bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Factor VIII Procoagulant Activity with Factor VIII Related Antigen
Authors: Armitage H. M.B.B.S.
Published: May 2019

Using the technique of coagulation in an agarose gel Following rapid two dimensional Immunoelectrophoresis, the relationship of factor VIII procoagulant activity (VIIIC) with factor VIII related antigen (VIIIRA) was studied in plasma from patients withvon Willebrand’s disease and carriers of haemophilia. In each case, VIIIC was closely associated with both the fast and slow moving forms of factor VIIIRA as demonstrated by the formation of fibrin in the clotting gel in a similar position to the precipitin arc in the antibody containing gel.

Mixtures of snail molecular weight VIIIC with no detectable antigen and factor VIIIRA devoid of clotting activity, from either (a) haemophilic plasma, (b) Dithiothreitol treated haemophilic plasma,(c) normal serum nr (d) von Willebrand serum were also studied using this technique. The samples of VIIIC and antigen were either electrophoresed in tandem or nixed in a test tube immediately prior to electrophoresis and an aliquot placed in a single well. Again fibrin formation occurred in the clotting gel in a similar position to the immune precipate. There was no peak of fibrin formation when the VIIIC was electrophoresed alone. All types of factor VIIIRA tested appeared to have an affinity for factor VIIIC and appeared to be capable of acting as a carrier protein.
Adsorption of Human Fibrinogen and Albumin on Polymethylmethacrylate (PMMA), Collagen and Elastin
Authors: Muggli R.
Published: May 2019

PMMA-slides were partially coated with a mixture of soluble and fibrillar collagen with Solubilized elastin. The slides were exposed for 2 min at 37°C under laminar flow 125I-fibrinogen or 131I-albumin in 0.9% NaCl at concentrations of 0.133 mg/ml and 2mg/ml respectively, and rinsed with 0.9% NaCl. From each slide two disks were punched out - on from the uncoated surface, the other from the portion coated with collagen or elastin - and the associated radioactivity measured. Compared to PMMA, adsorption of both plasma proteins was strongly reduced (2p <0.001) on collagen and elastin (Table, x±SD, n=10). Low adsorption was more marked for fibrinogen and on the elastin coated surface. Surface peeling could not account for the observed differences, since surface concentrations of fibrinogen did not differ significantly between surfaces exposed for 2 min, 4 min or 2 min followed by a 2 min rinse with 0.9% NaCl.

Conclusion. Results from studies on plasma protein adsorption on synthetic polymers are not necessarily transferable to natural. substrates and, consequently, to the in vivo situation.
Factor IX in the Human Fetus
Authors: Örstavik K.H. , Henriksson P.
Published: May 2019

Factor IX activity and factor IX antigen were determined in plasma from five male fetuses of gestational age 17-22 weeks. The fetuses were obtained from women undergoing abortions for medico-social reasons. The level of factor IX activity was between 0.04 and 0.05 units/ml in all five fetuses. Factor IX antigen was determined by the electroimmunoassay technique of Laurell using a precipitating rabbit antiserum to factor IX. The lower limit of detectability of the electroimmunoassay was reduced from about 0.12 units/ml to 0.02 units/ml by incubating the agarose gels following the electrophoresis with a peroxidase conjugated swine antiserum to rabbit IgG immunoglobulins. The three eldest fetuses had levels of factor IX antigen between 0.06 and 0.08 units/ml, whereas factor IX antigen could not be detected in the two youngest fetuses (twins of gestational age 17 weeks). The results indicate that the determination of factor IX antigen in fetal plasma may become of value for prenatal diagnosis of hemophilia B-.
Influence of the Carbohydrate Moiety in the Dysfibrinogenemia of Liver Disease
Authors: Martinez J. , Palascak J.E.
Published: May 2019

Human fibrinogen is a glycoprotein which contains 6 sialic acid residues per molecule. Enzymatic removal of sialic acid modifies its functional properties as indicated by shortening of the thrombin time due to enhanced asialofibrin monomer polymerization. The abnormal fibrinogen of liver disease contains an Increased amount of sialic acid and is functionally characterized by impaired fibrin monomer polymerization. The prolongation of its thrombin time correlates with its increased sialic acid content. Enzymatic cleavage of the excess sialic acid results in normalization of the thrombin time and the fibrin monomer polymerization. Quantitative labelling of sialic acid with (3H) demonstrates increased labelling of the abnormal fibrinogen compared to normal fibrinogen reflecting the sialic acid content of the abnormal molecule. The radioactivity of the labelled normal and abnormal fibrinogens after reduction and SDS-PAGE was limited to the Bβ and γ chains with 60% of the radioactivity in the Bβ chain and 40% in the γ chain. A similar distribution of radioactivity was found after removal of the excess sialic acid from the respective chains. β-galactose was also increased in the abnormal fibrinogen and paralleled the increase in sialic acid. These studies indicate that sialic acid is distributed normally on the chains of the abnormal fibrinogen of liver disease, but its increased content is responsible for the functional defect of the protein.
A Comparison of Glu- and Lys-Plasminogens: Binding to Fibrin and Effect on Lysis Rates
Authors: Whitaker A.N. , Gaffney P.J.
Published: May 2019

Partially activated (lys-) plasminogen (plgn) exhibits a greater affinity than native (glu-) plgn for fibrin. To complement previous data obtained using radio-labelled plgn we have studied a range of plgn concentrations, used functional assays (S-2251, caseino-lysis and binding to lysine sepharose), ensured that the fibrin is totally cross-linked, correlated affinities of plgn for fibrin with lysis rates when plgn was activated by SK, and compared buffer with plasma and serum systems containing native inhibitors. When fibrinogen or plasma was clotted in the presence of plgn then lys-plgn gave greater incorporation and faster lysis rates than glu-plgn. When washed fibrin was immersed in plgn lys-plgn again showed greater affinity than glu-plgn for fibrin, but on transfer to SK lysis rates were identical. In the most potent lysis system, immersion of fibrin in SK then transfer to plgn, lysis was slightly fasterin glu- than lys-plgn. Incorporation of purified glu-plgn into plasma fibrin exceeded that of native plasma olqn and the former promoted lysis more effectively. Binding of lys-plgn to fibrin was the more susceptible to inhibition by plasma or serum. The pertinence of these data to in vivo requirements for thrombolytic therapy is speculative, but clearly it cannot be assumed that lys-plgn must be more effective than glu-plgn, in promoting fibrinolysis, because of superior affinity for purified fibrin.
Amidino-Substituted Heterocycles as Probes of the Specificity Pocket of Proteases Involved in Coagulation and Fibrinolysis
Authors: Tidwell R. R. , Geratz J. D.
Published: May 2019

A series of ten newly synthesized amidine-substituted heterocycles were examined for their inhibitory effect against human and bovine thrombin, human factor Xa and plasmin, and bovine trypsin. Inhibition was competitive and reversible in all cases and the Kj values were taken to reflect binding conditions in the specificity pocket A remarkable inhibitor of the three clotting enzymes was found in 5-amidlnoindole. Compared to the standard inhibitor benzamidine, it proved to be thirty to forty times more effective against bovine and human thrombin, and factor-Xa. However b-amidinomdole proved to be the most potent inhibitor of plasmin and trypsin‘in order to explain the considerable activity of the indole derivatives, hydrophobic interactions, hydrogen bonding and charge transfer complex formation are considered Finallythe binding strength for thrombin as well as for trypsin was significantly reduced below pH 7.0. The loss in affinity may have resulted from protonation of the ammo acid triad of the catalytic site of the enzymes and consequent adverse conformational changes. This study was supported by U. S. Public Service Grants AM 10746 and HL 21540.
Also High Dose of Aspirin Prolongs Bleeding Time, But Later After Ingestion
Authors: Waiter E. , Siess R. , Zimmermann R. , Weber E.
Published: May 2019

O’Grady and Moncada (Lancet, 1978, ii, 780) found after ingestion of 0.3 g but not after 3.9g of aspirin a significant prolongation of the bleeding time, measured 2h after ingestion. This confirmed their unpublished findings in cats and rabbits, and also their suggestion, that aspirin as an antithrombotic agent should be used in small doses. We decided to test a intermediate dose of 1.5g in comparison to 0.3 and 4.0. Young healthy volunteers received in a double blind trial at random with 14 days interval the three doses. Bleeding time was measured and blood taken for collagen induced aggregation and blood levels of ASA and SA before, 2, 4 and 5.5 after ingestion of ASA. Bleeding time increased significantly 2 h after 0.3g ASA from 213 to 380 sec.(n=8,p <0.01), and from 181 to 408 after 1. g. The high dose of 4g led to a smaller prolongation from 224 to 342 after 2 h, but reached the low dose range after 4 h, 440 sec. (p < 0.01). Collagen-induced aggregation (1 μg/m 1 and 5 μg/ml) was independent from the digese of ASA reduced, beginning after two hours. Our findings do not confirm the result of O’Grady and Moncada. The slower increase of bleeding time after the high dose of ASA must be discussed in relation to ASA and SA blood-levels and reversible inhibition of cyclooxygenase in endothelial cells
Molecular Weight of Human Plasma Factor VIII.
Authors: Bolhuis P.A. , Sixma J.J.
Published: May 2019

Recently it has been postulated that native plasma factor VIII is of low molecular weight. We have investigated the molecular weight of VIII: C by agarose chromatography. Factor VIII: C was eluting at the void volume under the following conditions. 1) Blood anticoagulated with 10mM benzamidine 10mM ε-aminocaproic acid and diisopropyl-fluoro-phosphate. Gelchromatography was performed with 10mM benzamidine, 10mM ε-aminocaproic acid and huuman albumin 40 mg/ml) in Michaelisbuffer at 37° in the presence or absence of 2mM Ca2+. 2) Heparin plasma 4U/ml) and elution in barbital buffer, 3) citrated plasma in michaelisbuffer, 4 As (3). but after prevention of disulfide bridge formation by collection of the blood into 5mM iodoacetic acid, 10mM N-ethylmaleimide or ImM p-chloromercuriphenylsulphonic acid. Similar elution patterns were obtained with factor VIII purified from cryoprecipitate. Upon reduction the molecular weight of both purified and plasma factor VIII decreased and the lowest molecular weight form with measurable coagulant activity was about 480.000. Incubation at high ionic strength (0.25M CaCl2) resulted in dissociation and the activity was associated with a molecular weight of 50 - 100.000. Gel filtration at pH 6.0 also resuited in retardation of factor VIII on agarose columns. The data suggests that the in vivo molecular weight of factor VIII is 1-2x106 and that alterations are due to changes in the in vitro conditions.
Comparative Isoelectric Focusing Properties of Plasminogen Activators From Porcine and Human Tissues
Authors: Cole Edmond , Snopko Rose
Published: May 2019

Plasminogen activators were isolated from porcine heart, lung and kidney and from human heart and lung. Highly purified porcine heart activator has been shown to have plasminogen activating properties different from human urinary urokinase (UK). The tissue and urinary activators were subjected to isoelectric focusing in granulated dextran gel (Ultradex) over the pH gradient range 3.5 to 11.0, and activator activity was measured by bovine fibrin plate assay. Electrofocusing of Abbott UK revealed isoelectric forms at pI 8.6, 8.8, 9.2, 9.4 and above 9.8, while Serono UK gave forms at 8.2 and 8.6. In contrast, activators from porcine tissues commonly focused at about 7.3, although occasional preparations showed non-symmetrical activity profiles, and focusing of these preparations in a pH gradient 5 to 9 revealed major PI forms at 7.2 and 7.7. Activators from human heart and lung were more closely related to activators from porcine tissues than to UK. Since UK preparations probably contain proteolytically degraded molecules, tissue activators with lower isoelectric points may represent the native molecular forms. Further evidence also indicates that a more catalytically efficient form of tissue activator may be composed of an acceleratory protein and an amidase complexed to a plasminogen activator molecule. (Supported by USPHS NIH Grant HL-15817)
The Variability of β Thromboglobulin and Platelet Factor 4 in Healthy Subjects
Authors: Zahavi J. , Jones N.A.G. , Dubiel M. , Leyton J. , Kakkar V.V.
Published: May 2019

Plasma β TC was measured by radioimmunoassay (RIA)in 202 healthy subjects (age range 12-103); 111 young (mean age 25.2) 34 middle aged (MA) (mean age 55.6) and 57 old (mean age 82.2). Their mean ±1SE plasma β TG levels in ng/ml were 28.3 ± 1.5 (range 3-74), 31.9-2-70 (range 7-65) and 49.99 ± 2.9 (range 14-95) respectively. Plasma βTG level was significantly raised in the old subjects compared to young or MA (p ⩽ 0.0005). Furthermore the ratio of plasma β TG to platelet concentration in whole blood (PC) was higher in the MA subjects compared to the young (p ⩽ 0.009). Plasma platelet factor 4 (PF4) was measured by RIA in 4l healthy subjects, 11 young and 30 old and correlated to plasma βTG. A significant correlation between the 2 proteins was found in the 2 groups (r = 0.8337 in the young and r = 0.0602 in the old subjects), indicating that both proteins are released in-vivo from the same pool and presumably at the same rate. The mean plasma PF4 level in ng/ml was 14.6 (range 6-48) in the young and 18.2 (range 7.7-50) in the old and the ratio of the plasma PF4 to PC was higher in the old subjects (p ⩽ 0.04), These results suggest that in-vivo platelet activation and “release reaction” are increased in old and MA subjects compared to young, presumably due to atherosclerotic vascular changes. This enhanced platelet activity may reflect a pre-thtombotic state.
Hematologic Analysis Following Intravenous Calcium and Sodium Heparin Administration
Authors: Vagher J. P. , Caprini J.A. , Zuckerman L.
Published: May 2019

Twenty normals received in randomized order a dose of 1000 units each of calcium and sodium heparin intravenously seven days apart. The heparin used for preparation of the calcium salt was from the same batch as the sodium salt. Blood tests were obtained pre, 15 and 60 minutes after injection. Values of hematocrit, hemoglobin, RBC, WBC, prothrombin time and platelet adhesive index showed no significant response to the quantity of heparin. Lee White, activated partial thromboplastin time, activated clot time, thrombelastograph and thrombin calcium clot time doubled at 15 minutes. Heparin levels reached 0.4 U/ml (Anti X assay) at 15 minutes while factor X was decreased by 15% for both heparin salts. A differential response to the heparin salts was seen at 15 minutes where the FSP was increased (average difference ± standard error of the difference) by 1.6±. 6 ug/ml, fibrinogen decreased 49 ± 20 mg/ml and plasminogen dropped 2. 3 ± .6 mg/ml for the sodium salt compared to the calcium preparation. With the exception of fibrinogen, these statistically significant differences between the salts disappeared by 60 minutes. At 60 mins ATIII levels were slightly lower for the sodium heparin. Significant changes in C′3 , C′4 and serum calcium were noted with both heparins. These results suggest similar hematologic effects following intravenous sodium or calcium heparin except for an apparent increased fibrinolytic response at 15 minutes when the sodium salt was administered. Due to the small magnitudes of these fibrinolytic changes, these findings may be of questionable clinical significance, but merit further investigation at higher dose levels.
Utility of Indium-111 Labelled Platelet Scans in Assessing the Dynamics of Thrombovascular Lesions. An Experience with 70 Patients
Authors: Davis Harmon H. , Andrew Heaton W. , Siegel Barry A. , Heinrich Joist J. , Welch Michael J. , Sherman Laurence A.
Published: May 2019

In prior reports we have described 111In labelling of platelets and shown their effectiveness in scintigraphic imaging of thromboses and vascular injury in experimental animals and preliminarily in man (Lancet: June: 1185-1187,1978). Our current experience is with 70 patients. In 27 patients with transient ischemic attacks, 111In-platelet scans were positive in the neck for 17/34 carotid artery lesions, evident on angiograms. Scans were negative in 12/14 negative arterial angiograms. 3/6 patients with completed stroke’s had positive scans. 21 of these 33 patients were taking anticoagulant (AC) or antiplatelet drugs. Results were somewhat improved in patients off such drugs. Although mean platelets survival was not shortened, there was a greater SD as compared with normals (6.99±1.79 vs. 7.16±0.44 days). In venous thromboembolism 7/7 positive leg scintigrams were confirmed. Of six patients with pulmonary emboli, the only one not on AC, had 111In-accumulation locally in the suspected site in the lung. A miscellaneous group of thrombin were also detected. At present 111In-platelets cannot replace contrast angiography, but may te an initial diagnostic approach particularly in patients not on AC. More importantly, mIn-platelet accumulation is a physiological test and may be an index of thrombus growth activity and a potential guide to drug therapy, rather than a static anatomic measurement {angiogram).
Factor III Coagulant Antigen - A Measurement Independent of Biological Activity
Authors: Brown J.E. , Carton C.L. , Hougie C.
Published: May 2019

A fluid phase immunoradiometric assay (IRMA) specific for factor VIII coagulant antigen determinants (VIII:CAg) employing a human Fab’ fraction antibody has been used to assay purified bovine factor VIII. Bovine plasma, although 8-10 times as active in the one-stage clotting assay for VIII:C is only 40% as relative to human plasma in the in VIII:CAg and exhibits a parallel dose response curve. Thrombin (0.1 units/ml) enhances purified bovine VIII:C 20-fold or more but shows no effect on VIII:CAgΛ higher thrombin concentration (30 units/ml) destroys 97% of the VIII:C activity but only about 30% of the VIII:CAg. Similarly, both human and bovine serum retain about 70% of the VIII:CAg relative to the respective plasma levels. Trypsin (5 ug/ml1 hr 1 destroyed over 99.5% of the factor VIII:C in a purified bovine factor VIII preparation., but left a similarly high (70-90%) level of VIIl:CAg. EDTA-aged plasma used as an artificial substrate for factor VIII:C contains an undiminished level of VIII:CAg, but heated plasma (56°, 1 hr.) showed parallel losses (over 95%) of both VIII:C and VIII:CAg. The stability of factor VIII:CAg to protease treatment should permit characterization of purified factor VIII in caaes where biological activity is absent
Prenatal Diagnosis of Classic Hemophilia
Authors: Hoyer L.W. , Mahoney M.J. , Lazarchick J. , Firshein S. , Forget B. , Hobbins J.
Published: May 2019

The diagnosis of classic hemophilia at 18-20 weeks of gestation has been accomplished by immunoradiometrie assays f or factor VIII on ffitsl blood obtained by fetoscopy. We have analyzed plasma samples for six male fetuses at risk for severe hemophilia and nine control fetuses for which fetoscopy was carried out to attempt prenatal diagnosis of other genetic disorders. Factor VIII coagulant antigen (VIII:C(Ag)) was measured with a human anti-factor VIII by an imraunoradiometric assay (J. Clin. Invest. 62:1048, 1978), VIII:C(Ag) values were 17-94 u/dl for the control (non-hemophiiic) samples. Factor VIII-related antigen (VIIIR:Ag), measured using rabbit anti-human factor VIII, was 50-155 u/dl in these samples. The ratio of VIII;C(Ag) to VIIIR:Ag was greater than 0.23 in all control plasmas. Three of the fetuses at risk for hemophilia had factor VIII values in the control range. The pregnancies were carried to term and the three boys had normal coagulation values. Three other fetal plasmas had no detectable VIII:C(Ag) and normal content of VIIIR:Ag, The diagnosis of severe hemophilia was confirmed in each case by analysis of abortus blood. This method extends our capacity to provide genetic counseling for families in which there is a risk of severe hemophilia.
Isolation of a Crosslinked Peptide from Hitman Fibrin and Development of a Radioimmunoassay
Authors: Canfield R. , Lahiri B. , D’Alisa R. , Butler V. , Nossel H. , Birken S.
Published: May 2019

Factor XIIIa introduces up to six crossllnklng bonds per molecule of fibrin; the bonds between the γ chains on adjacent fibrin molecules form most rapidly. Since cross linking is essential for normal hemostasis and is likely to be important in tests to detect thrombosis, we have attempted to develop a radioimmunoassay that exhibits specificity for the γ chain crosslinks. The immunogen consisted of a 54 amino acid, crosslinked peptide, isolated from purified human γ-γ chains following CNBr cleavage, gel filtration on Sephadex G-50 and ion-exchange chromatography on SP-Sephadex. Amino acid analysis and Edman degradation through step 24 confirmed the sequence of Chen and Doolittle (Biochemistry 10: i486, 1971), and the two degradation steps that failed to liberate the expected PTH-amino acids matched the reported location of the Gin-Lys crosslinks. Antisera were obtained against this immunogen coupled either to bovine thyroglobulin or bovine serum albumin. All antisera elicited bound immunogen that was covalently coupled to ribonuclease radiolabeled with 125I as a tracer. The unlabeled γ-γ, crosslinked peptide effectively inhibited binding (0.03-0.08 picomoles for 50% inhibition), while with some antisera up to 500 times more of the 27 amino acid γ monomer peptide was required for the same degree of inhibition. Fibrinogen and fragment D also were poor Inhibitors. The results Indicate that it is possible by radioimmunoassay to distinguish the COOH-termlnal region of the γ-γ dlmer from that of uncrosslinked molecules.
Assay of Heparin in Plasma Using a Chromogenic Substrate and It’s Clinical Applications
Authors: Oguma Y. , Seya T. , Murakoshi T. , Yamauchi M. , Nagata H. , Hasegawa H.
Published: May 2019

Heparin (HR) has been used for cht treatment of thrombotic diseases. Many problems, however, still remain to be resolved in HR therapy. This paper deals with : 1) Clinical benefit of the assay of plasma HR by the chromogenic substrate (Kabi Diagnostica). 2) Correlation between plasma HR and APTT.3) Clinical usefulnesa of subcutaneous administration of HR.4) Correlation between the concentration of plasma AT III and the et-feet of HR. The determination of plasma HR by this procedure can bperformed easily, promptly and acculately in the range of 0.1-0.8 IU/ml of therapeutic HR concentration. Therefore, It Is quite effective for the evaluation and control of practical HR therapy. A significant correlation between the. HR concentration and APTT was observed in each case. However, each regression line was quite different. In many cases, the therapeutic HR concentration was continued by every 12 hre subcutaneous administration or HK calcium (250 IU/kg). But this procedure was not effective in a case of shock with DIC. If the patient’s plasma contains at least 501 of the AT III of normal values, there are no problems in HR therapy.
Heparin Levels Using the Chromogenic Substrate S-2222 During Low Dose Heparin and L9W Dose Heparin-Dihydroergotamin Prophylaxis After Gynecological Surgery
Authors: Briel R.C. , Wagner U. , Weselek R. , Kunz S.
Published: May 2019

In 178 patients undergoing hysterectomy, studies on heparin level in plasma (Coatest Kit Kabi) were carried out before and after surgery. Low dose heparin (LDH) and the combination LDH/dihydroergotamin (DHE) were administered 12-hourly (5000 I heparin) beginning 2 hours preop .. The controls were given acenocoumarol postop .. 36 patients were examined 3-hourly on the day of the operation. In 71 patients the I-125-fibrinogen-uptake-test for diagnosis of DVT was performed and blood sampling was carried out from day 0 (preop) daily until day 8. In 15 patients the fibrinoge test was positive. In addition heparin levels were studied daily from day 0 to 8 i 2 groups of 56 and 17 patients. Blood samples were taken 11-12 hrs and 7-8 hrs res after the last injection of LDH or LDH/DHE. On the day of surgery heparin levels had risen 3 hours after the first injection of LDH and LDH/DHE from 0 . 035 to 0.065 IU / ml resp .. After 9 hours in the LDH/DHE group the average values (0.043) were still statistically distinguishable from the original ones. In both groups heparin showe d a significant decrease on the first postoperative day, which was more marke in patients with positive J -fibrinogen-test. On the following days the heparin levels returned to the original values and remained at this level up to day 8. There were no differences between prophylaxis with LDH and the combination of LDH and DHE in the group in which blood samples were taken 7-8 hrs after the last injection there was no accumulation of heparin in either groups.
Prophylaxis of Venous Thromboembolism (VTE)
Authors: Genton E.
Published: May 2019

A major objective In management of VTE is prevention of the Initial or recurrent eplsocases. Patients at high risk of VTE are Identifiable, thus allowing application of prophylactic methods (proph.). Factors contributing to the development of VTE include stasis, vessel wall damage, or activation of platelet or coagulation systems, and proph. methods are available to influence each of these. Success of proph. requires proper selection and application of efficacious method, or combination of methods. Implicit is that consideration be given to the risk as regards; time of onset and duration; its mechanism; its intensity; and the type and Intensity of measure required to inhibit it. About treatment must be known; the proper method of application; the type and frequency of complications and ways to prevent them. Beginning treatment prior to initiation of thrombosis and continuing throughout the period of risk is crucial to success. clinical results indicate that patients at minimal to moderate risk of VTE are protected by pneumatic cuffs, low-dose heparin, dextran, oral anticoagulants, and possibly platelet suppressants, while higher risk requires oral anticoagulants, larger amounts of heparin, or possibly a combination of pneumatic devices with other modalities. “Secondary proph.” to prevent recurrence may require more potent measures than primary proph. Thus, efficacious proph. approaches are available for most patients, If properly chosen and applied.
Platelet Volume Distribution in Leukemia Patients Receiving Chemotherapy
Authors: Wajima T. , Maloney T.R
Published: May 2019

Platelet counts and volume distribution plots were obtained with a Coulter Counter Model ZBI attached to a multichannel particle size discriminator. The total platelet count was determined on the ZBI particle counter and corrected for hematocrit. Platelet Volume Distribution (PVD) was measured serially in sixteen patients (15 with acute myelocytic leukemia and one with chronic myelocytic leukemia in blast crisis) and correlated with clinical status. In normal controls the mode (peak channel) of PVD was between 14-20 (3.2-5.8μ3). In leukemias prior to treatment or in relapse the mode was shifted to the left (below channel 10) and most of the platelets were small (less than 3μ3). In patients achieving remission the mode and median of PVD shifted to the right (large platelets during recovery phase. In patients who failed to achieve remission the mode and median of PVD did not shift to the right, even though the platelet count rose to the normal range. Platelets from remission-relapse showed shift to the right in remission, and left shift pattern during relapse. In the patient with blast crisis who developed to marrow aplasia PVD remained left shifted. In relapse cases impaired platelet production in the marrow may release platelets of small volume. PVD can be used to monitor response to chemotheraphy.
Influence of Anticoagulant? Antiaggregant and Antifibrinolytic Drugs on the Walker-256-Carcinosarcoma of Rats
Authors: Köpetering H. , Hampe R. , Ludwig B. , Ganaainski J. , Ruakowaki H.
Published: May 2019

In order to find out, if there ia en influence of blood coagulation factors on tumura we determinad the effects of various anticoagulant drugs (Phenprocoumon, Arvinr , Acet.-salicyl.-acid) and the antifibrinolytics (EACA) on the development, metastasia formation and the ratxa of survival of the walker-256-tumour. Tumorcells were the subcutanously injected upon the back of the tail of female Whistar rats in a total number of 850. We tested the effect of Marcoumar by weekly controls of Quick’s test of every single rat. 52 % of the control survived, while up to 96 % of the rats which were treated with different doses of Marcoumar survived. (n=23 in each group). In another series only 25 % of control-anmals sunaved, but 64 % of the rats, which were treated with EACA and with ASA, and 33 % of the rats which were treated with Arvin, survived (n= 2-7 ,in every group) The spread of the tumour in Arvin-treated rats was most invasible. The effects of clotting mechanism on the four stages in the spreding tumour are being discussed.
The Effect of Acetylsalicylic Acid on the Proliferation of Cultivated Aortic Wall Cells
Authors: Mey J. , Schulte H. , Hauss H.
Published: May 2019

In former studies we showed that risk factors induce an acceleration of the proliferation of the arterial wall cells. Furthermore we examined the influence of acetylsalicylic acid (ASA) upon the proliferation of arterial wall cells of normal animals and of animals which had been damaged by risk factors. We received the following results:

1. ASA given to the cell culture inhibits the proliferation of aortic smooth muscle cells (ASMC), endothelial cells and adventitial cells of minipigs,

2. ASA given to the culture of ASMC of rats whi ch had been damaged by arterial hypertension, by staphylolysine or by atherogenic diet reduces their increased proliferation rate nearLy to normaL.

3. ASA-treatment of rats which had been damaged by injection of staphylolysine reduces the increased proliferation rate of ASMC of these rats nearly to normal.

4. It is remarkab le that the induced activation (by risk factors) and the induced inhi - bition (by ASA) of the cell growth persisted in the subcultures.

This behaviour is explained by the assumption that the arterial wall has different cell clones, characterized by different proliferation rates: the faster proliferating clones’ are activated by risk factors and the slowlier proliferating clones by ASA. These resuLts are relevant in prevention and therapy of arteriosclerosis.
Effect of Aspirin and of Indomethacin on Thrombin-Induced Changes in Platelet Transmembrane Potentials and pH Gradients
Authors: Laband A. M. , Simons E.R.
Published: May 2019

We have previously shown that α-thrombin induces a dose-dependent, depolarizatIon of the platelet membrane as well as an identically dose-dependent increase in the transmembrane pH gradient and in the secretion of serotonin. The effect of the nonsteroidal antiinflammatory drugs acetylsalicylic acid and indomethacin on these platelet parameters has now been investigated since several researchers have reported some decrease in serotonin secretion and/or in platelet aggregation induced by low concentrations of thrombin In the presence of these drugs. We report here that 10-3M acetylsalicylic acid alone does depolarize the platelet membrane, but that the net extent of depolarization attributable to subsequent addition of up to 0.05 U/ml of α-thrombin remains essentially unperturbed, as does the platelet transmembrane pH gradient and the serotonin secretion. Inhibition (up to 252) is occasionally detected at very low concentration of thrombin (~0.005 U/ml) 10-4M indomethacin elicits similar responses - including the depolarization - even though it is not capable of acetylatlng a membrane protein. These results support the reputed lack of dependence of thrombln-induced platelet response on the pathways (e.g. prostaglandin synthesis) known to be affected by these non-steroidal antiinflammatory agents. (Supported, In part, by NIH grant #HL015335 and by the King Foundation).
Histology of Rat Arterial Thrombosis
Authors: Wester J. , Mensvoort van F.W.J. , Meuleman D.G. , Delft van A.M.L.
Published: May 2019

In our arterial thrombosis model in male Wlstar rats repeated intimal injury was induced by indwelling cannulas in the aortas during periods ranging from 1 to 28 days. At the end of the cannulation periods the aortas have been processed for light microscopical observation on paraffin sections.

The cannulas caused severe intimal damage to the vessels with loss of the majority of the endothelial cella. Some medial damage was also observed, Several large thrombi, composed of platelet aggregates and polymerized fibrin, developed on the intima and around the cannula. In these thrombi cellular proliferation and connective tissue synthesis occurred and the thrombi became gradually organized. On the surface of the organized thrombi fresh platelet+fibrin thrombi were always present.

In conclusion in rat aortas with an indwelling cannula platelet aggregation and fibrin formation are apparently continuously going on , which is in agreement with studies on blood platelet kinetics in the same model (D.G. Meuleman, Thromb. Dfkthes. Haemorrh. 34 (1975) 586). Furthermore, the cell proliferation processes induced during organization of the thrombi may be of relevance for the pathology of atherothrombotic processes.
Recurrent Ventral Curvature with Long-Term Follow-up after Transverse Preputial Island Urethroplasty
Authors: Wang Chaoxu , Song Hongcheng , Zhang Weiping
Published: May 2019

Objective This study was aimed to assess the long-term outcomes of recurrent ventral curvature (VC) repaired in early childhood after transverse preputial island flap urethroplasty.

Materials and Methods A total of 378 patients underwent transverse preputial island flap urethroplasty between January 2000 and January 2005 at our hospital. Of these patients, 43 were invited for assessment of VC after puberty. The age at surgery, types of hypospadias, degrees of recurrent VC, and surgical procedures were analyzed.

Results The study included 43 patients with a mean age of 15.9 years (range, 12.3–17.9). The average age at the time of primary surgery was 1.9 years (range, 1.2–3.6). Of 43 patients, recurrent VC was identified in 14 (32.5%). In total, 8 out of 16 patients (50.0%) were successfully treated by urethral plate transection with skin release during the primary surgery, and 6 out of 27 patients (28.6%) underwent additional dorsal plication (DP; p = 0.093). Severe recurrent VC was observed in four, moderate curvature was observed in four, and mild curvature was observed in six cases. Recurrent VC was present more often in patients with complications (34.6 vs. 24.1%, p = 0.331), especially in severe urethral strictures that required open surgical reconstruction (p = 0.039).

Conclusion Although the patients in our study represent only a small portion of the overall hypospadias population, it is notable that 32.5% of these patients showed recurrent VC, including 28.6% of patients with transection plus DP. We suggest long-term follow-up of hypospadias at least during adolescence or even into adulthood.
Ponatinib Tyrosine Kinase Inhibitor Induces a Thromboinflammatory Response
Authors: Hamadi Abdullah , Grigg Andrew P. , Dobie Gasim , Burbury Kate L. , Schwarer Anthony P. , Kwa Faith A. , Jackson Denise E.
Published: May 2019

Both nilotinib, a second-generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukaemia (CML), and ponatinib, a third-generation TKI used in CML and Philadelphia positive acute lymphocytic leukaemia, have been associated with an increase in arterial occlusive events, in contrast to other TKIs such as imatinib and dasatinib. We have previously demonstrated evidence of a pro-thrombotic state associated with nilotinib, using microvascular and arterial thrombosis C57BL/6 mouse models. In this study, we examined ponatinib and determined if a calcium channel blocker could ameliorate the pro-thrombotic and pro-inflammatory phenotypes. In vitro treatment of whole human or murine blood with ponatinib and nilotinib increased platelet activation, adhesion and three-dimensional thrombi over time compared with vehicle control or other TKIs. Treatment of wild-type C57BL/6 mice with ponatinib and nilotinib but not imatinib, dasatinib or vehicle control for 4 hours significantly increased thrombus growth following ex vivo perfusion on collagen and FeCl3-induced vascular injury of mesenteric arterioles and carotid artery in vivo and increased plasma levels of soluble P-selectin, tumour necrosis factor-α, interleukin-6, interferon-γ and thromboxane B2 (TxB2). Ponatinib-treated CML patients had increased ex vivo thrombus formation and a pro-inflammatory phenotype compared with healthy controls. Pre-treatment of mice with the calcium channel antagonist, diltiazem, prior to ponatinib or nilotinib reversed the pro-thrombotic phenotype and the increase in cytokine levels. These observations suggest that the pro-thrombotic effect of nilotinib and ponatinib is partially related to calcium channel activation and TxA2 generation and this should be explored clinically as a mechanism to prevent vascular events.
Loading with Oral P2Y12 Receptor Inhibitors: To Crush or Not to Crush?
Authors: Alexopoulos Dimitrios , Dragasis Stylianos , Kafkas Nikolaos
Published: May 2019

Oral P2Y12 receptor inhibitors represent a mainstay treatment in patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. In the setting of ST-elevation myocardial infarction, when early platelet inhibition is highly desirable, the onset of action of oral P2Y12 receptor inhibitors is, however, delayed, likely due to delayed drug absorption. Crushing the tablets, which are to be used for patient loading with an oral P2Y12 receptor inhibitor, has been shown to provide earlier platelet inhibition than standard, integral tablets administration. Chewed ticagrelor tablets may also result in a similar effect. Such findings should be interpreted with caution, mainly due to the small number of patients enrolled and the nature (pharmacodynamic/pharmacokinetic) of the respective studies. Furthermore, in patients with out-of-hospital cardiac arrest, who remain comatose, crushing tablets is commonly applied in clinical practice for platelet P2Y12 receptor inhibition. In this review, we focus on current evidence regarding the role of crushed P2Y12 receptor inhibitor pills, analyzing clinical scenarios where most of the promise exists along with future expectations from this type of formulation. Large randomized studies are needed to draw firm conclusions regarding the clinical benefit of ‘crushing’ over the usual ‘not-crushing’ practice.
Development and Validation of an Ischemic and Bleeding Risk Evaluation Tool in East Asian Patients Receiving Percutaneous Coronary Intervention
Authors: Kang Jeehoon , Park Kyung Woo , Ki You-Jeong , Park Jiesuck , Rhee Taemin , Kim Chee-Hoon , Han Jung-Kyu , Yang Han-Mo , Kang Hyun-Jae , Koo Bon-Kwon , Nakamura Masato , Hamasaki Toshimitsu , Yokoi Hiroyoshi , Cohen David , Kim Hyo-Soo
Published: May 2019

Background The ischemic/bleeding risk of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) is still uncertain. We sought to develop a tool to predict ischemic and bleeding events in East Asians receiving 2nd generation drug-eluting stents (DESs) PCI.

Methods A pooled cohort of 13,172 East Asian patients receiving PCI with 2nd generation DES (the Grand DES cohort) was analyzed to develop a scoring system. A net score was calculated by subtracting the bleeding score from the ischemic score. External validation was performed in the HOST-ASSURE and NIPPON trials.

Results Among the total population, ischemic and bleeding events occurred in 195 patients (1.5%) and 166 patients (1.3%), respectively. The score to predict ischemic events included previous myocardial infarction (MI) or PCI, presentation as acute MI, anemia, stent diameter < 3 mm, and total stent length of ≥30 mm, while that for bleeding events included older age, low creatinine clearance, and anemia. C-statistics of the ischemic and bleeding model was 0.708 and 0.665, respectively. Patients with a net score of ≥1 had a higher ischemic risk compared with bleeding risk, and patients with a net score of ≤–1 had a higher bleeding risk compared with ischemic risk. The validation cohort showed a C-statistic of 0.647 for ischemic events and 0.633 for bleeding events.

Conclusion We developed a tool to predict ischemic and bleeding events in East Asian patients received PCI with 2nd generation DES. This system can be used to assess clinical event risks, and to determine the adequate duration of DAPT in East Asians.
Multiscale fractional order generalized information of financial time series based on similarity distribution entropy
Authors: Xu Meng , Shang Pengjian , Qi Yue , Zhang Sheng
Published: May 2019

This paper addresses a novel multiscale fractional order distribution entropy based on a similarity matrix (MFS-DistEn) approach to quantify the information of time series on multiple time scales. It improves the metric method of distance matrix in the original DistEn algorithm and further defines the similarity degree between each vector so that we could measure the probability density distribution more accurately. Besides, the multiscale distribution entropy based on similarity matrix combines the advantages of both the multiscale analysis and DistEn and is able to identify dynamical and scale-dependent information. Inspired by the properties of Fractional Calculus, we select the MFS-DistEn notation as the main indicator to present the relevant properties. The characteristics of the generalized MFS-DistEn are tested in both simulated nonlinear signals generated by the autoregressive fractionally integrated moving-average process, logistic map, and real world data series. The results demonstrate the superior performance of the new algorithm and reveal that tuning the fractional order allows a high sensitivity to the signal evolution, which is useful in describing the dynamics of complex systems. The improved similarity DistEn still has relatively lower sensitivity to the predetermined parameters and decreases with an increase of scale.
Efficient implementations of analytic energy gradient for mixed-reference spin-flip time-dependent density functional theory (MRSF-TDDFT)
Authors: Lee Seunghoon , Kim Emma Eunji , Nakata Hiroya , Lee Sangyoub , Choi Cheol Ho
Published: May 2019

Analytic energy gradients of individual singlet and triplet states with respect to nuclear coordinates are derived and implemented for the collinear mixed-reference spin-flip time-dependent density functional theory (MRSF-TDDFT), which eliminates the problematic spin-contamination of SF-TDDFT. Dimensional-transformation matrices for the singlet and triplet response spaces are introduced, simplifying the subsequent derivations. These matrices enable the general forms of MRSF-TDDFT equations to be similar to those of SF-TDDFT, suggesting that the computational overhead of singlet or triplet states for MRSF-TDDFT is nearly identical to that of SF-TDDFT. In test calculations, the new MRSF-TDDFT yields quite different optimized structures and energies as compared to SF-TDDFT. These differences turned out to mainly come from the spin-contamination of SF-TDDFT, which are largely cured by MRSF-TDDFT. In addition, it was demonstrated that the clear separation of singlet states from triplets dramatically simplifies the location of minimum energy conical intersection. As a result, it is clear that the MRSF-TDDFT has advantages over SF-TDDFT in terms of both accuracy and practicality. Therefore, it can be a preferred method, which is readily applied to other “black-box” type applications, such as the minimum-energy optimization, reaction path following, and molecular dynamics simulations.
Temperature and size dependent surface energy of metallic nano-materials
Authors: Zhang Xuyao , Li Weiguo , Kou Haibo , Shao Jiaxing , Deng Yong , Zhang Xianhe , Ma Jianzuo , Li Ying , Zhang Xin
Published: May 2019

In this study, we report a theoretical model for the temperature and size dependent surface energy of metallic nanomaterials. The model is verified by making a comparison with the available simulation and experimental data. Reasonable agreement has been observed between these results. This study reveals that the decrease of surface energy at high temperatures is caused by cohesive energy weakening and bond expansion. With the same nanomaterial size, the sequence of size effects on the surface energy from weak to strong is thin films, nanowires, and nanoparticles. In particular, this work can provide a theoretical basis for the prediction of size dependent surface energy of metallic nanomaterials at different temperatures, which can help in the understanding of the mechanical and thermodynamic properties of metal surfaces.
Polarization-dependent local conductivity and activation energy in KTiOPO4
Authors: Lindgren Gustav , Kalinin Sergei V. , Vasudevan Rama K. , Canalias Carlota
Published: May 2019

We study the local conductivity properties of KTiOPO4 using conductive atomic force microscopy in ultrahigh vacuum (UHV). We show that domains with opposite orientations have different conductivity values. We investigate the temperature dependence of the local conductivity and report a difference in the activation energy of 25% between different domains. Furthermore, we show that the local conductivity increases with the number of biased-scans. Finally, it is found that the domain wall conductivity previously observed at ambient conditions vanishes in UHV. Our results are discussed in terms of the screening effects and surface conditions.
Experimental investigation of drag characteristics of ventilated supercavitating vehicles with different body shapes
Authors: Jiang Yunhua , Jeong So-Won , Ahn Byoung-Kwon , Kim Hyoung-Tae , Jung Young-Rae
Published: May 2019

This paper presents an experimental investigation on drag characteristics and flow physics of ventilated supercavitating objects with different body shapes. The test model consists of a disk-type cavitator with two different forebodies (slender and blunt shape) and three different rear bodies (flat, shrinkage, and expanded shape). Experiments are conducted in a cavitation tunnel of the Chungnam National University. First, the drag forces acting on different body-combinations in fully wetted conditions are measured. The results show that the drag coefficients strongly depend on the body shapes. It explains in detail through particle image velocimetry measurements. Second, the drag characteristics are systematically examined over a broad range of ventilation rates. The formation and the drag characteristics of the foamy and clear supercavity flow are investigated for different Froude number conditions. The results reveal that the drag of the blunt forebody is smaller than that of the slender fore body in foamy cavity conditions. In ventilated supercavity conditions, supercavity shapes according to Froude numbers are examined and corresponding effects on drag characteristics are analyzed. The results show that the drag coefficients of the models with the expanded rear body are larger than that of models with the flat and shrinkage rear bodies until the cavity covers the body.