bluuebunny/crossref_metadata_2025 huggingface dataset:
Fibrinolytic Variables in Patients with Recurrent Venous Thrombosis: a Prospective Cohort Study
Authors: Roberts Jeremy , Roberts Robin , Johnston Marilyn , Stevens Pamela , Skingley Peter , Patrassi G. M. , Sartori M. T. , Hirsh Jack , Prandoni Paolo , Weitz Jeffrey , Gent Michael , Ginsberg Jeffrey , Crowther Mark
Published: March 2018

To determine whether fibrinolytic testing predicts recurrent venous thrombosis, we have performed a prospective cohort study in which 303 patients with a first episode of venous thromboembolism underwent comprehensive fibrinolytic testing while receiving oral anticoagulants, and after anticoagulants had been discontinued. They were then followed for up to 3 years for recurrent venous thrombosis. No systematic differences in the levels or activity of type 1 plasminogen activator inhibitor (PAI-1), tissue plasminogen activator (tPA) or euglobulin clot lysis times were detected between patients who did, or did not, suffer recurrent thrombosis. There were also no differences in these variables when patients whose initial thrombosis was idiopathic were compared to patients whose thrombosis occurred in the setting of a known thrombotic risk factor. Based on these results, neither measuring fibrinolytic parameters in patients with venous thromboembolism, nor modification of treatment based on the results of such testing, are justified. Our study also confirms that patients with idiopathic venous thromboembolism have a high risk of recurrence.
Like Fibrin, (DD)E, the Major Degradation Product of Crosslinked Fibrin, Protects Plasmin from Inhibition by α2-antiplasmin
Authors: Lee Agnes , Fredenburgh James , Stewart Ronald , Rischke Janice , Weitz Jeffrey
Published: March 2018

Plasmin generation is localized to the fibrin surface because tissue-type plasminogen activator (t-PA) and plasminogen bind to fibrin, an interaction that stimulates plasminogen activation over a hundred-fold. To ensure efficient fibrinolysis, plasmin bound to fibrin is protected from inhibition by α2-antiplasmin. (DD)E, a major soluble degradation product of cross-linked fibrin that is a potent stimulator of t-PA, compromises the fibrin-specificity of t-PA by promoting systemic activation of plasminogen. In this study we investigated whether (DD)E also protects plasmin from inhibition by α2-antiplasmin, facilitating degradation of this soluble t-PA effector. (DD)E and fibrin reduce the rate of plasmin inhibition by α2-antiplasmin by 5- and 10-fold, respectively. Kringle-dependent binding of plasmin to (DD)E and fibrin, with Kd values of 52 and 410 nM, respectively, contributes to the protective effect. When (DD)E is extensively degraded by plasmin, yielding uncomplexed fragment E and (DD), protection of plasmin from inhibition by α2-antiplasmin is attenuated. These studies indicate that (DD)E-bound plasmin, whose generation reflects the ability of (DD)E to stimulate plasminogen activation by t-PA, has the capacity to degrade (DD)E by virtue of its resistance to inhibition. This provides a mechanism to limit the concentration of (DD)E and maintain the fibrin-specificity of t-PA.
Platelets and Factor XI Bypass the Contact System of Blood Coagulation
Authors: Walsh Peter
Published: March 2018

Introduction

Factor XI is a plasma glycoprotein (concentration ∼30 nM) that was first identified by Rosenthal et al1 as a plasma coagulation factor deficiency in patients with abnormal hemostasis, particularly common among Ashkenazi Jews.2,3 In spite of recent advances in our understanding of the structure of factor XI and its gene, the structure-function relationships of the protein, and the molecular genetics of factor XI deficiency, considerable confusion about the physiologic role and clinical relevance of factor XI has arisen from both clinical and biochemical observations. One problem arises from the fact that, until recently, the only known pathway for activation of factor XI involved proteolytic activation by factor XIIa and interactions with coagulation proteins of the contact phase of blood coagulation.4-7 The problem arose from the clinical observation that patients with deficiencies of factor XI are subject to bleeding complications, whereas patients with deficiencies of the contact proteins are not.2,3,8-13 A related unanswered question concerns the lack of correlation in many reported patients between plasma levels of factor XI and the severity of clinical bleeding manifestations.2,3,8,9,13-15 In addition, some patients with severe factor XI deficiency experience significant bleeding complications, whereas others appear to be hemostatically normal. These clinical and biochemical observations have motivated investigations focused on alternative mechanisms for activation of factor XI independent of contact phase protein.19-22 Additional studies have focused on the identification and characterization of platelet factor XI, which is postulated to be an alternative splicing product of the factor XI gene. Platelet factor XI is present in platelet membranes and might substitute for plasma factor XI in hemostasis and account for the absence of bleeding complications in some patients with severe plasma factor XI deficiency.14,16-18,23-26 Studies addressing these two important and related problems are presented and discussed in this chapter.
Binding of Abciximab to αVβ3 and Activated αMβ2 Receptors: With a Review of Platelet-Leukocyte Interactions
Authors: Coller Barry
Published: March 2018

Introduction

Murine monoclonal antibody 7E3, as well as the derivatives of 7E3 used in vivo [7E3-F(ab’)2, 7E3 Fab’, mouse/human chimeric 7E3 Fab (c7E3 Fab; abciximab; ReoPro™)], inhibit platelet aggregation induced by physiologic and pathologic agonists by binding to the platelet glycoprotein (GP) IIb/IIIa receptor.1,2 This biological activity formed the basis of its development as an antithrombotic agent to prevent and treat plateletmediated ischemic cardiovascular disease. During its development, 7E3 was reported to also react with two other integrin receptors, the αVβ3 “vitronectin” receptor (CD51/CD61)3,4 and at least one activation-dependent conformation of the αMβ2 or “Mac-1” receptor (CD11b/CD18).5 Whereas both αVβ3 and αMβ2 have been implicated in a number of different physiologic and pathologic processes, it is possible that some effects of abciximab are due to its reactivity with one or the other of these receptors. Moreover, the reactivity of abciximab with these receptors opens up the possibility that abciximab, or other agents that inhibit these receptors, may be useful in preventing or treating disorders in which these receptors play a role. This review will address these issues.
Antiplatelet Therapy Using Cilostazol, a Specific PDE3 Inhibitor
Authors: Ikeda Yasuo
Published: March 2018

Introduction

Cilostazol, 6-[ 4-( l-cyclohexy l-IH-tetrazol-5yl ) butoxy ]-3, 4-dihydro-2 (1H)-quinolinone, is an antiplatelet/ antithrombotic agent that has been used since 1988 in several countries, including Japan, for treatment of chronic peripheral arterial occlusion. Cilostazol was also approved by the United States Food and Drug Administration (FDA) in 1999 for the treatment of intermittent claudication. Cilostazol not only inhibits platelet activation but also increases vasodilation.1,2 In addition, it has been also shown to inhibit vascular smooth muscle cell proliferation.3 These properties of cilostazol may also improve peripheral blood flow. The mechanism of these effects is mediated through elevated cyclic adenosine monophosphate (AMP), brought about by inhibition of cyclic nucleotide phosphodiesterase (PDE3) activity.4 In this chapter, the pharmacological properties, as well as the clinical efficacy of cilostazol, are briefly discussed.
CD4+ T Cell Response to Factor VIII in Hemophilia A, Acquired Hemophilia, and Healthy Subjects
Authors: Reding M.T. , Wu H. , Krampf M. , Okita D.K. , Diethelm-Okita B.M. , Key N.S. , Conti-Fine B.M.
Published: March 2018

Introduction

In spite of the significant advances in the treatment of hemophilia over the last 30 years, the development of antibodies that neutralize the procoagulant activity of factor VIII (factor VIII inhibitors) remains a serious complication of treatment with factor VIII products. Recent prospective studies of previously untreated patients with severe hemophilia have reported the incidence of inhibitor development to be approximately 20% to 25%.1-11 Factor VIII inhibitors may also develop in individuals without congenital factor VIII deficiency. Acquired autoimmune hemophilia occurs with an incidence of 0.2 to 1.0 per 1,000,000 per year in the general population.12,13 In both congenital and acquired hemophilia, anti-factor VIII antibody inhibitors are significant contributors to the morbidity and mortality of those affected. As such, these cases present difficult therapeutic challenges.

Much work over the last decade has focused on defining the epitopes on factor VIII to which inhibitor antibodies bind. While this work has clarified some of the mechanisms by which inhibitors neutralize the procoagulant function of factor VIII, our knowledge of the factor VIII-specific CD4+ T helper cells, whose activation is crucial for the synthesis of factor VIII inhibitors, remains quite limited. This review will, first, discuss how a better understanding of the cellular mechanisms involved in the immune response to factor VIII may lead to improved methods of long-term inhibitor suppression and, perhaps, even prevention of inhibitor development. Lastly, this review will describe the work in our laboratory that has begun to characterize the CD4+ T cell response to factor VIII in patients with hemophilia and in normal subjects.
Immunology of the Antiphospholipid Syndrome: Antibodies, Antigens, and Autoimmune Response
Authors: Roubey Robert A. S.
Published: March 2018

Introduction

The antiphospholipid syndrome (APS) is an autoimmune condition in which a group of autoantibodies are thought to play a direct role in the pathogenesis of thrombosis, fetal loss, and other clinical manifestations. This review will focus on the nature of these autoantibodies, the antigens they recognize, and mechanisms that may contribute to autoimmunity and the production of autoantibodies in patients with APS.
Disseminated Intravascular Coagulation
Authors: de Jonge Evert , van der Poll Tom , ten Cate Hugo , Levi Marcel
Published: March 2018

Introduction

A quick literature search in the MEDLINE databases from 1966 to 1998 using the search term disseminated intravascular coagulation (DIC) and related key words yields an impressive 11,921 manuscripts. Most of the published literature concerns the pathophysiology of DIC, which in its main features is now well understood. Other aspects of DIC, however, particularly those related to the definition, the relevance of the syndrome, and clinical management, remain unclear. Taking an evidence-based approach to the appropriate diagnosis and treatment of patients with DIC is difficult, in view of the lack of sound clinical trials. This is probably due to the fact that DIC is a poorly-defined syndrome with a widely variable intensity, often complicating a diversity of severe disorders that are themselves related to extensive morbidity and mortality.1,2 This chapter briefly reviews the clinical setting, incidence, and relevance of DIC and current insights into the pathogenesis of DIC. It also discusses the available knowledge on the clinical management of patients with this syndrome.

DIC is not a disease or a symptom but rather a syndrome, which is always secondary to an underlying disorder. The syndrome is characterized by a systemic activation of the blood coagulation system, which results in the generation and deposition of fibrin, leading to microvascular thrombi in various organs and contributing to the development of multiorgan failure. Consumption and subsequent exhaustion of coagulation proteins and platelets, due to the ongoing activation of the coagulation system, may induce severe bleeding complications, although microclot formation may occur in the absence of severe clotting factor depletion and bleeding.3 Derangement of the fibrinolytic system further contributes to intravascular clot formation (discussed later), but in some cases accelerated fibrinolysis (e.g., due to consumption of α2-antiplasmin) may cause severe bleeding. Hence, a patient with DIC can present with simultaneous thrombotic and bleeding problems, which obviously complicates treatment. Although there is no general consensus regarding the definition of DIC, the definition as put forward by Müller-Berghaus and colleagues in 1995 might be most appropriate: “Disseminated intravascular coagulation is an acquired syndrome characterized by the activation of intravascular coagulation up to intravascular fibrin formation. The process may be accompanied by secondary fibrinolysis or inhibited fibrinolysis.”4
The Role of Endothelial Cell-to-Cell Junctions in Vascular Morphogenesis
Authors: Bazzoni Gianfranco , Lampugnani Maria Grazia , Dejana Elisabetta
Published: March 2018

Introduction

Adhesion of endothelial cells (ECs) to one another and to the extracellular matrix is mediated by various surface receptors These surface receptors belong to several families of ubiquitously expressed cell adhesion molecules, such as cadherins integrins, immunoglobulins, and proteoglycans. Besides merely providing attachment sites, most adhesive receptors interac with cytoskeletal and cytoplasmic molecules and, thus, contribute to the regulation of cell morphology and signaling.

Adhesion requires refined modulation to sustain the process of new vessel formation or angiogenesis. Adjoining cells mus act in concert to finalize migration and proliferation and organize into a three-dimensional network of patent tubes. Some of the molecules involved in these cell-to-extracellular matrix and cell-to-cell interactions have now been characterized. The intracellular signaling pathways activated by these molecules are, on the contrary, still rather obscure. Moreover, the adhesive systems to matrix and neighboring cells can communicate,1-4 adding complexity and coordination to the process.
Diverse Roles of Macrophage Matrix Metalloproteinases in Tissue Destruction and Tumor Growth
Authors: Shapiro Steven
Published: March 2018

In the mouse, macrophage elastase is critical to macrophage proteolysis. The use of gene-targeting has uncovered both pathological roles, including destructive effects in aneurysm formation and emphysema, and physiological roles, such as tumor growth inhibition and regulation of inflammation. Translation of findings from mouse to human biology depends upon how well the disease models replicate the human conditions and the similarity of enzyme profile between species. We know that human MMP-12 is associated with these diseases, but as opposed to the mouse, other MMPs may also be of importance (MMP-9, and perhaps MMP-7, in particular). Our interpretation is that findings in mice reflect the critical role of macrophage proteolysis in these disease processes.
Acute Coronary Syndromes: Pathophysiology and Preventive Priorities
Authors: Zaman Azfar , Helft Gerard , Fayad Zahi , Fuster Valentin , Badimon Juan Jose
Published: March 2018

Introduction

Coronary atherosclerosis and its thrombotic complications are major causes of mortality and morbidity throughout the industrialized world. Atherosclerosis is a focal, pathological phenomenon characterized by the thickening and hardening of arteries due to accumulation of lipids, carbohydrates, blood products, fibrous tissue, and calcium deposits within the subendothelial space. Significant advances have been made in understanding the mechanisms underlying this disease process, and there is considerable evidence to show that plaque composition is a major determinant of the onset and severity of acute coronary syndromes. The ability to identify plaque composition and monitor its progression can, therefore, provide valuable information regarding the development of acute coronary syndromes and target areas for pharmacological intervention to reduce or prevent the socioeconomic impact of cardiovascular disease.

This chapter will describe the pathogenesis of plaque formation and rupture and assess the role of thrombus and thrombosis in the progression of atherosclerotic disease. Furthermore, we shall briefly discuss therapeutic interventions and speculate on possible targets for future research.
The mRNAs of Prekallikrein, Factors XI and XII, and Kininogen, Components of the Contact Phase Cascade Are Differentially Expressed in Multiple Non-hepatic Human Tissues
Authors: Neth Peter , Arnhold Marianne , Nitschko Hans , Fink Edwin
Published: March 2018

Recently RT-PCR studies had demonstrated the expression of plasma prekallikrein (PPK) mRNA in extrahepatic tissues. The questions arose whether that is illegitimate or regular expression, and whether the mRNAs of blood coagulation factors XI and XII, and high molecular weight kininogen, components of the contact activation cascade of blood coagulation are also expressed in non-hepatic tissues. These questions were addressed in the present study by employing quantitative RT-PCR. The relative mRNA levels of the respective proteins determined in 16 human tissues indicate legitimate extrahepatic transcription of at least three of the genes. Transcription of all genes was highest in the liver, but only PPK mRNA was detected in all 16 tissues, especially high levels in pancreas, kidney, testis, spleen and prostate. We conclude from these results that PPK is synthesized in significant amounts in non-hepatic tissues and that this locally synthesized PPK may have special local functions.
A New Approach in the Study of the Molecular and Cellular Events Implicated in Heparin-induced Thrombocytopenia
Authors: Khairy Mahnouch , Lasne Dominique , Brohard-Bohn Brigitte , Aiach Martine , Rendu Francine , Bachelot-Loza Christilla
Published: March 2018

Heparin-induced thrombocytopenia (HIT), a relatively common complication of heparin therapy, results of platelet activation, via the receptor for the Fc domain of IgG (FcγRIIa), by heparin-dependentantibodies, commonly directed against the heparin-platelet factor 4 (H-PF4) antigenic complex. Our strategy was to use whole blood allowing the study of leukocyte-platelet interactions. Experiments were performed with blood from healthy donors incubated with HIT patients’ plasma and different concentrations of heparin. We showed that 75% of the HIT patients’ plasma induced the formation of leukocyteplatelet-aggregates in a heparin-dependent-manner. The formation of leukocyteplatelet-aggregates induced by HIT plasma in the presence of heparin was (i) independent of the healthy blood donor FcγRIIa polymorphism, (ii) correlated with the levels of anti H-PF4 IgG antibodies contained in the patients’ plasma, and to a lesser extent to anti H-PF4 IgM antibodies, and (iii) was mediated by P-selectin. This report opens new prospects in the study of the molecular and cellular events implicated in HIT.
Role of the 4G/5G Polymorphism of PAI-1 Gene Promoter on PAI-1 Levels in Obese Patients
Authors: Vettor Roberto , De Pergola Giovanni , De Mitrio Vito , Saggiorato Graziella , Mea Paolo Della , Patrassi Giovanni Maurizio , Lombardi Anna Maria , Fabris Roberto , Girolami Antonio , Sartori Maria Teresa
Published: March 2018

As PAI-1, a cardiovascular risk factor linked to insulin-resistance, may be influenced by a 4G/5G gene polymorphism in disease states, we studied both PAI-1 plasma concentration (PAI-1:Ag) and 4G/5G polymorphism, and their relationship with anthropometric and endocrine-metabolic parameters in 93 obese patients and 79 lean normal subjects. In obese patients PAI-1:Ag levels were significantly increased, namely in males and in those with central obesity, and tightly related to the insulin-resistance parameters.

In obese patients the 4G/5G polymorphism was a determinant of PAI-1:Ag levels, which were highest in 4G/4G, intermediate in 4G/5G and lowest in 5G/5G genotype carriers. PAI-1:Ag levels were significantly associated with most of anthropometric and endocrine-metabolic parameters only in 4G allele obese carriers. Moreover, only in patients with central obesity was the relationship between genotype and PAI-1 concentration maintained, with the highest levels in the 4G/4G patients. In each genotype subset of patients with central, but not peripheral, obesity PAI-1:Ag levels were significantly increased compared to their lean counterparts.

In conclusion, the 4G/5G polymorphism may influence PAI-1 expression in obesity, with a crucial role in central but not peripheral adiposity. Since subjects with central obesity are at high risk for cardiovascular disease, the effects of the 4G/5G polymorphism on PAI-1 concentration may further enhance this risk.
Treatment of Intermittent Claudication with Mesoglycan – A Placebo-controlled, Double-blind Study
Authors: Gresele Paolo , Ferrari Gianni , Santoro Luigi , Gianese Francesco , Nenci Giuseppe ,   for the Mesoglycan Intermittent Claudication Group
Published: March 2018

Objective: To assess the effect of treatment with mesoglycan, a sulphated polysaccharide compound, on the walking capacity of patients with stage II peripheral arterial disease. Methods: Non-diabetic out-patients with intermittent claudication, duplex ultrasound evidence of peripheral atherosclerosis, ankle/arm index <0.80, systolic ankle pressure >50 mmHg, and absolute walking distance (AWD) between 100 and 300 m (standardised treadmill test) were eligible. After a 5-week run-in on single-blind placebo, patients were randomised to double-blind treatment with mesoglycan, 30 mg/day intramuscularly for 3 weeks followed by 100 mg/day orally for 20 weeks, or matching placebo. All patients received low-dose aspirin and lifestyle instructions. Clinical response was defined as an AWD increase at Week 23 >50% over baseline. Health-related quality of life and ischaemic events were assessed as secondary efficacy variables. Results: 242 patients were randomised and 237 were assessed for clinical response. Patients achieving clinical response were 59/118 with mesoglycan (50.0%) and 31/119 with placebo (26.1%; p <0.001). Geometric mean AWD increased from 192 to 298 m with mesoglycan, and from 192 to 238 m with placebo (p <0.001). Pain-free walking distance showed a non-significant increase with mesoglycan (p = 0.057). Changes in quality of life scores were in favour of mesoglycan. The rate of ischaemic events was 1/120 on mesoglycan and 6/122 on placebo (p = 0.053). The rate of non-ischaemic adverse events leading to treatment discontinuation was 7/120 and 4/122, respectively. Conclusion: Treatment with mesoglycan improves the walking capacity of patients with intermittent claudication, and might confer additional antithrombotic protection over that of aspirin.
The Fibrin Assay Comparison Trial (FACT): Correlation of Soluble Fibrin Assays with D-dimer
Authors: Zips Sybille , Ergül Hanimsah , Heene Dieter , Dempfle Carl-Erik ,   the FACT study group
Published: March 2018

Soluble fibrin (SF) is regarded as an indicator of acute fibrin formation and a precursor of fibrin thrombi. Using a set of clinical plasma samples, and fibrin derivatives, five assays for measurement of SF, including two chromogenic assays, two ELISA systems, and one latex-enhanced photometric immunoassay were compared. Correlation between SF assays was moderate (Spearman’s rho values between 0.344 and 0.805). Re-calibration with serial dilutions of desAABBfibrin monomer resulted in adjustment of the numerical scale of the assays without improving correlation.

All SF assays reacted with purified crosslinked fibrin derivatives. Using clinical plasma samples, Spearman’s rho of SF assays with D-dimer consensus values based upon results of 23 quantitative D-dimer assays were between 0.491 and 0.911.

Although all SF assays react with desAABB-fibrin monomer complexes, SF assays are heterogeneous concerning reactivity with fibrin compounds observed in clinical plasma samples. The prospect of a common calibrator for SF assays therefore seems to be remote.

Since SF assays react with crosslinked fibrin derivatives, it is not possible to clearly distinguish between acute fibrin formation, and fibrin dissolution on the basis of the results of current SF assays.
Attenuation by Fibrates of Plasminogen Activator Inhibitor Type-1 Expression in Human Arterial Smooth Muscle Cells
Authors: Lutzi Steffen , Ruef Johannes , Peter Karlheinz , Klar Ernst , Kübler Wolfgang , Sobel Burton , Bode Christoph , Nordt Thomas
Published: March 2018

Human atherosclerotic lesions exhibit increased expression of plasminogen activator inhibitor type-1 (PAI-1) that has been implicated in atherogenesis. Although vascular smooth muscle cells are a predominant source of PAI-1 expression potentially favorable modulation of PAI-1 expression by fibrates has not yet been characterized in these cells.

Human aortic smooth muscle cells were exposed to selected growth factors. PAI-1 expression was stimulated most powerfully by TGF-β (EC50 = 0.2 ng/ml, up to 12-fold increase). Gemfibrozil inhibited basal PAI-1 expression by 23% (p = ns) and TGF-β -induced PAI-1 expression by 52% (p = 0.017) whereas t-PA and total protein synthesis was not affected. Changes in PAI-1 protein accumulation reflected PAI-1 gene expression attributable to modulation of half-life of PAI-1 mRNA by gemfibrozil. Inhibition by other fibrates was less.

Gemfibrozil specifically attenuates TGF-β -induced PAI-1 expression in human arterial smooth muscle cells. Thus, fibrates are promising agents for normalizing increased PAI-1 expression in arterial walls in patients in whom PAI-1 expression is increased.
Increased Expression of Serine Palmitoyltransferase (SPT) in Balloon-injured Rat Carotid Artery
Authors: Carton Jill , Argentieri Dennis , Damiano Bruce , D’Andrea Michael , Uhlinger David
Published: March 2018

The response to vascular injury is a complex wound healing response involving cell proliferation, migration, remodeling and inflammation. In the present studies we employed a rat balloon angioplasty model of vascular injury to investigate the potential role of sphingolipid signaling in the response to vascular injury. The enzyme serine palmitoyltransferase (SPT) catalyzes the first committed step in de novo sphingolipid biosynthesis. We observed marked upregulation of expression of both SPT subunits in actively proliferating cells in injured vessels. This enhanced SPT expression occurs in de-differentiated fibroblasts and proliferating vascular smooth muscle cells. The upregulation is particularly apparent in the proliferating luminal edge of the neointima and the adventitial de-differentiated fibroblasts and may serve as a hallmark of this process. The possible functional consequences of this enzyme upregulation and its role in the response to vascular injury are suggested but remain to be determined.
Antiphospholipid Syndrome: Diagnostic Aspects of Lupus Anticoagulants
Authors: Arnout J.
Published: March 2018

Antiphospholipid syndrome (APS) is an autoimmune disorder in which antiphospholipid antibodies (aPL) are thought to be involved in the development of venous and/or arterial thrombosis. APL found in this syndrome are antibodies directed against a variety of phospholipid (PL) binding-proteins of which β2-glycoprotein I (β2GPI) and prothrombin are considered to be the major antigens. Some of these antibodies prolong PL-dependent clotting reactions and are termed lupus anticoagulants (LA). Autoimmune aPL which bind through β2GPI to cardiolipin are called anticardiolipin antibodies (aCL). Clinical studies indicate that LA is a stronger risk factor for thrombosis than aCL. The production of monoclonal antibodies against β2GPI and prothrombin has enabled us to understand the mechanism by which LA prolong coagulation in vitro. LA form bivalent antigen-antibody complexes with increased affinity for PL which compete with coagulation factors for the same catalytic surface. These LA positive monoclonal antibodies may be helpful in further improving the laboratory diagnosis of LA.
Protease Crosstalk with Integrins: the Urokinase Receptor Paradigm
Authors: Wei Ying , Chapman Harold
Published: March 2018

Migratory cells use both adhesion receptors and proteolytic enzymes to regulate their interaction with and response to extracellular matrices. Cooperation between integrins and proteases operates at several levels: integrin signaling induces proteases, proteases co-localize with integrins, and proteases regulate the interface between integrins and the intracellular cytoskeleton. One protease system intimately connected to integrins is the urokinase/urokinase receptor(uPAR)/plasmin system. Recent studies indicate urokinase promotes the ligand-like binding of its receptor to a set of β1 and β2 integrins, this binding in turn affecting integrin signaling and cell migration. The glycolipid anchor of uPAR associates with cholesterol-rich membrane rafts. Binding of uPAR to integrins may enrich integrin clusters with signaling molecules such as src-family kinases that localize to rafts and are important to integrin function. Signals derived from integrin/uPAR complexes promote the function of other integrins. Thus the urokinase/plasmin system coordinates with integrins to regulate cell: matrix interactions.
Treatment of Von Willebrand Disease
Authors: Mannucci Pier Mannuccio
Published: March 2018

In von Willebrand disease, there are two main options for the treatment of spontaneous bleeding episodes and for bleeding prophylaxis: desmopressin and transfusional therapy with plasma products. Desmopressin is the treatment of choice for most patients with type 1, who account for approximately 70 to 80 per cent of all cases with the disease. This non-transfusional hemostatic agent raises endogenous factor VIII and von Willebrand factor three- to fivefold and thereby transiently corrects both the intrinsic coagulation and primary hemostasis defects. In patients with the more severe type 3 and in the majority of those with type 2 desmopressin is not effective or is contraindicated, so that it is usually necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Concentrates treated with virus inactivation methods should be preferred to cryoprecipitate because they are equally effective and perceived as safer.
Extracellular Proteolysis and Angiogenesis
Authors: Pepper Michael
Published: March 2018

Extracellular proteolysis is an absolute requirement for new blood vessel formation, a process known as angiogenesis. This review will examine the role of the matrix metalloproteinase and plasminogen activator/plasmin systems during angiogenesis. Extracellular proteolysis has also been implicated in the generation of molecules with angioregulatory activity. These include, but are not limited to, angiostatin and endostatin. However, despite an abundance of data on their bioactivity, the molecular mechanisms by which these molecules achieve their effects are unknown. Anti-proteolysis, particularly in the context of angiogenesis, has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization.
Plasma Lipoproteins, Hemostasis and Thrombosis
Authors: Fernández José , Deguchi Hiroshi , Griffin John
Published: March 2018

Regulation of hemostasis and thrombosis involves numerous plasma factors that contribute to procoagulant and anticoagulant pathways. Lipid-containing surfaces provide sites where both procoagulant and anticoagulant enzymes, cofactors and substrates are assembled to express their activities. Plasma and lipoproteins can contribute to either procoagulant or anticoagulant reactions. Procoagulant lipids/lipoproteins include triglyceride-rich particles in plasma and oxidized low density lipoprotein (LDL) which can accelerate activation of prothrombin, factor X and factor VII. Potentially anticoagulant lipids and lipoproteins, each of which enhances inactivation of factor Va by activated protein C, include phosphatidylethanolamine, cardiolipin, the neutral glycosphingolipids glucosylceramide and Gb3 ceramide (CD77), and high density lipoprotein (HDL). Remarkably, treatment of hyperlipidemia with statins not only lowers lipids but also provides antithrombotic effects whose mechanisms remain to be clarified. We hypothesize that procoagulant and anticoagulant lipids and lipoproteins in plasma may contribute to a Yin-Yang balance that helps influence the up-regulation and down-regulation of thrombin generation.
Risk Factors in Venous Thromboembolism
Authors: Martinelli Ida
Published: March 2018

Venous thromboembolism is a serious disorder because of its potential complications, such as pulmonary embolism and the post-thrombotic syndrome. Inherited determinants of venous thromboembolism are only in part known, but in the past decades considerable progress has been made in the understanding of risk factors for the disease and their clinical impact. In particular, the development of molecular biology techniques and the increasing interest in their application, allowed an identification of two causes of inherited thrombophilia, i.e., factor V Leiden and the prothrombin G20210A mutation. Their recent discovery provided a new approach for improving the knowledge of inherited thrombophilia. In contrast to deficiencies of the naturally occurring anticoagulant proteins antithrombin, protein C and protein S, these two mutations cannot be considered true genetic defects, since they are nucleotide substitutions resulting in a more efficient coagulation process. Since they are rather common in the general populations of Caucasian descent and are associated with a moderate increased risk of venous thromboembolism, the effect of the interaction between inherited and environmental risk factors for venous thromboembolism has become an even greater field of interest. Prevention of first events and recurrences of venous thromboembolism can be optimized only through a knowledge of the main risk factors, their effect, and their interaction with environmental factors.
The Epidemiology of Venous Thromboembolism in the Community
Authors: Mohr David , Petterson Tanya , Lohse Christine , O’Fallon W. Michael , Melton L. Joseph , Heit John , Silverstein Marc
Published: March 2018

The incidence of venous thromboembolism exceeds 1 per 1000; over 200,000 new cases occur in the United States annually. Of these, 30% die within 30 days; one-fifth suffer sudden death due to pulmonary embolism. Despite improved prophylaxis, the incidence of venous thromboembolism has been constant since 1980. Independent risk factors for venous thromboembolism include increasing age, male gender, surgery, trauma, hospital or nursing home confinement, malignancy, neurologic disease with extremity paresis, central venous catheter/ transvenous pacemaker, prior superficial vein thrombosis, and varicose veins; among women, risk factors include pregnancy, oral contraceptives, and hormone replacement therapy. About 30% of surviving cases develop recurrent venous thromboembolism within ten years. Independent predictors for recurrence include increasing age, obesity, malignant neoplasm, and extremity paresis. About 28% of cases develop venous stasis syndrome within 20 years. To reduce venous thromboembolism incidence, improve survival, and prevent recurrence and complications, patients with these characteristics should receive appropriate prophylaxis.
Auswirkungen sozialer Ungleichheit auf Gesundheitschancen im Kindes- und Jugendalter und die Herausforderungen für die Präventions- und Versorgungsforschung
Authors: Götz N.-A. , Babitsch B.
Published: March 2018

Bereits im Kindes- und Jugendalter lassen sich Unterschiede in der Gesundheit in Abhängigkeit vom sozialen Status der Familie erkennen. Neben höheren Prävalenzen bei einer Vielzahl von Erkrankungen, drückt sich dies auch in einer höheren Belastung im Lebensalltag und geringeren, den Kindern/Jugendlichen zur Verfügung stehenden Ressourcen aus. Besonders stark sind diese sozial bedingten Unterschiede für die unter den Begriff der „neuen Morbidität“ gefassten Gesundheitsproblematiken ausgeprägt. So sind dreimal so viele Kinder/Jugendliche mit einem niedrigen Sozialstatus verglichen mit einem hohen Sozialstatus adipös. Kinder/Jugendliche erleben die sozial bedingten Unterschiede in ihrem Schul- und Familienalltag. Dies geht über eine materielle Deprivation hinaus und wird ggf. Teil der Wahrnehmung von realisierbaren Chancen sowie den Vorstellungen zur Lebensgestaltung und -führung. Der ‚Verwirklichungschancenansatz‘ setzt hier an und gibt wichtige Impulse, sogenannte Befähigungschancen als Basis für den Abbau von sozialer Ungleichheit anzusetzen. In Forschung und Praxis setzt dies voraus, den Fokus stärker auf die Ressourcen für Gesundheit und eine gesunde Entwicklung zu legen.
Ehrenamtliche Flüchtlingssprechstunde für Kinder und Jugendliche in Leipzig
Authors: Appelt P. , Hoppmann J. , Kiep H. , Schwarz S. , Kiess W. , Vollrath J.
Published: March 2018

Aufgrund steigender Flüchtlingszahlen im Sommer 2015 wurde eine pädiatrische Flüchtlingssprechstunde in der Erstaufnahmeeinrichtung „Ernst-Grube-Halle“ etabliert und zusammen mit der Johanniter-Unfall-Hilfe e. V. betrieben. Einmal wöchentlich wurden erkrankte und geschwächte Kinder durch Kinderärzte und Pflegepersonal mithilfe von Dolmetschern versorgt. Es konnte aufgezeigt werden, dass die Ernährung der Kleinkinder nur unzureichend sichergestellt war. Unter den Vorstellungsgründen waren besonders häufig fieberhafte Infekte der oberen Atemwege, Obstipation und Diarrhö. Einige schwer oder chronisch erkrankte Kinder konnten an spezialisierte Ambulanzen oder zur stationären Aufnahme an die Universitätsklinik Leipzig weitergeleitet werden. Nachdem Familien mit Kindern zunehmend und immer schneller dezentral untergebracht werden, wurde die Flüchtlingssprechstunde vorerst pausiert. Eine dauerhafte hausärztliche Versorgung für geflüchtete Kinder in Leipzig ist noch immer nicht sichergestellt, dies muss geändert werden.
Posttraumatische Belastungsstörung und Depression
Authors: Uhl I. , Illes F.
Published: March 2018

Traumatische Ereignisse gehen mit einem erhöhten Risiko zur Entwicklung psychischer Erkrankungen einher. Posttraumatische Belastungsstörungen (PTBS) treten häufig mit komorbiden Diagnosen auf, insbesondere depressiven Erkrankungen. In dem Artikel werden die Komorbidität von PTBS und Depression, die Symptomüberlappung sowie therapeutische Möglichkeiten diskutiert.

Patienten, die in Folge eines traumatischen Ereignisses eine Depression oder PTBS entwickeln, haben ein erhöhtes Risiko für die jeweils andere Erkrankung. Eine hohe Symptomüberlappung zwischen beiden Störungsbildern ist zu beachten. Verschiedene Faktoren beeinflussen die Effekte eines traumatischen Ereignisses, z. B. die Art der Traumatisierung, das Alter beim Ereignis, Vorerkrankungen oder psychosoziale Stressoren. Psychologische, neuroendokrine und genetische Faktoren werden als Prädiktoren für die Auswirkungen eines traumatischen Ereignisses diskutiert.

Bei der psychotherapeutischen und pharmakologischen Behandlung sollte die Komorbidität berücksichtigt werden. Allerdings besteht weiterer Forschungsbedarf, um die therapeutischen Strategien für Patienten mit komorbiden Störungen zu optimieren.
Neue Therapieoptionen bei Migräne
Authors: Dux M. , Meßlinger K.
Published: March 2018

Calcitonin gene-related peptide (CGRP), ein von primären Afferenzen freigesetztes vasoaktives Neuropeptid, steht im Fokus der pharmakologischen Migränetherapie. CGRP hat Wirkungen auf viele zentrale und periphere Funktionen, aber der migränefördernde Wirkungsmechanismus ist unklar. Derzeitige klinische und experimentelle Therapieprinzipien beruhen auf der Hemmung der CGRP-Freisetzung durch 5-HT1B/D-Agonisten (Triptane) oder der CGRP-Rezeptoren durch nicht peptidische Antagonisten (Gepante). Triptane sind bei einer Reihe von Patienten nicht ausreichend wirksam und können bei zu häufiger Anwendung einen Kopfschmerz bei Medikamentenübergebrauch verursachen, während die Weiterentwicklung der Gepante wegen lebertoxischer Nebenwirkungen unterbrochen worden ist. Neue hoffnungsvolle Entwicklungen in der Migränetherapie sind CGRP oder CGRP-rezeptorenblockierende monoklonale Antikörper, die in ersten klinischen Studien bei chronischer und häufiger Migräne geprüft worden sind. In diesem Übersichtsartikel werden die bekannten Wirkungen von CGRP in und außerhalb des trigeminalen Systems beleuchtet und auf dem Hintergrund der therapeutischen Effektivität sowie möglicher Nebenwirkungen bei der Blockierung des CGRP-Systems kritisch diskutiert.
Aktuelles zur Depressionstherapie
Authors: Laux G.
Published: March 2018

Die aktualisierte S3-Leitlinie/Nationale VersorgungsLeitlinie „Unipolare Depression“ bietet einen wichtigen Orientierungsrahmen für die evidenzbasierte Depressionsbehandlung (Pharmakotherapie, Psychotherapie, psychosoziale Interventionen, körperliches Training). Zu den neuen Therapien zählen angesichts der Lücke zwischen psychotherapeutischem Versorgungsbedarf und verfügbaren Ressourcen internetbasierte psychologische Therapieprogramme, die zumeist auf den etablierten Prinzipien der kognitiven Verhaltenstherapie basieren (iKVT). Zur Wirksamkeit liegen kontrollierte Studien und Metaanalysen vor, Daten zum Programm deprexis24® werden vorgestellt, Vor- und Nachteile erörtert.

Die Datenlage bezüglich Fahrtauglichkeit und Unfallrisiken depressiver Patienten ist limitiert, bei akuten, schweren Depressionen ist keine Fahrtauglichkeit gegeben, unter regelmäßigen Facharztkontrollen kann nach Remission für Gruppe 1 (Pkw) und Gruppe 2 (Lkw) von Fahreignung ausgegangen werden. Daten zur Frage der Fahrtauglichkeit unter Antidepressivatherapie liegen von naturalistischen und kontrollierten Patientenstudien vor. Nach zum Teil negativen Akuteffekten zeigen erfolgreich mit Antidepressiva behandelte Patienten in Fahrtauglichkeitstests günstigere Ergebnisse als unbehandelte Depressive. Die große interindividuelle Variabilität weist auf die Notwendigkeit einer individuellen Bewertung der Fahrtauglichkeit unter Berücksichtigung der psychopathologischen Leitsymptomatik, Krankheitsverlauf, Persönlichkeitsfaktoren, Attitüden sowie möglicher Kompensationsfaktoren hin.
Pathologischer Narzissmus und Destruktivität
Authors: Csef H.
Published: March 2018

Epidemiologische Studien haben eine Zunahme narzisstischer Störungen in den letzten Jahrzehnten nachweisen können. Narzissmus hat viele Gesichter. In der Gegenwart kommt offensichtlich vermehrt die destruktive Seite des pathologischen Narzissmus zum Ausdruck, die sich oft in Gewaltexzessen zeigt. Homizid-Suizid-Phänomene sind dabei häufig. In diesem Kontext wird die Ambivalenz des Narzissmus zwischen Autoaggression und Fremdaggression diskutiert.
Anatomical accuracy of interactive and automated rigid registration between X-ray CT and FDG-PET
Authors: Wolz G. , Nömayr A. , Hothorn T. , Hornegger J. , Römer W. , Bautz W. , Kuwert T.
Published: March 2018

Aim: Comparison of anatomical accuracy of softwarebased interactive (IRR) and automated rigid registration (ARR) of separately acquired CT and FDG-PET data sets. Patients, methods: Independently acquired PET and helical CT data from 22 tumour patients were registered manually using the Syngo advanced Fusion VC20H tool. IRR was performed separately for the thorax and the abdomen using physiological FDG uptake in several organs as a reference. In addition, ARR was performed with the commercially available software tool Mirada 7D on all of the patients. For both methods, the distances between the representation of 53 malignant lesions on PET and CT were measured in X-, Y-, and Z-direction with reference to a common coordinate system (X-, Y-, Z-distances). Results: The percentage of lesions misregistered by less than 1.5 cm was in X-direction 91% for IRR and 89% for ARR; in Y-direction 85% and 68%; in Z-direction 72% and 51%, respectively. The average X-, Y- and Z-distances for IRR ranged from 0.58 ± 0.55 cm (X-direction) to 1.17 ± 1.66 cm (Z-direction). For ARR, the average X-, Y- and Z-distances varied between 0.66 ± 0.61 cm (X-direction) and 1.81 ± 1.37 cm (Z-direction). Mixed effects analysis of the absolute X-, Y- and Z-distances revealed a significantly better alignment for IRR compared to ARR in Z-direction (p <0.01). Lesion size and localization either in thorax or abdomen had no significant influence on the accuracy of registration. Conclusion: For the majority of malignant lesions, manual image registration with the possibility to separately align different body segments was more accurate than the automated approach. Current software for ARR does not reach the anatomical accuracy reported for PET/ CT hybrid scanners.
Thrombophilia and pregnancy complications
Authors: Vormittag R. , Pabinger I.
Published: March 2018

Venöse Thrombosen und Lungenembolien sind die führende Ursache schwangerschaftsbedingter Morbidität und Mortalität. Frauen mit Thrombophilie haben ein erhöhtes Thromboserisiko während der Schwangerschaft und des Puerperiums. Bei Frauen mit hereditärem Thromboserisikofaktor wurde ein relatives Risiko von 3,4 bis 15,2 für eine schwangerschaftsassoziierte Thrombose festgestellt. Frauen mit vorangegangener Thrombose haben während der Schwangerschaft ein 3,5-mal höheres Rezidivrisiko als sonst.

Die Daten über eine Assoziation zwischen Thrombophilie und Aborten oder Präeklampsie sind widersprüchlich. Abgesehen von einer etablierten Risikoerhöhung für Aborte durch Antiphospholipid-Antikörper gibt es Hinweise für eine Bedeutung des Antithrombinmangels, der Hyperhomozysteinämie, des Faktor V Leiden, der Prothrombin- G20210A-Variation und des Protein-S-Mangels. Ein Zusammenhang zwischen Thrombophilie und Präeklampsie ist weniger gut belegt. Die Zahl verfügbarer, prospektiver Studien ist begrenzt, und diese fanden keine Risikoerhöhung in einem unselektionierten Patientengut mit Thromboserisikofaktor. Verfügbar sind Daten einer kontrollierten Studie über die Prävention eines Schwangerschaftsverlusts mittels niedermolekularem Heparin (NMH), welches eine starke positive Wirkung zeigte. Thrombophilie-Screening mag bei Frauen mit Aborten, insbesondere ab der 10 Schwangerschaftswoche, angezeigt sein und eine Prophylaxe mit NMH sollte bei jenen Frauen überlegt werden, bei denen eine Thrombophilie festgestellt wird. Weitere prospektive Studien und kontrollierte Interventionsstudien werden dringend benötigt.
Thrombocytopenia during pregnancy
Authors: Boehlen F.
Published: March 2018

Thrombocytopenia is observed in 6 to 15% of pregnant women at the end of pregnancy, and is usually moderate. Gestational thrombocytopenia (defined as a mild thrombocytopenia, occurring during the 3rd trimester with spontaneous resolution postpartum and no neonatal thrombocytopenia) is the most common cause of thrombocytopenia during pregnancy but a low platelet can also be associated with several diseases, either pregnancy specific or not, such as preeclampsia, HELLP syndrome, or idiopathic thrombocytopenic purpura (ITP). The differential diagnosis between ITP and gestational thrombocytopenia is clinically important with regard to the fetus, due to the risk of neonatal thrombocytopenia. However, this differential diagnosis is very difficult during pregnancy.

Thrombocytopenia which need to be investigated are the following: thrombocytopenia known before pregnancy, thrombocytopenia occurring during the 1st and 2nd trimester, platelet count < 75 G/l in the 3rd trimester or thrombocytopenia in case of pregnancy with complications. Investigations have to be discussed in function of history and clinical examination, gestational age and severity of thrombocytopenia.

No treatment is required in case of gestational thrombocytopenia. There are few data to distinguish management of ITP between pregnant and non-pregnant women but management is different because of the potential adverse effects of the treatment for the woman and/or the fetus, the requirement for a good hemostasis at delivery and the risk of neonatal hemorrhage. One important problem is that it is not possible to predict the risk of neonatal thrombocytopenia in babies born from women with ITP.