bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Heparin, Dermatan Sulfate and of their Association on the Inhibition of Venous Thrombosis Growth in the Rabbit
Authors: Carrie D , Caranobe C , Gabaig A M , Larroche M , Boneu B 
Published: July 2018

SummaryThis study compares the ability of unfractionated heparin, of dermatan sulfate, and of their simultaneous administration delivered as continuous intravenous infusion or as a single bolus injection to inhibit the growth of a standardized venous thrombosis in the rabbit.When delivered as continuous intravenous infusion for 4 h, heparin and dermatan sulfate inhibited thrombus growth in a dose dependent manner. The maximum antithrombotic effect of heparin was achieved at the dose of 0.15 mg kg–1 h–1 (25 U kg–1 h–1) which generated a mean plasma concentration of 1.8 µg ml–1 (0.31 U ml–1) and a 1.8 fold prolongation of the activated partial thromboplastin time (APTT) in comparison to the pretreatment value. A comparable antithrombotic effect was obtained with dermatan sulfate at the dose of 2 mg kg–1 h–1. This dose generated a mean plasma concentration of 30 µg ml–1 and a 1.3 fold APTT prolongation. Increasing these doses up to 10 fold did not improve the antithrombotic effect which did not overpass 60–70% of the controls. When the compounds were delivered simultaneously, the maximum antithrombotic effect (64%) was obtained with the following association: 0.06 mg kg–1 h–1 (10 U kg–1 h–1) for heparin and 1 mg kg–1 h–1 for dermatan sulfate. Increasing these doses up to 4 to 5 fold did not improve the antithrombotic effect. Heparin, dermatan sulfate and the association of both were also delivered as single bolus injections and the resultant antithrombotic effect was determined 4 h after saline infusion. Bolus doses of 0.15 and 0.30 mg kg–1 (25 and 50 U kg–1) of heparin or of 1 and 2 mg kg–1 of dermatan sulfate were ineffective. In contrast, the association of dermatan sulfate (2 mg kg–1) to heparin (0.15 or 0.30 mg kg–1) generated antithrombotic effects of 61 and 64% respectively in the absence of detectable residual plasma anticoagulant activities, 1 h after the bolus injections. These studies indicate that: (1) under continuous intravenous regimen, dermatan sulfate is as effective as heparin to inhibit venous thrombus growth when delivered at a 13 fold higher dose on a weight basis; (2) the coadministration of the two compounds under the same regimen does moderately improve the antithrombotic effect; (3) while each of these compounds were ineffective when delivered as a single bolus, their coadministration generated a dramatic antithrombotic effect for at least 4 h; (4) simultaneous activation of antithrombin III and of heparin cofactor II may therefore represent a valuable strategy to treat an established deep vein thrombosis.
Lysing Patterns of Retracted Blood Clots with Diffusion or Bulk Flow Transport of Plasma with Urokinase into Clots – a Magnetic Resonance Imaging Study In Vitro
Authors: Blinc A , Keber D , Lahajnar G , Stegnar M , Zidanšek A , Demsar F 
Published: July 2018

SummaryFresh retracted clots are known to be poorly lysable by fibrinolytic agents. We have studied whether lysis of retracted clots could be enhanced by bulk transport in comparison to pure diffusion of plasma containing urokinase (400 IU/ml) into the clots. Cylindrical retracted blood clots were occlusively glued by a polyester into plastic tubes and put in contact with plasma through the clot bases. One group of clots (perfused clots, n = 10) was placed under a pressure difference of 6 kPa (60 cm H20) which resulted in an average plasma flow of 0.97 ± 0.34 µl/min through the clot during the first hour. Another group of clots (non-perfused clots, n = 10) was incubated in the lytic plasma without a pressure difference. Clot sizes were measured during lysis by magnetic resonance imaging (MRI). Channels representing lysed areas penetrated into perfused clots with a velocity of 5.4 ± 1.6 mm/h (n = 10), whereas the boundaries of non-perfused clots subsided with a velocity of less than 0.1 mm/h. Eight of the 10 perfused clots were recanalized after 8 h and the sizes of the perfused group were reduced to 64.0 ± 10.7% of the initial values. The relative sizes of non-perfused clots after 8 h remained significantly higher: 95.0 ± 1.3%, p <0.005. In a separate experiment good agreement was obtained between the measured clot sizes by MRI and the residual radioactivity of 125I-fibrin in the clot. The strong dependence of lysis on the transport mechanism of plasma with urokinase into retracted clots suggests that local hemodynamic conditions in vivo are likely to influence the lysis of thrombi.
Aurin Tricarboxylic Acid Inhibits Platelet Adhesion to Collagen by Binding to the 509-695 Disulphide Loop of von Willebrand Factor and Competing with Glycoprotein Ib
Authors: Girma J P , Fressinaud E , Christophe O , Rouault C , Obert B , Takahashi Y , Meyer D 
Published: July 2018

SummaryAurin tricarboxylic acid (ATA) is known to inhibit ristocetin-induced platelet agglutination but not arachidonic acid-, epinephrine- or ADP-induced aggregation. Its capacity to abolish human von Willebrand factor (vWF)-platelet interactions was further investigated by measurement of platelet adhesion to collagen, platelet agglutination tests and binding studies. In flowing blood using parallel-plate perfusion chambers and human collagen, ATA inhibited platelet adhesion to completion in a dose-dependent manner only at the highest shear rate tested (2,600 s–1). It was without effect at 100 and 650 s–1. ATA completely abolished vWF-dependent platelet agglutination induced by ristocetin, botrocetin and asialo-vWF, respectively. 125I-vWF binding to ristocetin- and botrocetin-treated platelets, to heparin and to sulfatides as well as 125I-botrocetin binding to vWF was competitively inhibited by ATA. By contrast, binding of 125I-vWF to collagen was not affected. To further localize the domain of vWF interacting with ATA, experiments of inhibition of binding of selected 125I-monoclonal antibodies (MoAbs) to immobilized vWF by ATA were performed. Our data led to the conclusion that: 1) the interaction of ATA with vWF involves sequences of the A1 disulphide loop of vWF (residues 509–695) and close epitopes which interact with GPIb and 2) the inhibition of platelet adhesion by ATA occurs only at a high shear rate where vWF is known to play a key role. Thus ATA, which blocks the vWF/GPIb pathway by interfering with vWF and not with platelets, is a potential tool in preventing the early stages of thrombosis.
Arachidonate Transfer Between Platelets and Lipoproteins
Authors: Surya Ingrid I , Gorter Gertie , Akkerman Jan Willem N 
Published: July 2018

SummaryAlthough platelets have specific bindingsites for LDL and HDL, it is doubtful whether lipoproteins modulate platelet functions via receptor-mediated processes. We investigated platelet-lipoprotein interaction during prolonged incubation with concentrations of LDL and HDL that saturate the bindingsites within a few minutes. When [3H]arachidonate-labeled human platelets were incubated for 4 h with lipoproteins, part of the 3H-radioactivity transferred to LDL and to a lesser extent to HDL. The transfer was temperature-sensitive, unaffected by modification of lysine in LDL or indomethacin treatment of the platelets, and almost irreversible. [3H]arachidonate transfer to lipoproteins could be mimicked by incubating platelets with a high concentration of fatty acid free albumin. This showed, that the loss of 3H-radioactivity reflected a decrease in endogenous arachidonate, leading to impaired aggregation, secretion and thromboxane B2 formation in platelets after stimulation with thrombin but not with arachidonate. Thus, the decrease in platelet functions seen after long incubation with HDL is caused by depletion of platelet arachidonate. Despite an even stronger arachidonate depletion by LDL, this lipoprotein initiated arachidonate metabolism and secretion independent of specific binding sites for LDL on the platelet. Surprisingly, the major part of the secretion was preserved when the formation of prostaglandin endoperoxides/ thromboxane A2 was inhibited with indomethacin. These findings argue against a role for LDL and HDL receptors in the modulation of platelet functions and are more in favor of lipid exchange processes between platelets and lipoproteins.
Pentamidine: A Non-Peptide GPIIb/IIIa Antagonist – In Vitro Studies on Platelets from Humans and Other Species
Authors: Cox Dermot , Motoyama Yukio , Seki Jiro , Aoki Toshiaki , Dohi Miwako , Yoshida Keizo 
Published: July 2018

SummaryIn this paper we show that the non-peptide anti-parasite agent pentamidine is a broad spectrum anti-platelet agent with an IC50 of 1.1 µM in ADP-induced platelet aggregation in human platelet rich plasma (PRP). It had similar activity when collagen, arachidonic acid, platelet activating factor, thrombin and epinephrine were used. It had no effect on platelet intracellular cAMP levels. It inhibited 125I-fibrinogen, 125I-fibronectin and 125I-von Willebrand factor binding to ADP-activated fixed platelets with IC50 values of 160, 160 and 60 nM respectively. Pentamidine showed a high degree of species selectivity with slightly less activity in monkey and dog PRP and little activity in guinea pig, rabbit, rat and mouse PRP compared with human. This was similar to the other RGD analogues tested. This species specificity was shown to be dependent on the species of platelets and independent of the species of fibrinogen. Thus, pentamidine is a potent non-peptide inhibitor of fibrinogen binding to GPIIb/IIIa.
Thrombin Production, Inactivation and Expression during Open Heart Surgery Measured by Assays for Activation Fragments Including a New ELISA for Prothrombin Fragment F1+2
Authors: Boisclair Michael D , Lane David A , Philippou Helen , Sheikh Sajila , Hunt Beverley 
Published: July 2018

SummaryActivation of coagulation was studied during the peri-operative period in patients undergoing cardiopulmonary bypass (CPB) surgery using activation markers which have recently become available: prothrombin fragment F1 + 2 (F1 + 2), which is a measure of total thrombin generation, and thrombin-antithrombin complex, which is a measure of inactivation of free thrombin by antithrombin. Levels of the specific marker of fibrin breakdown, D-dimer, were also determined. F1 + 2 levels were assessed using a newly developed ELISA described herein which employs a neoantigen-specific capture antibody raised using a synthetic peptide; the latter antibody has been pre-adsorbed against prothrombin to ensure high specificity for F1 + 2.Increased generation of thrombin during surgery was clearly demonstrated despite maintenance of a high concentration of heparin during the period of extracorporeal blood circulation. There was a close association (r = 0.882) between the generation of thrombin (F1 + 2 levels) and its inhibition (TAT levels). Differences were noted, however, between the information provided by F1 + 2 and TAT, which are interpreted with regard to the different in vivo fates of F1 + 2 and thrombin. The enhanced activation and inhibition of coagulation observed during CPB was suppressed once physiological blood circulation was restored, with F1 + 2 returning to pre-surgical levels within 24 h after surgery. During the post-operative period D-dimer levels, which rose in concert with F1 + 2 and TAT levels, remained highly elevated, suggesting that not all of the generated thrombin was inactivated by antithrombin. It is concluded that heparin is only partially effective as an anticoagulant during CPB surgery. F1 + 2 is an unambiguous marker of thrombin generation and its measurement may be a useful means of evaluating more effective coagulation inhibitors in CPB.
Pharmacokinetics of Monoclonally-Purified and Recombinant Factor VIII in Patients with Severe von Willebrand Disease
Authors: Morfini M , Mannucci P M , Tenconi P M , Longo G , Mazzucconi M G , Rodeghiero F , Ciavarella N , De Rosa V , Arter A 
Published: July 2018

SummaryA monoclonally-purified factor VIII (FVIII) concentrate, containing little von Willebrand factor (vWF), was infused to 11 patients with severe von Willebrand disease and unmeasurable levels of plasma vWF. In comparison with the historical data obtained infusing hemophiliacs in the same conditions, monoclonally-purified FVIII had a significantly shorter half-life and faster clearance from plasma but similar in vivo recovery and volume of distribution. Two additional patients with severe von Willebrand disease were also infused with recombinant FVIII totally devoid of vWF. Half-life was very short and in vivo recovery low, with a larger volume of distribution than for monoclonally-purified FVIII. We conclude that in patients with severe von Willebrand disease the small amounts of vWF contained in the monoclonally-purified FVIII concentrate are not sufficient to stabilize infused FVIII, nor to support the normal circulation of endogenous FVIII that these patients produce at a normal rate.
Standards for Assay of von Willebrand Factor Concentrates: A Collaborative Study
Authors: Fricke W A , Lamb M A , Rastogi S C 
Published: July 2018

SummaryA multilaboratory collaborative study was undertaken to assess the feasibility of using a plasma standard for expressing the results of assays for the von Willebrand factor content of von Willebrand factor concentrates and of factor VIII concentrates. Thirteen laboratories tested six concentrates for von Willebrand factor antigen, ristocetin cofactor activity, and multimer content using the World Health Organization plasma standard for factor VIII/von Willebrand factor, 87/718, as a standard. Only a few assays were invalid because of nonparallelism or nonlinearity. Significant interlaboratory and interassay differences were found for both von Willebrand factor antigen and ristocetin cofactor activity. There was generally good agreement between the laboratories with respect to the multimer content in the preparations. With respect to assay validity, a plasma standard could be suitable for assaying concentrated preparations of von Willebrand factor.
Respective Roles of Antithrombin III and Alpha 2 Macroglobulin in Thrombin Inactivation
Authors: Fischer A M , Tapon-Bretaudiere J , Bros A , Josso F 
Published: July 2018

SummaryIn order to investigate the mechanism of thrombin inactivation in the presence of both antithrombin III (AT III) and α 2-macroglobulin (α 2 M), thrombin and the inhibitors have been purified from human material and thrombin inactivation studied using purified reagents either alone or added to defibrinated plasma. Comparison of clotting and amidolytic activities of residual thrombin allowed to measure the amount of thrombin bound to α 2 M. In a purified reagent system as well as in plasma, part of exogenous thrombin is bound to α 2 M. The amount of bound thrombin is related to α 2 M concentration. Conversely, previous plasma α 2 M depletion by immunoabsorption increases the consumption of heparin-cofactor activity by exogenous thrombin. Thus AT III and α 2 M compete for thrombin inactivation. This finding could be of practical interest in clinical situations associating high plasma α 2 M levels and a decrease of AT III concentration.
125I-Fibrinogen Leg Scanning: Reassessment of Its Role for the Diagnosis of Venous Thrombosis in Post-Operative Patients
Authors: Lensing Anthonie W A , Hirsh Jack 
Published: July 2018

SummaryObjective: To determine the reasons why 125I-fibrinogen leg scanning, a screening test which was reported to be very sensitive for the detection of post-operative thrombosis, has shown poor sensitivity in contemporary studies.Study Identification: English-language reports were identified through a Medline computer search (1965-1991), Current Contents, and an extensive manual search of the bibliographies in identified articles.Study Selection: Studies in orthopaedic or general surgical patients were reviewed that compared 125I-fibrinogen leg scanning with venography in all patients (accuracy studies) or in patients in whom 125I-fibrinogen leg scanning became positive (positive predictive value studies).Data Extraction: A systematic appraisal of study design and specific descriptive information concerning the selection of patients.Results of Data Synthesis: Six of the 15 studies which compared 125I-fibrinogen leg scanning with venography were level 1 studies (potential for bias minimized) and nine were classified as level 2 studies (potential for bias not minimized). In orthopaedic surgical patients, the pooled sensitivity of leg scanning for isolated calf vein thrombosis, for all venous thrombosis, and the pooled specificity were 55%, 45%, and 92% for the level 1 studies, respectively. These indices were 88%, 82%, and 79%, respectively for the level 2 studies (P <0.001). Only two (level 2) studies were found that evaluated the accuracy of leg scanning for venous thrombosis in general surgical patients.Conclusion: We conclude that leg scanning is an insensitive method for the screening of post-operative venous thrombosis in orthopaedic patients. Our findings call into question the validity of the many studies (including meta-analyses) evaluating prophylactic agents for venous thrombosis which used leg scanning as the only test for the assessment of efficacy.
Platelet Aggregation Induced in Vitro by Therapeutic Ultrasound
Authors: Chater B. V , Williams A. R 
Published: July 2018

SummaryPlatelets were found to aggregate spontaneously when exposed to ultrasound generated by a commercial therapeutic device. At a given frequency, aggregation was found to be a dose-related phenomenon, increasing intensities of ultrasound inducing more extensive and more rapid aggregation. At any single intensity, the extent aggregation was increased as the frequency of the applied ultrasound was decreased (from 3.0 to 0.75 MHz).Ultrasound-induced platelet aggregation was found to be related to overall platelet sensitivity to adenosine diphosphate. More sensitive platelets were found to aggregate spontaneously at lower intensities of sound, and also the maximum extent of aggregation was found to be greater. Examination of ultrasound-induced platelet aggregates by electron microscopy demonstrated that the platelets had undergone the release reaction.The observation that haemoglobin was released from erythrocytes in whole blood irradiated under identical physical conditions suggests that the platelets are being distrupted by ultrasonic cavitation (violent gas/bubble oscillation).It is postulated that overall platelet aggregation is the result of two distinct effects. Firstly, the direct action of ultrasonic cavitation disrupts a small proportion of the platelet population, resulting in the liberation of active substances. These substances produce aggregation, both directly and indirectly by inducing the physiological release reaction in adjacent undamaged platelets.
The Relationship of Plasma Fibrinogen, Erythrocyte Flexibility and Blood Viscosity
Authors: Dupont P. A , Sirs J. A 
Published: July 2018

SummaryMeasurements have been made of plasma fibrinogen concentration, erythrocyte flexibility and blood viscosity at shear rates from 5.75 to 230 sec−1 during and following surgery. In the post-operative period the plasma fibrinogen level in the patient rose to over 1,000 mg/dl and because there were subsequent complications, only returned to normal after 4 weeks. There was an associated change of erythrocyte flexibility, with a correlation coefficient of 0.98. The blood viscosity also varied with the plasma fibrinogen level, the effect being more pronounced at low shear rates. The internal viscosity of the red blood cell, calculated from the plasma viscosity and whole blood viscosity at 230 sec−1, decreases with increasing plasma fibrinogen concentration, in agreement with the direct measurements made of erythrocyte flexibility. It is proposed that at high shear rates an increase in plasma viscosity due to an elevation of fibrinogen concentration, is offset by a decrease in the rigidity of the erythrocytes, and these 2 effects counter-balance.
Participation of Hageman Factor Dependent Pathways in Human Disease States
Authors: Colman Robert W. , Wong Patrick Y. 
Published: July 2018

SummaryAbnormalities of Hageman factor dependent pathways have been described in a wide variety of human disease states. Congenital deficiencies of factor XII (Hageman trait) prekallikrein (Fletcher trait) and high molecular weight kininogen (Williams, Fitzgerald and Flaujeac traits) although resulting in profound in vitro changes, do not cause in vivo difficulties. In contrast, deficiency of Cl esterase inhibitor (hereditary angioedema) results in significant morbidity and mortality. Acquired diseases may exhibit decreased synthesis of these three proteins in cirrhosis and dengue fever. In vivo activation of factor XII initiated pathways occur in septic shock, disseminated or localized intravascular coagulation, typhoid fever, polycythemia vera, hyperbetalipoproteinemia, coronary artery disease, nephrotic syndrome, transfusion reactions, hemodialysis and extracorporeal bypass. Activation of both the intrinsic system and tissue mediators contribute to the vasomotor phenomena in carcinoid syndrome and postgastrectomy dumping. Roles for factor XII, prekallikrein and kininogen have been suggested in gouty arthritis, allergic disorders and cystic fibrosis but the evidence is not yet convincing in these disorders.
Reduction of Coagulation Factor XIII Concentration in Patients with Myocardial Infarction, Cerebral infarction, and other Thromboembolic Disorders
Authors: Alkjaersig Norma , Fletcher Anthony P. , Lewis Martin , Ittyerah Roy 
Published: July 2018

SummaryCoagulation factor XIII and plasma fibrinogen chromatographic assays have been performed serially in patients suffering from acute myocardial and cerebral infarction, and in others with disseminated intravascular coagulation. The findings were compared with 2 groups of “controls”; normal clinically-well subjects and hospitalized patients with cerebral infarction who exhibited minimal, stable, or improving neurological deficits. Substantial depression of factor XIII concentrations developed in the 3 patient groups, together with concomitant significant increases in the proportion and concentration of plasma high molecular weight fibrin(ogen) complexes (HMWFC). An inverse correlation (p<0.05) between coagulation factor XIII concentration and percentage of HMWFC was demonstrated in the early stages of the illness. These findings suggest that depression of coagulation factor XIII concentration in these states, is secondary to extra vascular or intravascular coagulation and may reflect its degree.