bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clues for Understanding the Structure and Function of a Prototypic Human Integrin: The Platelet Glycoprotein IIb/IIIa Complex
Authors: Calvete Juan J 
Published: July 2018

SummaryThe glycoprotein (GP) IIb/IIIa, a Ca2+-dependent heterodimer, is the major integrin on the platelet plasma membrane. On resting platelets GPIIb/IIIa is maintained in an inactive conformation and serves as a low affinity adhesion receptor for surface-coated fibrinogen, whereas upon platelet activation signals within the cytoplasma alter the receptor function of GPIIb/IIIa (inside-out signalling), which undergoes a measurable conformational change within its exoplasmic domains, and becomes a competent receptor for soluble fibrinogen and some other RGD sequence-containing plasma adhesive proteins. Upon ligand binding, further structural alterations trigger the association of receptor-occupied GPIIb/IIIa complexes with themselves within the plane of the membrane. The simultaneous binding of dimeric fibrinogen molecules to GPIIb/IIIa clusters on adjacent platelets leads to platelet aggregation, which promotes attachment of fibrinogen-GPIIb/IIIa clusters to the cytoskeleton (outside-in signalling). This, in turn, provides the necessary physical link for clot retraction to occur, and generates a cascade of intracellular biochemical reactions which result in the formation of a multiprotein signalling complex at the cytoplasmic domains of GPIIb/IIIa. Glycoprotein IMIIa, also called αIIbβ3 in the integrin nomenclature, plays thus a primary role in both platelet adhesion and thrombus formation at the site of vascular injury. In addition, the human glycoprotein Ilb/IIIa complex is the most thoroughly studied integrin receptor, its molecular biology and major features of its primary structure having been elucidated mainly during the last six years. Furthermore, localization of functionally relevant monoclonal antibody epitopes, determination of the cross-linking sites of inhibitory peptide ligands, proteolytic dissection of the isolated integrin, and analysis of natural and artificial GPIIb/IIIa mutants have recently provided a wealth of information regarding structure-function relationships of human GPIIb/IIIa. The aim of this review is to summarize these many structural and functional data in the perspective of an emerging model. Although most of the interpretations based on structural elements of this initial biochemical model require independent confirmation, they may help us to understand the structure-function relationship of this major platelet receptor, and of other members of the integrin superfamily, as well as to perform further investigations in order to test current hypotheses.
Hypercoagulability and High Lipoprotein(a) Levels in Patients with Central Retinal Vein Occlusion
Authors: Bandello Francesco , Vigano’ D’Angelo Silvana , Parlavecchia Mariella , Tavola Alessandra , Della Valle Patrizia , Brancato Rosario , D’Angelo Armando 
Published: July 2018

SummaryA series of coagulation parameters and lipoprotein(a) (Lp(a)) were explored in plasma from 40 patients with central retinal vein occlusion (CRVO, non-ischemic type n = 12; ischemic type n = 28) free of local and systemic predisposing factors, 1 to 12 months after the acute event. Forty age- and sex-matched patients with cataract served as controls. Prothrombin fragment 1.2 (FI.2), D-dimer, FVII:C - but not FVII: Ag - were higher and fibrinogen was lower in CRVO patients than in controls. Patients with non-ischemic CRVO had higher FI .2 and FVII:C and lower heparin cofactor II than patients with ischemic CRVO. Lp(a) levels greater than 300 mg/1 were observed in 12 patients with CRVO and in 4 controls (30% vs 10%, p <0.025). Patients with high Lp(a) - consistently associated with the S2 phenotype - had higher FVII:C, FVII:C/Ag ratio, and fibrinogen than the remaining CRVO patients. Plasma FI.2 and D-dimer correlated fairly in controls (r = 0.41) and patients with normal Lp(a) levels (r = 0.55), but they did not in the group of patients with high Lp(a) (r = 0.19), where the latter parameter was negatively related to D-dimer (r = −0.55). There was no dependence of the abnormalities observed on the time elapsed from vein occlusion. The findings of activated FVII and high FI.2, D-dimer, and Lp(a) are not uncommon in patients with CRVO. Increased thrombin formation with fibrin deposition and impaired fibrinolysis may play a role in the pathophysiology of CRVO and require specific treatment
Comparative Thrombolytic Properties of Tissue-Type Plasminogen Activator and of a Plasminogen Activator Inhibitor-1 -Resistant Glycosylation Variant, in a Combined Arterial and Venous Thrombosis Model in the Dog
Authors: Collen Désiré , Stassen Jean-Marie , Yasuda Tsunehiro , Refino Canio , Paoni Nicholas , Keyt Bruce , Roskams Tania , Guerrero J Luis , Lijnen Henri R , Gold Herman K , Bennett William F 
Published: July 2018

Summaryrt-PA-K, a variant of recombinant tissue-type plasminogen activator (rt-PA) with substitution of amino acids 296 to 299 with alanine (KHRR296-299AAAA) has increased fibrin-specificity and reduced sensitivity to plasminogen activator inhibitor-1; rt-PA-T, with threonine 103 replaced by asparagine has an additional glycosylation site and a reduced clearance; and rt-PA-N, with asparagine 117 mutagen-ized to glutamine lacks the high mannose carbohydrate side chain. We have investigated whether combination of these properties in a single molecule might yield an improved thrombolytic agent.The thrombolytic potency and fibrin-specificity of the combination mutant rt-PA-TNK was compared with that of rt-PA in a combined venous whole blood clot model and platelet-rich arterial eversion graft thrombosis model in dogs given intravenous heparin and aspirin. Infusion of 0.125 to 1.0 mg/kg over 60 min in groups of 4 to 5 dogs produced dose-dependent fibrin-specific venous clot lysis. The thrombolytic potency (percent lysis per mg compound administered per kg body weight) of rt-PA-TNK was significantly higher than that of rt-PA as evidenced by a higher maximal rate of lysis of 480 ± 100% versus 140 ± 40% within the 2 h observation period per mg of compound administered per kg body weight (mean ± SEM, p = 0.004) and a significantly lower dose of 0.08 ± 0.01 versus 0.21 ± 0.04 mg/kg body weight at which the maximal rate of lysis was obtained (p = 0.004). This higher thrombolytic potency was the result of a significantly reduced clearance (240 ± 32 versus 540 ± 49 ml/min, p = 0.002) and a similar specific thrombolytic activity (percent lysis per |ig/ml plasma antigen level). Arterial reflow was obtained with 1 mg/kg rt-PA and with 0.5 mg/kg rt-PA-TNK, but with each agent recanalization was consistently associated with cyclic reocclusion and reflow. The frequency of arterial recanalization was somewhat higher with rt-PA-TNK (10/12) than with rt-PA (4/12) (p = 0.07) but the total patency times during a 2 h observation period were similar.
Transport Phenomena and Clot Dissolving Therapy: An Experimental Investigation of Diffusion-Controlled and Permeation-Enhanced Fibrinolysis
Authors: Wu Jung-He , Siddiqui Khalid , Diamond Scott L 
Published: July 2018

SummaryWe have investigated the effects of diffusive and convective transport on fibrinolysis. Using a constant pressure drop (ΔP/L) from 0 to 3.7 mmHg/cm-clot to drive fluid permeation, various regimes of lytic agents were delivered into fine and coarse fibrin gels (3 mg/ml) and whole blood clots. Using plasmin (1 μM) delivered into pure fibrin or urokinase (1 μM) delivered into glu-plasminogen (2.2 μM)-laden fibrin, the velocity at which a lysis front moved across fibrin was greatly enhanced by increasing ΔP/L. Lysis of fine and coarse fibrin clots by 1 μM plasmin at ΔP/L of 3.67 and 1.835 mmHg/cm-clot, respectively, led to a 12-fold and 16-fold enhancement of the lysis front velocity compared to lysis without pressure-driven permeation. For uPA-me-diated lysis of coarse fibrin at ΔP/L = 3.67 mmHg/cm-clot, the velocity of the lysis front was 25-fold faster than the lysis front velocity measured in the absence of permeation. Similar permeation-enhanced phenomenon was seen for the lysis of whole blood clots. Without permeation, the placement of a lytic agent adjacent to a clot boundary led to a reaction front that moved at a velocity dependent on the concentration of plasmin or uPA used. Overall, these studies suggest that transport phenomena within the clot can play a major role in determining the time needed for reperfusion during fibrinolysis.
Tissue Extract and the Contact Reaction in Blood Coagulation
Authors: Biggs Rosemary , Nossel H. L 
Published: July 2018

Summary1. The addition of dilute brain extract to normal silicone collected plasma or to celite exhausted normal plasma produces an acceleration of thrombin formation similar to that of kaolin on normal plasma.2. When dilute brain extract is added to PTA or Hageman deficient plasma samples, the concentration of brain required to simulate the kaolin activated normal contact mechanism is similar to that required for normal plasma. When very dilute brain extract is used the reaction of the Hageman deficient sample is defective.3. When added to factor VIII or factor IX deficient plasma samples about ten times as much brain extract is required to produce the type of thrombin generation curve typically found on the addition of kaolin to silicone collected normal plasma.4. It is suggested that in normal haemostasis the contact phase may be initiated, in part at least, by weak tissue extracts liberated at a site of injury.
The Effect of Dextran of Various Molecular Weight on the Coagulation in Dogs
Authors: Bergentz Sven Erik , Eiken Oddvar , Nilsson Inga Marie 
Published: July 2018

Summary1. Infusions of low molecular weight dextran (Mw = 42 000) to dogs in doses of 1—1.5 g per kg body weight did not produce any significant changes in the coagulation mechanism.2. Infusions of high molecular weight dextran (Mw = 1 000 000) to dogs in doses of 1—1.5 g per kg body weight produced severe defects in the coagulation mechanism, namely prolongation of bleeding time and coagulation time, thrombocytopenia, pathological prothrombin consumption, decrease of fibrinogen, prothrombin and factor VII, factor V and AHG.3. Heparin treatment of the dogs was found to prevent the decrease of fibrinogen, prothrombin and factor VII, and factor V otherwise occurring after injection of high molecular weight dextran. Thrombocytopenia was not prevented.4. In in vitro experiments an interaction between fibrinogen and dextran of high and low molecular weight was found to take place in systems comprising pure fibrinogen. No such interaction occurred in the presence of plasma.5. It is concluded that the coagulation defects induced by infusions of high molecular weight dextran are due to intravascular coagulation.
Zur Reaktionskinetik des Kalziums in der Blutgerinnung
Authors: Göttinger E 
Published: July 2018

Zusammenfassung1. Die Abhängigkeit der Fibrinogenpolymerisation von der Kalziumionenkonzentration kann nur in Plasmen exakt untersucht werden, die durch Ionenaustausch entkalkt oder durch ÄDTA stabilisiert werden.2. Die Fibrinbildung ist von der vorhandenen Kalziumionenkonzentration quantitativ abhängig. 1 Teil zugesetztes Kalzium entspricht bis zu 1500 Teilen gebildeten Fibrins.3. Die Blutgase beeinflussen die Reaktion des Kalziums mit dem Gerinnungssystem zum Teil in typischer Weise.4. Andere Erdalkaliionen beeinflussen die Kalziumwirkung in charakteristischer Weise.5. Die zur Fibrinogenpolymerisation benötigten Mengen Kalzium und Thrombin liegen in der gleichen Größenordnung.
Nachweis eines Antiheparinfaktors in der gesunden und der arteriosklerotischen Gefäßwand
Authors: Hoffmeister Kl , Perlick E 
Published: July 2018

Zusammenfassung1. In wäßrigen Extrakten aus menschlichen Aortenwänden konnte eine deutliche Antiheparinaktivität nachgewiesen werden. Diese war jedoch erst nach einer Inkubation der Extrakte mit Heparin bei 37° C über 15 Minuten voll wirksam und konnte durch Erhitzen zerstört werden. Sie war bei —20° C mehrere Wochen lang lagerungsstabil.2. In makroskopisch normalen Aortenwänden war die Antiheparinaktivität am größten, sie ging mit zunehmendem Arteriosklerosegrad zurück. Die Untersuchungen weisen auf eine Abnahme der Gerinnungsaktivität der Gefäßwand bei zunehmender Arteriosklerose hin.
Zur Frage der Beeinflussung der Permeabilitätsverhältnisse im Bereich des Zentralnervensystems durch gerinnungshemmende und fibrinolytisch wirkende Stoffe
Authors: Liebaldt G , Matis P , Nagel W 
Published: July 2018

Zusammenfassende BesprechungDie therapeutisch üblichen Dosen der untersuchten Stoffe wurden unter Wahl eines feinstdispersen, gut schrankengängigen Farbstoffs bewußt überschritten. Die beobachteten Veränderungen dürfen deshalb nicht überbewertet werden. Sie zeigen aber, daß gerinnungshemmende und fibrinolytisch wirksame Körper im Zentralnervensystem die Permeabilitätsverhältnisse quantitativ, qualitativ und topisch unterscheidbar beeinflussen können. Die makroskopisch eindrucksvollen Unterschiede hinsichtlich der Färbung des Tubergebietes und der Umgebung (Liquemin streng lokalisiert; Marcumar, vor allem aber Actase und Streptokinase mehr diffus) deuten auf bestimmte Qualitätsunterschiede. Auffällig ist die besondere dyshorische Auswirkung des Heparins im Bereich des Ammonshorns gegenüber einer diesbezüglichen Bevorzugung der Tuberregion durch die anderen Präparate. Zwischen dieser organ-(region-)spezifischen Beeinflussung des Permeabilitätsverhaltens einerseits und einer organspezifischen Blutungsneigung bzw. einem organspezifischen Beitrag zur Blutstillung andererseits [s. hierzu (2)] dürften prinzipielle Beziehungen bestehen.Die Dissoziation von ausgeprägter Gerinnungshemmung und (hier subpleuraler) Blutung ist besonders bei dem dicumarolanalog wirkenden Marcumar in Bestätigung früherer Befunde (4, 6, 8, 10) deutlich, desgleichen für Liquemin (1, 7, 9), aber nur angedeutet nachweisbar.Aus unseren Untersuchungen ergibt sich 1. die Tatsache einer lokalen Spezifität der Schädigungsmöglichkeit innerhalb des ZNS, 2. die Notwendigkeit, diese Faktoren als Meßwerte zu berücksichtigen, und 3., daß gewisse Reaktionen von Versuchstieren, die zunächst kein befriedigendes pathologisch-anatomiches Äquivalent aufweisen (z. B. 3.), u. U. durch zentralnervöse Beeinflussung zu deuten sind.
Antiplasmin Deficiency in Polycythaemia: a Form of Thrombopathy
Authors: de Vries S. I , Braat-van Straaten M. A. J , Müller E , Wettermark M 
Published: July 2018

SummaryA marked fibrinolytic activity could be demonstrated in the blood of 10 patients with polycythaemia. In these cases fibrinolysis was considered the result of a deficiency an antiplasmin. It could be demonstrated that this naturally occurring inhibitor of fibrinolysis is present in normal platelets but is lacking in the patient’s own thrombocytes. This factor is probably attached to the surface of the thrombocytes. It could be removed by repeatedly washing. Lack of antiplasmin is a dysfunction of platelets and a form of thrombopathy. It does not respond on treatment with ACA or prednisone. In primary polycythaemia busulfan (Myleran) was considered to be the treatment of choice, whereas in 1 case of secundary erythrocytosis (Fallot’s tetralogy) the reaction on unroasted peanuts was unmistakable. In 4 more patients an alcoholic extract of peanuts was given, and promising results were obtained in 3 of them. The importance of this “thrombopathic type’ of fibrinolysis has been pointed out especially in view of surgical interventions.
Studies on the Coumarin Anticoagulant Drugs : The Assay of Warfarin and its Biologic Application
Authors: O’Reilly Robert A. , Aggeler Paul M. , Hoag M Silvija , Leong Lois 
Published: July 2018

SummaryA spectrophotometric method is described for the determination of warfarin in biologic fluids. The warfarin is extracted from the specimen with acidified ethylene dichloride, washed with mild alkali and recovered from the organic phase with strong alkali. The extinction is then measured spectrophotometri-cally at the ultraviolet absorption maximum for warfarin. Results of UV absorption spectrophotometry and countercurrent distribution analysis showed that the assay is specific for unchanged warfarin in plasma; in addition, it measures a probable metabolite of warfarin in urine. Further studies indicated that the metabolite may be hydroxy-warfarin.The method was applied in determining the absorption and elimination of warfarin after oral and intravenous administration. Gastrointestinal absorption of the drug was rapid and complete. With both routes the plasma concentrations and prothrombinopenic response were similar, and the rate of disappearance from the plasma followed an exponential decay curve. A correlation was found between rate of elimination and biologic response — the slower the rate of elimination, the more pronounced the depression of prothrombin complex activity. The application of this dual approach, the simultaneous study of the metabolic fate of the drug and the prothrombinopenic response, should provide a more rational basis for the therapeutic use of anticoagulant drugs.
Effect of Lecithin on the Fibrinolytic System in Guinea-Pig Serum
Authors: Olesen E. S 
Published: July 2018

SummaryLecithin preparations from egg yolk or from soya beans added to guinea-pig serum which is subjected to isoelectric precipitation produce fibrinolytic activity in the precipitates in a manner similar to that previously reported for anionic polyelectrolytes. The possible physiological significance of this observation is discussed.
The Ultrastructure of Rabbit Blood Platelet Aggregates
Authors: Hovig Torstein 
Published: July 2018

SummaryDifferent types of rabbit blood platelet aggregates formed in vitro were studied by means of electron microscopy.1. Aggregates were produced by addition of small amounts of thrombin to citrate-PRP. The platelets, rich in pseudopods, were lying close together with no detectable fibrin between them. Fibrin was observed only in the periphery of the aggregate. Varying structural changes, with loss of granules and mitochondria, occured in the platelets. The appearance of these aggregates was similar to that of the haemostatic platelet plug formed in vivo.
In clots of PRP induced by greater concentrations of thrombin, fibrin was readily detectable as bundles of fibres. Platelets with complete loss of internal structure were scattered in the fibrin framework.2. The platelets were usually loosely packed in thrombin-induced aggregates of washed platelets, with no visible fibrin between them. Considerable structural changes of the platelets were observed. Rods or filaments of electron-dense substance were observed inside the platelets.3. The platelets were lying close together in ADP-induced aggregates, but several free spaces could be observed between them. Small and inconsistent structural changes of the platelets appeared.4. Aggregates induced by saline extract of tendons demonstrated marked structural changes of the platelets, with loss of granules and mitochondria. Platelet membranes were mostly preserved. Several free spaces were observed between the platelets. No electron-dense substance indicative of fibrin was detected.The appearance of the different types of aggregates is compared and discussed in relation to the ultrastructure of the haemostatic platelet plug.
The Separation of Thromboplastin Formed from Pig’s Plasma in the Thromboplastin Generation Test
Authors: Cross M. J 
Published: July 2018

Summary1. Plasma thromboplastin has been formed from a mixture of pigs’ plasma, serum and platelets using a modification of the thromboplastin generation system of Biggs and Douglas (1953). The thromboplastic activity in the modified system was more stable than in the original system.2. A sediment with considerable thromboplastic activity has been obtained by centrifugation. This sediment was free of platelets and contained very little thrombin.3. The sediment when resuspended in buffer was fully active only in the presence of calcium and between pH 6.6 and 7.0. The activity slowly decreased at 0—4° C and rapidly at 65° C.4. The sediment rapidly converted prothrombin to thrombin in the absence of factor V.5. The activity of the sediment was unaffected when it was incubated with thrombin.
Factors which Influence the Bleeding Time
Authors: den Ottolander G. J. H , Bleijenberg A 
Published: July 2018

SummaryA prolonged bleeding time can be due to a vascular, plasmatic, or thrombocytic cause. On the basis of investigations in 8 patients with a prolonged bleeding time, these different forms are discussed.There appeared to be at least two plasmatic factors one of which is the bleeding factor of Nilsson. The demonstration of a thrombocytic cause is sometimes only possible with transfusions of normal platelet suspensions. A patient is described with a prolonged bleeding time due to an acquired thrombo-pathia, resulting from excessive haemorrhages and exchange transfusions.
Leucocyte Rheological Properties Are Altered in Patients with Diffuse Atherosclerosis
Authors: Galante Alberto , Pietroiusti Antonio , Magrini Andrea , Carta Sandro , Franceschelli Laura , Piccolo Paola , Pistolese Giuseppe Raimondo , Martelli Eugenio , Mastino Antonio , Matteucci Claudia , Grelli Sandro , Favalli Cartesio 
Published: July 2018

SummaryTo evaluate whether atherosclerosis may be associated with altered leucocyte rheology, we assessed leucocyte count (by Coulter counter), aggregation (by means of the leukergy test) and expression of adhesion molecules integrin LFA-1 and CD 44 (by means of immunofluorescence staining and flow cytometry) in 9 patients with carotid plus lower limb artery atherosclerosis (group A), 14 patients with carotid atherosclerosis only (group B) and 23 controls without atherosclerosis (group C). The level of LFA-1 (calculated as mean fluorescence channels - MFCs) on neutrophils, lymphocytes and monocytes was significantly higher (p <0.05) in group A and B patients than in controls (group A - mean ± SE : 383.77 ± 9.42 vs 295.45 ± 5.76; 474.22 ± 8.86 vs ± 7.84; 457.66 ± 12.03 vs 396.25 ± 4.37. Group B: 322.42 ± 6.36 vs 295.45 ± 5.76; 421.42 ± 7.21 vs 388.35 ± 7.84; 415.71 ± 7.73 vs 396.25 ± 4.37, respectively); furthermore, the MFC of LFA-1 on neutrophils was significantly different (p <0.05) between group A and B patients. The percentage of aggregated leucocytes was significantly higher (p <0.05) in group A patients (4.46 ± 1.07) than those in groups B (1.75 ± 0.38) and C (1.43 ± 0.25), whereas no significant difference was detected between groups B and C. Leucocyte number and expression of CD44 were not significantly different among the 3 groups. In conclusion, changes in leucocyte rheology are present in patients with atherosclerosis and may contribute to chronic ischaemia.
A Hemi-nested, Allele Specific, Whole Blood PCR Assay for the Detection of the Factor V Leiden Mutation
Authors: Sinclair Gary D , Low Sandra , Poon Man-Chiu 
Published: July 2018

SummaryWe describe a novel hemi-nested, allele specific whole blood PCR assay for detection of the factor V Leiden mutation associated with the plasma defect, activated protein C resistance. This assay utilizes 5 μl of whole blood without prior DNA extraction. The hemi-nested design, employing an outer primer pair in combination with nested, allele specific primers obviates the need for restriction enzyme digestion. PCR reactions are analysed directly on agarose or polyacrylamide minigels. The assay confirmed the genotypes of 50 individuals previously categorized by PCR and Mnll digestion, and has been subsequently utilized in the genotyping of 445 individuals referred for thrombosis studies.