bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep Vein Thrombosis During Oral Contraception. An Analysis Of 57 Patients
Authors: Bergqvist A , Bergqvist D , Hedner U 
Published: July 2018

A phlebographic and haemostatic analysis has been made of 57 patients developing deep vein thrombosis while on combined oral contraceptives containing 30 or 50 μg estrogen. The diagnosis was based on ascending phlebography. One patient had bilateral, 18 rightsided and 38 leftsided thrombosis. The leftsided dominance was seen only in patients taking 50 μg estrogen daily. The thrombotic process was significantly more extensive and more proximally located in patients with leftsided thrombosis. Thirty-three percent of the rightsided and 8% of the leftsided thrombi embolised, a difference which is significant. Six to twelve months after the acute thromboembolic episode an analysis was made of platelet function, the coagulation and fibrinolytic systems. Only 5/57 patients had an excessive increase of f. VIII:C (>250%) and none had low AT III levels. Thirty-two percent of the patients had a defect in their vessel wall fibrinolysis (a defective release capacity and/or a decreased fibrinolytic activity within the vessel wall) and these patients developed rightsided thrombosis significantly more often.Judging from our findings a defective vessel wall fibrinolysis seems to be of pathogenetic significance for the development of deep vein thrombosis especially on the right side during oral contraceptive medication. The more extensive leftsided thrombi seemed to be dependent on the estrogen dose and not to the same extent associated with an impaired vessel wall fibrinolysis.
Effects Of Bay g 6575 On Platelets And On Vascular PGI2 Production
Authors: MacIntyre D E , Salzman E W 
Published: July 2018

Bay g 6575 (1-[2-(β-naphthyloxy) ethyl]-3-methy1-2-pyrazolin-5-one) exerts a protective effect in several animal models of thrombosis. To elucidate its mechanism of action, we examined the effects of Bay g 6575 on platelets and on vascular PGI2 production. In vitro addition of Bay g 6575 (200 μM) to human citrated platelet rich plasma (PRP) did not inhibit aggregation induced by ADP or U44069, or augment inhibition of ADP-induced aggregation by PGD2, PGE1, PGI2 or papaverine. When added to isolated human or rat vascular rings, Bay g 6575 (200 μM) did not stimulate production of PGI2 or 6-oxo-PGF1α. Ex vivo studies one hour after administration of Baya g 6575 to rabbits (10 mg/kg, i.a.) or rats (100 mg/kg, p.o.) revealed no inhibition of ADP-induced aggregation or enhancement of the level of “circulating” PGI2 as measured by bio-immunoassay. When production of anti-aggregating activity by vascular rings from Bay g 6575 treated (B) and Control (C) rats were compared, in 6 of 8 experiments B inhibited more than C and B produced more 6-oxo-PGF1α than C (mean increase in B ± s.d.=74.3 ± 35.7%, range 42-135%). Production of antiaggregatory activity by “exhausted” C rings was enhanced by B>C platelet free plasma. In all cases, the inhibitor of aggregation produced by B and C rings acted on both human and rat PRP, and its effects could be reversed by anti-PGI1 antibodies that neutralize PGI2>6-oxo-PGE1>PGD2. When exogenous PGI2 was incubated with (exhausted) aspirin treated vascular rings, the duration of action of PGI2 was longer in the presence of B rings than C rings.Bay g 6575 has no direct effects on platelets or on vascular tissue. Its antithrombotic activity appears to be caused by regulation of PGI2 synthesis and metabolism, an effect mediated by factors, possibly Bay g 6575 metabolites, present in plasma after in vivo administration.
Adenosine 5’-O-(2-Thiodiphosphate) (ADP-β-S) Is A Partial Agonist At The ADP Receptor Of Human Platelets
Authors: Cusack N J , Hourani S M O 
Published: July 2018

ADP induces human platelet aggregation and inhibits the stimulation of platelet adenylate cyclase by prostaglandin E1 (PGE1), but analogues of ADP in which the diphosphate group is modified retain only weak aggregating activity. However, ADP-β-S, an ADP analogue in which a terminal phosphate oxygen is replaced by sulphur, is known to be equipotent with ADP as an inhibitor of PGE1-stimulated adenylate cyclase in purified human platelet membranes. We therefore tested ADP-β-S on intact human platelets. ADP-β-S induced human platelet aggregation and inhibited PGE1-stimulated adenylate cyclase, but in botn cases was less potent than ADP and only achieved 75% and 50% respectively of the maximal effects of ADP. Aggregation induced by ADP-β-S was competitively inhibited by ATP (50 μM), a known ADP antagonist.Both these actions of ADP could be inhibited by the simultaneous addition of ADP-β-S (50 μM). Aggregation induced by a stable endoperoxide analogue (11 ,9 -epoxymethano PGH2), which acts at a prostaglandin receptor rather than at an ADP receptor, was not inhibited by the simultaneous addition of ADP-β-S (50 μM). The behaviour of ADP-β-S towards human platelets is therefore tnat of a partial agonist at the ADP receptor.
Isofocusing Used To Study The Specificity Of The “Lupus Inhibitor”
Authors: Coots M C , Glueck H I , Miller M A 
Published: July 2018

This work was undertaken to investigate the clotting factor inhibition of the “Lupus Inhibitor”. Thiagarajan and Shapiro (Circulation 62: 279, 1980) showed that the “lupus anticoagulant" had immunologic specificity for the negatively charged phospholipids. However, in various case reports specific clotting factor inhibition has been described.In our studies, the adsorbed, heat defibrinat- ed (56°C, 30 min.) plasmas of 6 patients with the “Lupus Inhibitor” were separated by preparative isofocusing. The inhibitory peaks were identified, and the clotting factor specificity of each was determined using partially purified eluates and specific factor deficient plasmas. The inhibitory peaks had activity against factors X, XI and XII in 5 of the 6 patients. In 1 patient, activity was confined to factor XI. These findings verified the initial factor quantitations. Utilizing the sequential Russell’s viper venom time, X-Xa was inhibited to a greater degree’ than the factor V and the phospholipid in the formation of prothrombinase. The celite eluate inhibition test (for XI, XII inhibition) was abnormal in all six patients.Based on this study, the lupus inhibitor in these six patients was a heterogeneous collection of inhibitors directed against factors XII, XI and X rather than a homogeneous entity.
An Acquired Heparin-Like Anticoagulant In An 8 Month Old With Monoblastic Leukemia
Authors: Bussel J B , Steinherz P G , Miller D R 
Published: July 2018

Well documented heparin-like anticoagulants have been reported in association with malignancy only in 3 adults with multiple myeloma. We report an 8 month old white male with acute monoblastic leukemia with an initial WBC of 358, 000/ul who was treated with adriamycin and ARA-C, developed a severe coagulopathy, and died 3 days later of presumed pulmonary and/or CNS hemorrhage. Liver and renal functions were normal and lysozyme was 112 mg/dl. The coagulation data were as follows:The factor V level was 11% and 2%, the factor VIII level was 69% and 85%, and the platelet count was approximately 50,000/μl both days. The thrombin time with mixing was 59 secs and after adsorption with “hepasorb” the thrombin time was 33 secs. Coagulation parameters did not change despite the infusion of fresh frozen plasma, proplex, hemofil, and platelets.Additional studies revealed:
1) Progressive shortening of the thrombin time when increasing amounts of protamine and PF4 were added to patient’s plasma.
2) Patient’s urine prolonged the thrombin time of normal plasma. This effect was neutralized by protamine and PF4. Urine from another patient with AMOL in relapse did not prolong the thrombin time of normal plasma.
3) Mucopolysaccharides were detected in the patient’s urine by the Berry spot test.The data suggest that the major coagulation abnormality in this patient was a circulating heparin-like anticoagulant. This is the first case report of an endogenous heparin-like anticoagulant in leukemia.
Procoagulant (Tissue Factor) Activity Is Higher In Cells From Murine Sarcoma Sublines With Lower Metastatic Potential
Authors: Colucci M , Giavazzi R , Alessandri G , Semeraro N , Mantovani A , Donati M B 
Published: July 2018

It has been suggested that cancer cell procoagulant activity influences metastasis formation by promoting fibrin deposition around tumors. We have investigated the procoagulant activity of various tumor cell sublines with different metastatic capacity. These were derived from spontaneous lung nodules of mFS6, a benzopyrene-induced sarcoma in C57B1/6 mice. After one in vivo passage by s.c. implantation, the resulting tumor was cultured once in vitro till confluence; cells were then harvested from plastic bottles by trypsin treatment, and washed extensively after trypsin neutralization. Tumor cell procoagulant activity was measured by a one-stage clotting assay using autologous plasma. All the cells tested possessed thromboplastin-like activity since they shortened the recalcification time of normal and factor VUI-deficient plasma to a similar extent but had no activity on factor Vll-deficient plasma.They were, however, heterogeneous as regards the degree of procoagulant activity; the two cell lines with virtually no metastatic capacity showed 6-8 times higher procoagulant activity than the cells from the parent line; in contrast, the procoagulant activity of the two sublines with higher metastatic capacity did not differ significantly from that of the parent line.These findings support the hypothesis that fibrin is part of a defence reaction against cancer cell invasiveness.
Cancer Procoagulant: A Novel Vitamin K-Dependent Activity?
Authors: Donati M B , Delaini F , Colucci M , Vitti G De Beilis , Locati D , Poggi A , Semeraro N 
Published: July 2018

Cells from some experimental tumors have been found to possess a peculiar procoagulant activity, which directly activates coagulation factor X, independently of both the intrinsic and extrinsic clotting pathways. We report here that, in the Lewis Lung Carcinoma (3LL) model, such a cell procoagulant is inhibited by vitamin K-deficiency (either dietary or pharmacologically induced).Warfarin was given chronically to mice in drinking water from day 7 after i.m. tumor implantation at a schedule which maintained the prothrombin complex activity (thrombotest) at less than 5% of control values. Vitamin K-deficiency was also induced by feeding the mice with an appropriate diet at a schedule which gave a similar degree of plasma anticoagulation. At day 18 after tumor implantation macrophage- free 3LL cell suspensions obtained by spilling of necrosis- free tumor fragments were tested for their specific clot- promoting capacity by a one-stage recalcification time of factor VII-deficient plasma. 3LL cells from either group of vitamin K-deficient animals gave significantly longer clotting times than controls (84 ± 4 and 82 ± 3 sec versus 42 ± 2 sec, p< 0.001, n = 15 for each of the 3 groups) corresponding to 18-25% of the activity of controls.This effect was completely reversed by adding vit. K to drinking water of vitamin K-deficient animals. Administration of autologous prothrombin complex concentrate, sufficient to completely correct the thrombotest values for several hours before tumor cell harvest, did not modify the effect induced by vitamin K-deficiency on 3LL cells. This data suggests that cancer procoagulant may represent a new vitamin K-dependent activity; vitamin K-deficiency would thus display not only a plasmatic but also a “cellular” anticoagulant effect. The latter could be relevant to the reported antimetastatic effect of vitamin K-deficiency.
Distribution And Localization Of Urinary Procoagulant In The Human Kidney And Its Immunologically Cross-Reactive Substances In Various Exocrine Glands
Authors: Matsuda M , Aoki N 
Published: July 2018

Procoagulant purified from human urine (urinary procoagulant, UP) was found to be macroaggregates with a molecular weight of more than 2.0 × 107 on the basis of gel exclusion chromatography on Sepharose 4b. UP does not function as a proteolytic enzyme, but does facilitate the factor VIIa-catalyzed activation of factor X in the presence of calcium ions, thus it may be categorized as tissue factor. Similar procoagulant activity was found also in various secreta including milk, saliva, bile, gastric juice, pancreatic juice and sweat, in this order of potency. The activity in milk and saliva, for example, was 14 and 5 times as potent as urine, respectively. Monospecific antiserum against UP and its IgG fraction inhibited efficiently the procoagulant activity of these secreta as well as UP.An immunohistochemical study using the anti-UP antiserum revealed that the immunologically cross-reactive substances were distributed in the epithelial cells of these exocrine glands. In the kidney UP was distributed to the loop of Henle and distal convoluted tubules. In these areas UP was found in association with the luminal and intercellular borders as well as in the cytoplasm of epithelial cells. Both the descending and ascending limbs of Henle were equally stained. The cytoplasmic staining was patchy in distribution among cells of distal tubules and was predominantly localized in the supranuclear areas. Casts in the distal tubules were also positively stained.These findings suggest that UP is synthesized in the epithelial cells of these particular parts of nephron and is secreted into urine. It is also suggested that the immunologically cross-reactive substances are synthesized in the epithelial cells in various exocrine glands and are excreted into secreta.
Prostacyclin Synthesis By Cultured Vascular Smooth Muscle Cells : Influence Of Growth And Ageing
Authors: Larrue J , Rigaud M , Leroux C , Crockett R , Bricaud H 
Published: July 2018

The ability of arterial smooth muscle cells (SMC) to produce prostacyclin (PGI2) is well documented both in vivo and under culture conditions. Advanced atherosclerosis has been associated with a severe decrease in PGI2 synthesis by arteries and we recently demonstrated that PGI2 synthesis by cultured SMC from atherosclerotic aorta was significantly depressed. In the present experiments, changes in arachidonic acid (AA) cascade in cultured SMC were studied as a function of cell proliferation and ageing.SMC derived from explants of the medial layer of 2 years old rabbit aorta were grown under standard conditions (HAM F10 medium + 10 % Foetal Calf Serum). Prostaglandin synthetic activity was investigated by cell free homogenate radiochemical assays and confirmed by gaz chromatography - mass spectrometry determinations after 10 mn incubation with 2 nM AA.An age related decrease in PGI2 biosynthetic activity (expressed as pM/10PGI6 cells) was found in confluent cells from passages 5 to 22 (31.4 ± 3 vs 15.4 ± 5.6 respectively - p≤0,01 -). On the contrary, PGI2 generation was enhanced during the proliferative phase (day 2-5) (55.5 ± 11.8) when compared to confluent cells at the same (5th) passage (p≤0,01).These results are consistent with the enhanced PGI2 formation in early arterial proliferative lesion and the inhibition of SMC proliferation by cyclooxygenase inhibitors recently reported and indicate that PGI2 synthetic activity in arterial SMC may be a significant age-dependant endogenous factor involved in the pathogenesis of atherosclerosis.
Clotting And Chromogenic Substrate Assays Measure Separate Thrombin Activities
Authors: Milad M P , Hassouna H I 
Published: July 2018

Thrombin, the final serine protease responsible for the conversion of fibrinogen to fibrin, is known to have the ability to cleave other peptides in addition to those involved in blood coagulation. Many synthetic substrates were devised to be acted on by thrombin reflecting esterolytic, amidolytic and other cleaving properties. Antithrombin III, the major protease inhibitor of plasma, has been shown to bind the proteolytic properties of thrombin irreversibly. The purpose of this study was to determine whether all enzymatic properties are destroyed simultaneously or whether the inhibitor binds the active site leaving esterolytic functions intact.Purified α-thrombin was examined with fibrinogen, and H-D-Phe-Pip-arg-p-nitroanilide assays to prepare standard working curves relating units thrombin to the rate of fibrin endpoint or to the rate of production of chromophore. Then progressive antithrombin inactivation of seryl residue was examined by increasing concentrations of ATIII incubated with thrombin for five minutes and aliquots simultaneously examined for the ability to clot a standard fibrinogen solution and to cleave the synthetic substrate.The clotting activity decreased steadily with increasing antithrombin, whereas the esterase activity remained constant. The study provides further evidence to the observations of Chang et al (Biochemistry 18: 113, (1979)) that thrombin contains two functional sites, one highly specific for the fibrinopeptide region of fibrinogen and the second site relatively nonspecific, responsible for thrombin’s esterolytic activity. An important implication of this study is that clotting assays and chemical assays that use synthetic peptides reflect separate functional properties of the enzyme thrombin.
Significant Differences In Bleeding Time(BT) ᶓ Blood Loss (BL) Between Males ᶓ Females Following Aspirin(ASA) Ingestion
Authors: Young V P , Giles A R , Pater J , Corbett W E N 
Published: July 2018

Recent clinical studies suggest that ASA may reduce the incidence of thromboembolic events in males but not females. Similarly, studies in experimental animals have demonstrated sex differences in response to thrombotic stimuli ᶓ modifications of this by ASA. We have determined the effect of ASA on both BT ᶓ BL during the performance of a strictly standardised test in 40 normal male ᶓ female subjects.Duplicate 5mm incisions (1mm depth) were made on the volar surface of the forearm below a cuff maintained at constant pressure (40mm Hg) for exactly 45" prior to injury induction. Blood from the incisions was drawn into graduated micropipettes. Thus both BT (measured from time of injury induction to the time no more blood could be drawn into the pipette) ᶓ BL were measured. At the conclusion of the test, ASA (650mg) was ingested ᶓ the BT(BL) determined exactly 2 hrs. later. There were no differences in the means of BT or BL between the male and female groups preASA. Following ASA there was a significant increase in both BT ᶓ BL for each individual (p<0.01) although in females the post-ASA values frequently fell within the pre-ASA range for the group. In males the effect was more pronounced ᶓ the increase in both BT ᶓ BL was significantly more in males than females (p<0.01). There was a highly significant correlation (p<0.001) between BT ᶓ BL measured both pre- ᶓ post-ASA for both sexes.The basis for the differences noted remains obscure but it would appear unlikely that they relate to differences in the degree of inhibition induced in prostaglandin synthesis either in the platelet or vessel wall. It is possible that in males, platelet-vessel wall interactions are more dependant on ASA-inhibitable prostaglandin pathways than females or, alternatively, that ASA is modulating this interaction in a way that has yet to be identified.
Recovery Of Platelet Function After Aspirin Ingestion: In Vivo And In Vitro Studies
Authors: Bradlow B A , Chetty N , Birnbaum M 
Published: July 2018

Blood was taken from normal volunteers before and two hours after a 600mg oral dose of aspirin (ASA). Platelet rich plasma (PRP) was prepared from both samples. Mixtures of normal and ASA treated PRP were tested for aggregation responses and for production of thromboxane B2 (TXB2) by RIA (New England Nuclear). Normal aggregation responses were found when the mixture contained 26% of normal platelets (NP) with ADP, 40% NP with adrenalin, 54% NP with collagen and 52% NP with arachidonic acid (AA)(Mean Values). TXB2 production in the mixtures increased when the proportion of normal platelets was raised above 10 to 30%. These findings indicate partial restoration of platelet function by an admixture of 10-20% NP to ASA treated platelets although 50% NP was necessary to restore all functions tested. In vivo studies on seven volunteers given 300mg ASA showed partial recovery of malondialdehyde production after 72 hours, partial return of aggregation responses to collagen, ADP, adrenalin and AA at 96 hours and partial or full return of aggregation responses in all subjects by 120 hours. Since new platelets enter the circulation at the rate of 10-15% per day the results of our in vitro studies suggest that some recovery of platelet function might occur as soon as 24 hours after a dose of ASA and full recovery within 3-5 days. The longer recovery period indicated by the in vivo studies may be attributable to the effect of ASA on megakaryocyte cyclooxygenase.Conclusion: ASA administered once every 24 hours may be sufficient to suppress platelet function adequately and continuously but partial recovery of function might occur 48-72 hours after ASA ingestion.
Comparison Of The Effects Of Aspirin In Humans Ex Vivo In Platelet-Rich Plasma And Whole Blood
Authors: Nunn Barbara 
Published: July 2018

The effect of aspirin on human platelet function is usually assessed using platelet-rich plasma (PRP). Some preliminary results in vitro suggested that the effect of aspirin appears to be greater in PRP than whole blood. To explore this possibility further, a comparison of the effect of aspirin in humans ex vivo has been made taking measurements simultaneously in whole blood and PRP at 2 platelet concentrations. Blood samples (36ml) were drawn from 7 male volunteers after a light breakfast. Each took 300mg soluble aspirin and blood samples were drawn again 2 hours later. Blood was mixed with 0.1 volumes 129nM trisodium citrate. Some (30ml) was then centrifuged to prepare PRP and platelet -poor plasma (PPP) by standard techniques. Platelet concentration of some PRP was adjusted with PPP to equal that of the corresponding blood sample; the rest was adjusted to 350,000 per μl. Aggregation in response to collagen (Horm, Munich) was measured photometrically at 37°. Aggregation in 0.5ml aliquots of whole blood was measured after 4 min stirring with 154mM NaCl (control) or collagen at 37° as the fall in single platelet count determined using an Ultraflo- 100 whole blood platelet counter (Clay Adams). The concentrations of collagen producing a 50% maximal response (EC50) in PRP and blood were determined. Dose-ratios for each volunteer were calculated by dividing the EC50 obtained after aspirin by the corresponding value obtained before aspirin.The effect of aspirin was significantly (p<0.001) less in blood than PRP. Whether or not the results in whole blood more closely reflect the effect of aspirin in vivo remains to be determined.