bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lipoprotein(a) Concentrations in Women with a History of Severe Preeclampsia – a Case Control Study
Authors: Koopman Maria , Wolf Hans , Büller Harry , Prins Martin , van den Ende Abraham , van Pampus Maria 
Published: March 2018

SummaryA high concentration of lipoprotein(a) is associated with athero-sclerotic disease. Atheroma may develop in spiral arteries in both preeclamptic and normal pregnancies, but they are much more common in preeclampsia, particularly in the decidual segments. We hypothesized that a high concentration of lipoprotein(a) is associated with the development of preeclampsia.We studied 40 women with a history of severe preeclampsia, 35 women with a history of preeclampsia and the (H)ELLP syndrome and 67 controls with a normal obstetric history. Lipoprotein(a) levels were measured at least 10 weeks post partum in the second half of a normal menstrual cycle. None of the women in the study or the control group were pregnant or used oral contraceptives. Lipoprotein(a) levels over the 90th percentile of the lipoprotein(a) distribution of our control group (420 mg/l) were defined as abnormal. There was a statistically significant higher prevalence of abnormal levels of lipoprotein(a) in women with a history of severe preeclampsia (33%) in comparison with women with a history of preeclampsia and (H)ELLP syndrome (9%) and with the control group (10%).We found that a history of severe preeclampsia and spontaneous abortion was associated with elevated lipoprotein(a) levels as a post-hoc finding. Whether spontaneous abortion and high levels of lipo-protein(a) are related remains to be demonstrated.
Characterization of Native Human Thrombopoietin in the Blood of Normal Individuals and of Patients with Haematologic Disorders
Authors: Matsumoto Atsushi , Tahara Tomoyuki , Morita Haruhiko , Usuki Kensuke , Ohashi Hideya , Kokubo-Watarai Atsuko , Takahashi Kieko , Shimizu Eiko , Tsunakawa Hikaru , Ogami Kinya , Miyazaki Hiroshi , Urabe Akio , Kato Takashi 
Published: March 2018

SummaryThrombopoietin (TPO) isolated from thrombocytopenic plasma of various animal species has previously been shown to comprise only truncated forms of the molecule, presumably generated by proteolysis. Native TPO has now been partially purified from normal human plasma by immunoaffinity chromatography and was confirmed to be biologically active. Gel filtration in the presence of SDS revealed that TPO eluted in two peaks: a major peak corresponding to the elution position of fully glycosylated recombinant human TPO (rhTPO) consisting of 332 amino acid residues, and a minor peak corresponding to a smaller molecular size. Immunoblot analysis also revealed that most plasma-derived TPO migrated at the same position as fully glycosylated rhTPO, corresponding to a molecular size of ~80 to 100 kDa. Furthermore, the size distribution of circulating TPO in patients with various haematologic disorders did not differ markedly from that of plasma-derived TPO from healthy individuals. These results indicate that the truncation of circulating TPO is not related to disease pa-thophysiology, and that the predominant form of TPO in blood is a biologically active ~80- to 100-kDa species. The size distribution of TPO extracted from normal platelets was similar to that of TPO in plasma; the proportion of truncated TPO was decreased by prior incubation of platelets with hirudin, indicating that the endogenous truncated TPO, at least in platelet extract, was generated by thrombin-mediated cleavage.
Dermatan Sulphate for the Prevention of Postoperative Venous Thromboembolism in Patients with Cancer
Authors: Di Carlo Valerio , Agnelli Giancarlo , Prandoni Paolo , Coccheri Sergio , Franco Gensini Gian , Gianese Francesco , Mannuccio Mannucci Pier ,   for the “DOS” (Dermatan sulphate in Oncologic Surgery) Study Group
Published: March 2018

Summary
Background: Patients undergoing surgery for cancer are at high risk for venous thromboembolism (VTE). Agents that selectively inhibit thrombin, such as dermatan sulphate, have potential for a favourable benefit-risk ratio in the prevention of this complication.
Methods: Patients scheduled for elective abdominal, thoracic, gynecologic or urologic surgery for cancer resection, were randomised to dermatan sulphate (600 mg intramuscularly on the second day before surgery, then 300 mg once daily), or calcium heparin (5,000 IU subcutaneously t.i.d., starting 2 hours before operation). Both treatments were continued until postoperative day 7 or until adequate mobilisation was achieved. Bilateral venography was scheduled at the end of treatment. Venograms were centrally assessed in blind conditions. The study outcomes were VTE (venographically proven deep vein thrombosis [DVT] or symptomatic, objectively confirmed pulmonary embolism) and bleeding complications.
Results: At 27 centres, 842 patients were randomised and underwent surgery (418 dermatan sulphate, 424 heparin). Efficacy was assessed in 521 patients with adequate venography and/or confirmed pulmonary embolism. DVT was observed in a total of 96 patients; symptomatic non-fatal pulmonary embolism developed in 2 patients (one per group), who also had DVT at venography. Postoperative VTE occurred in 40 of 267 patients on dermatan sulphate, 15.0%, versus 56 of 254 patients on heparin, 22.0% (p = 0.033). Relative risk reduction was 32.7% (95% confidence interval, 3.1 to 53.2%). The rate of bleeding complications in all operated patients was 6.9% with dermatan sulphate and 7.5% with heparin (confidence interval for the absolute risk difference, -4.1 to 2.9%). The inhospital mortality rate was 1.2% and 1.4%, respectively.
Conclusions: In oncologic surgery, dermatan sulphate prevents VTE more effectively than heparin without increasing bleeding complications.
Role of Tissue Factor in Metastasis: Functions of the Cytoplasmic and Extracellular Domains of the Molecule
Authors: Sundaram Ranjini , Homer Robert , Garen Alan , Konigsberg William , Bromberg Michael 
Published: March 2018

SummaryTissue factor (TF) is a transmembrane glycoprotein that complexes with factor VIIa to initiate blood coagulation. It was reported in an earlier study that expression of high levels of TF in a human melanoma cell line promotes metastasis, and that the cytoplasmic domain of TF is required for this metastatic effect. To analyze the functions of the cytoplasmic and extracellular domains of TF in metastasis, two TF mutants were constructed; in one mutant alanine was substituted for each of the three serine residues in the cytoplasmic domain, preventing phosphorylation; in the other mutant alanine was substituted for four key residues in the extracellular domain, preventing binding of factor VIIa and consequently eliminating the initiation of blood coagulation by the TF-VIIa complex. Melanoma lines expressing high levels of either mutant form of TF were weakly metastatic in SCID mice, indicating that phosphorylation of the cytoplasmic domain and formation of a complex with VIIa by the extracellular domain are required for the full metastatic effect of TF. It was also found that increasing TF expression in human melanoma cells does not increase expression of vascular endothelial growth factor or promote growth and vascularization of tumors derived from the melanoma cells, suggesting that TF acts by a mechanism other than angiogenesis to promote metastasis.
Relationship of Plasminogen Activator Inhibitor-1 Levels following Thrombolytic Therapy with rt-PA as Compared to Streptokinase and Patency of Infarct Related Coronary Artery
Authors: Paganelli Franck , Christine Alessi Marie , Morange Pierre , Michel Maixent Jean , Lévy Samuel , Juhan Vague Irène 
Published: March 2018

Summary
Background: Type 1 plasminogen activator inhibitor (PAI-1) is considered to be risk factor for acute myocardial infarction (AMI). A rebound of circulating PAI-1 has been reported after rt-PA administration. We investigated the relationships between PAI-1 levels before and after thrombolytic therapy with streptokinase (SK) as compared to rt-PA and the patency of infarct-related arteries.
Methods and Results: Fifty five consecutive patients with acute MI were randomized to strep-tokinase or rt-PA. The plasma PAI-1 levels were studied before and serially within 24 h after thrombolytic administration. Vessel patency was assessed by an angiogram at 5 ± 1days. The PAI-1 levels increased significantly with both rt-PA and SK as shown by the levels obtained from a control group of 10 patients treated with coronary angioplasty alone. However, the area under the PAI-1 curve was significantly higher with SK than with rt-PA (p <0.01) and the plasma PAI-1 levels peaked later with SK than with rt-PA (18 h versus 3 h respectively). Conversely to PAI-1 levels on admission, the PAI-1 levels after thrombolysis were related to vessel patency. Plasma PAI-1 levels 6 and 18 h after SK therapy and the area under the PAI-1 curve were significantly higher in patients with occluded arteries (p <0.002, p <0.04 and p <0.05 respectively).The same tendency was observed in the t-PA group without reaching significance.
Conclusions: This study showed that the PAI-1 level increase is more pronounced after SK treatment than after t-PA treatment. There is a relationship between increased PAI-1 levels after thrombolytic therapy and poor patency. Therapeutic approaches aimed at quenching PAI-1 activity after thrombolysis might be of interest to improve the efficacy of thrombolytic therapy for acute myocardial infarction.
The 4G/5G Polymorphism in the Plasminogen Activator Inhibitor-1 Gene Is not Associated with Myocardial Infarction
Authors: Doggen C. J. M. , Bertina R. M. , Cats V. Manger , Reitsma P. H. , Rosendaal F. R. 
Published: March 2018

SummarySeveral studies have found an association between high plasminogen activator inhibitor-1 (PAI-1) levels and myocardial infarction. Whether this is causal or a consequence of atherosclerosis or tissue damage, remains unclear. Homozygous carriers of the 4G allele of the 4G/5G polymorphism in the PAI-1 gene have higher PAI-1 levels compared to carriers of the 5G allele in healthy persons in some studies, but not all. If PAI-1 levels are causally related to myocardial infarction, one would expect more homozygous carriers of the 4G allele among patients, provided that these carriers have high PAI-1 levels among healthy persons in that population. We investigated the distribution of this polymorphism in the “Study of Myocardial Infarctions Leiden” (SMILE), including 331 men with a myocardial infarction and 302 control subjects and measured PAI-1 antigen levels among the latter. Secondly, we looked into the association of cardiovascular risk factors with PAI-1 levels.We did not find an increase in risk of myocardial infarction in carriers of the 4G allele. Neither did we find an association, nor a trend, between the 4G/5G polymorphism and PAI-1 antigen levels in control subjects. Controls with obesity, hypertension, or who smoked had significant higher PAI-1 antigen levels compared with persons without these factors. High cholesterol and triglyceride levels were also associated with high PAI-1 antigen levels, and HDL-cholesterol levels showed an inverse association.We conclude that the 4G/5G polymorphism in the PAI-1 gene is not associated with the risk of myocardial infarction. As we did not find any association between this polymorphism and PAI-1 antigen levels in healthy persons, we cannot draw any conclusions about the causality of PAI-1 itself for myocardial infarction.
Glycoprotein IIb/IIIa Receptor Antagonist Tirofiban Inhibits Thrombin Generation during Cardiopulmonary Bypass in Baboons
Authors: Sun Ling , Hiramatsu Yugi , Gorman Joseph H. , Edmunds L. Henry , Rao A. Koneti 
Published: March 2018

SummaryPlatelets play a major role in coagulation mechanisms and anti-GPIIb-IIIa antibodies inhibit tissue-factor induced thrombin generation in in vitro studies. Tirofiban, a nonpeptide selective glycoprotein (GP) IIb/IIIa antagonist, preserves platelet number and function during cardiopulmonary bypass (CPB) in baboons. We tested the hypothesis that platelet inhibition by tirofiban inhibits thrombin generation in vivo. Four groups of baboons (n = 7-12) were perfused for 60 min; all groups received heparin (300 units/kg). The controls received only heparin. The low dose (0.1 μg/kg/min) and high dose (0.3 μg/kg/min) infusion groups received tirofiban for 60 min before and 60 min during CPB. The bolus plus low dose infusion group received a 15 μg/kg bolus before starting CPB and a low dose infusion (0.1 mg/kg/min) only during CPB. At end of CPB, compared to control group (2.99 ± 0.36 nM), prothrombin fragment F1.2 levels were lower (p <0.05) in low dose infusion group (1.65 ± 0.14 nM, mean ± SE) and high dose infusion group (1.71 ± 0.19 nM), but not bolus plus infusion group (2.69 ± 0.49 nM); they remained significantly lower after protamine administration. At end of CPB, thrombin-antithrombin complex levels were lower in high dose infusion group (40.0 ± 11.2 ng/ml, p <0.05) compared to control group (76.2 ± 7.3 ng/ml). These studies indicate that tirofiban inhibits not only platelet aggregation but also thrombin generation in vivo during CPB, and that this effect is demonstrable even in the presence of intense heparin anticoagulation. They underscore the important inhibitory effect of GPIIb-IIIa antagonists on thrombin generation.
The Use of a Rapid D-dimer Blood Test in the Diagnostic Workup for Pulmonary Embolism: A Management Study
Authors: van Marwijk Kooy Marinus , Pouwels Jos , Engelage Anneke , Kuipers Bart , Büller Harry , de Groot Marco 
Published: March 2018

Summary
Background. D-dimer assays have a potential to rule out pulmonary embolism in case of a normal test result. We studied the clinical utility of incorporating the SimpliRED D-dimer test result and clinical probability in the routine diagnostic work-up of patients with suspected acute pulmonary embolism. Methods. In a prospective management study 245 consecutive patients, hospitalised as well as outpatients, were included. A SimpliRED D-dimer test and perfusion/(ventilation) scintigraphy were obtained in all patients, whereas clinical probability was determined in the subgroup of patients with a non-diagnostic scan and normal D-dimer result. A diagnostic algorithm determined the necessity for further testing and decisions about treatment. All patients were followed up for 3 months. Results. In 54 patients (22%) with a normal lung scan and 50 patients (21%) with a high probability lung scan, antithrombotic therapy was withheld or started respectively, irrespective of the D-dimer result. A non-diagnostic lung scan was found in 137 (56%) patients, of whom 70 patients had an abnormal D-dimer test, in whom further testing was ordered. Of the remaining 67 patients with a non-diagnostic lung scan and normal D-dimer test 8 patients had a high clinical probability, and the subsequent ultrasonography and pulmonary angiography yielded pulmonary emboli in 1 patient. In the remaining 66 patients, pulmonary embolism was considered to be absent and antithrombotic treatment was stopped/withheld. During follow-up of these patients only one patient experienced a possible venous thromboembolic event (failure rate 1,5% ; 95% CI 0-8%). The SimpliRED D-dimer was normal in 6 of 61 patients with proven pulmonary embolism (sensitivity 90% ; 95% CI 80-96%). Conclusion. Our findings suggest that it is safe to withhold anticoagulant therapy in those patients with a non-diagnostic lung scan, a normal SimpliRED D-dimer test result, and without a high clinical probability. This results in a substantial decreased need for ultrasonography and pulmonary angiography. The SimpliRED should not be used in isolation to exclude pulmonary embolism.
Acute Release of Tissue Factor Pathway Inhibitor after In Vivo Thrombin Generation in Baboons
Authors: Kruithof Egbert , Kakkar Vijay , Lupu Florea , Lupu Cristina 
Published: March 2018

SummaryTissue factor pathway inhibitor (TFPI), the major downregulator of the procoagulant activity of tissue factor (TF), is synthesised by endothelial cells (EC) and acutely released in vitro after thrombin stimulation. Expression of TF on EC and subsequent thrombin generation occurs in vivo during sepsis or malignancy, inducing disseminated intravascular coagulation (DIC). The present study investigates the changes in plasma TFPI in relation to markers of in vivo thrombin generation induced by injection of factor Xa (FXa)/phospholipids in baboons at dosages leading to partial (48%) or complete fibrinogen depletion. The plasma concentrations of thrombin-antithrombin III (TAT) and fibrinopeptide A (FpA), as markers of in vivo generation of thrombin, were strongly enhanced after injection of FXa/phospholipids. TFPI levels, whether measured as antigen or activity, increased significantly in both treatment groups within few minutes, and were dependent on the dose of FXa/phospholipids. Significant positive correlations between plasma levels of TFPI and of TAT or FpA were observed. Altogether, our results indicate that experimentally induced in vivo generation of thrombin causes the acute release of TFPI, high-lighting a possible novel function of thrombin in downregulation of the coagulation process, potentially relevant for the outcome of DIC.
Phospholipid-bound Tissue Factor Modulates both Thrombin Generation and APC-mediated Factor Va Inactivation
Authors: Váradi Katalin , Siekmann Jürgen , Turecek Peter , Schwarz H. Peter , Marder Victor 
Published: March 2018

SummaryHemostasis is initiated by tissue factor (TF) exposed on cellular phospholipid (PL) membranes, leading to thrombin generation. The binding of thrombin to thrombomodulin (TM), activates the protein C pathway, resulting in the inactivation of factors Va and VIIIa by activated protein C (APC) and a negative feedback effect on thrombin generation. A new assay system was developed for simultaneous measurement of thrombin and APC generation in defibrinated plasma induced by large unilamellar PL vesicles complexed with full-length recombinant TF (TF:PL). TF:PL preparations with a low TF concentration induced an initial rate of thrombin generation below 100 nM/min, and resulted in less thrombin formation in the presence of TM than in its absence. In contrast, TF:PL preparations with a high concentration of TF induced a higher rate of thrombin generation, and APC-mediated feedback inhibition did not occur, despite maximal APC generation. We used the same TF:PL surfaces to study factor Va inactivation by APC in a non-plasma reaction system, and found an inverse correlation between TF surface density and the rate of factor Va inactivation. This observation suggests a previously unrecognized hemostatic effect of TF, namely a non-enzymatic surface density-based inhibition of the anticoagulant effect of APC. In this model, high concentrations and surface density of TF exert complementary effects by promoting the regular procoagulant cascade and by inhibiting the protein C pathway, thereby maximizing hemostasis after vascular injury.
The Inhibitory Effect of Recombinant Human Soluble Thrombomodulin on Initiation and Extension of Coagulation
Authors: Sugimoto Emika , Sata Minako , Asano Toshio , Mohri Mitsunobu 
Published: March 2018

SummaryRecombinant human soluble thrombomodulin (rhsTM) was compared with various anticoagulants for in vitro anticoagulant effects on thrombin generation, clotting time, and thromboelastography. rhsTM as well as APC reduced the level of the peak of the thrombin generation curve, but we did not observe any time-delay to reach the peak. This effect of rhsTM was diminished in PC-deficient plasma and was closely associated with the inhibitory effect on prothrombinase and factor Va. On the other hand, hirudin and argatroban delayed the time to reach the level of the peak, without reducing it. rhsTM and other anticoagulants except for activated protein C (APC) were found to have concentration-dependent anticoagulant activity by conventional clotting tests. However, the concentration of rhsTM for clotting time was slightly affected by anti-protein C antibody. Moreover, the concentration of rhsTM required to inhibit thrombin activity directly was 50 times higher than that needed to inhibit thrombin generation. The effect of rhsTM on clot development was compared with that of other anticoagulants by thromboelastography; rhsTM reduced the growth of the clot but had little effect on the time to activate clotting, while the other anticoagulants had the opposite effect. This effect of rhsTM was completely abolished by the addition of anti-protein C or anti-protein S antibody.These findings suggest that rhsTM attenuates blood clotting by reducing the level of generated thrombin through protein C activation and subsequent factor Va inactivation and prothrombinase inhibition.
Factor XI Dependent and Independent Activation of Thrombin Activatable Fibrinolysis Inhibitor (TAFI) in Plasma Associated with Clot Formation
Authors: Mosnier Laurent , Meijers Joost , Griffin John , Bouma Bonno 
Published: March 2018

SummaryThrombin Activatable Fibrinolysis Inhibitor (TAFI) also known as plasma procarboxypeptidase B is activated by relatively high concentrations of thrombin in a reaction stimulated by thrombomodulin. In plasma an intact factor XI-dependent feed back loop via the intrinsic pathway is necessary to generate sufficient thrombin for TAFI activation. This thrombin generation takes place after clot formation with consequent down-regulation of fibrinolysis. We developed a specific and sensitive assay for activated TAFI (TAFIa) and studied its factor XI-dependent generation during clot formation. In the absence of thrombomodulin, addition of 20 nM thrombin to normal plasma generated 5-10% of the amount of TAFIa generated by 20 nM thrombin in the presence of 8 nM thrombomodulin. Minimal activation of TAFI was detected in factor II deficient plasma when clotting was initiated by 20 nM thrombin. Addition of 320-640 nM of thrombin to factor II deficient plasma resulted in the same amount of TAFIa as in normal plasma, suggesting that ~50% of factor II has to be converted to thrombin for extensive activation of TAFI. A Mab that neutralizes activated factor XII had no effect on TAFI activation indicating that an intact contact system is not necessary for the activation of TAFI. The dependency of TAFI activation of factor XI was tested using a Mab that neutralizes activated factor XI. When plasmas from 13 healthy individuals were tested, this Mab reduced TAFI activation by 65% (range 35-89%). Our results indicate that activation of TAFI in serum after clot formation can be quantitated and that it takes place in both factor XI-dependent and factor XI-independent mechanisms.