Roles of PAR1 and PAR2 in viral myocarditis.

Viral myocarditis is estimated to cause ~20% of sudden death in people under the age of 40. A variety of viruses have been found to cause myocarditis including coxsackievirus B3 (CVB3). Many studies have been performed with CVB3 because there is a mouse model of CVB3-induced myocarditis.

Multiple roles of the coagulation protease cascade during virus infection.

The coagulation cascade is activated during viral infections. This response may be part of the host defense system to limit spread of the pathogen. However, excessive activation of the coagulation cascade can be deleterious.

New players in haemostasis and thrombosis.

The blood coagulation cascade is essential for haemostasis, but excessive activation can cause thrombosis. Importantly, recent studies have identified factors that contribute to thrombosis but not haemostasis. These include factor XII (FXII), tissue factor-positive microparticles (MPs) and neutrophil extracellular traps (NETs).

Tissue factor expression provokes escape from tumor dormancy and leads to genomic alterations.

The coagulation system links immediate (hemostatic) and late (inflammatory, angiogenic) tissue responses to injury, a continuum that often is subverted in cancer. Here we provide evidence that tumor dormancy is influenced by tissue factor (TF), the cancer cell-associated initiator of the coagulation system and a signaling receptor. Thus, indolent human glioma cells deficient for TF remain viable but permanently dormant at the injection site for nearly a year, whereas the expression of TF leads to a step-wise transition to latent and overt tumor growth phases, a process that is preceded by recruitment of vascular (CD105(+)) and myeloid (CD11b(+) and F4/80(+)) cells.

Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease.

Activation of coagulation and vascular inflammation are prominent features of sickle cell disease (SCD). Previously, we have shown that inhibition of tissue factor (TF) attenuates activation of coagulation and vascular inflammation in mouse models of SCD. In this study, we examined the mechanism by which coagulation proteases enhance vascular inflammation in sickle BERK mice.

The antithrombotic effects of statins.

Hypercholesterolemia is considered the primary risk factor for cardiovascular disease. An estimated 200 million prescriptions are issued per year for statins to treat hypercholesterolemia. Importantly, statins have additional beneficial effects independent of their effects on lipids.

Protease activated receptor-2 contributes to heart failure.

Heart failure is a major clinical problem worldwide. Previous studies have demonstrated an important role for G protein-coupled receptors, including protease-activated receptors (PARs), in the pathology of heart hypertrophy and failure. Activation of PAR-2 on cardiomyocytes has been shown to induce hypertrophic growth in vitro.

Coagulation, protease-activated receptors, and viral myocarditis.

The coagulation protease cascade plays an essential role in hemostasis. In addition, a clot contributes to host defense by limiting the spread of pathogens. Coagulation proteases induce intracellular signaling by cleavage of cell surface receptors called protease-activated receptors (PARs).

Contributions of thrombin targets to tissue factor-dependent metastasis in hyperthrombotic mice.

Background: Tumor cell tissue factor (TF)-initiated coagulation supports hematogenous metastasis by fibrin formation, platelet activation and monocyte/macrophage recruitment. Recent studies identified host anticoagulant mechanisms as a major impediment to successful hematogenous tumor cell metastasis.

Objective: Here we address mechanisms that contribute to enhanced metastasis in hyperthrombotic mice with functional thrombomodulin deficiency (TM(Pro) mice).

Hyperlipidemia, tissue factor, coagulation, and simvastatin.

Hyperlipidemia affects millions of people worldwide and is a major risk factor for cardiovascular disease. People with hyperlipidemia have elevated levels of serum cholesterol and an increased risk of thrombosis. Studies have suggested that oxidized lipoproteins, such as oxidized low-density lipoprotein (oxLDL), contribute to the development of a pro-thrombotic state.

Protease-activated receptor-2 regulates the innate immune response to viral infection in a coxsackievirus B3-induced myocarditis.

Objectives: This study sought to evaluate the role of protease-activated receptor-2 (PAR2) in coxsackievirus B3 (CVB3)-induced myocarditis.

Background: An infection with CVB3 leads to myocarditis. PAR2 modulates the innate immune response.

Circulating microparticle tissue factor, thromboembolism and survival in pancreaticobiliary cancers.

Background: Tissue factor (TF), the physiologic initiator of coagulation, is over-expressed in pancreatic cancer, and is associated with a pro-coagulant and pro-angiogenic state. We hypothesized that in patients with pancreaticobiliary cancers (PBC), elevated circulating microparticle-associated TF (MP-TF) activity would be associated with thrombosis and worsened survival.

Patients And Methods: Clinical data and plasma were obtained for consecutive patients with PBC seen at Roswell Park Cancer Institute from 2005-08.

Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients.

Patients with cancer have an increased risk for venous thrombosis. Interestingly, different cancer types have different rates of thrombosis, with pancreatic cancer having one of the highest rates. However, the mechanisms responsible for the increase in venous thrombosis in patients with cancer are not understood.

Fibrin facilitates both innate and T cell-mediated defense against Yersinia pestis.

The Gram-negative bacterium Yersinia pestis causes plague, a rapidly progressing and often fatal disease. The formation of fibrin at sites of Y. pestis infection supports innate host defense against plague, perhaps by providing a nondiffusible spatial cue that promotes the accumulation of inflammatory cells expressing fibrin-binding integrins.

Microparticle-associated tissue factor activity in patients with pancreatic cancer: correlation with clinicopathological features.

Background: Patients with pancreatic cancer have an unfavourable prognosis. A central role in pancreatic cancer progression has been suggested for tissue factor (TF), the main initiator of the blood coagulation cascade. We hypothesized that elevated levels of plasma microparticle (MP)-associated TF activity might indicate the presence of poorly differentiated pancreatic cancer, disease dissemination and infiltration of peripancreatic vessels.

Microvesicles as risk markers for venous thrombosis.

Microvesicles (MVs) are small (0.1-1 µm) membrane vesicles released from activated cells. The surface of MVs can be highly procoagulant due to the presence of the procoagulant protein tissue factor (TF) and of negatively charged phospholipids, such as phosphatidylserine.

Prothrombotic mechanisms and anticoagulant therapy in dogs with immune-mediated hemolytic anemia.

Objective: To review the pathophysiology of thrombosis in hemolytic disease, and the efficacy of thromboprophylaxis in dogs with immune-mediated hemolytic anemia (IMHA).

Data Sources: Computerized searches of Pubmed, INDEX VETERINARIUS, and the journal database of the Veterinary Information Network, and a manual search of bibliographies of published manuscripts.

Human Data Synthesis: Experimental data suggest that hemolysis leads to the induction of the potent procoagulant tissue factor on monocytes and endothelial cells and subsequent activation of coagulation.

Platelet ITAM signaling is critical for vascular integrity in inflammation.

Platelets play a critical role in maintaining vascular integrity during inflammation, but little is known about the underlying molecular mechanisms. Here we report that platelet immunoreceptor tyrosine activation motif (ITAM) signaling, but not GPCR signaling, is critical for the prevention of inflammation-induced hemorrhage. To generate mice with partial or complete defects in these signaling pathways, we developed a protocol for adoptive transfer of genetically and/or chemically inhibited platelets into thrombocytopenic (TP) mice.

Hepatocyte tissue factor activates the coagulation cascade in mice.

In this study, we characterized tissue factor (TF) expression in mouse hepatocytes (HPCs) and evaluated its role in mouse models of HPC transplantation and acetaminophen (APAP) overdose. TF expression was significantly reduced in isolated HPCs and liver homogenates from TF(flox/flox)/albumin-Cre mice (HPC(ΔTF) mice) compared with TF(flox/flox) mice (control mice). Isolated mouse HPCs expressed low levels of TF that clotted factor VII-deficient human plasma.