bluuebunny/crossref_metadata_2025_split huggingface dataset:
Platelet-Bound Prekallikrein Promotes Pro-Urokinase-Induced Clot Lysis: A Mechanism for Targeting the Factor XII Dependent Intrinsic Pathway of Fibrinolysis
Authors: Loza Jean-Pierre , Gurewich Victor , Johnstone Michael , Pannell Ralph 
Published: July 2018

SummaryClots formed from platelet rich plasma were found to be lysed more readily by low concentrations of pro-urokinase (pro-UK) than clots formed from platelet poor plasma. This was not a non-specific effect since the reverse occurred with tissue plasminogen activator. A mechanical explanation due to platelet-mediated clot retraction was excluded by experiments in which retraction was inhibited with cyto-chalasin B. Therefore, a platelet-mediated enzymatic mechanism was postulated to explain the promotion of fibrinolysis. Casein autography of isolated platelets revealed a ≈ 90 kDa band of activity which comigrated with plasma prekallikrein (PK)/kallikrein, a known activator of pro-UK. Furthermore, treatment of platelets with plasma PK activator (PPA), consisting essentially of factor XIIa, induced activation of pro-UK and of chromomgenic substrate for kallikrein (S-2302). This activity corresponded to approximately 40-200 pM kallikrein per 10
8 washed and gel filtered platelets per ml. The activation of pro-UK by PPA-pretreated platelets was dose-dependent and inhibited by soybean trypsin inhibitor but not by bdellin, a specific inhibitor of plasmin, nor by the corn inhibitor of factor XIIa. Kinetic analysis of pro-UK activation by kallikrein showed promotion of the reaction by platelets. The KM
of the reaction was reduced by platelets by ≈ 7-fold, while the kcat
was essentially unchanged. In conclusion, PK was shown to be tightly associated with platelets where it can be activated by factor XIIa during clotting. The activation of pro-UK by platelet-bound kallikrein provides an explanation for the observed platelet mediated promotion of pro-UK-induced clot lysis. Since pro-UK and plasminogen have also been shown to be associated with platelets, the present findings suggest a mechanism by which the factor Xlla-dependent intrinsic pathway of fibrinolysis can be localized and targeted to a thrombus.
A Comparative Study of Prothrombinase and Thrombin Inhibitors in a Novel Rabbit Model of Non-Occlusive Deep Vein Thrombosis
Authors: Hollenbach Stan , Sinha Uma , Lin Pei-Hua , Needham Kathy , Frey Lisa , Hancock Tom , Wong Arnold , Wolf David 
Published: July 2018

SummaryA quantitative and non-occlusive deep vein thrombosis model was developed in rabbits. We used this model to test the antithrombotic activity of the prothrombinase complex inhibitors factor rXai and its chemical analog glutamyl-glycyl-arginyl chloromethyl ketone inactivated human factor Xa (EGR-Xai), along with the thrombin inhibitors D-phenylalanyl-prolyl-arginyl chloromethyl ketone (PPACK) and heparin. Dose dependent effects of the inhibitors during constant infusion were monitored. Measurements included thrombus weights, hemostatic parameters and both cuticle and ear bleeding times. In this model, factor rXai and EGR-Xai had comparable in-vivo efficacy, and showed 80%-93% inhibition at plasma levels of 6.5 nM (rXai) and 8 nM (EGR-Xai). Effects on ex-vivo clotting times varied among the inhibitors. At 80-100% thrombus inhibition, factor rXai and EGR-Xai had no statistically significant effect, while PPACK extended thrombin clotting time (TCT) times 2.3-fold, and heparin prolonged both activated partial thromboplastin time (APTT), prothrombin time (PT) and TCT ex-vivo clotting times 6.9-, 1.2-, and 7-fold respectively. At these dosages, cuticle and ear bleeding times were prolonged for all inhibitors and showed increases of 177%-389% (cuticle) and 45%-129% (ear). Our results demonstrate that direct inhibition of prothrombinase complex assembly is effective in arresting venous thrombosis.
Effects of Recombinant Human Soluble Thrombomodulin (rhs-TM) on a Rat Model of Disseminated Intravascular Coagulation with Decreased Levels of Plasma Antithrombin III
Authors: Aoki Yoshikazu , Ohishi Rika , Takei Ryoichi , Matsuzaki Osamu , Mohri Mitsunobu , Saitoh Ken-ichi , Gomi Komakazu , Sugihara Taisuke , Kiyota Takao , Yamamoto Shuji , Ishida Torao , Maruyama Ikuro 
Published: July 2018

SummaryWe reported that recombinant human soluble thrombomodulin (rhs- TM) is effective for disseminated intravascular coagulation (DIC) in vivo, in mice and rats. In the present work, we investigated the effects of decreased plasma antithrombin III (ATIII) levels on anticoagulant effects of rhs-TM, as compared to findings with heparin, of which effect is lowered by the decreased plasma ATIII levels in patients with DIC. Rat plasma ATIII levels decreased when we mixed plasma with anti-rat ATIII antibody and the potential of heparin to prolong APTT or PT was markedly diminished. The potential of rhs-TM to prolong APTT and PT was not affected. In rats injected with anti-rat ATIII antibody, plasma ATIII levels decreased immediately. When the rats were infused with tissue factor (TF), DIC was induced. At doses of rhs-TM and heparin which were equally effective at inhibiting the decrease in platelet count and fibrinogen level in cuntiol rats treated with TF, only rhs-TM remained effective in preventing DIC in rats with reduced ATIII levels. Heparin was not effective, when administered to these rats with reduced ATIII levels. Therefore, rhs-TM effectively inhibits coagulation independent of ATIII levels, in contrast to heparin, which depends on the ATIII level.
Is Heparin the Ideal Anticoagulant for Cardiopulmonary Bypass? Dermatan Sulphate May Be an Alternate Choice
Authors: Brister Stephanie J , Ofosu Frederick A , Heigenhauser George J F , Gianese Francesco , Buchanan Michael R 
Published: July 2018

SummaryPerformance of cardiopulmonary bypass (CPB) during cardiac surgery requires the administration of high dose heparin to prevent CPB pump occlusion. However, this heparin use is associated with bleeding side-effects. Moreover, at the end of CPB, the heparin must be neutralized with protamine sulphate, which is also associated with adverse side-effects. A number of recent studies suggest that dermatan sulphate may be useful as an alternate anticoagulant to heparin. We determined whether CPB could be performed using dermatan sulphate instead of heparin, in an adult pig CPB model. When heparin was used, a high dose (> 200 U/kg, which generated > 3 anti-thrombin U/ml of plasma), was required to perform successful CPB and to maintain CPB pump patency. This dose was associated with a post CPB bleeding of ≈ 600 ml/2h. in contrast, successful CPB could be achieved when the pigs were given lower doses of dermatan sulphate than heparin, which in turn, were associated with less bleeding. We conclude that dermatan sulphate may be an alternate anticoagulant for cardiac surgery
Activation and Inactivation of Human Protein C by Plasmin
Authors: Váradi Katalin , Philapitsch Anton , Santa Thomas , Schwarz Hans Peter 
Published: July 2018

SummaryTransient procoagulant states resulting in failure of recanalization or rethrombosis of the reperfused artery during thrombolytic therapy might be due to an inhibitory effect of plasmin on the anticoagulant properties of protein C. We therefore studied the effect of plasmin on protein C (PC) and activated protein C (APC) using purified human proteins.Incubation of 70 nM purified human PC with 40-400 nM human plasmin resulted in rapid activation and subsequent inactivation of PC as measured by amidolytic and anticoagulant assays. The rates of activation and inactivation were dependent on the concentration of plasmin. Lower concentrations of plasmin resulted in higher peaks of generated APC and more sustained activity, while at higher concentrations, both activation and inactivation were more rapid. Anticoagulant activity appeared more sensitive to inactivation by plasmin than amidolytic activity; e. g., while amidolytic activity reached a maximum of 13.8 nM in 6 min and declined to approximately 6 nM after 30 min, anticoagulant activity reached its maximum of only 1.4 nM within 30 s and completely disappeared within 90 s.Plasmin rapidly destroyed both the anticoagulant and amidolytic activity of purified APC, with second order rate constants of 2.8 × 105 M−1 s−1 and 1.2 × 104 M−1 −1, respectively, for 70 nM APC. The rates of activation and subsequent inactivation were slowed by the presence of CaCl2. The second order rate constant of inactivation of APC amidolytic activity decreased to 6.6 × 103 M−1 s−1 in the presence of 5 mM CaCl2. Proteolytic degradation of both PC and APC corresponding to the loss of amidolytic activity was demonstrated on SDS-PAGE using 125I-labelled proteins. When normal human plasma was incubated with plasmin or streptokinase a substantial loss of PC anticoagulant activity was observed.These results in vitro suggest that plasmin modulates the anticoagulant properties of protein C in a way that might be of relevance for the success of fibrinolytic therapy.
Aprotinin Could Promote Arterial Thrombosis in Pigs: a Prospective Randomized, Blind Study
Authors: Samama Ch M , Mazoyer E , Bruneval P , Ciostek P , Bonnin Ph , Bonneau M , Roussi J , Bailliart O , Pignaud G , Viars P , Caen J P , Drouet L O 
Published: July 2018

SummaryHaemostatic properties of aprotinin could be associated with an increased risk of thrombosis. A randomized, blinded study was conducted to consider the potential thrombogenicity of aprotinin, using the Fobs’ model on femoral arteries in 12 pigs. The flow variations were measured by a pulsed Doppler in anaesthetised animals. Ear immersion bleeding time was performed. During the first part of the study, a stenosis was performed successively on both femoral arteries, each for a period of 30 min, without prior injury, to assess the integrity of the vessel, and to check that the arteries did not develop cyclic flow reductions (CFR), permanent cessation of flow (PCF) or partial thrombosis, when a stenosis is applied. Then the clamp was released and a bolus of placebo (saline), or aprotinin (4 millions KIU, followed by a continuous infusion of 1 million KIU · h−1), was administered. At the end of the bolus, the second part of the study began. Stenosis was applied to the arteries. If CRF, PCF, or partial thrombosis were observed without prior injury then the infused drug (aprotinin or saline) was considered a prothrombotic drug, and the opposite artery was studied. For each animal, right and left femoral artery segments were fixed and studied (morphologic study). Eighteen arteries were studied. In the aprotinin group, 6 arteries out of 8 developed an unexpected thrombosis, as compared with only 2 out of 10 arteries in the control group (p = 0.02). The morphologic study confirmed the occurrence of thrombosis in 4 out of 7 arteries in the aprotinin group, as compared with only 1 out of 9 in the control group. The ear immersion bleeding time was not different in either group. No difference could be demonstrated with regard to the values of activated partial thromboplastin time, prothrombin time and fibrinogen.Aprotinin may have promoted the development of thrombosis in the pig.
Adjusted Versus Fixed Doses of the Low-Molecular-Weight Heparin Fragmin in the Treatment of Deep Vein Thrombosis
Authors: Alhenc-Gelas M , Guernic C Jestin-Le , Vitoux J F , Kher A , Aiach M , Fiessinger J N ,   Fragmin-Study Group
Published: July 2018

SummaryTreatment monitoring based on a laboratory parameter increases the efficacy and safety of standard heparin therapy, but it is not known if this also applies to low-molecular-weight heparin (LMWH) therapy of acute deep vein thrombosis (DVT). In a prospective randomized trial involving 122 consecutive patients, group A (58 patients) received a weight adjusted dose of Fragmin (100 IU/kg) subcutaneously twice a day throughout the treatment period (10 days ± 1), while in group B (64 patients) the dosage was based on the results of an anti factor Xa (anti Xa) amidolytic assay to obtain a target concentration from 0.5 to 1 IU/ml. AntiXa and antithrombin activities were also measured retrospectively on frozen plasma from all patients. The two regimens were comparable in terms of hemorrhagic complications (4 in group A and 3 in group B). Bilateral ascending phlebography was performed before inclusion and at the end of LMWH treatment. Treatment efficacy, based on Marder’s score, did not differ between the two groups (p = 0.3). Dosage adjustment to between 0.5 to 1IU anti-Xa/ml does not therefore appear to improve the efficacy or safety of LMWH tieatment. However, correlations between the change in Marder’s score and both anti-Xa (p <0.001) and antithrombin activity (p <0.001) were observed, suggesting a relationship between the degree of FXa or thrombin inhibition and antithrombotic activity.
Relationship of Tissue Factor Pathway Inhibitor Activity to Plasma Lipoproteins and Myocardial Infarction at a Young Age
Authors: Moor Elisabeth , Hamsten Anders , Karpe Fredrik , Båvenholm Peter , Blombäck Margareta , Silveira Angela 
Published: July 2018

SummaryTissue factor pathway inhibitor (TFPI) activity was quantified in two cohorts of young male post-infarction patients and in population-based control subjects to explore the relationships between TFPI activity and plasma lipoproteins and to address the issue of coordinate regulation of factor VII and TFPI in hyperlipidaemia and premature coronary heart disease (CHD). Participants were investigated in the fasting state and after an oral fat load. Basal TFPI activity and factor VII antigen (VIIag) levels were found to be increased in the patients (TFPI activity 1.25 ± 0.23 vs 1.17 ± 0.20 U/ml, p <0.05; VIIag 537.7 ± 127.7 vs 479.4 ± 93.4 ng/ml, p <0.001). The parallel increase was accounted for by patients with hypertriglyceridaemic lipoprotein phenotypes. In contrast, the level of activated factor VII (VIIa) neither differed significantly between patients and controls, nor between patients with different lipoprotein phenotypes. The elevated TFPI activity in the patients was closely associated with the plasma level of dense low density lipoprotein (LDL) particles (r = 0.46, p <0.001) and with the plasma concentration of the small, dense high density lipoprotein (HDL) subspecies HDL3b (r = 0.34, p <0.01).
Apolipoprotein(a), Fibrinopeptide A and Carotid Atherosclerosis in Middle-Aged Men
Authors: Rankinen Tuomo , Väisänen Sari , Mercuri Michele , Rauramaa Rainer 
Published: July 2018

SummaryThe association between apolipoprotein(a) [apo(a)], fibrinogen, fibrinopeptide A (FPA) and carotid intima-media thickness (IMT) was analyzed in Eastern Finnish men aged 50 to 60 years. Apo(a) correlated directly with carotid bifurcation (r = 0.26, p = 0.001), but not with common carotid IMT. Men in the lowest quartile of apo(a) had thinner (p = 0.013) IMT in bifurcation [1.59 mm (95% Cl 1.49; 1.68)] compared to the men in the highest [1.91 mm (95% Cl 1.73; 2.09)] apo(a) quartile. The difference remained (p=0.038) after adjusting for confounders. Plasma fibrinogen was not related to carotid IMT, whereas FPA correlated with common carotid (r = 0.21, p = 0.016) and carotid bifurcation (r = 0.21, p = 0.018) IMT. These associations abolished after adjusting for the confounders. The data suggest that apo(a) associate with carotid atherosclerosis independent of other risk factors for ischemic cardiovascular diseases.
Thrombomodulin Induction by All-trans Retinoic Acid Is Independent of HL-60 Cells Differentiation to Neutrophilic Cells
Authors: Kizaki Keiichiro , Ishii Hidemi , Horie Shuichi , Kazama Mutsuyoshi 
Published: July 2018

SummaryThe expression of thrombomodulin (TM), an antithrombotic factor, was investigated during neutrophilic differentiation of the HL-60 human myeloblastic cell line treated with d\\-trans retinoic acid (ATRA) or dimethyl sulfoxide (DMSO). Differentiation of the cells into neutrophilic cells progressed in a time- and dose-dependent fashion with ATRA or DMSO, as confirmed by the characteristic appearance of nitroblue tetrazolium (NBT) reduction and phagocytic activities, without induction of nonspecific esterase activity. TM antigen and cofactor activity for thrombin-dependent protein C activation were not detected in untreated HL-60 cells and the cells cultured with DMSO, but were expressed in a time-dependent manner in the cells cultured with ATRA. The level of TM expression in the HL-60 cells was not dose-dependent on ATRA concentrations, but maximum TM expression was obtained at 10−7 M ATRA. TM expression levels decreased in cells cultured with greater than 10−6 M ATRA, although the extent of cell differentiation into neutrophilic cells progressed at the higher ATRA concentrations. Since the TM antigen levels in the ATRA-treated cells also paralleled the TM mRNA levels, the data suggests that TM induction in the HL-60 cells cultured with ATRA reflected the levels of TM biosynthesis and was independent of HL-60 differentiation into neutrophilic cells. It was postulated that the appearance of TM with cofactor activity in neutrophilic cells differentiated from leukemic cells may contribute to prevention of vascular thrombosis in differentiation therapy of patients with acute promyelocytic leukemia by ATRA.
Plasma D-Dimer as a Marker for Postoperative Deep Venous Thrombosis
Authors: Dunn Irene D , Hui Anthony C W , Triffitt Paul D , Crozier Ann E C , Gregg Paul J , Sinclair Marie E , Lynn Armstrong A , Mitchell Vivian E 
Published: July 2018

SummaryPlasma levels of D-dimer have been found useful as a marker of deep venous thrombosis in those patients in whom thrombosis is suspected, but their usefulness in postoperative screening is less clear. We have investigated the relationship of D-dimer to deep venous thrombosis in 90 patients after total hip and knee arthroplasty. From the first postoperative day the D-dimer levels were found to be highly significantly raised in patients with deep venous thrombosis. A combined result over the first six postoperative days in excess of 1200ng/ml correlated with thrombosis with a specificity of 100%, sensitivity of 45%, positive predictive value of 60%, and negative predictive value of 100%. However, individual estimations were not discriminatory.
French Multicentric Evaluation of Recombinant Tissue Factor (Recombiplastin) for Determination of Prothrombin Time
Authors: Roussi J , Drouet L , Samama M , Sié P , Bal C , Boudaoud L , Cazenave J P , Denninger M H , Droule Ch , Horellou M H , Levy G , Mazoyer E , Sampol J , Schved J F , Vergnes C 
Published: July 2018

SummaryRecombiplastin, a recombinant a human tissue factor, elaborated by Ortho Diagnostic Systems, produced by Baculovirus and relipidated with highly purified phospholipids, was tested as a new reagent for determining prothrombin time (PT) in a French multicentric study. Its intralaboratory- performances, including sensitivity, repeatability, reproducibility and stability, were explored to establish whether its use would reduce the interlaboratory dispersion of PT values, and therefore improve the standardization of oral anticoagulant treatment.The 9 university hospital hematology laboratories involved in this study used the same type of instrument (KC 10). For 10 consecutive days, they determined PTS on a normal plasma pool, plasma dilutions of 1/2, 1/3 and 1/8, 3 identical lyophilized calibrated plasmas, as well as plasmas from 20 normal subjects, 50 patients on oral anticoagulant therapy with Recombiplastin which has an International Sensitivity Index (ISI) of 1, and 2 commercial thromboplastin extracts (ISI #1 or 2). In the patients on anticoagulants, factors VII, X and V were measured when results were conflicting.The intra and interlaboratory reproducibilities of Recombiplastin, calculated on the basis of either PTS expressed in seconds, or of the International Normalized Ratio (INR), were good, with coefficients of variation (CV) similar to those observed with the 5 other reagents used by the different laboratories (2% <CV <8%).The stability of Recombiplastin was excellent, with no variation in PT after 72 h of incubation at 37° C.A normal PT of 12 s was obtained with Recombiplastin, similar to the values found for the reagents with ISI #2. In the patients on anticoagulants, Recombiplastin gave the longest coagulation times (PTRecombipiastin = 64.2 s vs PTNeoPlastin = 32.8 s, and PTThromborel = 54.4 s). These results suggest that Recombiplastin is highly sensitive to the changes in coagulation induced by anticoagulants. Recombiplastin was more sensitive to factor VII deficiency than any of the other reagents, even those with ISI #1.The coefficients of correlation between the INRS calculated on the basis of the PTS obtained with Recombiplastin and the INRS based on the PTS for other thromboplastins, were satisfactory (0.85 <R <0.95) but a breakpoint in the slope of the regression curves was observed when INR >4. This observation requires further investigation, particularly in connection with the exact ISI values for Recombiplastin and the other thromboplastins used in this study.In conclusion, Recombiplastin is stable and sensitive and gives accurate reproducible results. However, the behavior of Recombiplastin is slightly different from that of the commercial reagents whether their ISI is 1 or 2, and its use did not reduce the interlaboratory dispersion of PT values.
The Platelet Cytoskeleton
Authors: Fox Joan E B 
Published: July 2018

SummaryThe platelet cytoskeleton contains two actin filament-based components. One is the cytoplasmic actin filaments which fill the cytoplasm and mediate contractile events. The other is the membrane skeleton, which coats the plasma membrane and regulates properties of the membrane such as its contours and stability. In the unstimulated platelet, only 30-40% of the actin is polymerized into filaments; the rest is thought to be prevented from polymerizing by the association of thymosin β4 with monomeric actin and by the association of gelsolin with the barbed ends of pre-existing actin filaments. When platelets are activated, there is a rapid increase in actin polymerization; new filaments fill the extending filopodia and form a network at the periphery of the platelet. As a result of activation, myosin binds to cytoplasmic actin filaments, causing them to move towards the center of the platelet. As platelets aggregate, additional cytoskeletal reorganizations occur: GP Ilb-IIIa associates with adhesive ligand in a platelet aggregate; this results in the association of GP Ilb-IIIa, membrane skeleton proteins, and signaling molecules with cytoplasmic actin. Future studies should help to elucidate the significance of the cytoskeleton in regulating signal transduction events in platelets.
Antithrombotic Activity of Bay u3405, a Thromboxane A2-Antagonist, in Patients with Dacron Aortic Grafts: a Random Controlled Clinical Trial
Authors: Pieters H , Roodt J P , Badenhorst P N , van Wyk V , Schall R , Lötter M G , Hundt H K L , Nel C J C 
Published: July 2018

SummaryTwelve patients with Dacron aortic grafts participated in a placebo controlled, crossover trial to investigate the effect of Bay u3405, a thromboxane A2-receptor antagonist, on graft throm-bogenicity. During each treatment period (seven days, Bay u3405 or placebo), 111In-platelet survival and platelet deposition on the grafts were measured daily by γ-camera imaging and blood radioactivity analysis. Bay u3405 substantially reduced the deposition of platelets and the thrombogenic index, while platelet survival remained unchanged. The ex vivo platelet aggregation response to ADP and epinephrine was significantly inhibited. The bleeding time increased slightly but not to any clinically relevant extent, and no adverse side effects were recorded.Bay u3405 seems to be a safe and effective drug for the inhibition of platelet deposition on aortic Dacron grafts. The use of quantitative imaging techniques is also more sensitive than the measurement of platelet survival for the assessment of antiplatelet drug efficacy in patients with aortic grafts.