bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclic Nucleotide Phosphodiesterases and Human Arterial Smooth Muscle Cell Proliferation
Authors: Rybalkin Sergei , Bornfeldt Karin 
Published: March 2018

IntroductionSmooth muscle cells (SMCs) in the arterial wall are normally found in a contractile, nonproliferative state. These SMCs are continuously exposed to agents that elevate cyclic AMP (cAMP) and cyclic GMP (cGMP), such as prostacyclin and nitric oxide (NO) released from the endothelium. Both cAMP and cGMP potently inhibit SMC proliferation by antagonizing major signaling pathways induced by growth factors, such as platelet-derived growth factor. Different forms of injury to the endothelium result in proliferation of the SMCs and can develop into atherosclerosis, restenosis, or arterial thickening associated with neonatal pulmonary hypertension. In human adult aorta, cAMP and cGMP levels are tightly regulated by synthesis and degradation. The latter is mediated by at least two different cAMP phosphodiesterases (PDEs), PDE3 and PDE4, and three different PDEs that degrade mainly cGMP, PDE1A, PDE1B, and PDE5. Strikingly, expression of a new PDE that degrades both cAMP and cGMP, PDE1C, is markedly induced in proliferating SMCs from the same aorta in culture, whereas its expression is nondetectable in contractile aorta. We propose that, for a human arterial SMC to be able to efficiently proliferate, and perhaps even to undergo a phenotypic change from a quiescent to a proliferative phenotype, it has to efficiently degrade inhibitory cAMP and cGMP. In human SMCs, PDE1C is induced to degrade these cyclic nucleotides. Understanding the role of PDE1C in SMC proliferation may provide the basic information necessary for development of highly specific PDE1C inhibitors that target proliferating SMCs in cardiovascular disease.
Antibody-Mediated Disruption of the Annexin-V Antithrombotic Shield: A New Mechanism for Thrombosis in the Antiphospholipid Syndrome
Authors: Wu Xiao-Xuan , Rand Jacob 
Published: March 2018

IntroductionThe antiphospholipid (aPL) syndrome is a condition that manifests in patients as vascular thromboembolism or recurrent pregnancy loss together with laboratory evidence for the presence of antibodies against anionic phospholipid-protein complexes. For a recent comprehensive review, the reader is referred to Hughes et al.1 The syndrome was first proposed to be a distinct entity, called anticardiolipin syndrome, in 1985,2 and was later renamed antiphospholipid syndrome.3 The disorder was classified as “primary” in the absence of a concurrent autoimmune condition, such as systemic lupus erythematosus, or “secondary” in the presence of another such autoimmune disorder. Antiphospholipid antibodies are detected by their reactivity to anionic phospholipids (or protein-phospholipid complexes) in solid phase immunoassays, or by their inhibition of phospholipid-dependent coagulation reactions, known as the “lupus anticoagulant” effect. The ever-expanding, yet still insufficiently integrated, knowledge of this enigmatic disorder makes this area an intriguing subject for investigation.The pathophysiologic mechanism of this syndrome has remained obscure, resulting from the apparent multiplicity of antigenic determinants recognized by the antibodies. In addition, a large number of effects1 have been described for the antibodies in vitro and in cell culture systems. These effects, which include the paradoxical lupus anticoagulant (LAC) phenomenon, are a consequence of the numerous roles played by phospholipids in the hemostasis system and in a multitude of biologic processes. The purpose of this review is to introduce the reader to the current state of knowledge of the role of annexin-V in this disorder.
Recombinant Thrombomodulin and Activated Protein C in the Treatment of Disseminated Intravascular Coagulation
Authors: Maruyama Ikuro 
Published: March 2018

IntroductionThe blood coagulation cascade is regulated by the luminal surface of the endothelial cell lining.1 Endothelial cells synthesize tissue factor pathway inhibitor (TFPI), which, in part, binds to the cell surface glycosaminoglycans and inhibits factors Xa, VIIa, and tissue factor.2 Endothelial cells also produce and exhibit thrombomodulin (TM) on their luminal surface.3 TM is a kind of thrombin receptor that forms a 1:1 complex with thrombin. In this complex, thrombin activates protein C (PC) more than 1,000-fold more than thrombin alone. TM then loses its procoagulant activities, which include fibrinogen clotting, activation of factors V and VIII, and platelet activation. Thus, TM converts thrombin from a procoagulant protease to an anticoagulant. Pathologic states, such as an endothelial injury or perturbation or continuous rapid coagulation cascade activation, overcomes the endothelial regulating activity, resulting in the development of intravascular coagulation and the induction of disseminated intravascular coagulation (DIC). Theoretically, then, supplementing soluble TM or activated PC (APC) to reconstitute the endothelial coagulation regulation system in the circulation and regulate pathologically-activated blood coagulation could be beneficial. In this chapter, application of soluble TM and APC in the treatment of DIC is reviewed.
Redox Signals that Regulate the Vascular Response to Injury
Authors: Berk Bradford 
Published: March 2018

IntroductionReactive oxygen species (ROS), generated by a variety of extracellular and intracellular mechanisms, are novel signal mediators that regulate signal transduction events. In this discussion, ROS will refer to H2O2, O2-, and OH-. Data suggest that, following vascular injury, ROS production is increased. These ROS activate signal events that are required for the repair process. Three key findings from our laboratories support the concept that oxidative stress is an important stimulus in the vessel wall for vascular repair, vascular smooth muscle cell (VSMC) growth, and vascular lesion formation. First, following oversized balloon inflation-induced porcine coronary artery injury, there is increased production of oxygen radicals (O2-, H2O2, and OH-) in the vessel wall for several weeks.1 Second, administration of several antioxidants including probucol, vitamins C and E, and L-cysteine decreases neointimal proliferation and/or promotes vessel remodeling in pig and rat injury models.1-3 Third, in vitro, we have shown that ROS stimulate VSMC growth and activate signal events typical of VSMC mitogens.4,5
A scheme for the mechanism by which oxidative stress is proposed in Figure 1. The initial vascular injury produced by balloon inflation rapidly increases the local concentration of ROS, which stimulate further generation of ROS by multiple mechanisms including xanthine oxidase, NADH oxidase, phospholipases, and mitochondrial electron transport dysfunction. In the setting of VSMC growth stimulation (by platelet and VSMC-derived mitogens) and cytokine stimulation (by leukocytes), there is amplification of ROS generating systems. These processes cause the cellular redox state to become more oxidized. This establishes a self-perpetuating increase in ROS production. Next, changes in cellular redox state stimulate growthrelated signal transduction events. Until recently, VSMC growth was thought to be mediated largely by peptide growth factors. Published data from our laboratory show that ROS increase intracellular calcium, activate protein kinases, increase protooncogene expression, and stimulate DNA synthesis mitogens.4-6 However, the specific mechanisms by which the sustained oxidative stress present in the injured vessel stimulates VSMC growth remain undefined. Data presented indicate that redox sensitive signal pathways may be defined by specific activation of upstream mediators, which include phospholipases, small G proteins, and tyrosine kinases. Final effectors include serine-threonine kinases, such as the mitogen activated protein (MAP) kinases that activate specific transcription factors.
Treatment of Venous Thromboembolism
Authors: Bates Shannon , Hirsh Jack 
Published: March 2018

IntroductionVenous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common clinical problem. If untreated or inadequately treated, there is a high risk of fatal PE1 and recurrent venous thrombosis.2-4 The objectives of treatment are to prevent local extension of thrombus, embolization, and recurrent thrombosis.It is now widely accepted that VTE is a single disorder and, therefore, the treatment of venous thrombosis and PE is essentially the same. Four treatment modalities are available. Anticoagulant therapy prevents the growth of an existing thrombus or embolus, thrombolytic therapy accelerates the rate of dissolution of thrombi or emboli, caval interruption intercepts venous thrombi that break off and embolize, thereby preventing dangerous PE, and surgical therapy removes thrombi or emboli.
Do Heparins Do More than Just Treat Thrombosis? The Influence of Heparins on Cancer Spread
Authors: Hettiarachchi Rohan , Smorenburg Susanne , Ginsberg Jeffrey , Levine Mark , Prins Martin , Büller Harry 
Published: March 2018

IntroductionThe influence of unfractionated heparin (UFH) and other anticoagulants on the spread of cancer has been reported since the early 1960s.1 However, clinical studies investigating the use of heparins in cancer patients have not produced consistent results.2 Intravenous, adjusted-dose UFH for 5 to 10 days has been the standard initial treatment for venous thrombosis. More recently, subcutaneous, fixed-dose, low molecular weight heparins (LMWHs), which are fractions of the parent compound, have been shown to be safe and effective alternatives to UFH in the initial treatment for venous thromboembolism.3-5
In one of our randomized clinical trials comparing LMWH and UFH in the initial treatment of deep vein thrombosis (DVT), we observed an unexpected difference in 6-month mortality among cancer patients in favor of LMWH, which could not be attributed to a difference in the incidence of thrombotic or bleeding complications.6 A similar observation in favor of LMWH was reported in a subsequent study and in a meta-analysis of trials.7,8 The number of cancer patients included in these studies was small, and adjustment of the observed effect for the baseline characteristics of the cancer patients was not possible. However, these findings suggested an inhibitory effect of LMWH on tumor growth or metastasis, which is less apparent or absent for UFH, resulting in a beneficial effect on the survival of cancer patients. This hypothesis is supported by the observations, in experimental studies, that LMWH and low molecular weight heparan sulfate, in comparison to UFH, effectively suppressed angiogenesis, a process necessary for tumor growth and metastasis.9,10
On the other hand, animal studies that investigated the effect of chemically-modified heparins on the spread of cancer did not detect a superior anti-tumor effect of LMWH compared to UFH; both were found to inhibit metastasis.11,12 To date, the effect of LMWH on cancer survival in humans has not been investigated as a primary objective. If a consistent and beneficial effect of LMWH on mortality is indeed present, such a study would be warranted.We performed a meta-analysis of all available randomized clinical trials where LMWH was compared with UFH in the treatment of venous thromboembolism (VTE) to estimate the crude treatment effect of LMWH on mortality in cancer patients compared to UFH. Subsequently, we adjusted this treatment effect for age, gender, and primary malignancy site by reanalyzing data from three of those trials.3-5 This effect was further adjusted for other prognostic factors, including cancer histology, tumor stage, presence of metastases, duration of cancer, and concomitant use of cancer treatment, by analyzing individual patient data from the largest randomized trial.5
A Comparison of Danaparoid and Lepirudin in Heparin-induced Thrombocytopenia
Authors: Farner B. , Eichler P. , Kroll H. , Greinacher A. 
Published: March 2018

SummaryHeparin-induced thrombocytopenia (HIT) is a hypercoagulable syndrome strongly associated with thrombosis that is usually treated with drugs that inhibit factor Xa (danaparoid) or thrombin (lepirudin). In the present study the outcome of HIT-patients treated with danaparoid or lepirudin was compared using the single or combined endpoints of new thromboembolic complications (new TECs), amputations and/or death, and major bleeding. HIT-patients treated with lepirudin were enrolled in two prospective trials and patients, who were identified in the same two laboratories during the same time period, who were not enrolled into these studies but treated with danaparoid, were assessed retrospectively according to a standardized questionnaire. 126 danaparoid (60.3% female) and 175 lepirudin treated patients (58.3% female) fulfilled the same inclusion and exclusion criteria. In a time-to-eventanalysis the cumulative risk of combined endpoint was higher in HIT-patients without thromboembolic complication at baseline treated with danaparoid (usually in prophylactic dose 750 anti-factor Xa units b.i.d. or t.i.d. s.c.) as compared to lepirudin (aPTT adjusted) (P = 0.020). Whereas HIT-patients with TEC at baseline who were usually treated with therapeutic dose had a similar outcome in both treatment groups (P = 0.913). Major bleeding occurred in 2.5% (95% CI 0.5-7.0%) of danaparoid treated patients as compared to 10.4% (95% CI 6.3-15.9%) of lepirudin treated patients until day 42 (P = 0.009). This indicates that the efficacies of therapeutic doses of danaparoid or lepirudin in preventing death, amputation or new TEC in HIT-patients do not differ largely, but the risk of bleeding seems to be higher in lepirudin treated patients. The prophylactic dose of danaparoid approved in the European Union for HIT without TEC at baseline seems suboptimal. A prospective comparative trial is required to verify these preliminary conclusions.
Von Willebrand Factor-cleaving Protease in Childhood Diarrhoea-associated Haemolytic Uraemic Syndrome
Authors: Lämmle Bernhard , Nevard Corinne , Haycock George , Furlan Miha , Hunt Beverley 
Published: March 2018

SummaryA deficiency of von Willebrand factor (vWF)-cleaving protease, either due to a congenital deficiency or to the presence of a protease inhibitor of vWF-cleaving protease has been associated with thrombotic thrombocytopenic purpura (TTP). We have studied vWF-cleaving protease in diarrhoea-associated haemolytic uraemic syndrome (D+ HUS), which shares clinical features with TTP. 29 children with acute D+ HUS and 13 control children were studied.vWF-cleaving protease activity was normal (range 50-150%) in 39 of 42 plasma samples. Levels of protease activity between 25 and 50% were noted in plasma from two D+ HUS patients. One D+HUS patient, who had clinical features of TTP, had a vWF-cleaving protease inhibitor producing a severe deficiency of vWF-cleaving protease.Thus a deficiency of vWF-cleaving protease appears to be atypical in D+HUS. The detection of a vWF-cleaving protease inhibitor in one patient suggests it may be associated with infection such as E. coli 0157.
Diagnostic Accuracy of Triage Tests to Exclude Pulmonary Embolism
Authors: Lijmer Jeroen , Sanson Bernd-Jan , Büller Harry , Brandjes Dees , Mac Gillavry Melvin ,   the ANTELOPE-Study Group
Published: March 2018

SummaryWe performed a study in 403 prospectively included patients with suspected pulmonary embolism to compare the accuracy of a combination of the SimpliRED D-dimer assay and an intuitive clinical probability estimate with either one alone. Based on a conjoint diagnostic reference standard, including ventilation-perfusion lung scintigraphy and pulmonary angiography, the prevalence of pulmonary embolism was 31%. We demonstrated a high sensitivity (98%, 95% CI 95-100) and negative predictive value (94%, 95% CI 79-99) for the combination of the two tests. These figures were more favorable than for either test alone. The specificity of the combination was lower (11%, 95% CI 9-12) and consequently the proportion of patients in whom further diagnostic tests would have been avoided was only 8%. We conclude that the combined use of the SimpliRED test and the clinical probability estimate attains a higher sensitivity than either test alone. However, there remains a risk of false negatives and the exclusion efficiency is limited.
Increased Hepatic Fibrinogen Bβ-gene Transcription Is not enough to Increase Plasma Fibrinogen Levels
Authors: Rezaee F. , Maas A. , Koopman J. , Verheijen J. H. 
Published: March 2018

SummaryThe fibrinogen Aα, Bβ, and γ polypeptides are encoded by three separate genes, which are arranged in the order γ-α-β. In order to study the biosynthesis of fibrinogen in vivo we generated a line of transgenic mice carrying extra copies of the fibrinogen β-gene. To clone the mouse fibrinogen Bβ-chain gene, a mouse 129 Sv/Ev genomic cosmid library was screened, using the mouse fibrinogen Aα-, Bγ-chain cDNA. A clone containing the complete fibrinogen Bβ-chain gene including approximately 11-kb of the natural promoter region was identified and subsequently microinjected into mice. Southern blot analysis identified a founder that carried additional copies of the fibrinogen Bβ-chain gene. Transgenic offspring of this founder were interbred and heterozygous and homozygous transgenic mice were obtained. Northern blot analysis demonstrated approximately a 3-fold increase in fibrinogen Bβ mRNA in heterozygous mice as compared to wild-type, whereas homozygous transgenic mice showed approximately a 9-fold increase. The levels of the Aα and γ mRNAs in transgenic homozygous mice were not changed as compared to those in wild-type mice. Fibrinogen levels in plasma were not significantly increased in transgenic mice as compared to wild-type mice.These results indicate that: additional copies of the fibrinogen Bβ-chain gene lead to increased levels of the Bβ-chain mRNA in the liver; the increased levels of Bβ-chain mRNA in homozygous overexpression mice do not change the transcription levels of the two other fibrinogen mRNAs in vivo; the absence of an increased plasma fibrinogen level in the transgenic mice indicates that this level is not regulated solely by transcription of the Bβ-chain gene.
The Role of Factor XI in a Dilute Thromboplastin Assay of Extrinsic Coagulation Pathway
Authors: Xiong Shilong , He Xiaofan , Liu Fayi , Han Jianzhong , Li Juncheng , He Shilin , He Rong 
Published: March 2018

SummaryBlood coagulation has been thought to be composed of both intrinsic and extrinsic pathways. Recent evidence strongly supports the critical role of the extrinsic pathway in the initiation of blood coagulation. This investigation established an assay that examines the role of FXI in the thromboplastin-initiated (extrinsic) coagulation based on this new concept. Plasma clotting times were measured at different concentrations of thromboplastin with activated FXII inhibited (FXIIa-inhibited Diluted Thromboplastin Time, FXIIaiDTT). Only at low concentrations of thromboplastin was FXIIaiDTT of FXI-deficient plasma significantly prolonged than that of normal plasma. Depletion of FXI from normal plasma prolonged its FXIIaiDTT and replenishment of FXI shortened it. FXIIaiDTTs of both FVIII-deficient and FIX-deficient plasma were remarkably prolonged, and addition of normal plasma dose-dependently shortened it. Furthermore, earlier α-thrombin inhibition was directly correlated with decreasing FXa generation. The amount of FXa production was: platelet-rich plasma > platelet-poor plasma > FXI-deficient plasma. Therefore, our findings from the FXIIaiDTT assays not only support the critical role of extrinsic pathway in blood coagulation initiation, but also demonstrate the importance of FXI as an amplifier of thrombin generation in thromboplastin-initiated coagulation.
Regulation of PAI-1 Concentration in Platelets by Systemic Administration of Antisense Oligonucleotides to Rats
Authors: Pawlowska Zofia , Chabielska Ewa , Kobylanska Anna , Maciaszek Anna , Swiatkowska Maria , Buczko Wlodzimierz , Stec Wojciech , Cierniewski Czeslaw 
Published: March 2018

SummaryIn this report we tested the effect of oligodeoxyribonucleotides antisense to PAI-1 mRNA administered into rats on PAI-1 concentration in platelets. Low doses of the antisense oligonucleotide (MPO-16R) reduced PAI-1 activity, both in rat blood plasma and platelet lysates by 20.5% and 28.7%, respectively. There was no change in platelet count after treatment with MPO-16R but treated platelets showed lower aggregability as compared with controls (37 ± 13% and 54 ± 12%, respectively). In an experimental model of rat arterial thrombosis, low doses of MPO-16R caused a significant delay in the occlusion time (31.8%). These data further support for the role of PAI-1 as a major determinant of arterial thrombolysis resistance and for the first time demonstrate the possibility of reduction of platelet PAI-1 concentration by antisense approach.
Prospective Randomised Open-label Comparison of Danaparoid with Dextran 70 in the Treatment of Heparin-induced Thrombocytopaenia with Thrombosis
Authors: Chong B. H. , Cade J. F. , Magnani H. , Manoharan A. , Oldmeadow M. , Arthur C. , Rickard K. , Gallo J. , Lloyd J. , Seshadri P. , Gallus A. S. , Chesterman C. N. ,   The Australian HIT Study Group
Published: March 2018

Summary
Aim: To compare clinical outcomes in a randomised comparison of treatment with danaparoid sodium (a heparinoid), or dextran 70, for heparin-induced thrombocytopaenia (HIT) plus thrombosis. Methods: Forty-two patients with recent thrombosis and a clinical diagnosis of probable HIT who presented at ten Australian hospitals during a study period of six and one half years were randomly assigned to open-label treatment with intravenous danaparoid or dextran 70, each combined with oral warfarin. Thirty-four patients (83%) had a positive platelet aggregation or 14C-serotonin release test for HIT antibody. Twenty-five received danaparoid as a bolus injection of 2400 anti-Xa units followed by 400 units per hour for 2 h, 300 units per hour for 2 h, and then 200 units per hour for five days. Seventeen received 1000 mL dextran 70 on day one and then 500 mL on days 2-5. Patients were reviewed daily for clinical evidence of thrombus progression or resolution, fresh thrombosis or embolism, bleeding or other complications. The primary trial endpoint was the proportion of thromboembolic events with complete clinical resolution by the time of discharge from hospital. Results: With danaparoid, there was complete clinical recovery from 56% of thromboembolic events compared to 14% after dextran 70 (Odds Ratio 10.53, 95% Confidence Interval 1.6–71.4; p = 0.02). Clinical recovery with danaparoid was complete or partial in 86% of thromboembolic events compared with 53% after dextran 70 (Odds Ratio 4.55, 95% Confidence Interval 1.2–16.7; p = 0.03). Overall clinical effectiveness of danaparoid was rated as high or moderate in 88% of patients compared with 47% for dextran 70 (p = 0.01). One patient given danaparoid died of thrombosis compared with three patients given dextran 70. The platelet count returned to normal after a mean of 6.7 days with danaparoid and 7.3 days with dextran 70. There was no major bleeding with either treatment. Conclusion: danaparoid plus warfarin treatment for HIT with thrombosis is effective, safe, and superior to dextran 70 plus warfarin.