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While thrombosis is the leading cause of morbidity and mortality in the United States, an understanding of its triggers, progression, and response to anticoagulant therapy is lacking. Intravital fluorescence microscopy has advanced the study of thrombus formation by providing targeted, multi-color contrast. However, photodegradation of fluorophores limits the application in longitudinal studies (e.g., clot progression and/or dissolution). Fluorescent nanodiamond (FND) is a fluorophore which utilizes intrinsic fluorescence of chromogenic centers within and protected by the diamond crystalline lattice. Recent developments in diamond processing have allowed for the controlled production of nanodiamonds emitting in green or red. Here, the use of FND to label blood clots and/or clot lysis is demonstrated and compared to commonly used organic fluorophores. Model ex vivo clots were formed with incorporated labeled fibrinogen to allow imaging. FND was shown to match the morphology of organic fluorophore labels absent of photobleaching over time. The addition of tissue plasminogen activator (tPa) allowed visualization of the clot lysis stage, which is vital to studies of both DVT and pulmonary embolism resolution. [ABSTRACT FROM AUTHOR]

Background: Viscoelastic testing is a method of hemostatic analysis that provides a real-time, holistic view of ex vivo clotting. It allows for examination of both cellular and plasma protein contributions to clotting including platelet number and function, fibrin(ogen) function, and coagulation factor function. The method assesses physical clot properties during the transition of blood from a liquid to a gel state, either by measurement of clot shear modulus using physical force transduction or by measurement of clot resonance frequency using sonometric interrogation. Results are reported in a live trace, with different trace parameters reflecting different contributors to hemostasis. These reported parameters vary between testing platforms.Results: In the United States, there are several commonly used Food and Drug Administration (FDA)-approved viscoelastic instruments available on the market. Those instruments that use sonometric clot assessment are more recently available and allow for improved portability for use near the patient's bedside. These instruments generally feature different reagent kits that allow more specific interrogation of different hemostatic pathways. Viscoelastic testing can predict the results of traditional plasma-based coagulation assays and has the added benefit of detecting hypercoagulability and severe hyperfibrinolysis. Implementation of viscoelastic testing in many clinical settings is becoming widespread and has proven to be efficacious in reducing blood transfusion rates in many settings. An impact on overall mortality and morbidity has not yet been demonstrated.Conclusion: This article provides a narrative review of the basic principles of viscoelastic testing, including the science and technology behind the method, as well as currently available testing platforms and reagents. [ABSTRACT FROM AUTHOR]

Mechanical interactions between flowing and coagulated blood (thrombus) are crucial in dictating the deformation and remodeling of a thrombus after its formation in hemostasis. We propose a fully-Eulerian, three-dimensional, phase-field model of thrombus that is calibrated with existing in vitro experimental data. This phase-field model considers spatial variations in permeability and material properties within a single unified mathematical framework derived from an energy perspective, thereby allowing us to study effects of thrombus microstructure and properties on its deformation and possible release of emboli under different hemodynamic conditions. Moreover, we combine this proposed thrombus model with a particle-based model which simulates the initiation of the thrombus. The volume fraction of a thrombus obtained from the particle simulation is mapped to an input variable in the proposed phase-field thrombus model. The present work is thus the first computational study to integrate the initiation of a thrombus through platelet aggregation with its subsequent viscoelastic responses to various shear flows. This framework can be informed by clinical data and potentially be used to predict the risk of diverse thromboembolic events under physiological and pathological conditions. Author summary: Thromboembolism is associated with detachment of small thrombus pieces from the bulk in the blood vessel. These detached pieces, also known as emboli, travel through the blood flow and may block other vessels downstream, e.g., they may plug the deep veins of the leg, groin or arm, leading to venous thromboembolism (VTE). VTE is a significant cause of morbidity and mortality and it affects more than 900,000 people in the United States and result in approximately 100,000 deaths every year. Mechanical interaction between flowing blood and a thrombus is crucial in determining the deformation of the thrombus and the possibility of releasing emboli. In this study, we develop a phase-field model that is capable of describing the structural properties of a thrombus and its biomechanical properties under different blood flow conditions. Moreover, we combine this thrombus model with a particle-based model which simulates the initiation of the thrombus. This combined framework is the first computational study to simulate the development of a thrombus from platelet aggregation to its subsequent viscoelastic responses to various shear flows. Informed by clinical data, this framework can be used to predict the risk of diverse thromboembolic events under physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer (EOC) represents the most frequent cause of death in the United States from a cancer involving the female genital tract. Contributing to the overall poor outcome in EOC patients, are the metastases to the peritoneum and stroma that are common in this cancer. In one study, cDNA microarray analysis was performed on fresh tissue to profile gene expression in patients with EOC. This study showed a number of genes with significantly altered expression in the pelvic peritoneum and stroma, and in the vicinity of EOC implants. These genes included those encoding coagulation factors and regulatory proteins in the coagulation cascade and genes encoding proteins associated with inflammatory responses. In addition to promoting the formation of blood clots, coagulation factors exhibit many other biologic functions as well as tumorigenic functions, the ater including tumor cell proliferation, angiogenesis, invasion, and metastasis. Coagulation pathway roteins involved in tumorigenesis consist of factor II (thrombin), thrombin receptor (proteaseactivated eceptors), factor III (tissue factor), factor VII, factor X and factor I (fibrinogen), and fibrin and factor XIII. In a recent study we conducted, we found that factor XII, factor XI, and several coagulation regulatory proteins, including heparin cofactor-II and epithelial protein C receptor EPCR), were also upregulated in the peritoneum of EOC. n this review, we summarize evidence in support of a role for these factors in promoting tumor ell progression and the formation of ascites. We also discuss the different roles of coagulation actor pathways in the tumor and peritumoral microenvironments as they relate to angiogenesis, proliferation, invasion, and metastasis. . Since inflammatory responses are another characteristic of the peritoneum in EOC, we also discuss the linkage between the coagulation cascade and the cytokines/chemokines involved in inflammation. Interleukin-8, which is considered an important hemokine associated with tumor progression, appears to be a linkage point for coagulation and nflammation in malignancy. Lastly, we review findings regarding the inflammatory process yielded y certain clinical trials of agents that target members of the coagulation cascade in the treatment of cancer. Current data suggest that disrupting certain elements of the coagulation and inflammation processes in the tumor microenvironment could be a new biologic approach to cancer therapeutics. [ABSTRACT FROM AUTHOR]