bluuebunny/crossref_metadata_2025_split huggingface dataset:
APSAC VERSUS PLACEBO: THE FIRST PLACEBO CONTROLLED CORONARY RECANALISATION STUDY WITH PRE AND POST TREATMENTCORONARY ARTERIOGRAPHY
Authors: Timmis A D , Griffin B , Crick J C P , Flax J S , Sowton E , Cool D E 
Published: August 2018

40 patients entered the first double-blind placebo controlled invasive arteriographic study of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) for coronary recanalisation in acute myocardial infarction. Coronary arteriography was performed before and 90 minutes after a single intravenous injection of APSAC or matched placebo given over 2-5 minutes. Pre-treatment coronary arteriography was performed in all 40 patients 3.1 ± 1.2 hours after the onset of major symptoms of myocardial infarction. All coronary arteriograms were read blindly and scored according to the TIMI criteria by an independent cardiologist. Following randomisation occlusion of the infarct related coronary artery was demonstrable in 29 of the 40 cases at pre-treatment coronary arteriography. Patients were given either APSAC 30 units (n=l6) or matched placebo (n=13),3.3 ± 1.3 hours after the onset ofsymptoms. Repeat coronary arteriography was performed 90 minutes after administration of study drug. 9 of the 16 patients who received APSAC had demonstrable coronary recanalisation of the infarct related vessel compared with only one patient inthe placebo group (P 0.05).A third full diagnostic coronary arteriogram was performed three days after treatment and this showed persistent patency of all the recanalised coronary arteries except one in the APSAC group as well as late recanalisation in a further 4 cases, 3 of whom had received APSAC.Of the 11 patients who had patent infarctrelated arteries on initial arteriography, 4 received APSAC and 7 placebo. Patency was maintained in all these throughout the study period.There were haemorrhagic complications related to APSAC therapy. This data confirms the thrombolytic efficacy of APSAC in acute myocardial infarction, and indicates that the drug may be used safely by the intravenous route with a 56 per cent recanalisation rate at 90 minutes. Re-occlusion of the recanalised vessel was rare.
PROTEIN C TOCHIGI: AN ABNORMAL PROTEIN C CHARACTERIZED BY DEFECTIVE RELEASE OF ACTIVATION PEPTIDE BY THROMBIN
Authors: Matsuda M , Sakata Y , Sugo T , Tanabe S , Mimuro J , Murayama H 
Published: August 2018

A molecular abnormality of protein C (PC) has been found in an 18-year-old female who has been thrombophilic since she was one-year old. Detailed coagulation studies revealed that PC antigen was only 25% of normal while PC activity was substantially undetectable in her plasma. Other related plasma proteins including vitamin K-dependent blood coagulation factors, antithrombinin and plasminogen were all within normal limits.Family study demonstrated that her father, one of her paternal uncles andher half-bred sister had half-normal levels of both activity and antigen of PC. They thus appear to be heterozygotes for PC deficiency. Her mother had anormal level of PC as antigen but only60% of normal as activity. We thus presumed that nearly a half population ofPC was not properly functioning in hermother's plasma. By utilizing insolubilized monoclonal* antibodies against PC, we isolated both single-chain and two-chain forms of PC from the propositus' plasma. They were found to have normal molecular weights by SDS-PAGE, but they failed to exhibit amidolytic activity and to incorporate 3H-labeled DFP after thrombin-treatment. By immunoblotting and ELISA utilizing a monoclonal antibody that recognizes the activation peptide part of the heavy chain of PC, we found that cleavage of the activation peptide by thrombin was impaired totally in the proposi and partly in her mother’s PC. It is thus most probable that the propositus inherited PC deficiency from her father and a molecular abnormality of non-activatable protein C from her mother, respectively. Accordingly, all the PC molecules in the propositus’ plasma are non-functional, which may have culminated in the occurrence of cerebral thrombosis at the age of 1 and severe deep venous thrombosis and bilateral pulmonary embolisms at the age of 10.
MONOCLONAL ANTIBODIES OF THE IgM AND IgG CLASS SPECIFIC FOR CROSSLINKED FIBRIN DEGRADATION PRODUCTS
Authors: Gaffney P J , Creighton L J , Curry A , MacMahon B , Thorpe R 
Published: August 2018

Monoclonal antibodies (mabs) to crosslinked fibrin degradation products (XL-FDP) having the general formula D/Y[X]nY/D (known as X-oligomer) and D-D (known as D dimer) have been raised in balb/C mice by both a novel mtrasplenic and a conventional subcutaneous route of immunisation and by combinations of both these procedures. Mabs to X-oligomers (NIBn 52 and NIBn 123) obtained by an intrasplenic procedure have been demonstrated to crossreact only with X-oligomer in a 2-site ELISA procedure and not with D dimer or whole fibrinogen and have been shown to be of value m the examination of clinical material obtained from patients with various types of thrombosis and have also been useful in monitoring the efficacy of thrombolytic therapy. The X-oligomer mabs are immunoglobulins of the M class. It was demonstrated that their unique specificity for conformational epitopes on the large X-oligomer fragments does not reside in the IgM structure since alterative immunisation procedures have been used to generate mabs of the IgG class which have the same specificity. Using immunoglobulin class switching in culture rather than during immunisation was suggested by certain cell lines which produced both IgM and IgG specific for X-oligomer. This latter point needs rigorous validation.Immunoglobulin G type mabs to highly purified D dimer were raised by conventional subcutaneous immunisation of balb/C mice. One of these, NIBn-11, was found to crossreact with PVC-immobilised X-oligomer and D dimer but not with fibrinogen. However NIBn-11 did not bind to D dimer in a 2-site ELISA procedure while crossreactmg quite avidly with X-oligomer. This suggests that the D dimer epitope to which NIBn-11 is directed is expressed in some conformations and not m others and that these conformations are always expressed in the complex X-oligomer group of fragments. These mabs, whilst of value in measuring certain unique fibrin fragments m plasma, are useful in the epitope mapping of fibrinogen/fibrin and their plasmm-mediated
ORGANON 10172 VS. WARFARINTO PREVENT VENOUS THROMBOSIS AFTER HIP FRACTURE
Authors: Gerhart T , Yett H , Donovan A , Lee M A , Smith M , Salzman E W 
Published: August 2018

Deep venous thrombosis (DVT) remains a serious and frequent complication after fracture of the hip, and even the mostefficacious prophylactic agents, e.g., warfarin, may fail to prevent DVT in up to 2056 of cases. There is evidence that low molecular weight heparin or heparin-like agents may have advantages in antithrombotic prophylaxis with reduced hemorrhagic sideeffects in patients at risk of DVT. We are engaged in a randomized prospective trial comparing the antithrombotic effect ofwarfarin (PT 1.5x control)with that of Organon 10172, a mixture ofsulfated low molecular weight glycosamioglycans (750 anti-Xa u b.i.d. sc., begunpreop and continued 9 days, followe by warfarin). Diagnosis is by 125-1 fibrinogen scan and impedence plethysmography with confirmatory phlebography. At present71 patients have been admitted, and patient groups are comparable in age, sex, type of fracture, and all other significant respects. DVT has been diagnosed in 7of 36 patients given warfarin an in 1 of35 patients who received Organon10172. Pulmonary embolism has not beenencountered. GI bleeding has occurred twice on warfarin and once on Organon 10172 There has been no difference in estimated operative blood loss, transfusion requirements, or other major bleeding complications.One patient on warfarin died ofmyocardial infarction and pneumonia. There were no other adverse reactions.The study is still in progress. The present trend in the results suggests that the heparinoid Organon 10172 may be a promising new agent to prevent DVT in high risk patients, such as those with fractures of the hip.
DIHYDROERGOTAMINE-HEPARINPROPHYLAXIS OF DVT IN TOTAL HIP REPLACEMENT PATIENTS: A MULTICENTER TRIAL
Authors: Sasahara A A , Diserio F J 
Published: August 2018

We report on the results of a controlled, blinded, U.S. multicenter trial in theprophylaxis of postoperative DVT in total hip replacement patients. One hundred and forty-eight (148) patients were enrolled in this evaluation of two parallel treatment groups: (1) dihydroergotamine 0.5 mg with heparin 5000 units(DHE/5000),or (2) matching placebo. Treatment was administered subcutaneously preoperatively and continued three times a day (Q8h)for at least seven days. One hundred andtwenty-eight (128) of these were valid protocol compilers.Daily radiofibrinogen leg scans performed for the duration of treatment were followed by venographic evaluation on postoperative Day 7 or when the RFUT indicated a sustained positive reading for 48 hours. In 12 patients venography was not performed and these patients are not included in the efficacy analysis, as were eight other protocol violators. The venographically confirmed positive DVT rates for the consultant's review (protocol compilers) were 25% (16/63) for DHE/5000 and 52% (32/65) for placebo, a statistically significant difference in effective prevention of DVT (p=0.0021, two tailed Fisher's exact test)The incidence of proximal thrombi (popliteal and above) was reduced from 18.5% (12/65 patients) in the placebo group to 4.8% (3/63patients) in the group treated with DHE/Heparin (p=0.0255), while the incidence of extensive thrombi (<25% occlusion) was reduced from 24.6% (16/65 patients) to9.5% (6/63 patients) in the respective groups (p=0.0399).The most common side effect was injection site hematoma occurring in seven of the DHE/5000 patients and two of the placebo patients. One DHE/5000 patient discontinued treatment due to a side effect (injection site hematoma) attributable to drug and three placebo patients discontinued treatment due to side effects (two of these had confirmed pulmonary embolism).These data confirm previous investigations supporting the efficacy and safetyof DHE/5000 for the prevention of postoperative DVT in patients undergoing totalhip replacement.
CRYSTALLOGRAPHIC INVESTIGATION OF ANTITHROMBIN III.
Authors: Samama J P , Delarue M , Moras D , Petitou M , Lormeau J C , Choay J 
Published: August 2018

The plasma protein inhibitor anti thrombin III in its native form has been crystallized using standard techniques.The crystals diffract to about and belong to space group P41212 with cell parameters:a = b = 90.6<, c = 380.7<.The asymmetric unit contains three molecules of anti thrombin III.The self rotation function computed with the native data set indicates the presence of a non crystallographic three fold axis. Cross rotation function calculations using themodel of the cleaved α1,-antitrypsin (H. Loebermann at.,J. Mol. Biol.(1985) 177, 531) suggests tertiary structuresimilarities between the two plasma proteins.This is in agreement with the already described primary sequence homology of these glycoproteins but at variance with the model of active α1-anti trypsin inferred from the previous studies on the cleaved molecule.The technical assistance of M. Maman is deeply appreciated.
rt-PA THROMBOLYSIS VERSUS SURGICAL THROMBECTOMY OF PERIPHERAL BYPASS GRAFTS:A COMPARATIVE TRIAL
Authors: Graor R , Young J , Beven B , Hertzer N , Krajewski L , O'Hara P , Olin J , Ruschhaupt W 
Published: August 2018

Twenty-nine of 33 patients (88%) with thrombosed lower extremity bypass grafts had angiographic and clinical successful lysis of graft thrombi with rt-PA. Of the successful group, 18 were saphenous vein grafts and 11 PTFE grafts in the femoropopliteal-tibial position. Following lysis, 76% required a secondary procedure (2 PTA, 20 surgical repair and 7 required anticoagulation) to maintain patency.
A matched cohort of patients with bypass grafts who had surgical thrombectomy were compared to the rt-PA successfully treated grafts and analyzed for duration of patency after opening and limb salvage. The Kaplan-Meier curve compared both treatment groups and demonstrated improved graft survival in the rt-PA treated group (p=.01) (median graft survival rt-PA 195 days, surgery 30 days). Limb salvage was marginally significant (p=.064) in favor of the rt-PA treatment group. Single and multi-variant risk factor analysis found smoking and age of the graft adversely affected patency (p=.05 and p=.08 respectively). Graft type, age of the patient, diabetes mellitus, and high blood pressure were not significant factors (p> .15).Systemic fibrinolysis was identified to varying degrees. Mean decreases in the fibrinolytic constituents include: 59% decrease in clottable fibrinogen, 18% decrease in sulfite fibrinogen, 78% decrease in alpha-2 antiplasmin and varying degrees of increases in DDIMER, B-Beta1-42 and B-Beta15-42 coincident with the constituent changes.
Complications were unrelated to constituent changes. One patient had major bleeding secondary to graft anastomosis disruption.Thrombolysis with rt-PA is an effective and more durable adjunct treatment option for thrombosed bypass grafts, especially when combined with PTA or surgical repairto maintain patency.
FIBRINOLYTIC THERAPY IN ACUTE VERTEBROBASILAR STROKE
Authors: Del Zoppo G J , Bruckmann H , Ferbert A , Drummen R , Hacke W , Hacke W , Zeumer H 
Published: August 2018

Local intra-arterial administration of fibrinolytic agents has been successfully used to achieve recanalization in acute thrombotic stroke patients (Zeumer, H., J Neurol 231:287-294, 1985).65 consecutive patients with clinical signs of severe brainstem ischemia and angiographically demonstrated vertebrobasilar (VB) thrombotic occlusion were treated with antithrombotic therapy.22 patients (Group A) received antiplatelet/anticoagulant treatment. 43 patients (Group B) received local intra-arterial infusion of streptokinase or urokinase proximal to the thrombotic occlusion. In 19 patients of Group B (Group B1) arterial recanalization was achieved as demonstrated angiographically; in 24 patients (Group B2) the arterial occlusion could not be resolved. None of the patients in Group B2 survived.When clinically favorable (minimal/moderate deficit) and unfavorable (severe deficit/demise) outcomes are compared, the results are highly significant (B1 vs A; p <0.007; B1 vs B2; p <0.0003 .It was possible to describe the vascular conditions associated with angiographically unsuccessful fibrinolytic therapy (Group B2) and to identify the clinical conditions associated with an unfavorable clinical outcome in patients with successful lysis (Group B1). These data indicate that successful fibrinolytic therapy is associated with a beneficial clinical effect in VB thrombotic stroke.
TREATMENT OF ACUTE MASSIVE PULMONARY EMBOLISM WITH INTRAVENOUS VS. INTRAPULMONARY ARTERY ADMINISTERED RECOMBINANT TISSUE-TYPE PLASMINOGEN ACTIVATOR
Authors: Verstraete M 
Published: August 2018

Recombinant tissue-type plasminogen activator (rt-PA) was given to 34 patients with acute massive pulmonary embolism of less than five days and with an angiographic Miller index greater than 15. The regimen was 50 mg rt-PA over 2 hours followed by repeat angiography, and, if the Miller index was judged still to be above 15, by an additional dose of 50 mg over 5 hours. Heparin was given in a bolus of 5000 IU followed by 1000 IU per hour. The rt-PA preparation (Boehringer Ingelheim GmbH, G 11021) contained mainly two-chain rt-PA. The infusion route was at random in a peripheral vein (IV) or in the pulmonary artery (PA). Pulmonary angiographs were assessed blindly by a panel of five radiologists according to the protocol developed by Miller (Br Med J 1971). 19 patients were given rt-PA via the pulmonary artery, 15 patients received rt-PA intravenously. Eleven patients were postoperative (PA 9, mean 13± ]] SD days, IV 4, 7±3 daysSixteen patients (66%) received two infusions (PA 14; IV 8). The Miller index decreased from 25 ± 3 to 22 ± 6 (−12%) in the PA group and from 26 ± 2 to 22 ± 5 (−15%) in the IV group after the first infusion. In the patients who received a second infusion, the Miller index decreased to 16 ± 6 (−38%) after 100 mg in the PA group and to 16±;6 (−38%) in the IV group. The mean pulmonary artery pressure decreased from 30 ± 7 to 22 ± 6 (−27%) and further to 14 ± 5 (−53%) in the PA group and from 29 ± 7 to 22 ± 9 (−24%) after 50 mg and to 13 ± 5 (−55%) after 100 mg in the IV group. All these differences are significant (p < 0.01)Fibrinogen levels dropped 46% from baseline after 50 mg and 66% from baseline after 100 mg. Bleeding occurred in 16 patients, 5 of whom had recent surgery (mean 8 days, range 2-13)This pilot trial indicates that a prolonged infusion of rt-PA over 7 hours (100 mg) is superior to a single infusion over 2 hours (50 mg) and that infusion in the pulmonary artery does not offer a significant clinical benefit over the intravenous route. In case of life-threatening massive pulmonary embolism, treatment with rt-PA could be envisaged as early as from the third day after major surgery
CLEAVAGE PATHWAY,AND SPECIFICITY OF LEUCOCYTE ELASTASE AS COMPARED TO PLASMIN DURING FIBRINOGEN DEGRADATION
Authors: Goretzki L , Miller E , Henschen A 
Published: August 2018

Plasmin and leucocyte elastase are regarded as the two medically most important fibrin(ogen)-degrading proteolytic enzymes. There is, however, a considerable difference in information available about the cleavage specificities and fragmentation pathways of these two enzymes. Degradation by plasmin has been studied already for a long time in great detail so that now the time course of the degradation, the cleavage sites and the functional properties of many fragments are well known. In contrast, relatively little is known about the degradation by leucocyte elastase, except that the overall cleavage pattern resembles that obtained with plasminIn this investigation the leucocyte elastase-mediated degradation of fibrinogen has been examined by means of proteinchemi-cal methods. Human fibrinogen was incubated with human enzyme material for various periods of time and at some different enzyme concentrations. The split products formed at the various stages were isolated in pure form by gel filtration followed by reversed-phase high-performance liquid chromatography. The fragments were identified by N-terminal amino acid sequence and amino acid composition. The course of the degradation was also monitored by sodium dodecylsulfate-polyacrylamide gel electrophoresis. All cleavage patterns were compared with the corresponding patterns from plasmic degradation. It could be confirmed that X-, D- and E-like fragments are formed also with elastase. However, several early elastolytic Aα-chain fragments are characteristically different from plasmic fragments. The previously identified N-terminal cleavage site in the Aα-chain, i.e. after position 21, was found to be the most important site in this region of fibrinogen. The very early degradation of the Aα-chain N-terminus by elastase is in strong contrast to the stability against plasmin. Several cleavage sites in N-terminal region of the Bβ-chain were observed, though the low amino acid specificity of elastase partly hampered the identification. The γ-chain N-terminus was found to be as highly stable towards elastase as towards plasmin. The results are expected to contribute to the understanding of the role of leucocyte elastase in pathophysiologic fibrino(geno)lysis
MUTANT AND CHIMAERIC RECOMBINANT PLASMINOGEN ACTIVATORS
Authors: Piérard L , Jacobs P , Gheysen D , Hoylaerts M , Cravador A , Herzog A , Collen D , Bollen A 
Published: August 2018

In order to produce plasminogen activators (PA) more specific and more active than their natural counterparts, we designed recombinant genes encoding mutant forms of urokinase (u-PA) and chimaeric molecules combining fragments of tissue type plasminogen activator (t-PA) and of u-PA. The following constructs have been realized : 1°) u-PA where amino acids Arg156 and Lys158 have been replaced by Thr. The purpose of this approach was to obtain a prourokinase molecule displaying similar properties as the natural single chain urokinase (scu-PA) but resistant to the cleavage by plasmin ; 2°) u-PA where the second cleavage site, Lys135-Lys136, was also eliminated either by replacing amino acid 132 to amino acid 147 by a shorter link (Ser-Thr) as found in t-PA, or by replacing the two lysines by glutamine residues. The resulting molecules correspond thus to completely uncleavable scu-PA forms ; 3°) an hybrid composed of the finger domain of t-PA and of the B-chain of u-PA ; 4°) an hybrid made of the A-chain of t-PA and of the B-chain of u-PA ; 5°) an hybrid where the kringle 2 of t-PA has been inserted between the kringle domain and the B-chain of u-PA. The last three constructs have been made to confer the fibrin binding specificity of t-PA to the B-chain of u-PA.All recombinant DNAs were introduced, via an expression vector, into R1610 and CosI cells. Secretion of the recombinant products was monitored by ELISA and activities were assayed in an immobilized system involving a monoclonal antibody (AAU2) raised against 33K u-PA, plasminogen and the specific chromogenic substrate S2251. In this assay, all recombinant products, except the plasmin resistant (156-158) scu-PA, showed apparent specific activities comparable to the activity of natural two-chain u-PA. Potential interest of these new plasminogen activators in therapy will be discussed and further characterization of the new molecules will-be presented.
PROSTAGLANDIN E1 REDUCES ENDOCARDIAL PLATELET DEPOSITION AND INCREASES LEFT VENTRICULAR EJECTION FRACTION (LVEF) IN PATIENTS WITH CARDIOMYOPATHY (CMP)
Authors: Sinzinger H , Glogar H , Weidinger H , Sochor H , Auinger H , Weissel M , Fitscha P , Bergmann H , Granegger Susanne 
Published: August 2018

It is well known, that patients suffering from CMP exhibit a significantly enhanced thromboembolic risk. Thus, we examined in these patients platelet function (f3TG, PF4, TXB2-serum and plasma) and kinetics after 111-In-oxine sulphate (100μCi) labelling. In a total of 67 patients (50o,17g; 29-66a with a LVEF of < 30%) the following findings have been obtained.During γ-camera imaging and by engymetric monitoring using a portable detector system (Novo Int. Danmark) CMP-patients show an enhanced platelet deposition over the heart. Platelet half-life (1: 100-115h) is extremely shortened (< 50hrs). Prostaglandin (PG) E1 (prostavasin; α1-cyclodextrin PGE1; Sanol-Schwarz GmbH, Monheim, FRG) administered i.v. in a dose range of 5-50 ng/kg/min causes a significant (p< 0,01) increase in LVEF of 20-95% dose-dependently as measured by means of radioisotope technique.Furthermore, a diminution in the local platelet uptake over the heart starting at the 2nd day of continuous PGE1-infusion can be monitored.It is hypothetized, that PGE1 renders the endocardium less thrombogenic and increases LVEF by vasodilatation and decreasing the afterload. As PGE1 is metabo-lically degraded to a major extent during the first lung passage, the data after i.v. application are at least suggestive, that more stable PGE1-derivatives may contribute to this effect.It is therefore concluded, that PGE1 in a safe dose of 25ng/kg/min may appear in the future as an optimal long-term therapeutic agent in CMP-patients offering the benefit of significantly enhanced LVEF and decreased platelet deposition, which should result in a decreased thromboembolic risk in these patients.