bluuebunny/crossref_metadata_2025 huggingface dataset:
von Willebrand Factor and Factor VIII: C in Acute Cerebrovascular Disease
Authors: Catto Andrew J , Carter Angela M , Barrett Jennifer H , Bamford John , Rice Penny J , Grant Peter J
Published: July 2018

Background. Elevated von Willebrand factor (vWF) is a risk factor in the development of acute myocardial infarction. The importance of vWF and factor VIII :C in the pathogenesis of cerebrovascular disease (CVD) is poorly defined.

Methods and results. We studied 208 cases of stroke whose pathological type was defined by cranial computed tomography. Cerebral infarcts were grouped according to the Oxfordshire Community Stroke Project (OCSP) clinical classification. The results in patients were compared with 184 healthy reference subjects. In patients, vWF and FVIII: C levels were determined initially and after three months. Patients were followed prospectively for six months or until death.

Levels of vWF and FVIII :C were elevated initially (1.86 IU/ml and 2.20 U/ml respectively) and after 3 months (1.51 IU/ml and 1.90 U/ml) compared with a healthy reference population (1.26 IU/ml and 1.49 U/ml p = 0.0001). In the initial sample, vWF was associated with age (p = 0.01). FVIII: C was related to age (p = 0.04), gender (p = 0.007 higher for females) and a history of diabetes mellitus (2.56 U/ml vs. 2.16 U/ml in non-diabetics, p = 0.008).

Initial vWF levels were higher in subjects with large vessel disease (TACI/PACI) group compared with the small vessel disease (LACI) group [2.12 IU/ml, (n = 112) vs. 1.48 IU/ml (n = 59) respectively, p = 0.0001] and similarly in initial FVIII :C levels (2.43 U/ml vs. 1.87 U/ml, p = 0.0001).

Analysis of six-month case fatality, vWF levels were associated with risk of death [p = 0.01, OR 1.73 (1.12,2.66) for an increase of 1 U/ml], even after allowing for stroke type.

Conclusion. The relationship of vWF with stroke mortality has not previously been described. Although we have not demonstrated a causal role for vWF in the pathogenesis of CVD, elevated circulating levels of vWF may be associated with increased risk of death following stroke. A prospective study would be required to establish whether vWF is predictive for the development of CVD.
On the Relationship between Changes in the Deep Veins Evaluated by Duplex Sonography and the Postthrombotic Syndrome 12 Years after Deep Vein Thrombosis
Authors: Franzeck U K , Schalch I , Bollinger A
Published: July 2018

In a prospective study we performed color duplex ultrasonography to evaluate patency and valvular function of previous thrombosed veins 12 years after the acute thrombosis.

Normal clinical findings were found in 64% of the patients, mild postthrombotic skin changes in 28%, and marked trophic changes in 5%; only 1 venous ulcer occurred.

In 39 patients, 114 initially thrombosed vein segments were evaluated. Thirty-seven of 72 proximal segments were completely recanalized (23 with valvular incompetence) and 21 segments exhibited partial recanalization (19 with valvular incompetence). Superficial femoral vein segments were completely occluded in 19%, however, excellent collateralization was provided via the deep femoral vein. Thromboses of the posterior tibial vein demonstrated a high rate of recanalization with development of valvular incompetence in 52%.

Whereas obstruction and valvular incompetence as single factors led to a postthrombotic leg in 8.5% and 33%, respectively, the most frequent cause for the development of the postthrombotic syndrome was the combination of reflux plus obstruction in the deep veins (50%).

Compression therapy with elastic compression stockings is recommended for at least 5 years after the acute thrombosis.
Multicenter Retrospective Study on the Utilization of FEIBA in France in Patients with Factor VIII and Factor IX Inhibitors
Authors: Negrier C , Goudemand J , Sultan Y , Bertrand M , Rothschild C , Lauroua P ,   the members of the French FEIBA study group
Published: July 2018

Factor VIII or factor IX replacement is frequently impossible in inhibitor-developing hemophiliacs, because of the level of the inhibitor titer. Activated prothrombin complex concentrates are one of the available options to treat the bleeding episodes in such patients. However, the efficacy of these products and the associated thrombogenic risk, particularly in prolonged administration such as employed during surgeries, are important concerns for hemophilia care providers. We performed a multicenter retrospective study to evaluate the use of FEIBA (Factor Eight Bypassing Activity) in France, and data is presented on 433 bleeding episodes, including surgical procedures, concerning 60 patients from 15 hemophilia centers.

The efficacy was judged as good or excellent in 352 episodes (81.3%), poor in 73 episodes (16.9%) and non-existent in 8 episodes (1.8%). Minor and major surgical procedures were successfully performed using FEIBA as a second-line therapy after human or porcine factor VIII, and in some occasions FEIBA was utilized as the only substitution product. The tolerance was assessed as good in 428 episodes (98.8%), but in 5 cases adverse effects were reported. Only 3 patients out of 52 regularly evaluated (5.8%) were HIV-seropositive, and for two of them the seroconversion occurred prior to the first use of FEIBA. In contrast, 80.4% of the patients were HCV-seropositive. An anamnestic response after the administration of FEIBA was noted in 31.5% of cases. This study points out the main features of the use of FEIBA in France, and particularly the low HIV seroprevalence in the patients treated. The good efficacy and the excellent tolerance still confer to this product a place to consider in the therapeutic options for the treatment of inhibitor-developing hemophiliacs or in acquired hemophilia.
The Anticoagulant and Hemorrhagic Effects of DHG, a New Depolymerized Holothurian Glycosaminoglycan, on Experimental Hemodialysis in Dogs
Authors: Minamiguchi Kazuhisa G , Kitazato Keiko T , Sasaki Eiji , Nagase Hideki , Kitazato Kenji
Published: July 2018

We studied the use of depolymerized holothurian glycosaminoglycan (DHG) as an anticoagulant in experimental beagle-dog hemodialysis using a hollow-fiber dialyzer compared to that using unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and nafamostat mesilate (FUT). Effectiveness was based on 5 h hemodialysis and no marked clot deposition in the extracorporeal circuit. At effective doses, UFH and LMWH significantly prolonged template bleeding time, in sharp contrast to FUT and DHG, which scarcely prolonged bleeding time during hemodialysis. DHG prolonged activated partial thromboplastin time (APTT) about 6 times that of normal plasma and prolonged thrombin clotting time (TCT) markedly; FUT showed marked APTT prolongation but hardly prolonged TCT in the hemodialysis circuit at the effective dose. The anticoagulant profile of DHG thus differs completely from that of FUT. These results suggest that DHG may be useful as anticoagulant for hemodialysis with low hemorrhagic risk.
A 6-month Venographic Follow-up in 164 Patients with Acute Deep Vein Thrombosis
Authors: Holmström Margareta , Lindmarker Per , Granqvist Staffan , Johnsson Hans , Lockner Dieter
Published: July 2018

A total of 164 patients were recruited from a randomized trial comparing a low molecular weight heparin, dalteparin, given subcutaneously once daily with a continuous intravenous infusion of unfractionated heparin in the initial treatment of acute deep vein thrombosis. The primary objective of this follow-up study was to investigate whether there were any differences between the two treatment groups with respect to Marder score changes 6 months after the initial diagnosis using repeated venography. The secondary objectives were to analyse whether certain haemostatic and acute phase parameters or patient characteristics influenced the venographic outcome. Results: Complete lysis of the thrombus was observed in 38.4% of the patients and a partial lysis in another 54.3% assessed by venography 6 months after the acute event. Extension of the thrombus was seen in 7.3% of the patients. There were no significant differences in the change in mean Marder score before treatment and at the 6 month follow-up between the two treatment groups, irrespective of thrombus localisation. In a regression model, male gender, low levels of orosomucoid and increased levels of d-di- mer in plasma on day 5 were independently associated (p <0.05) with an enhanced absolute resolution of the thrombus at 6 months. No differences in symptoms and signs in the thrombotic leg at follow-up, comparing the treatment given, or thrombus extension at diagnosis and 6 months later, were demonstrated. Conclusion: Dalteparin given once daily subcutaneously was as effective as continuous intravenous infusion of unfractionated heparin in the initial treatment of deep vein thrombosis assessed by Marder score evaluation 6 months after the acute event.
Homocysteine Metabolism in Endothelial Cells of a Patient Homozygous for Cystathionine β-synthase (CS) Deficiency
Authors: Molen E F van der , Hiipakka M J , van Lith-Zanders H , Boers G H J , Heuvel L P W J van den , Monnens L A H , Blom H J
Published: July 2018

Homocystinuria due to cystathionine β-synthase (CS) deficiency is the most common inborn error of methionine metabolism. Patients with CS-deficiency have an extremely high risk of vascular disease. The underlying mechanism is still unsolved. Dysfunction of endothelial cells could be the trigger in the formation of atherosclerosis and thrombosis. Therefore, differences in cell function were studied between normal and CS-deficient human umbilical endothelial cells (HUVECs). Total homocysteine (tHcy) concentrations in culture media as a measure of homocysteine export increased in all cell lines, including the cell line with CS-deficiency, with constant amounts of approximately 2.5 μM every 24 h. von Willebrand factor (vWF), tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI-1) in culture media were used as markers of endothelial function and increased also with progression of culture time. The effects of additions of folate, vitamin B6 and methionine to the culture medium were studied. The homocysteine export and the markers of endothelial function did not differ between the control and the CS-deficient HUVECs under various test conditions. These data show that CS-deficient endothelial cells have normal homocysteine export and normal endothelial cell function. In CS-deficient patients the very high blood levels of homocysteine, probably due to deficient CS function in liver and kidney, seems to be the hazardous factor to endothelial cells, thus promoting atherosclerosis and thrombosis in CS-deficient patients.
Different Requirement of Intracellular Calcium and Protein Kinase C for Arachidonic Acid Release and Serotonin Secretion in Cathepsin G-activated Platelets
Authors: Rotondo Serenella , Evangelista Virgilio , Manarini Stefano , Gaetano Giovanni de , Cerletti Chiara
Published: July 2018

Previous studies have shown that platelet stimulation with cathepsin G rapidly results in cytoplasmic calcium ([Ca2+]j) increase and activation of protein kinase C (PKC). To elucidate the relationship between these two biochemical events and their relative contribution to the regulation of platelet response to cathepsin G, arachidonic acid (AA) release and serotonin (5HT) secretion were studied. Platelets made Ca2+- depleted and -permeable by treatment with A23187 were compared to intact platelets to better dissociate calcium changes from other receptor- stimulated events. AA release elicited by cathepsin G in intact platelets was prevented by the Ca2+ chelator BAPTA; in Ca2+-depleted, -permeable platelets AA was released in direct response to added Ca2+ and was not increased by simultaneous stimulation with cathepsin G. In intact platelets, PKC inhibition by Ro 31-8220 or PKC induction with PMA either enhanced or reduced, respectively, cathepsin G-induced AA release. Both BAPTA and Ro 31-8220 prevented 5HT secretion from intact platelets; however, in Ca2+-depleted, -permeable platelets, cathepsin G was able to evoke 5HT secretion and p47 phosphorylation independently of [Ca2+]j increase, both effects being hampered by Ro 31-8220. Ca2+ and PKC therefore regulate PLA2 activity and 5HT secretion in cathepsin G-stimulated platelets in a different manner: the former is mainly triggered by [Ca2+]j increase, while PKC represents the major factor in determining dense granule secretion.
Perturbation of Platelet Adhesion to Endothelial Cells by Plasminogen Activation In Vitro
Authors: Chen Hsiun-ing , Wu Yueh-I , Hsieh Yu-Lun , Shi Guey-Yueh , Jiang Meei-Jyh , Chang Wen-Chang , Chuang Woei-Jer , Kan Wai-Ming , Tang Ming-Jer , Jen Chauying J
Published: July 2018

To investigate whether the endothelium-platelet interactions may be altered by plasminogen activation, cultured human umbilical vein endothelial cells (ECs) were treated with tissue-type plasminogen activator (t-PA) in the presence of plasminogen, and platelet adhesion to ECs was subsequently measured by using a tapered flow chamber. Our results demonstrated that platelets adhered more readily to t-PA treated EC monolayer than to the control monolayer at all shear stress levels tested. This phenomenon was treatment time-dependent and dose-dependent, and it could be blocked by adding plasmin inhibitors, such as e-amino caproic acid and aprotinin. Adherent platelets on t-PA treated EC monolayer underwent more severe shape change than those on the control monolayer. While the extracellular matrix directly treated with t-PA attracted less platelets than the control matrix did, platelet adhesion to the matrix that was produced by t-PA-treated ECs was unaltered. These data suggest that t-PA treatment on ECs compromised antiplatelet-adhesion capability on their apical surface without altering the reactivity of their extracellular matrix towards platelets.
Coagulation Disorders Caused by Hydroxyethyl Starch
Authors: Treib Johannes , Haass Anton , Pindur Gerhard
Published: July 2018

Initially, hydroxyethyl starch (HES) was only characterized by its in vitro molecular weight (MW). This is not sufficient because HES is degraded in vivo. One relevant parameter that predicts the rate of enzymatic breakdown is the degree of substitution, a measure of the average number of hydroxyethyl groups per glucose unit. The higher this degree of substitution, the slower the break-down. In addition, because the glucose units can be substituted at carbon 2,3 and 6, different substitution patterns are possible. They are classified by their C2/C6 hydroxyethylation ratio. A higher C2/C6 ratio results in less metabolism of the starch in vivo and results in a larger in vivo MW. This in turn affects therapy, because the larger the in vivo MW, the longer is the duration of the volume effect of HES.

Of particular importance is the fact that HES with a high in vivo MW affects factor VIII/von Willebrand factor which can lead to an acquired von Willebrand syndrome. During a 10-day volume therapy with a medium-MW HES 200, a form that is difficult to metabolize, we observed an 80% drop in factor VIII/von Willebrand factor. Therapy with a medium-MW HES 200, a form that is easily degraded, and therapy with a low-MW HES 70 did not result in a relevant decline of factor VIII/von Willebrand factor.

This explains why hemorrhagic complications have been observed repeatedly in the United States after therapy with HES infusions, some of them lethal. In the United States high-MW HES 480 which is difficult to degrade is most frequently used and results in a larger in vivo MW and subsequent decrease in factor VIII/von Willebrand factor levels. In Europe, medium-MW HES 200 that is easily degraded and low-MW HES 70 are preferred. In the future, HES should be characterized by the in vivo, not the in vitro MW.
Variable Platelet Response to Low-dose ASA and the Risk of Limb Deterioration in Patients Submitted to Peripheral Arterial Angioplasty
Authors: Mueller Michael Rolf , Salat Andreas , Stangl Petra , Murabito Marco , Pulaki Sad , Boehm Dagmar , Koppensteiner Renate , Ergun Erdem , Mittlboeck Martina , Schreiner Wolfgang , Losert Udo , Wolner Ernst
Published: July 2018

A group of 100 patients with intermittent claudication (70 male, 30 female), treated with 100 mg ASA per day, were followed over 18 months after elective percutaneous balloon angioplasty. Platelet function was monitored over a period of 12 months by corrected whole blood aggregometry (CWBA). Upon stimulation by arachidonic acid (AA), adenosine diphosphate (ADP) and collagen, CWBA-results were obtained by an electronic acquisition and evaluation system correcting for hematocrit and platelet count of the blood sample.

All patients showed a completely inhibited platelet response to AA stimulation. Comparison of the CWB A-results with clinical parameters revealed that reocclusions at the site of angioplasty occurred exclusively in male patients for which CWBA failed to prove an inhibition of aggregation upon both agonists, ADP and collagen, and for these patients the risk of complication is at least 87% higher (p = 0.0093).

Only 40% of male patients show the expected effect of ASA on in vitro platelet aggregation at any given point in time and CWBA is capable of predicting those male patients which are at an elevated risk of reocclusion following peripheral angioplasty.
Aprotinin Reduces Blood Loss after Cardiopulmonary Bypass by Direct Inhibition of Plasmin
Authors: Ray Michael J , Marsh Neville A
Published: July 2018

The effectiveness and mechanism of aprotinin reduced bleeding after cardiopulmonary bypass surgery was studied in a double blind randomised study of 106 patients undergoing valve replacement surgery. Aprotinin therapy was associated with significant reduction in perioperative bleeding and postoperative blood transfusion requirements. Although initially tissue plasminogen activator (t-PA) activity was lower in the aprotinin than placebo group, as surgery proceeded this difference was reversed due to less plasminogen activator inhibitor-1 release in the aprotinin group. This indicates that aprotinin-mediated suppression of fibrinolysis as demonstrated by reduced D-dimer concentration was not related to t-PA. Furthermore, similar perioperative reduction of plasminogen levels in aprotinin and placebo groups indicated a similar degree of conversion of plasminogen to plasmin. However, less plasmin bound with alpha 2-antiplasmin in the plasma in the aprotinin group as it was already complexed with aprotinin where it remained protected from the natural inhibitor on the intact fibrin surface. The reduced fibrinolytic activity of the aprotinin group was thus brought about by the complexing of aprotinin with the plasmin which was bound to the fibrin surface.
Ultrasound Reversibly Disaggregates Fibrin Fibers
Authors: Braaten Julie V , Goss Rachel A , Francis Charles W
Published: July 2018

Ultrasound accelerates fibrinolysis in vitro and in vivo, primarily through non-thermal mechanisms including cavitation. We have previously observed that ultrasound reversibly increases flow through fibrin gels, a property primarily determined by the structure of the fibrin matrix. Therefore, the effect of ultrasound on the ultrastructure of fibrin gels was examined using scanning electron microscopy. Non-cross- linked fibrin gels were fixed and prepared for microscopy before, during and after exposure to 1 MHz ultrasound, and quantitative analysis of fiber population density and diameter was performed. Gels exposed and fixed in the presence of ultrasound exhibited an increase in density of 65 ± 26% (mean ± SD) at 4 W/cm2 (p <0.000001) accompanied by a decrease in fiber diameter of 27 ± 9% (p <0.000001). Gels fixed 15 min following ultrasound exposure showed no significant change in either density or diameter compared to unexposed gels, indicating that the ultrasound-induced change in fiber structure was reversible. Factor XIII-crosslinked fibrin gels exhibited no change in population density or diameter when exposed to ultrasound. These results indicate that ultrasound exposure causes reversible disaggregation of uncrosslinked fibrin fibers into smaller fibers, an effect that may alter flow resistance and create additional binding sites for fibrinolytic components, improving fibrinolytic efficacy.
Antithrombin Acts as a Negative Acute Phase Protein as Established with Studies on HepG2 Cells and in Baboons
Authors: Niessen R W  L M , Lamping R J , Jansen P M , Prins M H , Peters M , Taylor F B , de Vijlder J J  M , ten Cate J W , Hack C E , Sturk A
Published: July 2018

Patients with sepsis or after major surgery have decreased plasma levels of the anticoagulant protein antithrombin. In such patients elevated levels of interleukin-6 (IL-6) are present and this interleukin is known to induce positive and negative acute phase responses. To investigate the possibility that antithrombin acts as a negative acute phase response-protein we performed studies on the human hepatoma cell line HepG2 in vitro and baboons in vivo. HepG2 cells were treated with recombinant human IL-6, ILß3, or combinations of the latter two, and tested for production of antithrombin, fibrinogen and prealbumin (transthyretin). This treatment resulted in a dose dependent increase in fibrinogen concentration (with a maximum effect of 2.8-2.9-fold) and a dose dependent decrease in prealbumin (with a maximum effect of 0.6-0.7-fold) and antithrombin concentrations (with a maximum effect of 0.6-0.8-fold). Simultaneous treatment of the HepG2 cells with IL-6 (1,000 pg/ml or 2,500 pg/ml) and IL-1β (25 pg/ml), provided more extensively decreased prealbumin (0.8 and 0.6-fold, respectively) and antithrombin concentration (0.7 and 0.6-fold, respectively) compared to the single interleukin treatment at these concentrations. Baboons treated with 2 µg IL-6 · kg body-weight-1 · day1 showed increased plasma CRP levels (59-fold, p <0.05) and decreased prealbumin (0.9-fold, p <0.05) and antithrombin (0.8-fold, p <0.05) plasma levels, without evidence for coagulation activation. Our results indicate that antithrombin acts as a negative acute phase protein, which may contribute to the decreased antithrombin plasma levels observed after major surgery or in sepsis.
Administration of Antioxidant Vitamins Does Not Alter Plasma Fibrinolytic Activity in Subjects with Central Obesity
Authors: Rifici Vincent A , Schneider Stephen H , Chen Yaoju , Khachadurian Avedis K
Published: July 2018

In vitro studies suggest that oxidized low density lipoprotein inhibits fibrinolysis by stimulating the production of plasminogen activator inhibitor -1 (PAI). We assessed the effects of dietary antioxidant vitamins for four weeks on three indices of copper mediated oxidation of very low and low density lipoproteins (VLDL+LDL) and plasma fibrinolytic activities in 15 male subjects with central obesity, a condition associated with increased PAI activity. Vitamin administration resulted in a decrease in production of thiobarbituric acid reactive substances from 29.3 ± 3.9 to 13.6 ± 3.5 nmoles/mg VLDL + LDL protein (mean ± SE, p <0.003), an increase in the lag phase of conjugated diene formation from 94.8 ± 5.5 to 225.0 ±31.9 min (p <0.001) and an increase in reactivity of lysine residues from 73.6% ± 4.8% to 86.8% ± 3.6% (p <0.034) demonstrating a reduction in the susceptibility of the lipoproteins to oxidation. However, antioxidant vitamins had no effect on plasma PAI activity, PAI antigen, tissue-type plasminogen activator activity and antigen, fibrinogen and fibrin degradation products. These results do not support the hypothesis that lipoprotein oxidation is a significant cause of impaired fibrinolysis in men with central obesity.
Inhibition of Thrombin Generation in Plasma by Inhibitors of Factor Xa
Authors: Prasa D , Svendsen L , Stürzebecher J
Published: July 2018

A series of inhibitors of factor Xa (FXa) were investigated using the thrombin generation assay to evaluate the potency and specificity needed to efficiently block thrombin generation in activated human plasma. By inhibiting FXa the generation of thrombin in plasma is delayed and decreased. Inhibitor concentrations which cause 50 percent inhibition of thrombin generation (IC50) correlate in principle with the Ki values for inhibition of free FXa. Recombinant tick anticoagulant peptide (r-TAP) is able to inhibit thrombin generation with considerably low IC50 values of 49 nM and 37 nM for extrinsic and intrinsic activation, respectively. However, the potent synthetic, low molecular weight inhibitors of FXa (Ki values of about 20 nM) are less effective in inhibiting the generation of thrombin with IC50 values at micromolar concentrations.

The overall effect of inhibitors of FXa in the thrombin generation assay was compared to that of thrombin inhibitors. On the basis of similar Ki values for the inhibition of the respective enzyme, synthetic FXa inhibitors are less effective than thrombin inhibitors. In contrast, the highly potent FXa inhibitor r-TAP causes a stronger reduction of the thrombin activity in plasma than the most potent thrombin inhibitor hirudin.
Akute Autoimmunthrombozytopenie bei Sarkoidose
Authors: Berger H. H. , Busse Petra , Loreth R. M.
Published: July 2018

Bei einem 35jährigen Patienten mit Sarkoidose im Stadium I trat nach einer Analfistelresektion ein kontinuierlicher Abfall der Thrombozyten bis 4 T/μl mit entsprechender klinischer Manifestation der dadurch bedingten hämorrhagischen Diathese auf. Nach Ausschluß einer heparinassoziierten Thrombozytopenie (HAT) und einer malignen hämatologischen Systemerkrankung wurde unter der Ausschlußdiagnose Autoimmunthrombozytopenie eine Hochdosis-Immuntherapie mit einem hochkonzentrierten Immunglobulinpräparat durchgeführt. Dies führte zu einem raschen Anstieg der Thrombozytenzahl, welcher auch nach Beendigung der Immunglobulingabe anhielt. Aufgrund des klinischen Verlaufes konnte die Diagnose einer Autoimmunthrombozytopenie bestätigt werden. Die vorangegangene Inhalationsnarkose muß als mögliches Triggerereignis angesehen werden.
Repeated Exercise Induces Release of Soluble P-Selectin in Patients with Intermittent Claudication
Authors: Kirkpatrick U J , Mossa M , Blann A D , McCollum C N
Published: July 2018

Controversy exists as to whether exercise in patients with intermittent claudication causes a harmful biochemical effect associated with an ischaemia-reperfusion injury of skeletal muscle. We report on exercise-induced changes in neutrophil activation, soluble P-selectin and von Willebrand factor in 34 patients with intermittent claudication and 12 matched controls.

Von Willebrand factor (vWF) showed a cyclical pattern of response to exercise in control subjects (rising from 103 ± 8 to 119 ± 7 U/dl); claudicants did not show this pattern but had higher levels of vWF throughout (p <0.03). There was no consistent pattern of response in neutrophil hydrogen peroxide production to exercise in either claudicants or control subjects. Soluble P-selectin levels increased after exercise, but this only reached statistical significance after repeated exercise in claudicants (rising from 320 ± 28 to 357 ± 28 ng/ml). This rise in soluble P-selectin after exercise may indicate progressive platelet activation which may contribute to the excess cardiovascular mortality that claudicants are prone to.
Mechanism of Inhibitory Action on Platelet Activation of a Phospholipase A2 Isolated from Lachesis muta (Bushmaster) Snake Venom
Authors: Fuly André L , Machado Olga L T , Alves Elias W , Carlinis Célia R
Published: July 2018

Crude venom from Lachesis muta exhibited procoagulant, proteolytic and phospholipase A2 activities. A phospholipase A2, denoted LM-PLA2 was purified from L. muta venom to homogeneity, through a combination of chromatographic steps involving gel-filtration on Sephacryl S-200 HR and reverse phase chromatography on a C2/C18 column. LM-PLA2 presented a single polypeptide chain with an isoelectric point at pH 4.7 and apparent molecular weight of 17 kDa. Partial aminoacid sequence indicated a high degree of homology for LM-PLA2 with other PLA2 from different sources.

LM-PLA2 displayed a potent enzymatic activity as measured by indirect hemolysis of red blood cells but it was neither lethal when injected i.p. into mice nor did it present anticoagulant activity. Furthermore, LM-PLA2 displayed a moderate inhibitory activity on the aggregation of rabbit platelets induced by low levels of ADP, thrombin and arachidonate. In contrast, platelet aggregation induced by high doses of collagen was strongly inhibited by LM-PLA2 as well as ATP-release. Treatment of the protein with p-bromophenacyl bromide or 2-mercapto-ethanol, as well as thermal inactivation studies, suggested that the platelet inhibitory effect of LM-PLA2 is dependent on its enzymatic activity. Thus, the platelet inhibitory activity of LM-PLA2 was shown to be dependent on the hydrolysis of plasma phospholipids and/or lipoproteins, most probably those rich in phosphatidylcholine. Surprisingly, lyso-phosphatidylcholine released by LM-PLA2 from plasma was shown to preferentially inhibited collagen-induced platelet aggregation, in contrast to other PLA2s, whose plasma hydrolytic products indistinctly affect platelet’s response to several agonists.
Naturally Produced Extracellular Matrix Is an Excellent Substrate for Canine Endothelial Cell Proliferation and Resistance to Shear Stress on PTFE Vascular Grafts
Authors: Schneider A , Chandra M , Lazarovici G , Vlodavsky I , Merin G , Uretzky G , Borman J B , Schwalb H
Published: July 2018

Purpose: Successful development of a vascular prosthesis lined with endothelial cells (EC) may depend on the ability of the attached cells to resist shear forces after implantation. The present study was designed to investigate EC detachment from extracellular matrix (ECM) precoated vascular prostheses, caused by shear stress in vitro and to test the performance of these grafts in vivo. Methods: Bovine aortic endothelial cells were seeded inside untreated polytetrafluoro-ethylene (PTFE) vascular graft (10 X 0.6 cm), PTFE graft precoated with fibronectin (FN), or PTFE precoated with FN and a naturally produced ECM (106 cells/graft). Sixteen hours after seeding the medium was replaced and unattached cells counted. The strength of endothelial cell attachment was evaluated by subjecting the grafts to a physiologic shear stress of 15 dynes/cm2 for 1 h. The detached cells were collected and quantitated. PTFE or EC preseeded ECM coated grafts were implanted in the common carotid arteries of dogs. Results: While little or no differences were found in the extent of endothelial cell attachment to the various grafts (79%, 87% and 94% of the cells attached to PTFE, FN precoated PTFE, or FN+ECM precoated PTFE, respectively), the number of cells retained after a shear stress was significanly increased on ECM coated PTFE (20%, 54% and 85% on PTFE, FN coated PTFE, and FN+ECM coated PTFE, respectively, p <0.01). Implantation experiments in dogs revealed a significant increase in EC coverage and a reduced incidence of thrombus formation on ECM coated grafts that were seeded with autologous saphenous vein endothelial cells prior to implantation. Conclusion: ECM coating significantly increased the strength of endothelial cell attachment to vascular prostheses subjected to shear stress. The presence of adhesive macromolecules and potent endothelial cell growth promoting factors may render the ECM a promising substrate for vascular prostheses.
Trypsin- and SLIGRL-induced Vascular Relaxation and the Inhibition by Benzamidine Derivatives
Authors: Glusa Erika , Saft Andrea , Prasa Dagmar , Stürzebecher Jörg
Published: July 2018

Serine proteinases are involved in several physiological processes and elicit profound cellular effects in a variety of tissues. Besides the thrombin receptor a second receptor, activated by trypsin, the proteinase-activated receptor 2 (PAR-2), was cloned and characterized. Both enzymes generate a new extracellular N-terminus by limited proteolytic cleavage which functions as tethered ligand to activate the receptor. Synthetic peptides corresponding to the sequences of the newly generated N-terminus are able to mimic the effects of the enzymes.

In porcine pulmonary arteries trypsin and the receptor-derived peptide SLIGRL elicited an endothelium-dependent transient relaxation of PGF2α-precontracted vessels. The EC50 values for trypsin and SLIGRL amounted to 1.1 ± 0.2 nM and 5.4 ± 0.6¼M, respectively. Trypsin and SLIGRL caused a homologous desensitization but thrombin and the thrombin receptor-activating peptide SFLLRN were still able to elicit pronounced relaxant effects. The trypsin- and SLIGRL-induced relaxant responses were markedly diminished after blockade of the nitric oxide synthesis by NG-nitro-L-arginine methyl ester (200 ¼M) and were absent in endothelium-denuded vessels. Indomethacin and hirudin did not influence the relaxant effects. The effect of trypsin but not that of SLIGRL was blocked by the proteinase inhibitor aprotinin suggesting that only proteolytically active trypsin activates the receptor. Benzamidine derivatives of the 3-amidinophenylalanine type with different affinity for trypsin and thrombin inhibited the vascular effects of trypsin (IC50 0.007-0.7 ¼M) correlating with its antitrypsin activity.

The data suggest that the vascular effects of trypsin and SLIGRL are mediated through activation of PAR-2 which differs from the thrombin receptor.
Antithrombotic Effect of Two Low Molecular Weight Thrombin Inhibitors and a Low-Molecular Weight Heparin in a Caval Vein Thrombosis Model in the Rat
Authors: Eriksson B I , Carlsson S , Halvarsson M , Risberg B , Mattsson C
Published: July 2018

A sensitive thrombosis model with a high reproducibility was developed in the rat, utilizing stasis of the caval vein and a standardized surgical trauma as the only thrombogenic stimuli. Since no procoagulant substances were used, the results of the present study might be relevant in a clinical situation. The antithrombotic effect of two recently synthesized low-molecular-weight thrombin inhibitors have been compared to dalteparin, (Fragmin) a low-molecular-weight heparin fragment. Each compound was studied at 8 different doses with 10 rats in each group. On a gravimetric basis, the thrombin inhibitor melagatran was twice as potent as dalteparin (ED50 16 and 33 µ/kg per h, respectively). The second thrombin inhibitor, inogatran, had an intermediate effect, with an ED50 of 24 µLg/kg per h. No differences in antithrombotic effect were, however, found when the compounds were compared at anticoagulant equivalent doses (same APTT prolongation). A 50% reduction in the mean thrombus weight was obtained when APTT was prolonged to 1.2 to 1.3 times the pretreatment value.
Thrombotic Events during Oral Anticoagulant Treatment: Results of the Inception-cohort, Prospective, Collaborative ISCOAT Study
Authors: Palareti Gualtiero , Manotti Cesare , D’Angelo Armando , Pengo Vittorio , Erba Nicoletta , Moia Marco , Ciavarella Nicola , Devoto Gianluigi , Berrettini Mauro , Leali Nicoietta , Poggi Mario , Legnani Cristina , Musolesi Serena , Coccheri Sergio ,   ISCOAT Study Group (Italian Study on Complications of Oral Anticoagulant Therapy)
Published: July 2018

The paper reports on rate and type of thrombotic events occurring during the observational, prospective, inception-cohort, multicenter ISCOAT study. 2,745 unselected, daily practice patients, consecutively referring to 34 Italian anticoagulation clinics to monitor the oral anticoagulant treatment, were included in the study from beginning of their first anticoagulant course. During a total follow-up of 2,011 patient-years of treatment 70 thrombotic events (3.5 per 100 patient years) were recorded in 67 patients: 20 fatal (1%), 39 major (1.9%) and 11 minor (0.6%). 34/70 events occurred within the first 90 days of treatment (relative risk - at multivariate analysis - of <90 days vs. >90 = 20.6, C.I. 12.7-33.5; p <0.0001). The risk was higher in patients aged >70 y (1.62, C.I. 1.0-2.61; p <0.05), and when indication for anticoagulant treatment was peripheral/cerebral arterial disease (1.84, C.I. 1.01-3.36; p <0.05). The frequency of thrombotic events was 17.5% when international normalised ratio (INR) levels were <1.5, decreasing to 2.3% for INRs within the 2-2.99 category (relative risk of INRs <2.0 vs. >2 = 1.88, C.1.1.16-3.07; p <0.05).

The recorded rate of thrombotic events was lower than that reported in the few available studies. A greater risk should be expected during the first 90 days of treatment, when anticoagulation levels are <2.0 INR, in patients > 70 years and in those with cerebrovascular/peripheral arterial disease.
Activation of Coagulation and Fibrinolysis in Childhood Diarrhoea-associated Haemolytic Uraemic Syndrome
Authors: Nevard Corinne H F , Jurd Karen M , Lane David A , Philippou Helen , Haycock George B , Hunt Beverley J
Published: July 2018

Diarrhoea-associated haemolytic uraemic syndrome (D+ HUS) is usually caused by verotoxin producing Eschericia coli. We hypothesized that verotoxin binding to glomerular endothelial cells causes localised endothelial cell activation and thus activation of coagulation and reduction of fibrinolytic potential. We also proposed that treatment with fresh frozen plasma or dialysis would not affect these changes. Markers of activation of coagulation and fibrinolysis were measured in 30 children with acute D+ HUS serially, in healthy children and in children on dialysis.

In acute D+ HUS, levels of thrombin-antithrombin III complex and prothrombin fragment 1+2 were significantly increased (p <0.001). The source of thrombin generation was unclear. Factor Xlla levels were increased in patients and controls with renal failure. Factor VIIa levels were not significantly raised in children with acute D+ HUS. D-dimers were increased, but fibrinolytic potential as measured by fibrin plate was reduced. Levels of plasminogen activator inhibitor antigen and activity and tissue plasminogen activator antigen were increased.

Neither peritoneal dialysis nor administration of blood products, the most common treatments, altered parameters of coagulation or fibrinolysis.
Presence of P2X1 Purinoceptors in Human Platelets and Megakaryoblastic Cell Lines
Authors: Vial Catherine , Hechier Béatrice , Léon Catherine , Cazenave Jean-Pierre , Gachet Christian
Published: July 2018

Human platelets are thought to possess at least two subtypes of purinoceptor, one of which, coupled to G-proteins, could be the P2Y1 receptor (Léon et al. 1997). However, it has been suggested that the unique rapid calcium influx induced by ADP in platelets could involve P2X1 ionotropic receptors (MacKenzie et al. 1996) and the aim of this study was thus to investigate the presence of P2X purinoceptors in platelets and megakaryoblastic cells. Using PCR experiments, we found P2X1 mRNA to be present in human platelets and megakaryoblastic cell lines. In platelets, the selective P2X1 agonist αβMeATP induced a rise in intracellular calcium only in the presence of external calcium and this effect was antagonized by suramin and PPADS. Repeated addition of a�MeATP desensitized the P2X1 purinoceptor but only slightly affected the ADP response, while no calcium response to αβMeATP was observed in megakaryoblastic cells. These results support the existence of functional P2X1 purinoceptors on human platelets and the presence of P2X1 transcripts in megakaryoblastic cell lines.
Bile Duct Injury in Children: Is There a Role for Early Endoscopic Retrograde Cholangiopancreatography?
Authors: Aljahdali Akram , Murphy James
Published: July 2018

Introduction Liver injury is common among pediatric abdominal trauma. Nonoperative management is the standard of care in isolated stable liver injuries. Bile leak is not an uncommon complication in moderate- and high-grade injuries.

Case series Three pediatric patients (age: 10–15 years) suffered grade IV liver injuries secondary to blunt abdominal trauma. All developed significant bile leak treated nonoperatively with endoscopic retrograde cholangiopancreatography (ERCP), and patients 1 and 2 were treated with bile duct stent alone. Patient 3 required laparotomy for bile peritonitis and abdominal compartment syndrome followed by interval ERCP and bile duct stent.

Conclusion Traumatic bile leaks if not recognized and managed early can result in significant morbidity. This paper describes the presentation and treatment of three pediatric patients with blunt liver trauma complicated by significant bile leaks that were managed successfully with ERCP and bile duct stent. This paper demonstrates the importance of early detection of bile leak to prevent bile peritonitis. Abdominal imaging 4 to 5 days postinjury can help in detecting bile accumulation. We believe that ERCP and bile duct stent are becoming the standard of care in diagnosing and treating traumatic bile leak. This paper confirms the safety and feasibility of this technique in the pediatric population.
Evaluation of the Painful Total Hip Arthroplasty
Authors: Eyberg Blake , Jacofsky David , Hess Shane
Published: July 2018

The total hip arthroplasty (THA) remains as one of the most successful procedures improving function and quality of life. However, despite its success, failures do occur. The workup of a painful THA should be methodical, prioritizing the most likely to least likely etiologies. Intrinsic and extrinsic sources of pain must be evaluated from data collected through an accurate history, detailed physical examination, laboratory analysis, and imaging interpretation.
Long-term ecology of investors in a financial market
Authors: Musciotto Federico , Marotta Luca , Piilo Jyrki , Mantegna Rosario N.
Published: July 2018

The cornerstone of modern finance is the efficient market hypothesis. Under this hypothesis all information available about a financial asset is immediately incorporated into its price dynamics by fully rational investors. In contrast to this hypothesis many studies have pointed out behavioral biases in investors. Recently it has become possible to access databases that track the trading decisions of investors. Studies of such databases have shown that investors acting in a financial market are highly heterogeneous among them, and that heterogeneity is a common characteristic of many financial markets. The article describes an empirical study of the daily trading decisions of all Finnish investors investing Nokia stock over a time period of 15 years. The investigation is performed by adapting and using methods and tools in network science. By investigating daily trading decisions, and by constructing the time-evolution of statistically validated networks of investors, clusters of investors—and their time evolution— which are characterized by similar trading profiles are detected. These clusters are performing distinct trading decisions on time scales ranging from several months to twelve years. These empirical observations show the presence of an ecology of groups of investors characterized by different attributes and by various investment styles over many years. Some of the detected clusters present a persistent over-expression of specific investor categories. The study shows that the logarithm of the ratio of pairs of statistically validated trading decisions is different for different values of the market volatility. These findings suggest that an ecology of investors is present in financial markets and that groups of traders are always competing, adopting, using and eventually discarding new investment strategies. This adaptation process is observed over a multiplicity of time scales, and is compatible with several conclusions of behavioral finance and with the assumptions of the so-called adaptive market hypothesis.
Effect of structural disorder and Coulomb interactions in the superconductor-insulator transition applied to boron doped diamond
Authors: McIntosh R. , Mohanta N. , Taraphder A. , Bhattacharyya S.
Published: July 2018

The effect of disorder, both structural (non-diagonal) and on-site (diagonal), is studied through the inhomogeneous Bogoliubov-de Gennes (BdG) theory in narrow-band disordered superconductors with a view towards understanding superconductivity in boron doped diamond (BDD) and boron-doped nanocrystalline diamond (BNCD) films. We employ the attractive Hubbard model within the mean field approximation, including the short-range Coulomb interaction between holes in the narrow acceptor band. We study substitutional boron incorporation in a triangular lattice, with disorder in the form of random potential fluctuations at the boron sites. The role of structural disorder was studied through non-uniform variation of the tight-binding coupling parameter where, following experimental findings, we incorporate the concurrent increase in structural disorder with increasing boron concentration. We illustrate stark differences between the effects of structural and on-site disorder and show that structural disorder has a much greater effect on the density of states, mean pairing amplitude and superfluid density than on-site potential disorder. We show that structural disorder can increase the mean pairing amplitude while the spectral gap in the density of states decreases with states eventually appearing within the spectral gap for high levels of disorder. This study illustrates how the effects of structural disorder can explain some of the features found in superconducting BDD and BNCD films such as a tendency towards saturation of the Tc with boron doping and deviations from the expected BCS theory in the temperature dependence of the pairing amplitude and spectral gap.
Effects of strain rate on grain boundary evolution in Ti-55531 alloy
Authors: Lv Ya-ping , Li Shao-jun , Zhang Xiao-yong , Chen Chao , Zhou Ke-chao
Published: July 2018

Ti-55531 alloy with an acicular α initial microstructure was hot-compressed at 998 K using strain rates of 0.001 and 1 s−1. The effects of strain rate on the fragmentation of acicular α were investigated using electron backscatter diffraction (EBSD) from the standpoint of grain boundary evolution, e.g. low/high angle boundaries (LABs/HABs), the evolution of microtexture and the destruction of the Burgers orientation relationship (BOR) at α/β boundaries. Changes in the LAB fraction and average misorientation up to equilibrium indicate that the formation of LABs and a subsequent transition to HABs are prerequisites for the fragmentation of acicular α. The weakening of microtexture results from the formation of LABs/HABs in acicular α and the destruction of the BOR at α/β boundaries.
Deconstructing Latin American development: postdevelopment critical theory or Marxist political economy?: A reply to Munck
Authors: Veltmeyer Henry
Published: July 2018

Munck (2018) provides us with a thoughtful reflection on the lessons that can be drawn for the Left from a review of recent Latin American experiences and debates. I am in total agreement with his central point regarding the critical importance of these experiences and debates for augmenting the global Left by the provision of theoretical and political tools that can be used for the Left to come to terms with the forces at work in the current phase of world capitalist development – and inmoving forward. On the other hand, I disagree with the way that he conceptualizes the challenge that recent developments in Latin America presents the Left.