bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Comparative Study of the Anticoagulant and Antithrombotic Effects of Unfractionated Heparin and a Low Molecular Weight Heparin (Fraxiparine®) in an Experimental Model of Human Venous Thrombosis
Authors: Diquélou Armelle , Dupouy Dominique , Cariou Roger , Sakariassen Kjell S , Boneu Bernard , Cadroy Yves 
Published: July 2018

summaryWe have compared the anticoagulant and the antithrombotic effects of unfractionated heparin(Calciparine®)and low molecular weight heparin(Fraxiparine®)in an experimental human venous thrombosis model.One single subcutaneous injection of Calciparine® or Fraxiparine® was administered to healthy male volunteers at one month intervalin a randomised and cross-over design.Ten subjects received doses used in man for preventing venous thrombosis(5,000 IU and 3,075 IU,respectively),and seven other subjects received curative doses (12,500 IU and 6,150 IU, respectively).Thrombus formation was measured 3 h and 8 h after drug administration.Non-anticoagulated humanblood was drawn for 5 min directly from an antecubital vein over confluent cultured endothelial cells positioned in a parallel-plate perfusion chamber.The cells were previously stimulated for 4 h with lipopolysaccharides(10 µg/ml) and interleukin 1β(50 U/ml),resulting in optimal expression of biological active tissue factor.The wall shear rate at the cell surface was 50 s-1 and mimicked venous blood flow conditions.Immunologically quantified fibrin deposition on the stimulated cells was reduced only by curative doses of Calciparine® and Fraxiparine® at 3 h(3.4 ± 0.8 versus 1.0 ± 0.2 µg/cm2 and 2.6 ± 0.8 versus 1.0 ± 0.1 µg/cm2, respectively,p ≤0.05).The influence of Calciparine® and Fraxiparine® on the formation of thrombin and fibrin was determined by measuring the plasma levels of thrombin-antithrombin III complexes and fibrinopeptide A (FPA) in blood samples collected distally to the perfusion chamber.The generation of these markers was significantly inhibited (50-83%) by both prophylactic and curative doses of Calciparine® and Fraxiparine®(p ≤0.05).However, Fraxiparine® still significantly inhibited the thrombin and fibrin generation at 8 h (p ≤0.05), whereas Calciparine® did not.The antithrombotic effects of both heparins were correlated with their plasma activities as measured by the antifactor Xa or the antithrombin assays.Thus,it appears in this model that Calciparine® and Fraxiparine® produce comparable antithrombotic effects at clinically comparable doses. However Fraxiparine® has a longer-lasting anticoagulant activity than Calciparine®. These results are ingood agreement with clinical observations in man,and thus in favour of our model of human venous thrombogenesis for further studies of antithrombotic molecules.
Immunohistochemical Localization of a Novel Peptide, Prostacyclin-Stimulating Factor (PSF), in Human Tissues
Authors: Masakado Mitsunorl , Umeda Fumio , Takei Akira , Hashimoto Toshihiko , Suelshi Katsuo , Nawata Hajime 
Published: July 2018

SummaryIn a recent study, we purified and cloned a newly identified bioactive factor that stimulates prostacyclin (PGI2) production by vascular endothelial cells (ECs) using conditioned medium (CM) from cultured human diploid fibroblast cells. The present study was undertaken to clarify whether PSF is expressed in ECs and vascular smooth muscle cells (SMCs) of human tissues at a protein level. In an immunohistochemical study of seven human autopsy cases, all arteries in all lungs (n = 4) and kidneys (n = 6) examined stained positive to variable extents for PGI2-stimulating factor (PSF). PSF was predominantly expressed by SMCs in the media of small arteries. Staining for PSF was weaker in SMCs of aortic media (n = 3) and strong in SMCs of vaso vasorum (n = 3). PSF staining was also found in the SMCs of human bronchi (n = 4). Immunoblot analysis confirmed that PSF is present in CM from cultured bovine aortic SMCs.
Collagen-Mediated Platelet Aggregation: The Role of Multiple Interactions between the Platelet Surface and Collagen
Authors: Santoro Samuel A , Cunningham Leon W 
Published: July 2018

SummaryAlthough the requirement for collagen fibrils to initiate platelet aggregation is well established, there has been no satisfactory explanation for this requirement. One possibility is that multiple simultaneous and linked interactions between collagen and the platelet surface must occur to initiate the release reaction and subsequent aggregation.Direct evidence in support of this proposal was obtained by examination of the ability of collagen crosslinked in a random manner with glutaraldehyde to initiate platelet aggregation. Collagen crosslinked with 0.25 % glutaraldehyde is only a slightly less effective aggregating agent than native fibrillar collagen. Further studies revealed that whereas native triple helical cross-linked collagen is an effective aggregating agent, denatured crosslinked collagen is ineffective.It thus appears that crosslinking of platelet receptor sites by multiple simultaneous and linked interactions with a rigid collagen matrix is required to initiate platelet aggregation. The precise steric relationship of the collagen sites does not appear to be of great importance.
Fat Emulsion Infusion Potentiates Coagulation Activation during Human Endotoxemia
Authors: van der Poll Tom , Coyle Susette M , Levi Marcel , Boermeester Marja A , Braxton Carla C , Jansen Patty M , Hack C Erik , Lowry Stephen F 
Published: July 2018

SummaryIntravenous fat emulsions are frequently given to malnourished patients who are prone to suffer from infectious complications. As injection of low dose endotoxin represents a model to study the human response to acute infection, we sought to determine the effect of lipid emulsion infusion on endotoxin-induced activation of the hemostatic mechanism in man. Ten healthy men received a bolus intravenous injection of endotoxin (lot EC-5; 20 U/kg) midway through a 4-h infusion (125 ml/h) of either dextrose 5% (n = 5) or Intralipid 20% (n = 5). Lipid infusion potentiated endotoxin-induced coagulation activation, as indicated by higher plasma levels of the prothrombin fragment FI + 2 and of thrombin-antithrombin III complexes (both p <0.05 for the difference between groups). However, lipid infusion did not influence the fibrinolytic response to intravenous endotoxin, as reflected by similar increases in the levels of tissue-type plasminogen activator and plas-min-α2-antiplasmin complexes in both groups. Endotoxin-induced appearance of plasminogen activator inhibitor type I was enhanced by lipid infusion (p <0.05). These data suggest that fat emulsion infusion may enhance the tendency towards thrombotic complications in patients with infections.
Effects of Chronic Factor VIII Substitution on Immune Parameters in HIV Seronegative Haemophiliacs: a Comparison between Cryoprecipitate and Factor VIII Concentrate
Authors: Allersmaa D P , Smld W M , van der Does J A , van der Meer J , Briët E 
Published: July 2018

SummaryChronic substitution therapy of HIV-negative haemophiliacs with factor VIII products can result in abnormalities of ex-vivo measured immune parameters. To assess a possible relation between these abnormalities and product purity, we analyzed two groups of HIV-negative HCV-positive haemophiliacs, one treated with cryoprecipitate exclusively, the other with more purified factor VIII concentrates. Compared to age matched non-transfused male controls, increased numbers of white cells, granulocytes, IgG and IgM levels and decreased CD4+/CD8+ ratios were found in both patient groups. In the concentrate receivers, the numbers of mononuclear cells, CD4+, CD8+ and CD3+/HLA-DR+ cells indicating activated T-cells, were higher than in the cryoprecipitate group. In conclusion, both cryoprecipitate and intermediate/high purity concentrate recipients showed immune parameter abnormalities. These abnormalities tended to be somewhat more pronounced in patients treated with concentrates. By now there is no indication of the clinical relevance of the abnormalities in previously treated HIV seronegative haemophiliacs.
Platelet Reactivity In Vitro in Relation to Thromboxane in Healthy Pregnancy
Authors: Horn E H , Hardy E , Cooper J , Heptinstall S , Rubin P C 
Published: July 2018

SummaryThere is substantial evidence of increased platelet reactivity in vivo and in vitro during pregnancy. Previous in vitro studies suggest that platelets from pregnant women show increased sensitivity to agonists, the response to which has a thromboxane dependent component. The aim of this study was to determine whether this is due to increased activity of the thromboxane biosynthetic pathway or to increased platelet sensitivity to the effects of thromboxane. During pregnancy, platelets were more sensitive to the pro-aggregatory effects in vitro of the thromboxane mimetic U46619, in whole blood and in platelet rich plasma, compared to those from non-pregnant controls. The difference in extent of U46619-induced platelet aggregation between groups was abolished in the presence of a high concentration of the specific thromboxane antagonist ICI 192605, but not by prior incubation of blood with aspirin. Platelets from pregnant women were significantly less sensitive to inhibition of arachidonic acid induced activation by the thromboxane synthetase inhibitor dazmegrel, but there was no change in platelet cyclic AMP accumulation under these conditions. Arachidonic acid induced platelet thromboxane B2 production was similar in pregnant and non-pregnant subjects. In conclusion, platelets are more sensitive to the activating effects of thromboxane during pregnancy, but there is no change in the intrinsic reactivity of the thromboxane biosynthetic pathway.
A Novel Platelet Activating Factor Antagonist, SM-12502, Attenuates Endotoxin-induced Disseminated Intravascular Coagulation and Acute Pulmonary Vascular Injury by Inhibiting TNF Production in Rats
Authors: Murakami Kazunori , Okajima Kenji , Uchiba Mitsuhiro , Johno Masayoshi , Okabe Hiroaki , Takatsuki Kiyoshi 
Published: July 2018

SummaryAdult respiratory distress syndrome and disseminated intravascular coagulation are important pathologic conditions affecting the outcome of patients with sepsis. To elucidate the possible therapeutic efficacy of SM-12502, a novel platelet activating factor antagonist, on acute lung injury and disseminated intravascular coagulation in sepsis, we investigated the effect of SM-12502 on an endotoxin (ET)-induced septic model in rats. SM-12502 prevented ET-induced increases in pulmonary vascular permeability and ET-induced histologic changes, such as leukocyte infiltration and pulmonary interstitial edema, 6 h following the administration of ET (5 mg/kg). SM-12502 also inhibited the decrease in fibrinogen and the increase in fibrin and fibrinogen degradation products observed following ET administration. SM-12502 prevented increases in the serum concentration of tumor necrosis factor (TNF) 90 min following ET administration in vivo, and significantly inhibited the production of TNF-α by ET-stimulated monocytes in vitro.These findings suggest that SM-12502 attenuates the actions of endotoxin by the inhibition of TNF production
Decreased Potency Of Factor VIII Concentrates
Authors: Kasper C K 
Published: July 2018

Plasma factor VIII recoveries after infusions of factor VIII concentrates into patients with classic hemophilia have been measured in this laboratory for 14 years. Recently, we observed a decline in the in vivo recovery of factor VIII per factor VIII unit infused. In 1980, plasma factor VIII levels were measured by a one-stage APTT-based assay before and 10 min after 150 infusions of 46 lots of 3 brands of factor VIII concentrate produced in the U.S.A. Our pooled normal plasma reference was calibrated against WHO International Standard 2 and results expressed in International factor VIII units. Observed in vivo factor VIII recovery was compared to the value expected from calculations based on the unitage stated on the label. The ratio of observed/expected recovery averaged 56% per lot for brand A, 60% per lot for brand B, and 103% per lot for brand C. In vitro assays were performed on 22 lots on 36 occasions, and the ratio of observed/labelled units average 46% per lot for brand A, 53% for brand B and 75% for brand C. The two-stage factor VIII assay method of Pool and Robinson was also used to assay plasma samples from 18 infusions, and results averaged 135% of the one-stage values for infusions of brand A, 160% for brand B, and 109% for brand C. (Brand A is assayed by the manufacturer by a two-stage method, brands B and C by one-stage methods.)Decreased clinical efficacy was observed when postinfusion plasma factor VIII levels were lower than customary. The decline in potency of brands A and B has necessitated more frequent assay of patients and use of larger amounts of concentrate, with greatly-increased expense. Investigation of the effect of different assay methods and different factor VIII standards and references on the apparent factor VIII content of concentrates has begun.
LDL-Induced Cell Injury. An Effect Of LDL Independent Of Specific Binding And Uptake Of LDL
Authors: Børsum T , Henriksen T , Carlander B 
Published: July 2018

LDL can injure endothelial cells in culture. HDL can inhibit this injurious effect of DDL. This effect of LDL seems to be independent of the LDL-receptor pathway since LDL-receptor negative cells were also injured. Ehdocytotic uptake of LDL appear not to be necessary for the DDL- induced cell injury to occur because LDL can injure both endothelial cells and erythrocytes at 4°C. By using radioactive 125I-DDL an increasing amount of 125I-LDL was shown to be associated with the cell with increasing concentrations of 125I-LDL in the incubation medium. A corresponding increase in cell injury as measured by 51Cr-release was observed. Presence of HDL in the incubation medium reduced both the cell associated radioactivity and the 51Cr-release. Thus, a relationship between the amount of 125I-DDL associated with the cell and the degree of cell injury was present.In conclusion, association of DDL to the cell surface seems to be closely related to the mechanism by which DDL can induce cell injury. Any kind of endocytotic uptake of DDL is not a prerequisite for the occurrence of DDL-mediated cell injury.
Enhancement Of The Effect Of Bradykinin On Microvascular Permeability By A Peptide Derived From Fibrinogen
Authors: Eriksson M , Gerdin B , Saldeen T 
Published: July 2018

Some low molecular weight fibrin degradation products (LMW-FDP) cause increased microvascular leakage in the dorsal skin of the rat. Two peptides earlier termed 6A and 6D seem to cause most of this effect. As unfractioned LMW-FDP potentiate bradykinin we have investigated how the leakage due to bradykinin is affected by the peptides 6A and 6DMethods. Different concentrations of peptide 6A (Ala-Arg- Pro-Ala-Lys), 6D (Ser-Gln-Leu-Gln-Lys-Val-Pro-Pro-Glu-Trp-Lys), inhibitors of kininase I and II (arginine and SQ14,225) were tested alone as well as together with different concentrations of bradykinin. The substances were injected in the previously shaved dorsal skin of 125I-albumin treated rats. The radioactivity content in the skin was measured in each injection site and the effect on microvascular permeability was calculated.Results. Thirty minutes after an injection of 6A or SQ14,225 together with bradykinin the leakage due to each mixture was greater than the sum of each substance per se. The response was dose-dependant. Simultaneous application of 6A, bradykinin and SQ14,225 caused a further increase in microvascular permeability. 6A and arginine had only marginal action upon the leakage due to bradykinin. 6A did not potentiate the effect of bradykinin after 5 min, while SQ14,225 showed a slight potentiation, however less than after 30 min. SQ14,225 itself was without effect.Discussion. As peptide 6A did not potentiate bradykinin after 5 min in contradiction to SQ14,225 it seems that their effects are not completely identical. The dramatical effect of SQ14,225 and the limited effect of arginine indicate that kininase II is the principle enzyme degrading bradykinin in rat skin. The effect of peptide 6A, even at low concentrations, indicate that this peptide, apart from its intrinsic effect on microvascular permeability, also can be of pathophysiologic significance in inflammatory states as potentiator of bradykinin.
Models Of Granulocyte-Mediated Endothelial Injury In Vitro
Authors: Vercellotti G , Flynn P , Weisdorf D , Lammi-Keefe C J , Jacob H , Moldow C F 
Published: July 2018

To determine the role of neutrophil (PMN) induced vascular injury during inflammation an in vitro model of endothelial damage was investigated. Injury to human umbilical vein endothelial cells (EC) labeled with 51Cr or 14c sodium arachidonate was monitored by specific release of these labels or their products. Several agents were capable of triggering PMN to induce significant EC injury: these include activated serum complement (C') opsonized particles, serotonin , phorbol myristate acetate, and the lipid A moiety of endotoxin. PMN must adhere closely to the EC for effective cytotoxicity, since agents which retard PMN adherence (cytochalasin B, methyl prednisolone) inhibit 51Cr release.Lyscsorcal proteases did not mediate PMN induced endothelial injury since there was no correlation between release and injury, and soluble stimuli which did not release lysosomal contents induced injury. Free radical scavengers such as SOD/catalase, and a-tocopherol significantly reduced PMN mediated endothelial injury implying that PMN generated reactive oxygen species were responsible for this damage.To further study PMN mediated endothelial injury, other inflammatory agents were also utilized. C' activated PMN’s exposed to Ibuprofen (I) (50 μg/ml) but not Aspirin (ASA) (200 μg/ml) induced no EC injury (51cr releasey Furthermore, it was shown that I inhibits O-
2 production, blocks release of PMN lysozyme and glucuronidase, and inhibits aggregation of C' stimulated PMN’s. ASA at doses of 500 μg/ml (clinically toxic), failed to inhibit these in vitro activities. This data suggests that I’s anti-inflammatory affect may be expressed through inhibition of PMN functions. Since I and ASA both inhibit cyclooxygenase, but only I modulated PMN induced endothelial injury, these agents may provide useful probes to elucidate PMN-endothelial interactions in vivo.
The Influence Of Red Cell Size On Platelet-Vessel Wall Interaction
Authors: Aarts P A M M , Sixma J J , Sakariassen K S , Bolhuis P A , Heethaar R M 
Published: July 2018

The hematocrit is one of the main factors influencing platelet adherence to the vessel wall. Raising the hematocrit causes an increase on platelet accumulation of about one order of magnitude.These studies disregard the influence of the red cell size. We have studied this effect using an annular perfusion chamber according to Baumgartner, with human umbilical arteries and a steady flow system. Perfusions were performed with reconstituted blood consisting of the appropriate washed red cells, aspirin treated and 51Cr labelled human platelets and human plasma. Perfusions were at a calculated vessel wall shear rate of 800 sec-1 for 5 min at 37°C. Platelet adherence was measured by 51Cr counting and controlled by morphometry. Human, goat and rabbit red blood cells were utilized. Human red blood cells (mean cell volume 100 f1) increase platelet adherence sevenfold, as the hematocrit increases from 0 to 60%. Human erythrocyte ghosts had a similar effect. Goat erythrocytes (m.c.v. 25 f1) caused no increment in adherence in the same hematocrit range. Rabbit erythrocytes (m.c.v. 70 f1) caused an intermediate increase in adherence.These data indicate that the red cell size is of major importance for platelet adherence. They may be explained by postulating that red cell rotation is responsible for diffusivity.
Depressed Responsiveness To Adrenaline In Platelets From Apparently Normal Human Donors – A Familial Trait
Authors: Scrutton M C , Bruckdorfer K R , Hutton R A 
Published: July 2018

Decreased responsiveness to adrenaline has been observed in 5 out of approximately 150 apparently normal unrelated human donors. In 4 donors, familial studies have shown that this trait is inherited. Three of the donors, as well as their affected relatives, exhibit depressed responsiveness to collagen and vasopressin but normal responsiveness to ADP and thrombin in association with the decreased responsiveness to adrenaline. The other two affected donors exhibit normal responsiveness to most other agonists although in one instance depression of responsiveness to vasopressin and absence of a secretory response to ADP may be associated with the decreased adrenaline response.Normal responsiveness can be restored in all instances either by incubating the platelet-rich plasma at 20°C or by addition at 37°C of a low concentration of the divalent cation ionophore, A-23187. No such effect results from addition of an adenylate cyclase inhibitor. All affected platelets have normal ATP and ADP contents, cholesterol to phospholipid ratios, and composition of the phospholipid classes. Mixing experiments demonstrate the absence of a circulating inhibitor of platelet function and suggest that the defect resides in the platelets. We conclude that depressed responsiveness of human platelets to adrenaline may result from a defect in Ca2+ mobilisation to the cytosol. The observed selectivity in the agonists affected may indicate that the stimulus-response coupling pathways converge at the level of an increase in cytosolic Ca2+ concentration.
Dextran Sulfate Induced Activation Of Prekallikrein In Normal Plasma And Inactivation Of Kallikrein
Authors: Graaf F V D , Keus J F A , Rietveld A , Vlooswijk R A A , Bouma B N 
Published: July 2018

Addition of dextran sulfate (DXS; Mr 500.000) to normal human plasma (n.h.p.) at 4° C results in the generation of kallikrein amidolytic activity. Maximum kallikrein activity is generated after 7 minutes in n.h.p., while no kallikrein activity is generated in Factor XII and Prekallikrein (PK) deficient plasma and only small amounts (8%) in High Mr Kininogen (HMWK) deficient plasma. Anti Factor XII, anti PK or anti HMWK added to n.h.p. blocked the formation of kallikrein activity. This shows that Factor XII, PK and HMWK are necessary for optimal activation of PK.By adding 125I-PK to n.h.p. followed by activation with DXS it was shown that the appearance of kallikrein activity is paralled by limited proteolysis of 125I-PK, as judged on reduced SDS gels. The same cleavage fragments were observed as obtained by activation of purified PK by ²-Factor XIIa (28.000 Mr form). Addition of 131I-HMWK and 125I-PK or 131I-HMWK rand I-Factor XII to normal plasma followed by activation with DXS indicated on SDS gels a similar rate of cleavage for HMWK and PK whereas Factor XII was cleaved less extensive.Inactivation of kallikrein in plasma was studied at 37°C after activation with DXS at 4°C. Kallikrein was rapidly inactivated, reaching a plateau after 4 minutes of 10% of its maximum activity. In Cj inhibitor deficient plasma kallikrein was less rapid inactivated and a plateau of 30% was reached after 9 minutes. 125I-PK was added to n.h.p. prior to activation at 4°C and inactivation at 37°C. This plasma was analyzed by crossed immunoelectrophoresis. Radioactivity was detected in the precipitin peak using anti C1 inhibitor and anti α2-macroglobulin (β2M) but not with anti antithrombin III. Using purified proteins it was shown that C1 inhibitor inhibited kallikrein amidolytic activity completely, whereas α2M inhibited this activity only to 25% of its original activity. This remaining amidolytic activity is that of the α2M-kallikrein complex. Complexes of kallikrein and inhibitor and kallikrein and α2M were observed on SDS gels in the presence and absence of reducing agents.