Thrombotic Pathways Research Articles

Proteomic Analysis of the Systemic Response to Radiographic Contrast Media

Abstract Introduction Radiographic contrast media (RCM) have numerous effects on the hemostatic system, inflammatory pathways, and vascular endothelium. Given the increasing number of high-risk patients undergoing radiographic procedures, more information regarding the systemic effects of RCM is needed. Methods Blood samples prior to baseline, 4 and 24 h following elective coronary angiography in 10 patients, were subjected to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Data are presented as the ratio of the protein mass at 4 (iTRAQ4) and 24 h (iTRAQ24) compared to baseline. A ratio >1.0 and a ratio <1.0 indicate production and consumption, respectively, relative to baseline. Results In this sample, we identified 102 proteins with a confidence interval of ≥90%. Six proteins were identified at each time point in all patients. Of the proteins identified, apolipoprotein A-I, apolipoprotein A-II, complement C3, fibrinogen beta chain, immunoglobulin α, and prothrombin revealed an iTRAQ ratio <1.0 at 4 h when compared to baseline (all with p value <0.05) and a trend toward baseline levels at 24 h. Conclusions Systemic administration of RCM results in a variety of alterations to the proteome. Of interest, there is activation of the thrombotic and inflammatory pathways as well as an interaction with lipoprotein metabolism. These changes are most pronounced at 4 h but may persist through 24 h and may be of clinical relevance in patients at risk for thrombotic- and inflammatory-mediated consequences of atherosclerosis.

Editorial: Inflammation, Thrombosis and Vascular Biology: Translating Ideas into Cardiovascular Research and Therapy

Advances in basic and clinical sciences over the past decades have substantially improved our understanding of inflammatory and thrombotic pathways implicated in atherogenesis. It is now clear that multiple genetic and environmental factors interfere with the natural course of atherosclerosis in early life and lead toward premature clinical manifestations in the adolescence and in the middle age. Importantly, various molecular and cellular agents with pro-atherogenic properties have been identified, and similarities have been found between atherosclerotic vascular disease, chronic inflammatory disorders and cancer [1, 2], all of which can be viewed as diseases of premature aging. Identification of common pathways of aging, and premature morbidity and mortality in these disorders has prompted the search for therapeutic means with universal beneficial effects. In fact, over the past decade, we have witnessed a strong emphasis on anti-inflammatory effects of cardiovascular drugs, such as angiotensin converting enzyme inhibitors (ACE-I), statins, aspirin, which are believed to reduce incidence of vascular events by acting not only on their primary therapeutic targets but also on the inflammatory process [3].

Editor’s Note

HomeCirculationVol. 120, No. 24Editor’s Note Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBEditor’s Note Jane E. Freedman, MD Jane E. FreedmanJane E. Freedman Search for more papers by this author Originally published15 Dec 2009https://doi.org/10.1161/CIRCULATIONAHA.109.915512Circulation. 2009;120:2407Diseases related to thrombosis are a major cause of morbidity and mortality. This year, an estimated 1.26 million Americans will have a new or recurrent myocardial infarction. In addition, ≈2.3 to 3.2 million people are currently affected with atrial fibrillation in the United States, with up to a 7% risk of embolic stroke leading to ≈100 000 strokes per year. Importantly, thrombus formation is responsible for the majority of acute coronary syndromes and embolic strokes, as well as diseases due to venous thrombosis. The importance of the identification of novel ways to regulate thrombosis, particularly ones that are readily adaptable as therapeutic targets, has contributed to the development of new drugs to prevent arterial thrombosis in the clinical settings of unstable coronary syndromes, stent thrombosis, peripheral arterial occlusion, and thrombotic stroke.As the number of patients with thrombotic diseases grows, there has been continued interest in the development and appropriate use of antithrombotic and platelet inhibitor therapies. Thus, as our understanding of hemostasis and thrombosis continues to evolve, so does the development of agents directed toward treating relevant cardiovascular and thromboembolic diseases. This development continues to be fueled by scientific discovery, the growing number of patients and indications for antithrombotics, and unmet medical needs with currently available therapies. Novel groups of therapeutics are being developed while existing therapies are being further studied for expanding indications, enhanced combinations, and safety profile. There has been continued development of coagulation inhibitors, with new formulations being developed. Oral thrombin inhibitors have progressed with both successes and failures. Targets for antiplatelet drugs continue to be defined, leading to novel therapies as well as the development of additional agents in already successful classes. The use of genetics and individually guided dosing with anticoagulants and antithrombotics holds the promise of fewer side effects and complications, particularly with bleeding.The goal of this series is to highlight the rapid development and ongoing evolution that have defined new treatments in hemostatic and thrombotic pathways and uncovered their therapeutic relevance. There have been significant advances in the development of platelet inhibitors. In the area of ADP receptor antagonists, there is the development of agents with rapid onset and shorter half-lives or drugs that are reversible and would allow for urgent surgical procedures. New direct and reversible P2Y12 antagonists might be attractive alternatives to existing thienopyridines. Also, during the last decade, there has been growing development of therapies that target platelet adhesion and activation. The hope is that these specific targets will allow for separation of platelet inhibition from bleeding.In addition, this series will highlight the utility and limitations of nutritional supplements and vitamins and their role in platelet thrombosis. It will also highlight potential side effects of supplements, most notably bleeding. The importance of new anticoagulants and combination antithrombotic therapies will be examined. In a related topic, the emerging role of bleeding as a major factor in limiting the benefit of therapies will be considered. A central goal in the use of these therapies is the development of useful tools to guide treatment that will maintain vascular patency while minimizing bleeding complications. The hope is that this update will both highlight the many new antithrombotic drugs that are being intensively studied as well as highlight the tight link between treating thrombosis and bleeding. In summary, the diseases that lead to thrombotic occlusions are a major source of morbidity and mortality, and enormous strides have been made during the past decade in the development and use of antithrombotic and platelet inhibitor therapies. Previous Back to top Next FiguresReferencesRelatedDetailsCited By Burns F Intestacy Law In Australia, England and Singapore - Another Aid to Social Sustainability in an Ageing Population?, SSRN Electronic Journal, 10.2139/ssrn.2255245 December 15, 2009Vol 120, Issue 24 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.109.915512 Originally publishedDecember 15, 2009 PDF download Advertisement SubjectsAcute Coronary Syndromes

Transforming growth factor-β–induced protein (TGFBIp/β ig-h3) activates platelets and promotes thrombogenesis

AbstractTransforming growth factor-β–induced protein (TGFBIp)/βig-h3 is a 68-kDa extracellular matrix protein that is functionally associated with the adhesion, migration, proliferation, and differentiation of various cells. The presence of TGFBIp in platelets led us to study the role of this protein in the regulation of platelet functions. Upon activation, platelet TGFBIp was released and associated with the platelets. TGFBIp mediates not only the adhesion and spread of platelets but also activates them, resulting in phosphatidylserine exposure, α-granule secretion, and increased integrin affinity. The fasciclin 1 domains of TGFBIp are mainly responsible for the activation of platelets. TGFBIp promotes thrombus formation on type I fibrillar collagen under flow conditions in vitro and induces pulmonary embolism in mice. Moreover, transgenic mice, which have approximately a 1.7-fold greater blood TGFBIp concentration, are significantly more susceptible to collagen- and epinephrine-induced pulmonary embolism than wild-type mice. These results suggest that TGFBIp, a human platelet protein, plays important roles in platelet activation and thrombus formation. Our findings will increase our understanding of the novel mechanism of platelet activation, contributing to a better understanding of thrombotic pathways and the development of new antithrombotic therapies.

Abstract 4940: Inflammatory Thrombotic Interactions in Young Type 1 Diabetes Subjects: Effects of Glycaemic Control

The inflammatory and thrombotic pathways have a crucial role in the development of coronary artery disease, and inflammatory thrombotic markers predict cardiovascular events. Although the atherosclerotic process in type 1 diabetes (T1DM) starts at an early age, little is known about inflammatory markers and clot structure in this population. The aims of this study were to investigate C-reactive protein (CRP), complement C3 (C3) and fibrin clot structure/fibrinolysis in children and young adults with T1DM, the effects of improving glycaemic control on these parameters and complement/fibrin interactions affecting clot structure/function. In 47 children (14±3yrs) C3 levels were higher in T1DM than controls (1.13±0.24 versus 0.83±0.24mg/ml respectively; p<0.001), whereas CRP levels were no different. Clot final turbidity (FT), an indicator of clot density, was higher in diabetes children compared with controls, and lysis time longer (599±18 and 516±17 secs, respectively, p=0.02). In 18 young adults with T1DM (23±5yrs) a 1.3% reduction in HbA1c was associated with a decrease in C3 levels from 1.09±0.05 to 0.96±0.05mg/ml (p<0.05), with no effect on CRP levels. Improving glycaemic control reduced FT and shortened lysis time from 601±21 to 550±19 secs (p=0.02). Clot FT and lysis correlated positively with C3 plasma levels (r=0.39 and r= 0.585, respectively; p<0.01). C3 incorporation into the plasma clot was 26% and 19% in T1DM and controls respectively, a difference that failed to reach statistical significance. However, clots made from plasma-purified fibrinogen diabetes patients exhibited a 71% increase in lysis time in the presence of purified C3, whereas this increase was only 41% using fibrinogen purified from controls (p=0.03). These results demonstrate that young children with T1DM already have evidence of inflammatory thrombotic processes as indicated by elevated C3 levels, a denser clot structure and prolonged clot lysis times. Interactions between C3 and fibrin occur in non-diabetic subjects, but are significantly enhanced in the presence of diabetes. Improving glycaemic control is associated with reduction in C3 levels and favourable changes in clot structure/function, which is potentially due to a direct effect of C3 on clot lysis.

The consequences of HIV infection and antiretroviral therapy use for cardiovascular disease risk: shifting paradigms

To explore the mechanisms by which HIV infection and antiretroviral therapy (ART) may increase risk for atherosclerotic cardiovascular disease (CVD), with attention to the implications of earlier initiation of ART (i.e. at higher CD4 cell counts than currently recommended by guidelines). Compared with the general population, HIV-infected patients who receive ART have a greater burden of subclinical and clinical atherosclerotic disease. Findings from a recent international treatment interruption trial (SMART) have redirected attention from ART-related drug toxicity toward a better appreciation for the consequences of untreated HIV infection, which may increase CVD risk through inflammation, upregulation of thrombotic pathways, and ultimately early vascular damage and dysfunction. In addition, CVD risk may increase with some ART, and this risk may be class-specific and/or drug-specific. Compared with untreated HIV, ART may increase or decrease risk of CVD. Reliable data on the relative risk do not exist. A randomized trial of early ART will provide the best data for assessment of the net risks and benefits of ART use on CVD.

The impact of acute and chronic exercise on thrombosis in cardiovascular disease

There is now a large and impressive literature showing that people who engage in chronic aerobic exercise or who have better cardiovascular fitness levels, tend to live longer and have lower levels of cardiovascular disease (CVD). However, there is a paradox, as acute aerobic exercise has been associated with an increased risk of CVD events. There are now a number of review articles suggesting that the differential benefits of chronic, relative to acute, exercise might be due to thrombotic changes, though the majority of this data is derived from healthy individuals. However, acute exercise is of greater concern and chronic exercise of greater benefit to patient populations. In addition, these higher risk groups tend to present with more complex profiles, e.g. they may be taking medications that influence thrombotic pathways. As such, the current review has focused on newer information relating to exercise, physical activity and thrombosis in patient populations, and highlights some of the growing area's in the field. For example, the impact of warm-up exercise, the interaction of medications, and issues surrounding the optimal volume and intensity of exercise.

Immune versus thrombotic stimulation of platelets differentially regulates signalling pathways, intracellular protein-protein interactions, and α-granule release

In addition to haemostasis, platelets mediate inflammation and clearance of bacteria from the bloodstream. As with platelet-platelet interactions, platelet-bacteria interactions involve cytoskeletal rearrangements and release of granular content. Stimulation of the immune Toll-like receptor 2 (TLR2) on the platelet surface, activates phosphoinositide-3-kinase (PI3K) and causes platelet activation and platelet-dependent thrombosis. It remains unknown if platelet activation by immune versus thrombotic pathways leads to the differential regulation of signal transduction, protein-protein interactions, and alpha-granule release, and the physiological relevance of these potential differences. We investigated these processes after immune versus thrombotic platelet stimulation. We examined selected signalling pathways and found that phosphorylation kinetics of Akt, ERK1/2 and p38 differed dramatically between agonists. Next, we investigated platelet protein-protein interactions by mass spectrometry (MS)-based proteomics specifically targeting cytosolic factor XIIIa (FXIIIa) because of its function as a cytoskeleton-crosslinking protein whose binding partners have limited characterisation. Four FXIIIa-binding proteins were identified, two of which are novel interactions: FXIIIa-focal adhesion kinase (FAK) and FXIIIa-gelsolin. The binding of FAK to FXIIIa was found to be altered differentially by immune versus thrombotic stimulation. Lastly, we studied the effect of thrombin versus Pam(3)CSK(4) stimulation on alpha-granule release and observed differential release patterns for selected granule proteins and decreased fibrin clot formation compared with thrombin. The inhibition of PI3K caused a decrease in protein release after Pam(3)CSK(4)- but not after thrombin-stimulation. In summary, stimulation of platelets by either thrombotic or immune receptors leads to markedly different signalling responses and granular protein release consistent with differential contribution to coagulation and thrombosis.

Stimulation of Toll-like receptor 2 in human platelets induces a thromboinflammatory response through activation of phosphoinositide 3-kinase.

Cells of the innate immune system use Toll-like receptors (TLRs) to initiate the proinflammatory response to microbial infection. Recent studies have shown acute infections are associated with a transient increase in the risk of vascular thrombotic events. Although platelets play a central role in acute thrombosis and accumulating evidence demonstrates their role in inflammation and innate immunity, investigations into the expression and functionality of platelet TLRs have been limited. In the present study, we demonstrate that human platelets express TLR2, TLR1, and TLR6. Incubation of isolated platelets with Pam(3)CSK4, a synthetic TLR2/TLR1 agonist, directly induced platelet aggregation and adhesion to collagen. These functional responses were inhibited in TLR2-deficient mice and, in human platelets, by pretreatment with TLR2-blocking antibody. Stimulation of platelet TLR2 also increased P-selectin surface expression, activation of integrin alpha(IIb)beta(3), generation of reactive oxygen species, and, in human whole blood, formation of platelet-neutrophil heterotypic aggregates. TLR2 stimulation also activated the phosphoinositide 3-kinase (PI3-K)/Akt signaling pathway in platelets, and inhibition of PI3-K significantly reduced Pam(3)CSK4-induced platelet responses. In vivo challenge with live Porphyromonas gingivalis, a Gram-negative pathogenic bacterium that uses TLR2 for innate immune signaling, also induced significant formation of platelet-neutrophil aggregates in wild-type but not TLR2-deficient mice. Together, these data provide the first demonstration that human platelets express functional TLR2 capable of recognizing bacterial components and activating the platelet thrombotic and/or inflammatory pathways. This work substantiates the role of platelets in the immune and inflammatory response and suggests a mechanism by which bacteria could directly activate platelets.

Viral Anti-Inflammatory Proteins: The Potential for Immunotherapeutic Applications in Cancer

Complex viruses such as herpes, poxvirus, HIV and influenza subvert the immune system, blocking host antiviral defenses. The innate immune inflammatory response represents the first line of defense against invading pathogens. This first line of defense also initiates cellular healing after infection or injury. With tumors, however, the innate immune response is a classic double-edged sword, with the capacity to promote or terminate tumor progression. The proliferation and invasion of many cancers as well as metastasis have now been linked with an increase in many of the molecular signals that drive inflammation. Inflammatory responses are mediated by endothelial cells in the arterial walls and by neutrophils, monocytes /macrophages and T lymphocytes in the circulating blood. Activated cells release chemokines, cytokines, serine proteases in the thrombotic and thrombolytic pathways, apoptotic serine and cysteine proteases, and growth factors that accelerate cellular proliferation, migration and invasion. We are investigating potential therapeutic applications of virus-derived immune-modulating proteins, as immunotherapeutics for use in disease states driven by excessive inflammatory responses. In this review we will describe the roles of excess inflammatory responses in cancer and discuss potential applications of viral anti-inflammatory proteins for the treatment of cancer with special emphasis on immunemodulating proteins that target chemokine and serine protease pathways. These immune-modulating proteins represent a new class of naturally occurring, virus-derived immunomodulating drugs. While the rest of this special issue will be discussing virus induced disease, here we will discuss the potential for harvesting viral immune-modulating proteins as a new class of immunotherapeutic.

Heparin Alters Viral Serpin, Serp-1, Anti-Thrombolytic Activity to Anti-Thrombotic Activity

Serine protease inhibitors (serpins) regulate coagulation and inflammation. Heparin, a glycosaminoglycan, is an important cofactor for modulation of the inhibitory function of mammalian serpins. The secreted myxoma viral serpin, Serp-1 exerts profound anti-inflammatory activity in a wide range of animal models. Serp-1 anti-inflammatory and anti-atherogenic activity is dependent upon inhibition of the uPA / uPA receptor thrombolytic complex. We demonstrate here that heparin binds to Serp-1 and enhances Serp-1 inhibition of thrombin, a human pro-thrombotic serine protease, in vitro, altering inhibitory activity to a more predominant anti-thrombotic activity. Heparin also facilitates the simultaneous thrombin-mediated cleavage of Serp-1 and prevents formation of a serpin-typical SDS-resistant complex, implying mutual neutralization of Serp-1 and thrombin. In a cell-based assay, heparin facilitates Serp-1 reversal of cellular activation by stabilizing cellular membrane fluidity in thrombin-activated monocytes. In conclusion, heparin and other GAGs serve as cofactors enhancing Serp-1 regulation of local thrombotic and inflammatory pathways

Cardiovascular complications of obstructive sleep apnea

Obstructive sleep apnea (OSA) is a common disorder with an increasing public health burden. It is characterized by repeated upper airway narrowing and closure, leading to apneas, hypopneas and increased respiratory effort-related arousals. Continuous positive airway pressure is an effective modality of treatment for OSA. Apart from being responsible for daytime sleepiness and cognitive impairment, OSA has been implicated in various systemic diseases, particularly of the cardiovascular system. This article reviews some of the extensive literature implicating OSA in the development of cardiovascular diseases and describes the intermediary pathophysiologic mechanisms involved. Repetitive nocturnal oxygen desaturation and reoxygenation and increased intrathoracic pressure changes related to OSA result in the intermediary pathophysiologic mechanisms that affect the neural, humoral, thrombotic, inflammatory and metabolic pathways responsible for the development of cardiovascular disorders. This review also examines evidence that suggests that OSA may be a specific cause of certain cardiovascular disorders.

Control of atherosclerotic plaque vulnerability: Insights from transgenic mice

Atherosclerosis is a complex, progressive disease of the large systemic arteries. This multi-factorial disease is characterized by accumulation of lipids, cells and extracellular matrix in the vessel wall. The quest to unravel the molecular mechanisms leading to progression of human atherosclerotic plaques has lead to the development of a variety of animal models. Mice are easily amendable to transgenesis and multiple mutant and inbred strains have been generated in which potential regulators are manipulated and subsequently studied for effects on the development and progression of atherosclerosis. The scope of this review is to discuss the relevance, advantages and disadvantages of genetically-engineered mice to investigate mechanisms of plaque vulnerability. Features of human vulnerable lesions, such as large lipid-rich necrotic cores, active inflammation, matrix remodeling and signs of intraplaque hemorrhage are represented in mouse lesions. Here, we will discuss how atherosclerosis is modified by manipulations in apoptosis, lesional lipid metabolism, inflammatory pathways, matrix remodeling and thrombotic pathways in genetically-engineered mice, emphasizing the insights that have been gained from these studies for the control of plaque vulnerability.

Cocaine and thrombosis: a narrative systematic review of clinical and in-vivo studies

PurposeTo systematically review the literature pertaining to the link between cocaine and either arterial or venous thrombosis.ProceduresNarrative systematic review of Medline, CINAHL, Embase, Psycinfo and Cochrane databases supplemented by hand trawling of relevant journals and reference lists up to April 2007. In-vivo studies and those with clinical endpoints were included in the review.ResultsA total of 2458 abstracts led to 186 full-text papers being retrieved. 15 met the criteria for inclusion in the review. The weight of evidence would support cocaine as a pro-thrombotic agent. There is evidence of it activating thrombotic pathways. The effect of cocaine upon clinical endpoints has not been quantified though there is evidence of an association between cocaine and myocardial infarction particularly amongst young adults. Cocaine may also be a causal agent in cerebrovascular accident though studies lacked sufficient power to determine a statistically significant effect. There is a gap in the evidence pertaining to the issue of cocaine and venous thrombosis.ConclusionClinicians should consider questioning for cocaine use particularly amongst young adults who present with cardiac symptoms. More epidemiological work is required to quantify the effect of cocaine upon both arterial and venous clotting mechanisms.

Intertwining of thrombosis and inflammation in atherosclerosis

Purpose of review The aim of this article is to highlight the importance of thrombotic processes in the development and complications of atherosclerotic vascular disease. Recent findings Thrombin generated at sites of vascular inflammation activates major atheroma-associated cells including endothelial cells, platelets, smooth muscle cells, monocytes, and macrophages. Thrombin-activated cells produce a plethora of inflammatory mediators, such as regulated upon activation normal T cell expressed presumed secreted, macrophage migration inhibitory factor, and CD40 ligand, that promote atherosclerotic lesion formation and atherothrombotic complications of vascular disease. Additionally, thrombin-induced inflammatory mediators stimulate tissue factor procoagulant activity within atheroma to initiate a positive feedback loop where thrombin activation launches inflammatory signals that lead to further thrombin activation. Platelets, the main cellular effectors of the thrombotic system, also play a central role in the biology of atherosclerosis by producing inflammatory mediators and directing leukocyte incorporation into plaques through platelet-mediated leukocyte adhesion. Summary New research has identified signaling pathways that intertwine thrombotic and inflammatory pathways with the development and progression of atherosclerosis. These signaling pathways contain positive feedback loops that propagate atherogenesis. Targeting molecular regulators at the interface of thrombosis and inflammation simultaneously may reduce thrombosis and inflammation, thus breaking pathological cycles that promote atherosclerosis and associated thrombotic complications.

Effects of low osmolar contrast (iomeprol) on haemorheology and platelet activation in patients with coronary artery disease

Non-ionic low osmolar contrast agents are widely used during coronary angiography. As these agents cause activation of thrombotic pathways in vitro, this may have potentially significant clinical impact. However, limited evidence exists as to their in vivo effects from selective coronary cannulation. We initially performed an in vitro experiment to assess the effect of serial contrast (Iomeprol 300, Bracco) dilution on platelet indices [mean platelet count (MPC), platelet volume (MPV), platelet granularity (MPG)]. The in vivo effect of contrast injection on platelet activation markers [soluble P-selectin (sPsel), soluble CD40 ligand (sCD40L)], MPC, MPV, MPG, haemoglobin and haematocrit was subsequently determined in 35 patients (mean age 58 +/- 11; 22 males) undergoing cardiac catheterisaton. No significant in vitro effect of contrast on MPC or MPV was seen but there was a significant increase in MPG (p = 0.40, 0.10 and 0.01, respectively). In the in vivo study, there was a reduction in mean haemoglobin and haematocrit levels, suggesting an average increase in plasma volume of 6.5 +/- 5.8%. The in vivo effect of Iomeprol was associated with an unadjusted reduction in sPsel concentrations (p = 0.04) and MPV (p < 0.05), with denser platelets (p < 0.05). There was no difference in MPC or sCD40L concentration (both p = NS). After adjustment for the haemodilution effect, no significant reduction in P-sel levels was seen with contrast (p = 0.27), although the adjusted post-contrast change in MPG (p = 0.01), MPC (p = 0.01) and sCD40L (p < 0.05) levels were significant. Low osmolar contrast led to a minimal effect on soluble and physical indices of platelets within the coronary artery, primarily due to plasma volume expansion.

Intertwining of thrombosis and inflammation in atherosclerosis

The aim of this article is to highlight the importance of thrombotic processes in the development and complications of atherosclerotic vascular disease. Thrombin generated at sites of vascular inflammation activates major atheroma-associated cells including endothelial cells, platelets, smooth muscle cells, monocytes, and macrophages. Thrombin-activated cells produce a plethora of inflammatory mediators, such as regulated upon activation normal T cell expressed presumed secreted, macrophage migration inhibitory factor, and CD40 ligand, that promote atherosclerotic lesion formation and atherothrombotic complications of vascular disease. Additionally, thrombin-induced inflammatory mediators stimulate tissue factor procoagulant activity within atheroma to initiate a positive feedback loop where thrombin activation launches inflammatory signals that lead to further thrombin activation. Platelets, the main cellular effectors of the thrombotic system, also play a central role in the biology of atherosclerosis by producing inflammatory mediators and directing leukocyte incorporation into plaques through platelet-mediated leukocyte adhesion. New research has identified signaling pathways that intertwine thrombotic and inflammatory pathways with the development and progression of atherosclerosis. These signaling pathways contain positive feedback loops that propagate atherogenesis. Targeting molecular regulators at the interface of thrombosis and inflammation simultaneously may reduce thrombosis and inflammation, thus breaking pathological cycles that promote atherosclerosis and associated thrombotic complications.

Myxoma viral serpin, Serp-1, a unique interceptor of coagulation and innate immune pathways

Serpins maintain haemostasis through regulation of serine proteinases in the thrombotic and thrombolytic pathways. Viruses encode serpins that can alter thrombotic and thrombolytic responses producing, in some cases, disseminated intravascular coagulation (DIC). However, it has not been precisely defined how viral serpins induce these profound responses. The rabbit myxoma viral serpin, Serp-1 inhibits urokinase- and tissue-type plasminogen activators (uPA and tPA), plasmin and factor Xa in vitro and exhibits remarkable anti-inflammatory activity in various animal models. The effects of Serp-1 on activation of human platelets, endothelial cells, monocytes and T cells that mediate thrombosis and innate immune responses were therefore examined. We found that Serp-1 attenuated platelet and mononuclear cell adhesion to fibronectin and collagen. Serp-1 similarly inhibited monocyte migration into the peritoneum. Serp-1 inhibition of monocyte migration was lost in uPA receptor (uPAR) deficient mice. Serp-1 bound to the plasma membrane surface and altered uPA activation of endothelial cells (p=0.001), thrombin activation of platelets (p=0.021) and phorbol ester activation of endothelial (p=0.047), monocyte (p=0.011) and Jurkat T cells (p=0.012) as measured by intracellular calcium. Modulation of cellular activation was confirmed by membrane fluidity analysis. Microarray analysis of Serp-1 treated endothelial cells revealed alterations in Inositol 1,4,5-triphosphate receptor type II (ITPR2) a calcium-regulating gene. This study demonstrates the unique capacity of a viral serpin, Serp-1 to modify adhesion, activation, gene expression and calcium homeostasis in a wide range of cells that regulate coagulation and inflammation. Endothelial cells potentially represent a pivotal regulatory point for Serp-1 anti-inflammatory activity.

Thrombin's faces revealed: cellular effects include induction of neoangiogenesis

Thrombin's faces revealed: cellular effects include induction of neoangiogenesis

Early statin treatment following acute myocardial infarction and 1-year survival

The shear stress and hypoxia in the pulmonary artery in patients with pulmonary arterial hypertension(PAH) causes endothelial dysfunction, smooth muscle proliferation and activation of thrombotic pathways leading to in situ thrombosis. Targeting the thrombotic pathways is a proposed mechanism to slow disease progression and improve survival. Over the years, the survival in patients with PAH has improved due to multiple factors with the increased use of anticoagulation as one of them. Both European Respiratory Society/European Society of Cardiology and American College of Cardiology/American Heart Association guidelines make grade II recommendations for using anticoagulation in PAH. The guidelines are based on weak observational studies with high risk of bias which have only studied warfarin as the choice of anticoagulation. In this article, we review the pathophysiology, rationale and the current literature investigating the role of anticoagulation in PAH.