Showing papers in "Seminars in Thrombosis and Hemostasis in 2010"
TL;DR: A goal of future work is to identify therapeutic targets on tumor blood vessel endothelial cells that have lost this requirement for maintenance, and to target antiangiogenic cancer therapies directed at VEGF-A or its receptors.
Abstract: The blood vessels supplying tumors are strikingly heterogeneous and differ from their normal counterparts with respect to organization, structure, and function. Six distinctly different tumor vessel types have been identified, and much has been learned about the steps and mechanisms by which they form. Four of the six vessel types (mother vessels, capillaries, glomeruloid microvascular proliferations, and vascular malformations) develop from preexisting normal venules and capillaries by angiogenesis. The two remaining vessel types (feeder arteries and draining veins) develop from arterio-venogenesis, a parallel, poorly understood process that involves the remodeling of preexisting arteries and veins. All six of these tumor vessel types can be induced to form sequentially in normal mouse tissues by an adenoviral vector expressing vascular endothelial growth factor (VEGF)-A164. Current antiangiogenic cancer therapies directed at VEGF-A or its receptors have been of only limited benefit to cancer patients, perhaps because they target only the endothelial cells of the tumor blood vessel subset that requires exogenous VEGF-A for maintenance. A goal of future work is to identify therapeutic targets on tumor blood vessel endothelial cells that have lost this requirement.
367 citations
TL;DR: Microparticles (MP) are vesicular structures released from cells upon activation, malignant transformation, stress, or death as discussed by the authors, which can be derived from the plasma membrane (shed microvesicles), produced by endosomal pathway (exosomes), or arise from membrane blebs of apoptotic cells.
Abstract: Microparticles (MP) are vesicular structures released from cells upon activation, malignant transformation, stress, or death. MP may be derived from the plasma membrane (shed microvesicles), produced by endosomal pathway (exosomes), or arise from membrane blebs of apoptotic cells. The terms microparticles or microvesicles (MV) are often used as general and interchangeable descriptors of all cellular vesicles, but a more rigorous terminology is still to be established. The cargo of MP/MV consists of proteins, lipids, and nucleic acids (DNA, mRNA, microRNA), all of which may be transferred horizontally between cells. In cancer, oncogenic pathways drive production of MP/MV, and oncoproteins may be incorporated into the cargo of MV (oncosomes). Oncogenic pathways may also stimulate production of MP/MV harboring tissue factor and involved in cancer coagulopathy. In addition, the cargo of MV may include several receptors, antigens, bioactive molecules, and other species capable of stimulating tumor progression, immunotolerance, invasion, angiogenesis, and metastasis. MP emanate not only from tumor cells but also from platelets, endothelium, and inflammatory cells. Indeed, circulating MP/MV harbor molecular information related to cancer-related processes and may serve as a reservoir of prognostic and predictive biomarkers to monitor genetic tumor progression, angiogenesis, thrombosis, and responses to targeted therapeutics.
270 citations
TL;DR: This review addresses flow cytometry limitations in microparticle measurement that may be subdivided into three domains: sizing, probing, and counting and covers the various standardization strategies and technological improvements that have been proposed to overcome these limitations.
Abstract: Circulating microparticles are submicron vesicles released from cell membranes in response to activation or apoptosis. Acknowledgment of their role both as markers and pathogenic effectors in thrombosis, inflammation, and the spread of cancer has increased the interest of their measurement in clinical practice. However, assessment of their clinical use is impeded by technological issues. Among the different methodologies available, flow cytometry is the most commonly used technique. This review addresses flow cytometry limitations in microparticle measurement that may be subdivided into three domains: sizing, probing, and counting. This article also covers the various standardization strategies and technological improvements that have been proposed to overcome these limitations. New tools using size-calibrated beads and recent progress in instrumentation have opened new avenues to improve detection of microparticle populations of smaller sizes. Significant optimization in microparticle detection is also expected from the use of new fluorescent dyes and the establishment of practical recommendations. Finally, absolute counting of microparticles will also benefit from adapted bead-based strategies or, alternatively, from the generalized availability of volumetric systems. Overall, recent technological improvements maintain flow cytometry as a highly competitive analytical method to measure microparticles. Challenging these evolutions in pathological situations is a mandatory step to validate their real impact in clinical practice.
204 citations
TL;DR: Although mounting evidence strongly supports beneficial cardiovascular effects of moderate red wine consumption in most populations, clinical advice to abstainers to initiate daily alcohol consumption has not yet been substantiated in the literature and must be considered with caution on an individual basis.
Abstract: The term FRENCH PARADOX was coined in 1992 to describe the relatively low incidence of cardiovascular disease in the French population, despite a relatively high dietary intake of saturated fats, and potentially attributable to the consumption of red wine. After nearly 20 years, several studies have investigated the fascinating, overwhelmingly positive biological and clinical associations of red wine consumption with cardiovascular disease and mortality. Light to moderate intake of red wine produces a kaleidoscope of potentially beneficial effects that target all phases of the atherosclerotic process, from atherogenesis (early plaque development and growth) to vessel occlusion (flow-mediated dilatation, thrombosis). Such beneficial effects involve cellular signaling mechanisms, interactions at the genomic level, and biochemical modifications of cellular and plasma components. Red wine components, especially alcohol, resveratrol, and other polyphenolic compounds, may decrease oxidative stress, enhance cholesterol efflux from vessel walls (mainly by increasing levels of high-density lipoprotein cholesterol), and inhibit lipoproteins oxidation, macrophage cholesterol accumulation, and foam-cell formation. These components may also increase nitric oxide bioavailability, thereby antagonizing the development of endothelial dysfunction, decrease blood viscosity, improve insulin sensitivity, counteract platelet hyperactivity, inhibit platelet adhesion to fibrinogen-coated surfaces, and decrease plasma levels of von Willebrand factor, fibrinogen, and coagulation factor VII. Light to moderate red wine consumption is also associated with a favorable genetic modulation of fibrinolytic proteins, ultimately increasing the surface-localized endothelial cell fibrinolysis. Overall, therefore, the "French paradox" may have its basis within a milieu containing several key molecules, so that favorable cardiovascular benefits might be primarily attributable to combined, additive, or perhaps synergistic effects of alcohol and other wine components on atherogenesis, coagulation, and fibrinolysis. Conversely, chronic heavy alcohol consumption and binge drinking are associated with increased risk of cardiovascular events. In conclusion, although mounting evidence strongly supports beneficial cardiovascular effects of moderate red wine consumption (one to two drinks per day; 10-30 g alcohol) in most populations, clinical advice to abstainers to initiate daily alcohol consumption has not yet been substantiated in the literature and must be considered with caution on an individual basis.
198 citations
TL;DR: This review critically appraises studies examining the abnormalities in the hemostasis pathway in patients with CKD, as well as the therapeutic options that are currently available to treat these individuals.
Abstract: Chronic kidney disease (CKD) is a growing global health problem. CKD is typically associated with a prothrombotic tendency in the early stages of the disease, whereas in its more advanced stage, that is, end-stage renal disease, patients suffer from a prothrombotic tendency and, in many cases, a bleeding diathesis. The exact etiology behind the coexistence of these conflicting hemostatic disorders is poorly understood. This review critically appraises studies examining the abnormalities in the hemostasis pathway in patients with CKD, as well as the therapeutic options that are currently available to treat these individuals.
178 citations
TL;DR: The existence of the overlapping clinical syndromes of VICC and thrombotic microangiopathy in snake envenoming is the likely reason for the mistaken idea that snakebite causes DIC.
Abstract: The most common coagulopathy associated with snake envenoming worldwide is venom-induced consumption coagulopathy (VICC), which results from activation of the coagulation pathway by snake toxins including thrombin-like enzymes, prothrombin activators, and factor X activators. VICC has often been likened to disseminated intravascular coagulation (DIC) because of the elevated D-dimer, prolonged prothrombin time, and low fibrinogen. However, VICC is not characterized by other important features of DIC, such as evidence of systemic microthrombi and end-organ failure. In addition, the time course of VICC differs with rapid onset and resolution, and the mechanism of initiation of coagulation activation differs because thrombin generation in DIC is mediated by the tissue factor/factor VIIa pathway. In a proportion of patients with VICC, a clinical syndrome consistent with thrombotic microangiopathy has been reported and is characterized by acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia. This thrombotic microangiopathy appears to only occur in conjunction with VICC but in several different snakes worldwide including vipers and elapids. Consistent with thrombotic microangiopathy, it progresses despite the resolution of the coagulopathy, suggesting a distinct but related process. The existence of the overlapping clinical syndromes of VICC and thrombotic microangiopathy in snake envenoming is the likely reason for the mistaken idea that snakebite causes DIC.
158 citations
TL;DR: The various quantitative and qualitative defects of fibrinogen associated withThrombosis, the tests that may predict the thrombotic risk, as well as some preventive or therapeutic approaches are discussed.
Abstract: Fibrinogen contributes to thrombosis risk in different ways. Indeed, various mutations in the fibrinogen genes predispose to thrombosis. At the same time, high levels of fibrinogen are also associated with thrombotic complications. Although the underlying causative mechanisms are not clear, this most likely involves the associated inflammatory and hypercoagulable states. In the last few years, particular attention has focused on the polymorphisms of fibrinogen genes involved in increased fibrinogen levels or fibrinogen qualitative changes. The association between dysfibrinogenemia and risk of thrombosis is well known, and some mechanisms have been clearly identified. Paradoxically, some patients with either hypofibrinogenemia or afibrinogenemia may also suffer from severe thromboembolic complications. The management of these patients is particularly challenging because they are not only at risk of thrombosis but also of bleeding. This review discusses the various quantitative and qualitative defects of fibrinogen associated with thrombosis, the tests that may predict the thrombotic risk, as well as some preventive or therapeutic approaches.
138 citations
TL;DR: Current data suggest a potential prognostic role of circulating MP for identification of subjects prone to develop cardiovascular complications, and their levels increase in patients with cardiovascular diseases; specific cardiovascular medications also affect plasma MP levels.
Abstract: Microparticles (MP) are shed membrane vesicles released by various cell types following apoptosis or activation. MP circulate in human plasma and also accumulate in atherosclerotic lesions. A growing body of evidence has highlighted their involvement in inflammation, angiogenesis, coagulation, and the regulation of vascular tone. MP may therefore contribute to the initiation and development of atherosclerosis and its complications. Plasma MP originate from platelets, leukocytes, erythrocytes, and endothelial cells, and their levels increase in patients with cardiovascular diseases; specific cardiovascular medications also affect plasma MP levels. Most recent data suggest a potential prognostic role of circulating MP for identification of subjects prone to develop cardiovascular complications.
131 citations
TL;DR: Thromboelastography (TEG), a time-sensitive dynamic assay of the viscoelastic properties of blood, closely parallels the CBM, permitting timely, goal-directed restoration of hemostasis via POC monitoring of coagulation status, and the emerging role of POC TEG.
Abstract: Current recommendations for resuscitation of the critically injured patient are limited by a lack of point-of-care (POC) assessment of coagulation status. Accordingly, the potential exists for indiscriminant blood component administration. Furthermore, although thromboembolic events have been described shortly after injury, the time sequence of post-injury coagulation changes is unknown. Our current understanding of hemostasis has shifted from a classic view, in which coagulation was considered a chain of catalytic enzyme reactions, to the cell-based model (CBM), representing the interplay between the cellular and plasma components of clot formation. Thromboelastography (TEG), a time-sensitive dynamic assay of the viscoelastic properties of blood, closely parallels the CBM, permitting timely, goal-directed restoration of hemostasis via POC monitoring of coagulation status. TEG-based therapy allows for goal-directed blood product administration in trauma, with potential avoidance of the complications resulting from overzealous component administration, as well as the ability to monitor post-injury coagulation status and thromboprophylaxis. This overview addresses coagulation status and thromboprophylaxis management in the trauma patient and the emerging role of POC TEG.
125 citations
TL;DR: A review of the range of assays for measuring circulating TF antigen and activity that have been published and comment on some of the crucial preanalytical and analytical variables that influence the results and their interpretation is addressed.
Abstract: Tissue factor (TF) is a transmembrane protein that initiates coagulation following contact with factor VII/VIIa. Recent experimental evidence, in particular from animal models, suggests an important role for circulating TF in thrombosis. This has led to a growing interest in the measurement of TF in whole blood and in cell-free plasma, where functionally active TF is carried on cell-derived microparticles. In this review, we address the range of assays for measuring circulating TF antigen and activity that have been published. We comment on some of the crucial preanalytical and analytical variables that influence the results and their interpretation.
98 citations
TL;DR: Data indicate that regular EQA/proficiency testing is needed for global hemostasis devices, and some centers returned results that were sufficiently different from those obtained by other participants to predict alterations in patient management decisions.
Abstract: Global hemostasis devices are currently being employed in operating rooms to assess the bleeding risk and outcomes for patients undergoing surgery. Two devices currently available are the TEG (Thromboelastograph; Haemoscope Corp., Niles, IL) and the ROTEM (Rotation Thromboelastometer; Pentapharm GmbH, Munich, Germany). Both measure the speed of clot formation, the strength of the clot when formed, and clot fibrinolysis kinetics. The two devices use different parameters so no cross comparisons of results can be made. The devices are usually operated by a member of the operating team and not a laboratory scientist; thus their testing and performance is generally not laboratory controlled, despite quality control being required to ensure reliable results. The UK National External Quality Assessment Scheme (NEQAS) for Blood Coagulation has undertaken a series of exercises evaluating the provision of External Quality Assessment (EQA) material for these devices. A series of four studies have taken place using lyophilized plasmas as the test material. Up to 18 TEG users and 10 ROTEM users have been involved in testing two samples per study, for a total of eight samples tested. The samples were normal plasmas, factor VIII or XI deficient samples, or normal plasmas spiked with heparin. The precision of the tests varied greatly for both devices, with coefficients of variances ranging from 7.1 to 39.9% for TEG and 7.0 to 83.6% for ROTEM. Some centers returned results that were sufficiently different from those obtained by other participants to predict alterations in patient management decisions. Our data indicate that regular EQA/proficiency testing is needed for these devices.
TL;DR: It is hoped complement blockers will offer patients a better chance to avoid ESRD and provide a better quality of life as plasmatherapy does not appear to influence the outcome of aHUS with membrane cofactor protein mutation.
Abstract: Plasmatherapy has become empirically first-line treatment in atypical hemolytic uremic syndrome (aHUS), although no prospective controlled trials have been conducted. Patients with mutations that induce complete or partial factor H (FH) quantitative deficiency may be controlled by plasma infusions (PI), but plasma exchanges appear more efficient than PI in patients with mutations that result in a mutant dysfunctional FH in the circulation. Early treatment is crucial. Long-term prophylactic plasmatherapy appears more efficient to prevent end-stage renal disease (ESRD) than plasmatherapy only during relapses. However, the longest follow-up with preserved renal function under plasmatherapy is only 6.5 years. Plasmatherapy does not appear to influence the outcome of aHUS with membrane cofactor protein mutation, and its efficacy in patients with factor I, C3, or factor B mutations is suggested by a few reports. We hope complement blockers will offer patients a better chance to avoid ESRD and provide a better quality of life.
TL;DR: The relevance of the cross-talk between inflammation and coagulation is underlined by the results of the treatment of severe systemic infection with modulators of coagulations and inflammation.
Abstract: Severe infection and inflammation almost invariably lead to hemostatic abnormalities, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation. Systemic inflammation as a result of severe infection leads to activation of coagulation, due to tissue factor-mediated thrombin generation, downregulation of physiological anticoagulant mechanisms, and inhibition of fibrinolysis. Proinflammatory cytokines play a central role in the differential effects on the coagulation and fibrinolysis pathways. Vice versa, activation of the coagulation system may importantly affect inflammatory responses by direct and indirect mechanisms. Apart from the general coagulation response to inflammation associated with severe infection, specific infections may cause distinct features, such as hemorrhagic fever or thrombotic microangiopathy. The relevance of the cross-talk between inflammation and coagulation is underlined by the results of the treatment of severe systemic infection with modulators of coagulation and inflammation.
TL;DR: Clinical and biological evidence supports the hypothesis that therapy with ESAs might not be ultimately beneficial or advantageous in patients with anemia of chronic disorders, and these drugs should not be routinely used as an alternative to blood transfusion unless future studies affirm safety and clinical benefits within these populations.
Abstract: The synthesis of erythropoiesis-stimulating agents (ESAs), especially recombinant human erythropoietin, has provided a new therapeutic option for the treatment of patients with various forms of anemia, including that of chronic renal disease, malignancy, hematologic disorders, prematurity, and acquired immune deficiency syndrome. These agents are effective in improving the hematologic response and reducing the need for red blood cells transfusion, and they also appear to have a positive effect on some health-related quality-of-life indicators. The incidence of side effects and survival, however, remains highly uncertain, and several studies have recently highlighted the problem of an increased trend of tumor progression, mortality and thrombotic complications, especially venous thromboembolism, in patients undergoing therapy with ESAs. Specifically, the biological background underlying the prothrombotic effects of ESAs is multifaceted (polycythemia/hyperviscosity syndrome, hypertension, thrombocytosis, platelet hyperactivity, activation of blood coagulation) and context dependent, and it most likely requires the presence of additional prothrombotic factors. Nevertheless, this clinical and biological evidence supports the hypothesis that therapy with ESAs might not be ultimately beneficial or advantageous in patients with anemia of chronic disorders, and these drugs should not be routinely used as an alternative to blood transfusion unless future studies affirm safety and clinical benefits within these populations.
TL;DR: This review discusses endothelial heterogeneity from a morphological standpoint and the latest developments in the understanding of the components, structure, and function of the endothelial specific organelles that form the hallmark of these phenotypes.
Abstract: Vascular endothelium lines the entire cardiovascular system where it performs a series of vital functions by its control of microvascular permeability, vessel wall tone, coagulation and anticoagulation cascades, lipid homeostasis, inflammation, angiogenesis, and vasculogenesis. The vertebrate endothelial cells display a remarkable heterogeneity in terms of morphology, molecular makeup, and functional output. This heterogeneity was documented very early by electron microscopy studies that established morphologically recognizable endothelial phenotypes in vascular beds of different organs and, moreover, within the different vascular segments of each organ. This review discusses endothelial heterogeneity from a morphological standpoint and the latest developments in our understanding of the components, structure, and function of the endothelial specific organelles that form the hallmark of these phenotypes.
TL;DR: Investigation of the functional consequences of oxidized low-density lipoprotein (oxLDL) uptake on platelet function and interaction with the endothelium demonstrates that activated platelets internalize oxLDL and thatOxLDL-laden platelets activate endothelia, inhibit endothelial regeneration, and promote foam cell development.
Abstract: Platelets are involved in the initiation of atherosclerosis by adherence to inflamed endothelium. Monocytes bind to these platelets and transmigrate into the vessel wall, transforming into macrophages and foam cells. We have previously shown that lipid-laden platelets are phagocytosed by macrophages. In this study we investigated the functional consequences of oxidized low-density lipoprotein (oxLDL) uptake on platelet function and interaction with the endothelium. Human platelets were isolated from healthy donors and activated by adenosine diphosphate. Immunofluorescence microscopy and flow cytometry revealed that oxLDL is located intracellularly in vesicles. With mepacrine costaining and confocal microtomography, we were able to identify dense granules as the vesicles that contain oxLDL. OxLDL-laden platelets induced intercellular adhesion molecule 1 expression in endothelial cells more than exogenous native LDL, oxLDL, and oxLDL-negative platelets. Furthermore, oxLDL-laden platelets induced foam cell development from CD34(+) progenitor cells. On endothelial regeneration, oxLDL-laden platelets had the opposite effect: The number of CD34(+) progenitor cells (colony-forming units) able to transform into endothelial cells was significantly reduced in the presence of oxLDL-platelets, whereas native LDL had no effect. Our results demonstrate that activated platelets internalize oxLDL and that oxLDL-laden platelets activate endothelium, inhibit endothelial regeneration, and promote foam cell development. Platelet oxLDL contributes significantly to vascular inflammation and is able to promote atherosclerosis.
TL;DR: In this review the coagulation abnormalities, clinical manifestations, and the presently known pathophysiologic mechanisms of DIC in patients with hematologic malignancies are discussed, focusing on the most extensively studied condition of APL.
Abstract: Disseminated intravascular coagulation (DIC) significantly contributes to the bleeding and thrombotic complications in patients with hematologic malignancies. As shown in other cancer settings, an underlying condition of activation of the coagulation system leading to a prothrombotic state of chronic or subclinical DIC is detectable. A variety of disease- or treatment-related factors may affect this condition, enhancing the risk of thrombosis or of bleeding and further triggering mechanisms of DIC in this setting. An overt DIC is diagnosed in approximately 15% of patients with acute leukemia, and bleeding manifestations prevail over thrombosis, with the highest and most harmful clinical impact in acute promyelocytic leukemia (APL). Pathogenic mechanisms include a series of intrinsic properties of malignant cells, able to directly activate the coagulation system or to stimulate prothrombotic effects by the host cells. Moreover, chemotherapy or concomitant infections play an important concurrent role. In this review the coagulation abnormalities, clinical manifestations, and the presently known pathophysiologic mechanisms of DIC in patients with hematologic malignancies are discussed, focusing on the most extensively studied condition of APL. Current approaches and open issues for the management and treatment of these patients are also reviewed.
TL;DR: The potential benefit of the complement inhibitor eculizumab for the treatment of aHUS is discussed and advances in understanding of the pathogenesis of atypical HUS suggest that complement inhibition may be used as treatment for the disease.
Abstract: Hemolytic uremic syndrome (HUS) is a disease characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and renal impairment. Often HUS is triggered by Shiga-like toxin- producing ESCHERICHIA COLI. Less common is atypical HUS (aHUS), which is caused by defective complement control. aHUS is associated with mutations in genes encoding complement regulatory proteins in ~50% of patients with this syndrome. Furthermore, autoantibodies that inactivate to factor H have also been linked to the disease. Initial triggers include infections, use of endothelial-affecting drugs, malignancies, transplantation, and pregnancy. Advances in our understanding of the pathogenesis of atypical HUS suggest that complement inhibition may be used as treatment for the disease. We discuss the potential benefit of the complement inhibitor eculizumab for the treatment of aHUS.
TL;DR: This review highlights the concept of the generation of microparticles from platelets and their precursor cells, megakaryocytes, and special emphasis is placed on the mechanisms ofmicroparticle formation and novel functions for microparticle in normal physiology and disease states.
Abstract: Platelet microparticles are the most abundant cell-derived microparticle subtype in the circulation. Yet the mechanism by which platelet microparticles are formed is poorly defined. This review highlights the concept of the generation of microparticles from platelets and their precursor cells, megakaryocytes. Special emphasis is placed on the mechanisms of microparticle formation and novel functions for microparticles in normal physiology and disease states.
TL;DR: This review summarizes the state-of-the-art knowledge regarding endothelial cell responses to the proinflammatory cytokines tumor necrosis factor alpha, interleukin-1beta, and the bacterial product lipopolysaccharide and culminates into a mainly theoretical model of possible intracellular control mechanisms that can assist to ultimately explain the molecular causes of endothelial heterogeneity.
Abstract: Microvascular endothelial cells play an essential role in inflammatory diseases. Functional heterogeneity between microvascular segments in normal organ homeostasis has been appreciated for a long time, and more recent studies have revealed heterogeneity in endothelial reactivity to inflammatory stimuli as well. This review summarizes the state-of-the-art knowledge regarding endothelial cell responses to the proinflammatory cytokines tumor necrosis factor alpha, interleukin-1beta, and the bacterial product lipopolysaccharide. It focuses on similarities and differences in reactivity between endothelial cell subsets in vitro and endothelial cells in their pathophysiological environment in vivo, and culminates into a mainly theoretical model of possible intracellular control mechanisms that can assist to ultimately explain the molecular causes of endothelial heterogeneity. The last part of this review contains some pharmacological considerations, and, with the aim to further unravel the molecular basis of in vivo endothelial heterogeneity, descriptions of new techniques that will be essential to achieve this.
TL;DR: The thromboelastography trace provides a graphical and numerical representation of the viscoelastic changes associated with fibrin polymerization and considers the factors that most influence the characteristics of the trace, be they preanalytical, analytical, or clinical.
Abstract: The thromboelastography trace provides a graphical and numerical representation of the viscoelastic changes associated with fibrin polymerization. When used with whole blood, the shape of this trace is a composite of the effects of white and red cell content and composition, platelet number and function, fibrinogen concentration, as well as coagulation protein function and balance. The trace is also influenced by pharmacological agents such as anticoagulants, antiplatelet therapy, and coagulation factor supplementation. As such the main role of this technology has been as a point-of-care device to guide transfusion of blood components. Recently the technology has moved from the cardiac and hepatic surgical settings, where most of the early work was focused, into other areas of hemostatic monitoring. New applications for pharmaceutical monitoring and patient screening are being explored. This review gives a broad overview of the applications of the technology. In particular it considers the factors that most influence the characteristics of the trace, be they preanalytical, analytical, or clinical.
TL;DR: The performance of anti-FH autoantibodies screening at the very onset of the disease in all cases of HUS is proposed to first make the proper diagnosis as early as possible, and second to support an appropriate therapy including early plasma exchanges and immunosuppressive treatments.
Abstract: Non-Shiga toxin-associated hemolytic uremic syndrome (atypical HUS) is a rare form of thrombotic microangiopathy that associates hemolytic anemia, thrombocytopenia, and acute renal failure. The disease has been demonstrated to be linked with a complement alternative pathway dysregulation due to genetic defects but also to development of autoantibodies to factor H (FH), the main plasmatic alternative pathway regulatory protein. In this review, we summarize the more recent data of this autoimmune form of HUS at the level of epidemiology and its clinical and biological features. We propose the performance of anti-FH autoantibodies screening at the very onset of the disease in all cases of HUS to first make the proper diagnosis as early as possible, and second to support an appropriate therapy including early plasma exchanges and immunosuppressive treatments.
TL;DR: New tests are being explored for utility in DIC, and some additional tests may be useful on a case-by-case basis, depending on the proposed cause of the DIC or their local availability, for example, clot waveform analysis is useful but currently limited to a single instrument.
Abstract: The diagnosis of disseminated intravascular coagulation (DIC) relies on clinical signs and symptoms, identification of the underlying disease, the results of laboratory testing, and differentiation from other pathologies. The clinical features mainly depend on the underlying cause of the DIC. The laboratory diagnosis of DIC uses a combination of tests because no single test result alone can firmly establish or rule out the diagnosis. Global tests of hemostasis may initially provide evidence of coagulation activation and later in the process provide evidence of consumption of coagulation factors, but their individual diagnostic efficiency is limited. Fibrinolytic markers, in particular D-dimer, are reflective of activation of both coagulation and fibrinolysis, so that a normal finding can be useful for ruling-out DIC. Decreased levels of the natural anticoagulants (in particular, antithrombin and protein C) are frequently observed in patients with DIC, but their measurement is not normally incorporated into standard diagnostic algorithms. New tests are being explored for utility in DIC, and some additional tests may be useful on a case-by-case basis, depending on the proposed cause of the DIC or their local availability. For example, clot waveform analysis is useful but currently limited to a single instrument. Also, procalcitonin is an inflammatory biomarker that may be useful within the context of septic DIC, and activated factor X clotting time is an emerging test of procoagulant phospholipids that also seems to hold promise in DIC.
TL;DR: This review highlights the recent advance in the understanding of platelets being distinctly regulated and regulating cells that contribute immensely to the healing process from the very initial stage to the late events of tissue regeneration.
Abstract: Platelets, as the first cellular response after disruption of vascular and/or tissue integrity, cover any existing injury within our body. But is the regenerative potential of platelets limited to providing a cellular patch for wounds? This review highlights the recent advance in our understanding of platelets being distinctly regulated and regulating cells that contribute immensely to the healing process from the very initial stage to the late events of tissue regeneration. For instance, the intrinsic actions of platelets as a regenerative cell, the participation of platelets in angiogenic processes, and the interplay of platelets and circulating stem and progenitor cells, as well as potential therapeutic implications, are addressed. Although we are starting to understand the underlying mechanisms connecting platelets to the components of tissue regeneration just mentioned, many aspects remain to be elucidated. The demand to invest research in this area is underscored by the fact that platelets or platelet-derived molecules are already applied in clinical contexts such as connective tissue regeneration, whereas other research fields have largely neglected platelet effects going beyond their participation in the coagulation cascade. Understanding the mechanisms connecting platelets to tissue regeneration, however, will inevitably open novel options in regenerative medicine.
TL;DR: Thromboelastography is often used in animals to monitor the effect of different pro- and anticoagulant drugs and often performs better at this task than conventional coagulation assays.
Abstract: Thromboelastography (TEG) has been used in experimental animal studies since the early 1960s and in a routine clinical setting for the past decade From the data currently available, it is clear that both the scope and limitations of TEG in animals resemble those observed in humans TEG has been used to diagnose hypercoagulability in animals with disseminated intravascular coagulation, various types of cancer, and critical illness Its ability to detect and monitor animals with various types of coagulopathies has been well established, both clinically and in experimental studies TEG is often used in animals to monitor the effect of different pro- and anticoagulant drugs and often performs better at this task than conventional coagulation assays TEG is already well established in veterinary medicine, and with the rapid dissemination of the technique currently taking place, we can expect to see a wide variety of interesting animal data published in the near future
TL;DR: The characterization of the structure and function of the rVWF drug product is described, with a focus on its in vitro platelet aggregation and matrix protein binding functions.
Abstract: The complex structure, large size, and multiple posttranslational modifications of von Willebrand factor (VWF) presented a technological challenge for the production of recombinant VWF (rVWF). Nonetheless, we developed an rVWF product for treating von Willebrand disease, whereupon rVWF is coexpressed with recombinant factor VIII (rFVIII) in Chinese hamster ovary cells used to produce rFVIII for the treatment of hemophilia A. Here we describe the characterization of the structure and function of the rVWF drug product, with a focus on its in vitro platelet aggregation and matrix protein binding functions. Electron microscopy and multimer analysis revealed a highly organized structure for the rVWF protein, with a homogeneous multimer distribution including ultrahigh molecular weight multimers. The specific activity for binding to collagen and platelets mediated by ristocetin is higher in rVWF than in commercial plasma-derived VWF-FVIII complex products. The affinity and binding capacity of rVWF to FVIII is comparable to VWF in plasma. rVWF effectively binds to platelets and promotes platelet adhesion under shear stress similar to VWF in human plasma.
TL;DR: It is proposed that the interaction of HMGB1 and RAGE is a key component initiating and sustaining the inflammatory response in inflammatory cardiomyopathy eventually leading to heart failure, andHMGB1-antagonizing gene therapy represents a new therapeutic strategy.
Abstract: Heart failure is an increasingly prevalent disorder with considerable morbidity and mortality. Although many causal mechanisms such as inherited cardiomyopathies, ischemic cardiomyopathy, or muscular overload are easily identified in clinical practice, the events that determine the progression of cardiac injury to heart failure and adverse ventricular remodeling are still unclear. Yet there is compelling evidence that inflammatory mechanisms contribute to the progression of heart failure. High-mobility group box-1 (HMGB1) is a newly recognized potent innate "danger signal" that is released by necrotic cells and by activated immune cells. HMGB1 signals via the receptor for advanced glycation end-product (RAGE) and members of the toll-like receptor (TLR) family. We have demonstrated an important role for HMGB1 and RAGE in the pathogenesis of early- and late-phase complications following ischemia/reperfusion (I/R) injury of the heart. In addition, enhanced postmyocardial infarction remodeling in type 1 diabetes mellitus was partially mediated by HMGB1 activation. We propose that the interaction of HMGB1 and RAGE is a key component initiating and sustaining the inflammatory response in inflammatory cardiomyopathy eventually leading to heart failure. Thus HMGB1-antagonizing gene therapy represents a new therapeutic strategy.
TL;DR: Some anatomical and physiological features that distinguish pulmonary artery, capillary, and vein endothelium are addressed and current understanding regarding the stimulated secretion of VWF and P-selectin in pulmonary artery and capillary endothelia is reviewed.
Abstract: Quiescent pulmonary endothelium establishes an antithrombotic, anti-inflammatory surface that promotes blood flow. However, the endothelium rapidly responds to injury and inflammation by promoting thrombosis and enabling the directed transmigration of inflammatory cells, such as neutrophils, into the alveolar airspace. Although the endothelial cell signals responsible for establishing a prothrombotic surface are distinct from those responsible for recognizing circulating neutrophils, these processes are highly interrelated. Von Willebrand factor (VWF)-stimulated secretion plays an important role in thrombus formation, and P-selectin surface expression plays a key role in neutrophil binding necessary for transmigration. Both VWF and P-selectin are located within Weibel-Palade bodies in pulmonary arteries and arterioles, yet Weibel-Palade bodies are absent in capillaries. Despite the absence of the Weibel-Palade bodies, pulmonary capillaries express both VWF and P-selectin. The physiological and pathophysiological significance of these observations is unclear. In this review, we address some anatomical and physiological features that distinguish pulmonary artery, capillary, and vein endothelium. In addition, we review our current understanding regarding the stimulated secretion of VWF and P-selectin in pulmonary artery and capillary endothelium. This information is considered in the context of vasculitis and pneumonia, two pathophysiological processes to which the stimulated secretion of VWF and P-selectin contribute.
TL;DR: In ischemia/reperfusion injury of the liver, platelets appear to play a dual role, and platelet-derived serotonin appears vital for liver regeneration following a partial liver resection.
Abstract: Platelets play a pivotal role in thrombosis and hemostasis, but an increasing variety of extra-hemostatic functions of platelets are being recognized This review summarizes recent advances in the understanding of the role of platelets in various pathologies involving the liver In ischemia/reperfusion injury of the liver, platelets appear to play a dual role On one hand, platelets bind to the activated sinusoidal endothelium and induce apoptosis of these cells; on the other hand, platelet-derived serotonin assists in repair of the ischemic tissue Furthermore, platelets are attracted to the liver following systemic inflammatory stimuli, but the significance of this finding is still unclear Platelets and platelet-derived serotonin appear vital for liver regeneration following a partial liver resection Finally, platelets and platelet-derived serotonin aggravate viral hepatitis by affecting the microcirculation in the liver
TL;DR: Current knowledge regarding the interactions of the pathogen and its virulence factors with cells in the intestine, bloodstream, kidney, and brain are summarized.
Abstract: The typical form of hemolytic uremic syndrome (HUS) is associated with enterohemorrhagic ESCHERICHIA COLI (EHEC) infection. The disease process is initiated and perpetuated by interactions between the pathogen or its virulence factors and host cells, as well as the host response. During EHEC-associated HUS, alterations occurring at the intestinal mucosal barrier and in the circulation, as well as on endothelial cells and other target-organ cells, lead to cell activation and/or cytotoxicity, and trigger a prothrombotic state. This review summarizes current knowledge regarding the interactions of the pathogen and its virulence factors with cells in the intestine, bloodstream, kidney, and brain. Mechanisms of bacterial colonization, toxin circulation, and induction of target organ damage are discussed.