bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Risk Factors for Thrombosis
Authors: Bertina Rogier 
Published: March 2018

IntroductionA diagnosis of venous thrombosis is made each year in about 0.1% of Western populations. In the majority of cases, the diagnosis is based on objective evidence for an obstruction of the circulation by a blood clot that either formed locally or developed elsewhere in the circulation. The interest in the pathogenesis of this hemostatic process has increased enormously during the past 20 years and, as a consequence, substantial progress has been made in understanding the multifactorial nature of the disease, where interactions between genetic and environmental factors result in the formation of an obstructive thrombus at a specific time and at a specific location. Frequently, these thrombi are found in the elderly in the superficial and deep veins of the legs. Thrombi may also occur in younger individuals and in the veins of the brain, mesentery, liver, or retina.The episodic nature of the disease points out the importance of acquired and/or environmental factors in thrombosis. The disease also has strong genetic components, given the many reports of familial clustering of thrombotic events1-3 and the fact that 20% to 30% of patients with a first thrombotic event report at least one first-degree relative with thrombosis.4
The search for molecular risk factors for venous thrombosis remains intensive. Over the years, this research has been facilitated by new insights in the regulation of blood coagulation and by the development of new research methods, especially in the field of molecular genetics. Today, at least one genetic defect can be found in about 70% of the families with thrombophilia.5
Initial studies focussed on patients and their relatives (family studies). Such studies are very useful but can be hampered by selection bias. In other words, we know these families because the proband and some of his/her relatives have experienced thrombosis. Therefore, later studies used groups of unrelated patients and healthy controls (patient-control studies). One of the limitations of these studies is that they need to be very large to identify the less common risk factors.The concept of venous thrombosis as a multifactorial disease has received much attention in recent years.6-8 One of the reasons is that some of the newly discovered genetic risk factors concern single point mutations that are quite common in the general population (e.g., factor V Leiden, prothrombin 20210A allele).9,10 As a result, studies focussing on the interaction of these mutations with other relatively common risk factors (e.g., use of oral contraceptives,11,12 pregnancy,13 surgery,14 but also lupus anticoagulant15 or mild hyperhomocysteinemia16,17) have become feasible. In addition, researchers will continue to learn more about the relationship between these common molecular risk factors and the clinical phenotypes, namely deep vein thrombosis, pulmonary embolism, superficial thrombosis, and first versus recurrent events.
Thromboembolism and Pregnancy
Authors: Ginsberg Jeffrey 
Published: March 2018

IntroductionAntithrombotic therapy during pregnancy is used for the treatment and prophylaxis of venous thromboembolic disease, for the prevention and treatment of arterial embolism associated with valvular heart disease and/or prosthetic heart valves, for the prevention of fetal growth retardation and pregnancy loss in patients with antiphospholipid antibodies, and in patients with pregnancy-induced hypertension. Since antithrombotic agents have the potential to produce complications in both the mother and fetus, their use during pregnancy raises concerns. Guidelines are difficult to establish because the evidence upon which recommendations are based is derived primarily from poor-quality studies. This chapter reviews the fetal and maternal effects of antithrombotic agents including oral anticoagulants, unfractionated heparin, low molecular weight heparins (LMWH), and aspirin, and provides recommendations for their use during pregnancy.
Inherited Thrombophilia and Pregnancy Loss
Authors: Brenner Benjamin 
Published: March 2018

IntroductionA successful pregnancy is dependent on the development of adequate placental circulation. Abnormalities of placental vasculature may result in a number of gestational pathologies, including first and second trimester miscarriages, intrauterine growth retardation (IUGR), intrauterine fetal death (IUFD), placental abruption, and preeclampsia.1
Approximately 5% of women experience two or more consecutive abortions. Habitual abortions, defined as three or more spontaneous recurrent pregnancy losses, may affect as many as 1% to 2% of women of reproductive age. The discovery of an association between recurrent pregnancy loss, and antiphospholipid antibodies, specifically lupus anticoagulant, and anticardiolipin antibodies increased interest in a possible acquired thrombotic autoimmune cause.The inherited thrombophilias are a group of genetic disorders of blood coagulation resulting in an increased risk of thrombosis. Today, a full understanding of the inherited thrombophilias is becoming increasingly important in the management of high-risk gestations. Several reports over the last three years have suggested that not only are these disorders associated with an increased risk of thromboembolic disease during pregnancy and puerperium, but they are also associated with an increased incidence of vascular pathologies, resulting in poor gestational outcome.2
This review will cover recent data concerning thrombophilia and vascular placental pathology, potential pathophysiologic mechanisms for this association, and available therapeutic modalities for prevention of placental vascular thrombosis in order to maximize successful gestational outcome.
Long-Term Treatment of Venous Thromboembolic Disease
Authors: Hutten Barbara , Koopman Maria , Büller Harry , Prins Martin 
Published: March 2018

IntroductionAfter an initial 5- to 10-day course of treatment with either unfractionated or low molecular weight heparin, secondary prophylaxis is usually prescribed to patients with venous thromboembolic disease for a variable period of time. The primary aim of both initial and secondary treatment is to prevent recurrent thrombotic events, including deep vein thrombosis and fatal pulmonary embolism. This objective has to be achieved at a minimal risk of bleeding. There is general consensus that the initial treatment should be with low molecular weight or unfractionated heparin. For secondary prophylaxis, however, there are currently several options. Among these are continued unfractionated heparin or low molecular weight heparin and oral vitamin K-antagonists. In addition, compression stockings and caval vein filters are available.In this chapter, we will first examine the available evidence for each of these options, then discuss the results of randomized trials that have studied the duration of secondary prophylaxis. Finally, we will attempt to synthesize this information using decision analytic techniques.
Mechanisms of Hypercoagulability
Authors: Dahl Ola 
Published: March 2018

IntroductionPatients undergoing major traumas, major joint replacement surgery, and neurosurgery are at high risk for postoperative deep vein thrombosis (DVT). Even if modern low molecular weight heparin is given as prophylaxis, the frequency of DVT remains high in these patients.1-7 This may indicate that some patients possess a certain “heparin resistance,” due probably due to an overwhelming procoagulant activity and/or because the hypercoagulable state lasts for a longer time than presently assumed. Tissue factor (TF) is the primary cellular initiator of blood coagulation and the most potent trigger of blood clotting known today.8 Adventitia surrounding the major blood vessels, the brain, and the bone marrow are structures with high levels of TF.9 Elective hip replacement surgery, which is a fairly well-standardized procedure that involves a great deal of damage to the bone marrow, is therefore, well-suited as a model to study the mechanisms of hypercoagulability.
Anticoagulation in the Setting of Epidural or Spinal Anesthesia/Analgesia
Authors: Thompson Gale 
Published: March 2018

IntroductionThe focus of this chapter is on the word “analgesia,” as used in the title. Although the traditional role of the anesthesiologist is to provide anesthesia, or total pain relief, for surgical procedures in the operating room, it is no longer possible to be considered a “compleat” anesthesiologist by ending patient care at the time that the surgical patient is turned over to the recovery room nurse. There is a growing specialty and societal expectation that the anesthesiologist will smooth the pathway for recovery by using specific drugs and techniques to control postoperative pain. Usually the postoperative period includes a period of 1 to 5 days.Why has the treatment of postoperative pain become such an issue? Can postoperative pain be effectively controlled in a more cost-effective manner than through the use of parenteral narcotics? In reality, narcotic drugs are not a cheap or effective approach. For example, any patient or nurse who has experienced post-thoracotomy pain control via the epidural route vs parenteral injections will testify to a preference for the epidural.1,2 When pain treatment is effective, there are multiple physiologic and economic spin-offs, such as better wound healing, decreased pulmonary infection rates, improved gastrointestinal function, shortened hospitalization time, and considerable savings of health care dollars.3-7
Reduction of Pain Episodes and Prothrombotic Activity in Sickle Cell Disease by Dietary n-3 Fatty Acids
Authors: Tomer Aaron , Kasey Suha , Connor William , Clark Scott , Harker Laurence , Eckman James 
Published: March 2018

SummaryThe effects of dietary n-3 fatty acids (n-3FAs) on the frequency of pain episodes and ex vivo blood tests of thrombosis have been evaluated in patients with sickle cell disease (SCD) utilizing a doubleblind, olive oil-controlled clinical trial. Dietary n-3FA therapy (0.1 g/kg/d) was provided as menhaden fish oil (0.25 g/kg/d) containing 12% eicosapentaenoic acid (EPA), and 18% docosahexaenoic acid (DHA). Within 1 month dietary n-3FAs exchanged with n-6FAs in plasma and erythrocyte membrane phospholipids (p <0.01 in all cases).Treatment with dietary n-3FAs for 1 year reduced the frequency of pain episodes requiring presentation to the hospital from 7.8 events during the preceding year to 3.8 events/year (p <0.01; n = 5). By contrast, subjects receiving control dietary olive oil (n = 5) experienced 7.1 pain events/year, compared to 7.6 during the previous year (p >0.4). The reduction in episodes in n-3FA-treated subjects was also significant when compared to control subjects (p <0.01). Dietary n-3FA therapy was not associated with hemorrhagic, gastrointestinal or other adverse effects.Compared to 10 asymptomatic African-American controls, sickle cell subjects demonstrated significantly increased pretreatment: 1) flow cytometric expression of platelet membrane P-selectin (CD62p; p <0.01) and annexin V binding sites (p = 0.02); 2) plasma levels of platelet-specific secretory proteins platelet factor 4 (PF4) and -thromboglobulin (TG) (p <0.01 in both cases); 3) plasma products of thrombin generation, prothrombin fragment 1.2 (F1.2) and thrombin:antithrombin (TAT) complex (p <0.01 in both cases); and 4) plasma levels of thrombolytic products, D-dimer and plasmin:antiplasmin (PAP) complex (p <0.01 in both cases). Treatment with dietary n-3FAs concurrently decreased plasma levels of F1.2, D-dimer, and PAP (p <0.05, compared to olive oil controls), implying that the reduction in pain events was related to n-3FA-dependent inhibition of thrombosis. We conclude that dietary n-3FAs reduce the frequency of pain episodes perhaps by reducing prothrombotic activity in sickle cell disease.
High Prevalence of the I278T Mutation of the Human Cystathionine β-Synthase Detected by a Novel Screening Application
Authors: Linnebank Michael , Homberger Anja , Junker Ralf , Nowak-Goettl Ulrike , Harms Erik , Koch Hans 
Published: March 2018

SummaryClassical homocystinuria due to cystathionine beta-synthase deficiency is one of the disorders revealing a high risk of thromboembolic events and vascular disease. This autosomal-recessively inherited metabolic disorder is considered to be rare with an estimated prevalence of 1:130,000 in the German population. In this study, we developed a novel multiplex PCR generating allele specific fragment lengths to analyse individual genotypes of the two most frequent cystathionine beta-synthase alterations, the I278T mutation, which is worldwide found on up to the half of homocystinuric alleles, and the adjacent polymorphism 844ins68. Screening of 200 unrelated German control subjects revealed a frequency of heterozygosity of 1.5% for I278T corresponding to a calculated frequency of homozygosity of 1:17.800. Our data indicate that homocystinuria due to cystathionine β-synthase deficiency is a frequently unrecognized disorder resulting in a high risk of thromboembolic events.
Platelet Reactivity in Acute Coronary Syndromes: Evidence for Differences in Platelet Behaviour between Unstable Angina and Myocardial Infarction
Authors: Mathur Anthony , Robinson Monique , Cotton James , Martin John , Erusalimsky Jorge 
Published: March 2018

SummaryPrevious work has shown that P-selectin and mean platelet volume, two markers associated with platelet reactivity, are elevated in acute coronary syndromes. This study investigated the possibility that these markers may define unstable angina (UA) and acute myocardial infarction (MI) as two separate conditions based on platelet behaviour. Mean platelet volume (MPV) was higher in UA patients (n = 15) than in those diagnosed with MI (n = 15) (10.7 ± 0.25 fL, vs. 9.8 ± 0.27 fL, P = 0.005). Platelet count was lower in UA than in MI (215 ± 13 × 109/L vs. 271 ± 20 × 109/L, P = 0.03). The percentage of platelets expressing P-selectin was higher in MI than in UA (9.1 ± 1.9% vs. 4.2 ± 0.85%, P = 0.03). This parameter was positively correlated with MPV in UA (r = 0.5, P = 0.04) but negatively correlated in MI (r = -0.6, P = 0.01), with no correlation for ACS as a whole (r = –0.32, P = 0.1). Our results suggest that in MI there is an acute process of generalised platelet activation that is unrelated to changes in MPV, whereas in UA there is an ongoing process of platelet consumption that leads to an increase in platelet size to compensate for a persistent decrease in platelet count. This study suggests that there is a fundamental difference in platelet biology between these two diseases.
Homozygous and Compound-heterozygous Type I Plasminogen Deficiency Is a Common Cause of Ligneous Conjunctivitis
Authors: Zeitler Petra , Seregard Stefan , Ozcelik Ugur , Anadol Deniz , Luchtman-Jones Lori , Meire Francoise , Mingers Anne-Marie , Schambeck Christian , Kreth Hans Wolfgang , Schuster Volker 
Published: March 2018

SummarySevere type I plasminogen deficiency has been recently linked to ligneous conjunctivitis, a rare and uncommon form of chronic conjunctivitis. In this study, eight unrelated ligneous conjunctivitis patients living in different parts of the world were examined. All affected subjects from which plasma was available displayed absent or markedly reduced plasminogen antigen and plasminogen functional activity. Molecular genetic studies of seven patients identified a Lys19 → Glu mutation in two boys in a homozygous state, and in two girls in a compound-heterozygous state in which the second plasminogen gene carried a missense (Arg134 → Lys) and a nonsense mutation (Cys133 → Stop), respectively. A fifth patient was shown to be homozygous for a frameshift mutation in plasminogen exon 14 (Gly565ins-G). In two unrelated subjects with ligneous conjunctivitis no mutations in the plasminogen gene were identified. Our results suggest that the Lys19 → Glu mutation is the most prevalent mutation in the plasminogen gene of patients with ligneous conjunctivitis.
Recruitment of Labelled Monocytes by Experimental Venous Thrombi
Authors: McGuinness C. L. , Humphries J. , Waltham M. , Burnand K. G. , Collins M. , Smith A. 
Published: March 2018

Summary
Objective. Infusing monocytes that have been stimulated to produce fibrinolytic activators and factors that regulate cell proliferation, migration and maturation, might enhance venous thrombus resolution. The aim of this study was to determine the time course of infused monocyte recruitment into venous thrombus in an appropriate model of this disease. Design and Methods. Thrombus was induced in the inferior vena cava of male Wistar rats using reduced flow (80-90% stenosis). The vessel wall was examined at 1hr by scanning electron microscopy. Resolving thrombi with surrounding vena cava were obtained at 1, 7, 14 and 21 days after induction (n = 8). Sections, taken at 0.5 mm intervals (10-15 sections per thrombus), were stained using haematoxylin, Martius Scarlet Blue and antibodies against monocytes, platelets and fibrin. Sections from human venous thrombi (n = 4) were similarly stained. The area occupied by monocytes (in relative pixel units, RPU) was determined using computer aided image analysis. Peripheral rat blood monocytes were extracted, fluorescently labelled and injected intravenously into 7 rats prior to thrombus induction. Vena cava with thrombus was harvested 1 h, 2, 3, 4, 7, 14 and 25 days after induction and their fluorescence measured. The fluorescent content of the caval wall and thrombus was analysed in greater detail at 2 and 25 days after thrombus induction (n = 4 at each time interval). Results. Experimental thrombi were structurally similar to human thrombus and resolved within 14-21 days. Scanning electron microscopy showed minimal endothelial damage at 1 h with signs of early thrombus formation (platelet, red cell leukocyte and fibrin deposition). Neutrophils were the predominant leukocyte in the thrombus at 1 day, with monocytes making up only 0.3% (0.04% sem) of the area of the thrombus. There was a steady increase in thrombus monocyte content and by 21 days the percentage area of thrombus covered by monocytes had increased by over 35 fold to 11.5% (2.3% sem) (p <0.001). Initially, monocytes appeared around the edge of the thrombus and became more evenly distributed through the thrombus as resolution progressed. Labelled monocytes could be found in the circulation up to 1 week after infusion. The fluorescent content (RPU) of the thrombus increased over 25 days (mean RPU At 2 days 0.012, sem 0.005; mean RPU at 25 days 1.062, sem 0.252, p = 0.008). The number of labelled monocytes in the vessel wall peaked at 2 days and decreased thereafter.
Adenovirus-mediated Expression and Packaging of Tissue-type Plasminogen Activator in Megakaryocytic Cells
Authors: Chuang Joseph , Schleef Raymond 
Published: March 2018

SummaryPlatelets release large quantities of plasminogen activator inhibitor 1 (PAI-1) that plays an important role in maintaining the integrity of fibrin-rich thrombi. In addition, tissue-type plasminogen activator (t-PA), a key physiological regulator of fibrinolysis, has been detected in platelet α-granules at low abundance. This information raises the possibility of enhancing t-PA expression in megakaryocytes as a means to enhance the fibrinolytic properties of platelet α-granules and target PAs directly to fibrin clots. This study was initiated to investigate adenovirus (Ad)-mediated expression and packaging of t-PA into α-granules-like structures in the megakaryocytic cell line MEG-01. Ad/t-PA infection of phorbol myristate acetate (PMA)-differentiated MEG-01 cells increased cellular t-PA levels by 120 fold (1580 ± 130 ng/106 cells at 5 MOI) in comparison to non-or Ad/β-gal-infected cells. Fluorescence-activated cell sorter (FACS) analysis indicates that Ad/t-PA-infected cells yielded a homogenous shift in the t-PA staining profile with a 4-fold shift in mean fluorescence in comparison to non- or Ad/β-gal-infected cells. For the isolation of α-granule-like structures, MEG-01 cell homogenates were fractionated by differential centrifugation and two consecutive Percoll density gradients. Fibrin autography of storage granules revealed a prominent lytic zone at Mr 66 kD comigrating with free t-PA. Quantitative analyses indicate that a 16-fold elevation in t-PA antigen within storage granules in comparison to non- or Ad/β-gal-infected cells. To document the ability of t-PA to be stored in a rapidly-releasable form in these cells, we isolated platelet-like particles from the supernatant of differentiated cells and determined that particles from Ad/t-PA-infected cells display a 4-8 fold enhanced secretion of t-PA following treatment with the classical secretagogue calcium ionophore 23187, ADP, or thrombin. Confocal immunofluorescence microscopy analysis indicates that Ad/t-PA mediated productive expression of t-PA in murine megakaryocytes. These data provide support for the concept of increasing the expression of t-PA in megakaryocytes as a means to alter the hemostatic properties of α-granules.
Abbreviations: Ad, Adenovirus; t-PA, tissue-type plasminogen activator; PAI-1, plasminogen activator inhibitor 1; PMA, phorbol myristate acetate; ELISA, enzyme-linked immunosorbent assay; CM, conditioned media; vWF, von Willebrand factor; ECL, enhanced chemiluminescence; PA, plasminogen activator.
Thrombin-induced MCP-1 Expression Involves Activation of the p22phox-containing NADPH Oxidase in Human Vascular Smooth Muscle Cells
Authors: Viedt C. , Nguyen K. , Beer S. , Kreuzer J. , Busse R. , Görlach A. , Brandes R. P. 
Published: March 2018

SummaryActivation of vascular smooth muscle cells (VMSC) by thrombin induces the expression of the chemokine, monocyte chemoattractant protein-1 (MCP-1). We investigated in cultured human and rat VSMC whether reactive oxygen species (ROS) derived from the vascular NADPH oxidase contribute to this effect. Exposure of cultured VSMC to thrombin rapidly increased ROS formation, phosphorylation of p38 MAP kinase as well as the expression of MCP-1. Specific inhibition of the p22phox subunit of the vascular NADPH oxidase using either p22phox neutralizing antibody or p22phox antisense oligonucleotides attenuated thrombin-induced ROS generation. Furthermore, thrombininduced p38 MAP kinase activation as well as MCP-1 expression were impaired by antioxidants as well as by p22phox antisense oligonucleotides. Inhibition of p38 MAP kinase diminished the thrombin-induced expression of MCP-1. Conclusion: Thrombin, by activating a p22phoxcontaining NADPH oxidase, elicits ROS generation and activation of p38 MAP kinase in VSMC. The subsequent induction of MCP-1 expression highligts the crucial role of the p22phox-containing NADPH oxidase in thrombin-induced signal transduction in VSMC.