitopes lie entirely N-terminal to the thrombin cleavage site. By flow cytometry and fluorescence microscopy of human platelets and mega- karyoblastic CHRF-288 cells, these antibodies were found to recognize intact receptors and receptors activated by the agonist peptide, SFLLRN, but not receptors whose N-terminus had been cleaved by thrombin or cathepsin G. Incubating CHRF-288 cells with thrombin released pre-bound antibody from the cell surface. An assay based upon the antibodies was able to detect a fragment containing the original receptor N-terminus in the supemate of thrombin-treated human plate lets. The concentration of the fragment obtained with platelets from 15 normal donors was 4.8 ± 0.9 pmol per 109 platelets (mean ± sem), which is similar to the value expected if all of the thrombin receptors present on human platelets have been cleaved. Taken together, these results demonstrate that 1) following receptor cleavage a fragment containing the original N-terminus of the receptor is released from the platelet surface, 2) based upon epitope mapping, this fragment is at least 15-20 residues long, 3) it is possible to quantitate the receptor fragment in the supemates of cells exposed to thrombin, and 4) the results of the quantitation suggest that on platelets all of the receptors have been cleaved and 100% of the fragment is present in the cell supemate. Depending on it survival time, measurements of the receptor fragment in blood or urine samples may eventually prove to be a useful marker for thrombin receptor activation in vivo.
Absence of Synergism Between Tissue-Type Plasminogen Activator (t-PA), Single-Chain UrokinaseType Plasminogen Activator (scu-PA) and Urokinase on Clot Lysis in a Plasma Milieu In Vitro
Authors: Collen D , De Cock F , Demarsin E , Lijnen H R , Stump D C 
Published: July 2018

SummaryA potential synergic effect of tissue-type plasminogen activator (t-PA), single-chain urokinase-type plasminogen activator (scuPA) or urokinase on clot lysis was investigated in a whole human plasma system in vitro. The system consisted of a human plasma clot labeled with 125I-fibrinogen, immersed in titrated whole human plasma, to which the thrombolytic agents were added. Clot lysis was quantitated by measurement of released 125I, and activation of the fibrinolytic system in the surrounding plasma by measurements of fibrinogen and α2-antiplasmin.t-PA, scu-PA and urokinase induced a dose-dependent and time-dependent clot lysis; 50 percent lysis after 2 h was obtained with 5 nM t-PA, 20 nM scu-PA and 12 nM urokinase. At these concentrations no significant activation of the fibrinolytic system in the plasma was observed with t-PA and scu-PA, whereas urokinase caused significant α2-antiplasmin consumption and concomitant fibrinogen degradation. The shape of the dose-response curves was different; t-PA and urokinase showed a log linear dose-response whereas that of scu-PA was sigmoidal.
Proposal for Objective Evaluation of the Performance of Various Functional APC-resistance Tests in Genotyped Patients
Authors: Freyburger G , Javorschi S , Labrouche S , Bernard P 
Published: July 2018

SummaryThe aim of the present study was to evaluate the relative performance of five screening methods for APC resistance caused by the factor V:Q506 mutation: the original method Coatest® APC™ Resistance Chromogenix, a modified method using the same reagents but a predilution 1+4 of the plasma in a factor V deficient plasma from Stago (Stago deficient V) or from Chromogenix (V-DEF Plasma), the Coatest® APC™ Resistance V (Chromogenix), and Accelerimat™ from bioMérieux. Normalization was done against a pool of normal plasmas for the methods from Chromogenix. The study included 350 subjects, 219 were genotyped (174 FV:R506R, 42 FV:Q506R, 3 FV:Q506Q) and most of them were assessed by more than one method. Uncertainty in predicting the FV genotype was evaluated by statistical analysis, which provided a way to quantitate the performance of the different diagnostic approaches. Performance of each test was evaluated by its sensitivity, specificity, R.O.C. curves, positive and negative likelihood ratios (LR), and the overall performance was determined by two parameters derived from the LR curves : the maximum LR value obtained at the crossover of the two curves, and the distance between the two curves for LR = 10. Coatest® APC™ Resistance V and Accelerimat™ were proven to be the methods most able to discriminate for factor V:Q506, while normalization was not shown to improve the screening performance. The original method from Chromogenix was confirmed to undergo many influences (factor XII, PAI-1, thrombin- antithrombin complexes, antithrombin III, hematocrit). Although a very good improvement was provided by the newest methods, they were shown to be influenced by protein S and/or factor V levels in the sample plasma.
Thrombin and Its Precursor in Human Cerebrospinal Fluid
Authors: Smirnova Irina V , Salazar Andres , Arnold Paul M , Glatt Sander , Handler Michael , Festoff Barry W 
Published: July 2018

SummaryThe blood coagulation cascade proteolytic enzyme, thrombin, affects many cell types, including neurons and astrocytes, in which it prevents process outgrowth and induces significant morphological degeneration and even cell death. Since thrombin may contribute significantly to pathological conditions in the central nervous system (CNS), where it is synthesized locally, we measured the levels of thrombin and its precursor, prothrombin, in the cerebrospinal fluid (CSF) of 67 individuals from 6 groups: non-neurologic controls (NNC); spinal degenerative disease (SDD); peripheral nerve disease (PND); cerebrovascular, neuroimmune and seizure disorders and tumor (CNSD); traumatic brain injury (TBI) and neurodegenerative disorders (NDD). We employed a sensitive chromogenic assay utilizing the thrombin specific tripeptide substrate, S-2238, to evaluate CSF levels of thrombin and prothrombin. The latter estimated after its conversion to active enzyme by the snake venom prothrombinase, ecarin. No measurable active thrombin was detected in these CSF samples. However, activatable prothrombin was measured in all groups. The mean activatable prothrombin concentrations (in nM) were 7.26 ± 3.39 (NNC); 8.85 ± 3.09 (SDD); 6.78 ± 2.58 (PND); 6.33 ± 3.87 (CNSD); 5.10 ± 1.86 (TBI), and 7.80 ± 3.27 (NDD). Duncan’s multiple comparison test showed significant reduction (p <0.05) in prothrombin levels of the TBI group. Our data suggests that the prothrombin zymogen gains access to the CSF, likely-across either an intact or compromised blood-brain barrier (BBB), in increased amounts with age. Reduced levels in TBI patients may have diagnostic and/or prognostic value.
First synthesis of (±)-myristicyclin A
Authors: Kubo Shinichiro , Mori Naoki , Watanabe Hidenori , Takikawa Hirosato 
Published: July 2018

ABSTRACT
The first synthesis of myristicyclin A, which was isolated from the Papua New Guinean plant Horsfieldia spicata, is described. The synthesis features acid-mediated hydroarylation reaction to form a dihydrocoumarin moiety, construction of the 2,8-dioxabicyclo[3.3.1]nonane skeleton under acidic conditions, and regioselective Friedel-Crafts acylation at a later stage.