bluuebunny/crossref_metadata_2025_split huggingface dataset:
Secondary Prevention In Coronary Heart Disease - Beta- Blockade, Surgery, And Control Of Primary Risk Factors
Authors: Julian D G 
Published: July 2018

Numerous factors are involved in the progression of coronary atherosclerosis and the development of its complications and it is probable that different sub-sets of patients will respond best to different therapies. Combination therapies are probably most appropriate for some patients.Randomised studies have been completed with a number of beta-blockers after infarction including alprenolol, practolol, propranolol, oxprenolol and timolol. Although it is questionable if benefits are conferred on the total population treated, it seems probable that one or more of these drugs diminish the risk of death (especially sudden death) in patients who start the drug in the convalescent phase following infarction. They probably do not prolong in those with a good prognosis nor in those whose left ventricular function is severely compromised.The European Coronary Artery Surgery Trial demonstrated, in a randomised study of a highly significant improvement in prognosis in men under 65 with angina who had undergone coronary artery bypass grafting for three vessel coronary disease. The prognostic value of surgery after myocardial infarction remains to be established.No satisfactory randomised controlled trials have established the prognostic value of controlling hyperlipidaemia or hypertension in patients with coronary heart disease, nor have they proven the effectiveness of exercise programmes or the stopping of smoking. However, the cessation of smoking after myocardial infarction is almost certainly beneficial.
The Mechanism Of Inhibition Of Fibrin Assembly By Fragment D
Authors: Williams J , Hantgan R , Knoll D , McDonagh J , Hermans J 
Published: July 2018

Measurements of clot rigidity and fiber thickness indicate that fragment D is a potent inhibitor of fibrin assembly. At physiological ionic strength, D concentrations in excess of 2 moles D/mole fibrinogen lead to a large decrease in clot rigidity and fiber thickness. Above 14 moles D/mole fibrinogen, gelation is inhibited. The molecular weight and radius of gyration of the fibers, determined by light scattering, confirm that short oligomers result, composed of 3 fibrin monomer molecules at 120 moles D/mole fibrinogen and 9 monomers at 14.4 moles D/mole fibrinogen. If D is added to a solution of long protofibrils, no inhibition is observed. Apparently the polymerization of monomers to protofibrils is blocked by D, but not lateral association.Inhibition of protofibril growth was studied in 0.5 M NaCl, pH 7.4, where lateral association is limited by the ionic strength. Stopped-flow light scattering data show a small decrease in the initial rate of polymerization and a slightly prolonged t½ ; the final intensity is less than that for a solution of long protofibrils. This result suggests that fragment D binds to the growing protofibrils with a small effect on the initial polymerization rate, but exerts its inhibitory effect by limiting the later stages of protofibril growth. Measurements of the length of the inhibited protofibrils, calculated from diffusion coefficients obtained by dynamic light scattering, confirm that polymers containing as few as 15 monomers have been obtained. Negative stain electron microscopy also shows a clear limitation of polymer growth under these conditions.Fragment D interferes with fibrin formation by directly blocking the first assembly step: bimolecular polymerization of activated fibrin monomer molecules to form protofibrils. Fragment D apparently occupies a site normally occupied by a fibrin monomer molecule, thus forming a dead-end complex which cannot undergo further assembly.
Binding Of Plasminogen And Vascular Plasminogen Activator To Fibrin And The Fibrin Alpha-Chain
Authors: Lloyd D A , Cederholm-William S A , Sharp A A 
Published: July 2018

Investigation of the mechanism of plasminogen activation in the presence of fibrin has shown that fibrin acts as a regulatory and catalytic surface for both the reaction between activator and fibrin and between activator and plasminogen. Plasminogen (mol wt 84,000) and vascular activator form stable complexes with fibrin. We have carried out studies to determine the location of these binding sites in the fibrin structure.METHODS: Human plasminogen (mol wt 84,000) was iodinated with 125-I and vascular plasminogen activator was partially purified from venous occlusion plasma by chromatography on lysine-Sepharose. Sepharose coupled fibrinogen, fibrin monomer, fragments E and D and isolated fibrin alpha chain were prepared and the interactions between plasminogen and vascular activator studied.RESULTS: Plasminogen (mol wt 84,000), plasmin and vascular activator each showed affinity for Sepharosebound fibrin monomer and fibrin alpha chain. In addition the affinity of the vascular activator for fibrinogen and fragment E was increased by treatment with thrombin.CONCLUSION: The alpha chain of fibrin brings together plasminogen activator and plasminogen in such a way as to produce plasminogen activation resulting in the early degradation steps of fibrin.
Monoclonal Antibodies Against Factor Viii Procoagulant Activity
Authors: Sultan Y , Sola B , Avner Ph , Maisonneuve P , Jeanneau C 
Published: July 2018

Monoclonal antibodies against the factor VIII/Von Willebrand molecule were obtained using the hybridoma technique. Splenocytes of mice immunized with a commercial preparation of high purity antihemophilic factor were fiised with a non secreting myeloma cell line SP 2/0. Hybrid cells were cloned twice by limiting dilution. Among 8 antibodies reacting with purified F.VIII/VW factor in a solid phase radio immunoassay, two of them showed an inhibitory activity against the procoagulant activity of the antihemophilic factor. This inhibitory activity was not detected in culture supernatants. Presumably in corelation with subtances of the culture medium interfering with the coagulation process and masking the neutralizing activity. However the anti VIIIc activity was demonstrated in the ascitic fluid obtained from mice injected with hybridoma cells.The specific anti VIIIc neutralizing activity of F4 115 monoclonal antibody is dependent on Ig concentration, time of incubation, temperature and Ph. In contrast with most of anti VIIIc inhibitors occuring in multitransfured hemophiliac, neutralization was more rapid and highier at 4° than 37°C. This neutralizing activity is absorbed by normal plasma or purified F.VIII preparation, however it is not absorbed by plasmas of a limited number of severe hemophilic and severe Von Willebrand patients. The study of a larger patients population is in progress.The second antibody F4 415 showed different inhibitory properties. Inhibition of the procoagulant activity is independent of incubation time butdependent on temperature and similarly more active at 4°C.These monoclonal antibodies provide new tools to investigate the procoagulant piece of the F.VIII molecule
A Simplified Immunoradioactive Assay For Human Factor VIII Coagulation Antigen
Authors: Thomas K B , Howard M A , Koutts J , Firkin B G 
Published: July 2018

Normal human factor VIII (FVIII) is a high molecular weight glycoprotein expressing two measurable biological activities, FVIII procoagulant activity (VIII:C) and von Willebrand factor activity (vWf). The corresponding antigenic moieties are referred to respectively as FVIII coagulation antigen (VIII:CAg) and FVIII related antigen (VIII: RAg). Since VIII:C is extremely labile measurement of VIII: CAg is of importance for pre-natal diagnosis of haemophilia where VIII:C is reduced and von Willebrand’s disease (vWd) where all measurable parameters of FVIII are reduced.Current immunoradiometric assays for VIII:CAg depend on both the availability of high titre human antibodies directed against VIII:C and the possibility of preparing highly specific 125I-IgG from human antiserumWe have developed a solid phase immunoradiometric assay for VIII:CAg. FVIII in a test sample binds to human anti- VIII:C IgG immobilised on the surface of a polystyrene tube. The bound FVIII is detected using rabbit 125I-anti human FVIII-IgG. The standard curve was linear for dilutions of normal pooled plasma (NPP) of 1/5 to 1/500. The lower limit of the assay was 0.002U/ml of NPP. Using this assay the concentration of VIII:CAg correlated well with the VIII:C levels in the plasma from normal individuals (r=0.84, n=15). Homozygote vWd patients had undetectable levels of VIII:CAg, VIII:C, VIII:RAg or vWf activities. Patients with haemophilia A with less than O.OlU/ml VIII:C could be divided into two groups on the basis of the VIII:CAg assay, CRM and CRMf. Markedly reduced levels of VIII:CAg were detected in serum.The advantage of this assay over the previously available assays for VIII:CAg are that smaller volumes of high titre human anti VIII IgG are required and the time consuming step of preparing 125I-human anti VIII-IgG is eliminated. The rabbit 125I-IgG specific for human VIII is the same as used in routine immunoradiometric assays for FVIII:RAg
Correlation Of Haematological Parameters In Deep Vein Thrombosis
Authors: Donaldson D R , Crow M J , Davies G A , Rajah S M , Watson D A 
Published: July 2018

We have evaluated the response of certain haema to logical parameters in patients undergoing elective thoracotomy for pulmonary and oesophageal disease. These patients are part of a continuing DVT study in which prophylaxis is randomised to either i) Heparin 5000 iu 8 hourly s.c. (Group A) or ii) Heparin 2500 iu + Dihydroergotamine (DHE) 0.5 mg 8 hourly s.c. (Group B). Prophylaxis was commenced at the time of premedication and continued for 10 days. DVT was diagnosed by I125 Fibrinogen uptake test, with confirmatory venography if positive. The haema to logical parameters investigated were Antithrombin III (AT III), Euglobulin Clot Lysis Time (ECLT), plasma $-Thromboglobulin (β-Tg), platelet Factor 4 (PF4) and Heparin level. All investigations were performed pre-op. and day 6 post-op. (AT III and ECLT were also measured on day 3).A total of 50 patients have completed the study to date with 25 patients in each treatment group. Eleven patients have developed DVT - 5 in Group A and 6 in Group B. There was no significant difference between the pre-op. values in either group. The post-op. AT III values of patients developing DVT were lower than the two treatment groups. ECLT was significantly prolonged in the two treatment groups post-op. compared to the pre-op. values (p < 0.05 (A) and p < 0.01 (B)), but was not prolonged post-op. in the patients who developed DVT. Plasma β-Tg and PF4 were raised pre-op. with further increases post-op. in all groups. Plasma Heparin concentrations in Group B (0.122 iu/ml) were lower than for Group A (0.182 iu/ml) and the DVT group (0.176 iu/ml).These findings indicate that none of the haematological investigations were able to delineate ‘at risk’ patients. However the development of DVT was significantly correlated (p < 0.05) with the post-op. AT III and ECLT. The use of DHE in the dose cited above did not apparently inhibit the platelet release reaction
Subcutaneous Versus Intravenous Administration Of Heparin In The Treatment Of Acute Venous Thrombosis
Authors: Johnsson H , Andersson G , Holmgren H , Nilsson E , Ljungberg B , Wilhelmsson S , Zetterquist S 
Published: July 2018

Ninety-five patients with acute deep venous thrombosis (DVT) in the leg were randomly allocated to either two daily subcutaneous injections (S.C.) or to continuous intravenous infusion (I.V.) of heparin for at least five days. Before entering the trial the existence of a thrombus was confirmed with phlebography and in about two thirds pletysmography and thermography (DevethermR, infrared temperature scanning) was performed at well. Immediately after heparin treatment phlebography was repeated in one third of the patients and in the others a new pletysmography and thermography was performed. The non-invasive procedures are then repeated again after 1, 3, 6 and 12 months (and once a year). In most patients the thrombi were localized in the popliteal-femoral veins and all patients had local symptoms. The amount of heparin required to maintain a prolongation of the APT-time 1 1/2 to 3 1/2 times was the same in both groups and the daily dosages varied between 25.000 and 50.000 units. In two patients, one of whom on salicylates the S.C. administration was stopped due to local haematoma. Major bleeding complications occurred in totally 4 patients, two on heparin I.V. By phlebography a partial thrombolysis was registered in about 25% of the patients after heparin treatment independent of administration route, and in no patient the thrombus progressed in size. By pletysmography and thermography an improvement was demonstrated in about one third immediately after heparin treatment and these improvements were not less pronounced in the S.C. group. Only one major, non-fatal pulmonary embolus (heparin I.V.) occurred.Thus, S.C. administration of heparin seems to be as efficient and safe as administration of heparin I.V. in the treatment of patients with acute DVT.
The Role Of Calcium In Platelet Microtubule Assembly- Disassembly
Authors: Kikuchi M , Ikeda Y , Handa M , Matsuda S , Muraki H , Toyama K , Yamamoto M , Watanabe K , Ando Y 
Published: July 2018

Microtubules exist in a dynamic equilibrium between polymerized and depolymerized forms in human platelets, playing a major role to maintain the discoid shape of platelets. It has been previously shown that the interaction of aggregating agents with platelets leads to a rapid but transient disassembly of microtubules. ( Steiner and Ikeda, J.Clin. Invest. 63:443,1979 ) In this paper, the role of calcium in the equilibrium between assembled and disassembled microtubules was investigated. The respective pools of soluble and polymerized tubulin were “frozen” by addition of a glycerol-dimethyl sulfoxide-containing medium to platelet rich plasma, preincubated with 2 µM A23187 for various time intervals. The two pools of tubulin were estimated by measuring the colchicine binding activities of total and polymerized tubulin according to the method of Wilson.Resting platelets were found to contain 56.2 ± 2.7 µg tubulin per 109 platelets, of which 56.7 % was in polymerized form. Addition of A23187 to platelet rich plasma produced a transient decrease in the pool of polymerized tubulin within 30 sec., followed by a return to base-line values within 2 min.. TMB-8, a known intracellular calcium antagonist, abolished this transient decrease in polymerized tubulin induced by A23187 in a concentration dependent manner, while indomethacin or acetylsalycylic acid did not.These findings may indicate the important role of intracellular calcium in microtubule assembly-disassembly.
Platelet Interaction With Basement Membrane Proteins
Authors: Balleisen L , Rauterberg J , Risteli J , Rohde H , Timpl R 
Published: July 2018

Basement membranes consist mainly of two components: non-fibrillar type IV collagen and the non-collagenous glycoprotein laminin (m.w.900.000) which is capable to interact with cell surfaces. The collagenous protein was studied in form of two major fragments comprising together the total mass of the molecule. 7-S collagen which resembles the crosslinking domain of type IV collagen was isolated after collagenase digestion and consisted of four triple helices aligned in a parallel fasion (m.w.360.000). The major triple helical domain of type IV collagen (m.w.450.000) could be obtained by a acid extraction but had lost most of the 7-S domain.Interaction with platelets was examined in aggregation, cell spreading and fibrin clot retraction assays including the determination of malondialdehyde formation. 7-S collagen was the most active component in all three assays. Aggregation was induced by as little as 25 µg/ml and was confirmed by electronmicroscopy. When compared to interstitial collagens, however, 10-20 fold higher amounts of 7-S collagen are required to produce the same effects. Acid extracted type IV collagen possessed virtually no activity. Laminin did not aggregate platelets but promoted strongly their attachment and spreading on a plastic substrate. Thus both basement membrane proteins apparently interact with platelets in different ways via distinct domains of the molecules.
The Effects Of Ticlopidine Hydrochloride On Bleeding Time And Platelet Function In Man
Authors: Ellis D J , Roe R L , Bruno J J , Cranston B J , McSpadden M M 
Published: July 2018

Ticlopidine hydrochloride (T) was given to healthy male and female subjects in doses ranging from 125-500 mg/day for up to 8 days to study the rate of onset and offset of action and to define the optimal dosage for inhibition of platelet function tests.Template bleeding time (BT) using the Simplate® device and ex vivo platelet aggregation were done every day from the start of dosing through the post-dosing period until platelet function had returned to baseline.Achievement of maximal bleeding time prolongation and maximal inhibition of platelet aggregation induced by ADP, collagen, and epinephrine required 3-5 days of dosing. Rate of onset was higher at higher drug doses. Post-dose return to baseline took 4-8 days.BT prolongation was dose-dependent with 2.0 × prolongation at 125 mg/d, 2.5 × at 250 mg/d, 3.4 × at 375 mg/d and 4.7 × at 500 mg/d.At steady state, ADP aggregation (1st and 2nd phase) was inhibited by 50-60%, epinephrine aggregation was inhibited by 40-80%, and collagen aggregation was inhibited by 5580%. Inhibition was dose-dependent. Arachidonic acid (1 × 10-3M) induced aggregation was not inhibited. ATP release during collagen aggregation was inhibited by 20-50% and malondialdehyde production induced by thrombin was inhibited 20-55%, both in a dose-related fashion.Ticlopidine hydrochloride is a potent inhibitor of platelet function with a broad spectrum of activity and a delayed onset and offset of action. The drug is neither a prostaglandin synthetase nor a phosphodiesterase inhibitor and appears to act by a novel mechanism.
Substrate Specificity Of Bovine Thrombin And Factor Xa Toward Peptide Para-Nitroanilide Substrates
Authors: Lottenberq Richard , Jackson Craig M 
Published: July 2018

Kinetic parameters were obtained for commercially available chromogenic substrates with bovine alpha thrombin and Factor Xa. Enzyme concentrations were determined by active site titration using p-nitrophenyl- p-guanidinobenzoate. Initial rate studies were performed at 25 deg. C at pH 7.8. Non-linear least squares procedures were utilized to determine Michaelis constants (Km’s) and catalytic constants (kcat’s) for an assumed simple Michaelis-Menten model for the hydrolytic reaction. For several substrates with very high Km’s, the second order rate constant, kcat/Km, was the only parameter that could be accurately obtained, although estimates for the two kinetic parameters could be calculated from linearized forms of the Michaelis-Menten equation. Twenty peptide-anilide substrates were evaluated with thrombin. For those substrates for which completely valid parameters could be determined, Km estimates ranged from 0.43 to 360 uM; kcat values varied from 0.060 to 130/second. The kcat/Km values ranged from 500 to 93,000,000 liter/mole/second. Twenty-one peptide-anilide substrates were evaluated with Factor Xa. The Km range was 35 to 1300 uM; kcat range 0.071 to 260/second. The kcat/Km values ranged from 15 to 1,900,000 liter/mole/second. Effects of pH, ionic strength, temperature and concentration of polyethylene glycol in the reaction mixture were also determined.Inferences regarding the substrate specificity of thrombin and Factor Xa that can be drawn from these data will be discussed.
Kinetic Description Of Conversion Of Bovine Prethrombin 2 To Thrombin
Authors: Carlisle Thomas L , Jackson Craig M 
Published: July 2018

Bovine Factor Xa slowly converts Prethrombin 1 to thrombin plus Fragment 2. Inclusion of Ca2+ increased the rates of Prethrombin 1 consumption, Prethrombin 2 production and thrombin formation detected by SDS polyacrylamide gel electrophoresis or by thrombin assay. Ca2+ also increased the rate of thrombin formation from equimolar mixtures of Prethrombin 2 and Fragment 2 (Prethrombin 2/Fragment 2) by approximately 1.8 fold. Calcium ion thus increases the rate of both proteolyses required to generate thrombin from Prethrombin 1. Studies using Factor Xa (des light chain residues 1-44) indicated that this effect of Ca2+ required the region of Factor Xa containing gamma-carboxyglutamic acid.Factor Va markedly lowered the apparent Km of Factor Xa for Prethrombin 2/Fragment 2, with decreases greater than 20 fold observed under some conditions. The apparent maximum velocity also increased by up to 50 fold. The extent of increase was greater at higher concentrations of Factor Va, and was about 6 fold greater in the presence of Ca2+ than in its absence. Factor Va binding to Factor Xa (forming XaVa with enhanced substrate binding and/or catalytic efficiency), and Factor Va binding to Prethrombin 2/Fragment 2 (forming a substrate more readily bound and/or cleaved) must be considered among the possible explanations for these effects. Previous qualitative observations suggest that these effects of Factor Va on activation of Prethrombin 2/ Fragment 2 are important in understanding the activation of prothrombin.
A Novel Anti-Thrombotic Heparinoid (ORG 10172) Devoid Of Bleeding Inducing Capacity: A Survey Of Its Pharmacological Properties In Experimental Models In Rats
Authors: Meuleman D G , Dedem G Van , Hobbelen P M J , Moelker H C T 
Published: July 2018

The pharmacological profile of a heparinoid (Org 10172) was assessed In experimental thrombosis and bleeding models In rats. Org 10172 Inhibited thrombus formation In arteriovenous shunts dose dependently (ID50=5 mg/kg i.v.); heparin USP had an ID50 of 0,4 mg/kg I.v. in the same model. Taking the effective dose ratio of the compounds into account both Org 10172 and heparin USP similarly reduced the 125I-fibrin content In thrombi; Org 10172 however affected less the 51Cr-labeled platelet content in the thrombi than heparin USP.Heparin USP progressively prolonged bleeding at doses of 1 mg/kg i.v. and higher, whereas Org 10172 showed no increase in bleeding over a dose range of 50-200 mg/kg i.v. The benefit (anti-thrombotic)/risk (bleeding) ratio is at least 20-fold higher than for heparin USP.In vitro Org 10172 did not Inhibit the collagen-Induced release of serotonin from platelets, in contrast to heparin USP. Org 10172 was at least 500 times less active In enhancing the thrombin-AT III Interaction than heparin USP, it showed a very small increase In APTT and had about 6% of the factor Xa- inhibiting activity of heparin USP. The improved profile of the drug may be attributed to these quite different effects on blood platelet function and the coagulation pathway.