bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteolysis, Cell Adhesion, Chemotaxis, and Invasiveness Are Regulated by the u-PA-u-PAR-PAI-1 System
Authors: Blasi Francesco 
Published: March 2018

IntroductionHigh levels of urokinase-type plasminogen activator (u-PA), of its inhibitor (plasminogen activator inhibitor (PAI)-1), or of its receptor (u-PAR, CD87) are strong prognostic indicators of relapse in human cancers. In addition, many in vitro data show that u-PA, PAI-1, and u-PAR have a profound influence on cell migration. This set of molecules regulates surface proteolysis, cell adhesion, and chemotaxis through different mechanisms. Binding to u-PAR strongly stimulates the activation of pro-u-PA and, hence, of plasminogen, resulting in localized production of the broad-spectrum serine protease, plasmin, which can digest extracellular matrix proteins or activate latent motogenic factors. Chemotaxis is induced through an u-PA-dependent conformational change in u-PAR, which uncovers a very potent chemotactic epitope(s) that acts through a pertussis toxin-sensitive step and activates intracellular tyrosine kinases. In addition, cell adhesion is affected by an u-PA-dependent exposure of u-PAR epitope(s), which interact with vitronectin (VN), integrins, and caveolin, thus modifying the substrate specificity. Thus, u-PA binding can transform u-PAR from a simple receptor for u-PA into a pleiotropic ligand for other surface molecules.All of these processes are regulated by the u-PA inhibitor, PAI-1. Inhibition of cell adhesion and migration by PAI-1 on VN occurs because the same region of VN is required for interaction with PAI-1, u-PAR, and integrins. PAI-1, however, also affects u-PAR occupancy by triggering the internalization of the u-PA-u-PAR complex, the degradation of u-PA, and the recycling of free u-PAR. Available data suggest that cells respond to a “stop” signal, due to the PAI-1-dependent internalization and degradation of u-PA. Cells also respond to a “go” signal through the stimulation of surface-proteolysis, exposure of chemotactic epitopes, and recycling of u-PAR to novel surface positions. Finally, cells respond to a “pause” signal through transient u-PAR-dependent adhesion stages, thus shifting the cells between an “adhesion-mode” and a “migration-mode.”
Structure and Function of von Willebrand Factor
Authors: Ruggeri Zaverio 
Published: March 2018

IntroductionThe reader will find here a concise summary of established notions on the structure and function of von Willebrand factor (vWF), followed by a brief discussion of selected recent advances that illustrate how this molecule supports platelet function in hemostasis and thrombosis. A comprehensive review of the topic is beyond the scope of this chapter and may be found elsewhere.1-3
Von Willebrand Factor in Thrombotic Thrombocytopenic Purpura
Authors: Lämmle Bernhard , Furlan Miha 
Published: March 2018

IntroductionThrombotic thrombocytopenic purpura (TTP), a disseminated form of thrombotic microangiopathy, was initially described by Moschcowitz in 1924.1 TTP is defined by a pentad of findings, including severe thrombocytopenia, intravascular hemolysis with erythrocyte fragmentation, neurologic deficit, renal dysfunction, and fever.2–4 The thrombocytopenia occurs in the presence of normal or even increased numbers of megakaryocytes in the bone marrow, suggesting increased consumption. Platelet aggregates, found in the microcirculation, contain little if any fibrin polymers, indicating that activation of coagulation and fibrin formation may be secondary and limited in extent.About one-third of patients experience recurrent acute episodes at irregular and unpredictable intervals, whereas the majority of patients who recover from an acute TTP event experience no relapse and no persistent organ failure. TTP is usually classified as relapsing if complete remissions occurred between acute events and as chronic if complete recovery did not occur between bouts.Genetic predisposition to TTP has been shown in several siblings suffering from recurrent TTP.5 Thus, cases of TTP can be further divided according to whether the disease has a familial or genetic component or is not heritable. Acute episodes of TTP may be triggered by viral or bacterial infection, autoimmune disorders, bone marrow transplantation, drug therapy, cancer, chemotherapy, and pregnancy.3,4 The incidence of TTP is estimated to be two to eight cases per million people per year.3,6 Until four decades ago, the mortality rate was virtually 100% but has since decreased to less than 20% after introduction of plasma therapy. Still, there were more than 4,500 TTP-associated deaths recorded in the United States between 1968 and 1991.6
Risk Factors for Venous Thrombotic Disease
Authors: Rosendaal F.R. 
Published: March 2018

IntroductionVenous thrombosis occurs in about 1 per 1,000 individuals per year.1,2 It usually affects the deep veins of the leg, but may occur in other sites, such as the upper extremities, cerebral sinus, liver and portal veins, or retinal veins. It also may occur in the superficial veins, usually in the leg. The predilection of thrombosis occurring in the leg is the result of the upright position of man, with the resulting slow antigravitational flow of blood in the veins of the leg. Embolization occurs when parts of the clot dislodge and are transported by the blood flow, usually through the heart to the vasculature of the lungs.3
Thrombosis is a serious disorder. It may be fatal by pulmonary embolism, although this is rare (case fatality rate of venous thrombosis is estimated at 1% to 2%). A common, and often disabling, consequence of deep vein thrombosis is postthrombotic syndrome, with symptoms ranging from discoloration to pain and ulceration.4 Because thrombosis is not very rare and often has serious consequences, prophylactic treatment is focussed on preventing first events and recurrences through adequate knowledge about risks and risk factors.5
APTT Revisited: Detecting Dysfunction in the Hemostatic System Through Waveform Analysis
Authors: Toh Cheng Hock 
Published: March 2018

IntroductionDespite extensive investigations in both experimental and clinical disseminated intravascular coagulation (DIC), much remains to be learned about this condition of hemostatic dysfunction. Although the technological armory available to the clinical investigator has expanded enormously since the early 1980s, particularly with regard to immunologically-based testing, the sobering fact is that prognosis has remained dismally unchanged.1 Although some of the new laboratory approaches can identify DIC at an early enough stage to allow for useful clinical intervention, most require a level of stringency in performance that is not attainable in the routine clinical setting.2 The pace of acute DIC precludes many of these specific tests, and reliance is still based on traditional screening assays, such as the prothrombin time (PT), activated partial thromboplastin time (APTT) and platelet count (Plt). These tests lack specificity on an individual basis and are only useful in DIC if there is further determination of fibrinogen (Fgn) and fibrin breakdown products (fdp)/D-Dimers.3 However, changes in these battery of tests seldom occur together. As a result, the realization of DIC is often only made after serial testing, with the inevitable delay and consequent jeopardization of patient critical care.4 The numerous failures of new therapies in sepsis and DIC testifies to this problem of a lack of early definition in the disease process to forewarn the clinician of more timely intervention.5 The gold standard must, therefore, be a single, rather than multiple, assay system that is both sensitive and specific for early DIC and simple and rapid to perform. It is therefore, not too surprising that such a test has remained elusive for such a considerable length of time.In the context of complex scenarios, the simplest of approaches can often be the most rewarding. Such an axiom could fit with the description of APTT transmittance waveform analysis as a useful test in DIC that could also potentially lead to an improved understanding of the condition.
New Discoveries with Mice Mutant in Endothelial and Platelet Selectins
Authors: Hartwell Daqing , Wagner Denisa 
Published: March 2018

IntroductionThe selectin family of adhesion receptors consists of three members: P-, E-, and L-selectin. P-selectin is constitutively present in the α-granules of platelets and Weibel-Palade bodies of endothelial cells and is rapidly translocated to the cell surface upon activation. E-selectin is synthesized and expressed by activated endothelial cells, whereas L-selectin is constitutively expressed by leukocytes. All three selectins support the rolling of leukocytes on endothelium, which is a prerequisite to firm adhesion and extravasation of leukocytes mediated by integrins and members of the immunoglobulin superfamily.1,2 More recently, it has been demonstrated that P- and E-selectin also support platelet rolling in venules, which will be discussed below. In addition, P-selectin expressed on the surface of activated platelets also mediates platelet-leukocyte adhesion.3,4
Since the discovery of the selectins, considerable efforts have been devoted to uncover the functions of these molecules. The development of genetically engineered animals deficient in one or more of the adhesion receptors has provided a unique opportunity and an alternative approach to antibody-blocking experiments for defining the contribution of each of the molecules in normal physiology and pathological conditions. At this time, mice deficient in a single selectin, all combinations of two of the selectins, and all three selectins have been produced by gene targeting.5-10 In this chapter, we will discuss some of the recent findings obtained using mice deficient in P-selectin alone (P-/-), both P- and E-selectin (P/E-/-), and mice expressing Pselectin with a deleted cytoplasmic domain (ΔCT).
Prophylaxis of Venous Thromboembolism Following Orthopedic Surgery: Mechanical and Pharmacological Approaches and the Need for Extended Prophylaxis
Authors: Hull R.D. , Pineo G.F 
Published: March 2018

IntroductionMajor orthopedic surgery, particularly total joint replacement or hip fracture, represents a high risk of future development of postoperative venous thromboembolism and warrants the routine use of prophylaxis with either mechanical devices or pharmacological agents. The aim of prophylaxis is to prevent fatal pulmonary embolism (PE) and the morbidity of deep vein thrombosis (DVT), particularly the development of post-thrombotic syndrome. Patterns of clinical practice, with respect to the prevention of venous thromboembolism and the appropriate use of anticoagulants for the treatment of thrombotic disease, have been strongly influenced by recent consensus conferences.1,2 Rules of evidence for assessing the literature have been applied to all recommendations regarding the prevention and treatment of thrombotic disease. These results were extrapolated using evidence gleaned from major clinical disorders and are based only on nonrandomized clinical trials or case series.1-3 Data from a large number of Level I clinical trials in patients undergoing orthopedic surgery have provided answers to many of the questions regarding prophylaxis of venous thromboembolism. In this review, we will discuss the prevention of venous thromboembolism following orthopedic surgery and discuss some of the controversial issues where further studies are required.
Prevention of Venous Thromboembolism After Neurosurgery
Authors: Agnelli Giancarlo 
Published: March 2018

IntroductionThe optimal strategy for the prevention of venous thromboembolism in patients undergoing neurosurgery has been a matter of debate for many years,1 and it is currently under review because of the results of recent clinical trials. This issue is, indeed, of particular clinical interest because of the neurosurgeons’ fear of bleeding complications, potentially associated with the use of anticoagulants, and the high incidence of venous thromboembolism. Preventing venous thromboembolism is of crucial importance in neurosurgery patients for reasons that go beyond its high incidence. The management of patients who develop venous thromboembolism immediately after neurosurgery is rather complicated, due to the risks connected with the administration of therapeutic doses of heparin and warfarin. In addition, the insertion of a vena caval filter, which is frequently required, is rather expensive and not without risk. Thus, in neurosurgery, even more than in other clinical settings, the optimal strategy for the management of venous thromboembolism is its prevention.The purpose of this paper is to review the epidemiology of venous thromboembolism in neurosurgery, its biological risk factors, and the results of clinical trials that have studied the prevention of venous thromboembolism in this clinical setting.
Thrombolysis in Acute Cerebrovascular Disease: Indications and Limitations
Authors: Ringleb Peter , Stingele Robert , Hacke Werner 
Published: March 2018

IntroductionLarge-scale trials have shown that thrombolytic therapy reduces mortality and preserves left ventricular function in patients with acute myocardial infarction (AMI). As most ischemic strokes are thromboembolic in origin,1 there appears to be a rationale for the use of thrombolytic agents in the management of ischemic stroke.Thrombolytic agents differ in their mechanisms of action, but in general, they act by promoting the conversion of plasminogen into plasmin, resulting in fibrin degradation and clot dissolution. Streptokinase and recombinant tissue plasminogen activator (rt-PA) are the agents that have been the most widely investigated in stroke studies. Ancrod, the active agent in the venom of the Malayan pit viper, is primarily considered an anticoagulant, although it does stimulate endogenous t-PA release from the vascular endothelium and may enhance local thrombolysis. Urokinase is used in local, intra-arterial thrombolysis but has not been subjected to large clinical trials since computed tomography (CT) diagnosis became widely available.
A Cell-based Model of Hemostasis
Authors: Monroe Dougald , Hoffman Maureane 
Published: March 2018

SummaryBased on our work and that of many other workers, we have developed a model of coagulation in vivo. Many workers have demonstrated mechanisms by which cells can influence the coagulation process. Nonetheless, the prevailing view of hemostasis remains that the protein coagulation factors direct and control the process with cells serving primarily to provide a phosphatidylserine containing surface on which the procoagulant complexes are assembled. By contrast, we propose a model in which coagulation is regulated by properties of cell surfaces. This model emphasizes the importance of specific cellular receptors for the coagulation proteins. Thus, cells with similar phosphatidylserine content can play very different roles in hemostasis depending on their complement of surface receptors. We propose that coagulation occurs not as a “cascade”, but in three overlapping stages: 1) initiation, which occurs on a tissue factor bearing cell; 2) amplification, in which platelets and cofactors are activated to set the stage for large scale thrombin generation; and 3) propagation, in which large amounts of thrombin are generated on the platelet surface. This cell based model explains some aspects of hemostasis that a protein-centric model does not.
Adipose Tissue Expression of Gelatinases in Mouse Models of Obesity
Authors: Maquoi E. , Holvoet P. , Mertens A. , Lupu F. , Morange P. , Alessi M. C. , Juhan-Vague I. , Lijnen H. R. 
Published: March 2018

SummaryFollowing the observation by Brown et al. (Am J Physiol 1997; 272: C937-49) that primary rat adipocytes in culture secrete gelatinase A (MMP-2), we have evaluated gelatinase expression in adipose tissue with the use of mouse models of obesity. Wild-type mice were kept on a standard fat diet (SFD) or on a high fat diet (42% fat, HFD) and genetically obese db/db mice were kept on SFD; gonadal and subcutaneous fat pads were removed and analysed ex vivo. These studies revealed that: 1) the HFD induced adipocyte hypertrophy; 2) after 32 weeks, significantly higher levels of 70 kDa (p <0.05) and 65 kDa proMMP-2 (p < 0.01) were observed in extracts of gonadal fat pads of mice on HFD; 3) the contribution of active MMP-2 to the total level was comparable in SFD and HFD groups (20 to 30%); and 4) gelatinase B (MMP-9) was not consistently detected. These findings were confirmed by gelatin zymography and by mRNA determination using competitive RT-PCR. The presence of MMP-2 in the adipose tissue was confirmed immunologically and its localization in adipocytes revealed by immunogold electron microscopy. The potential functional role of MMP-2 in adipose tissue remains to be determined.
Factor V Leiden and Factor V R2 Allele: High-throughput Analysis and Association with Venous Thromboembolism
Authors: Benson Jane , Ellingsen Dorothy , El-Jamil Muhydine , Jenkins Meredith , Miller Connie , Dilley Anne , Evatt Bruce , Hooper Craig 
Published: March 2018

SummaryThrombophilia is a multigenic disease in which the combination of genetic polymorphisms increases the risk of deep vein thrombosis (DVT). The rapid identification of these genetic combinations requires high-throughput analysis of single nucleotide polymorphisms (SNPs). The TaqMan® fluorogenic 5’→3’ nuclease assay (PE/Applied Bio-systems, Foster City, CA) with custom-designed primers, probes and controls has provided a highly efficient platform for high throughput. This assay was used to rapidly detect two SNPs, FV Leiden (G1691A) and FV A4070G (R2 allele), in a study of 6295 subjects. With one thermal cycler, we completed sample set-up, PCR and analysis on 84 samples in 3 h with an additional 12 wells containing 4 “no template controls” (NTC), 4 “allele-1 controls”, and 4 “allele-2 controls” in a 96-well plate. When additional thermal cyclers were used and more assays were set up while the initial sets of reactions were in the PCR machines, the output could correspondingly be increased. The TaqMan® assay was extremely accurate, avoided contamination by using uracil-N-glycolase (UNG) in a single, closed tube, and offered the possibility for additional automation with robotic equipment to implement the PCR. This TaqMan® assay facilitates high throughput to screen large populations quickly and economically while utilizing a simple protocol that requires minimal expenditure of personnel time. Our results demonstrated a prevalence of the R2 allele of 11.9% in U.S. Caucasians, 5.6% in African-Americans, 13.4% in Asian or Pacific Islanders and 11.3% in Hispanics. No association between venous thromboembolism and the R2 allele was noted, and furthermore no interaction with FV Leiden was observed.
Increased Brain Natriuretic Peptide as a Marker for Right Ventricular Dysfunction in Acute Pulmonary Embolism
Authors: Tulevski Igor , Hirsch Alexander , Sanson Bernd-Jan , Romkes Hans , van der Wall Ernst , van Veldhuisen Dirk , Büller Harry , Mulder Barbara 
Published: March 2018

SummaryRight ventricular (RV) function is of major prognostic significance in patients with acute pulmonary embolism (PE). The aim of the present study was to evaluate the role of neurohormone plasma brain natriuretic peptide (BNP) in assessing RV function in patients with acute PE.BNP levels were measured in 16 consecutive patients with acute PE as diagnosed by high probability lung scintigraphy or pulmonary angiography. Twelve healthy age-matched volunteers served as controls. All 16 patients underwent standard echocardiography and blood tests during the first hour of presentation. In the patient group, survival was studied for a period of 30 days. Plasma BNP levels in patients with acute PE were higher than in controls (7.2 [95% CI 0.4 to 144.6] versus 1.4[95% CI 0.4 to 4.6] pmol/L, p = 0.0008). Plasma BNP was significantly higher in 5 patients with RV dysfunction compared to 11 patients with normal RV function (40.2 [95% CI 7.5 to 214.9] versus 3.3 [95% CI 0.4 to 24.9] pmol/L, p = 0.0003). RV systolic pressure was not significantly correlated with BNP (r = 0.42, p = ns).In conclusion, plasma BNP neurohormone levels might be of clinical importance as a supplementary tool for assessment of RV function in patients with acute PE.
The ATP-Gated P2X1 Ion Channel Acts as a Positive Regulator of Platelet Responses to Collagen
Authors: Toth-Zsamboki Emese , Thys Chantal , Tytgat Jan , Vermylen Jos , Oury Cecile , Hoylaerts Marc 
Published: March 2018

SummaryATP is a potent agonist of the P2X1 ion channel, mediating a rapid, quickly desensitized influx of Ca2+. In hirudinized PRP, containing apyrase, the two stable selective P2X1 agonists, α,β-methylene ATP, and L-β, γ-methylene ATP induced extracellular Ca2+-dependent fast and reversible platelet shape change, leading to desensitization of the P2X1 ion channel. Preincubation with HPLC-purified ADP potently antagonized the subsequent α, β-methylene ATP- and L-β, γ-methylene ATP-evoked platelet shape change. Accordingly, upon heterologous expression of P2X1 in Xenopus oocytes, HPLC-purified ADP acted as an antagonist of the ATP-induced current, but was inactive itself. Since ATP and ADP are co-released from dense granules during platelet activation, we investigated whether the P2X1 ion channel is involved in the response of platelets to collagen. We found that platelet shape change and aggregation induced by low concentrations of collagen were strongly inhibited after selective desensitization of P2X1 with its agonists or by pretreating the platelets with a low concentration of ADP (0.5 μM), that antagonizes the P2X1 channel without desensitizing the P2Y1 receptor. Our data suggest that, during collagen-initiated platelet activation, the early secretion of ATP results in the activation of the P2X1 ion channel, which plays a role as a positive regulator of further platelet responses.
Characteristics of Anticoagulant Therapy and Comorbidity Related to Overanticoagulation
Authors: Penning-van Beest Fernie , Meegen Erik van , Rosendaal Frits , Stricker Bruno 
Published: March 2018

SummaryThe risk of hemorrhage when using coumarin anticoagulants sharply increases when the International Normalised Ratio (INR) is ≥6.0. We performed a prospective cohort study with a nested case-control design among 17,056 outpatients of an anticoagulation clinic to determine the incidence of overanticoagulation and to study the association between overanticoagulation and characteristics of anticoagulant therapy and comorbidity. The incidence rate of an INR ≥6.0 was 7.8 per 10,000 treatment days in prevalent users on the starting date and 22.5 per 10,000 treatment days in incident users during the study period. 300 cases with an INR ≥6.0 were compared with 302 randomly selected matched controls with an INR within the target zone. Patients on acenocoumarol had an increased risk of an INR ≥6.0 compared to patients on phenprocoumon. Regarding comorbidity, impaired liver function, congestive heart failure, diarrhea and fever were risk factors for overanticoagulation. Increased monitoring of INR values if risk factors are present or avoidance of risk factors could prevent excess anticoagulation and potential bleeding complications.