Tissue-specific hemostasis in mice

Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 12/2005; 25(11):2273-81. DOI: 10.1161/01.ATV.0000183884.06371.52
Source: PubMed


Blood coagulation is essential to maintain hemostasis in organisms with a vascular network. Formation of a fibrin-rich clot at a site of vessel injury is a highly complex process that is orchestrated by the coagulation protease cascade. This cascade is regulated by 3 major anticoagulant pathways. Removal of a clot is mediated by the fibrinolytic system. Defects in the regulation of clot formation lead to either hemorrhage or thrombosis. Tissue factor, the primary cellular initiator of blood coagulation, is a transmembrane receptor that is expressed in a tissue-specific manner. The 3 major anticoagulants are tissue factor pathway inhibitor, antithrombin, and protein C, the latter requiring a transmembrane receptor called thrombomodulin for its activation. Tissue factor pathway inhibitor and thrombomodulin are expressed by endothelial cells in a tissue-specific manner, whereas antithrombin and protein C circulate in the plasma. Fibrinolysis requires the activation of plasminogen to plasmin, which is mediated by tissue-type plasminogen activator and urokinase-type plasminogen activator. Interestingly, tissue-type plasminogen activator is expressed by a subset of endothelial cells of discrete size and location. These observations, together with the phenotypes of mice that have defects in the procoagulant, anticoagulant, and fibrinolytic pathways, indicate that hemostasis is regulated in a tissue-specific manner.

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    • "Decreased levels of fibrin lead to hemorrhage because of impaired hemostasis. Again, increased levels of fibrin result in intravascular thrombosis (Mackman 2005). According to the traditional view of blood coagulation, the initial phase of coagulation is triggered by the extrinsic pathway whereas amplification of the coagulation cascade is triggered by the intrinsic pathway (Mackman et al. 2007). "
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    ABSTRACT: Tissue Factor (TF), a membrane bound glycoprotein, is the cellular initiator of the protease blood coagulation cascade. TF is a component of tissue factor/factor VII (TF/FVII) complex which plays key roles in extrinsic coagulation pathway. According to the traditional view of blood coagulation, although the initial phase of coagulation is triggered by the extrinsic pathway, the amplification of the coagulation cascade is triggered by the intrinsic pathway. Emerging experimental evidences show a broad range of biological functions of TF including hemostasis, thrombosis, hypercoagulability etc. In addition to the role of TF as an initiator of coagulation cascade, TF is also involved in many cancer-related processes like tumor growth, angiogenesis, metastasis etc. It is now widely recognized that a strong correlation exists between TF expression and breast cancer and plasma TF concentration has been found to be up-regulated in primary and recurrent breast cancer patients. TF-induced thrombin can activate several members of the protease activated receptor (PAR) family. Expression of protease activated receptor 1 (PAR1) is both required and sufficient to promote growth and invasion of breast carcinoma cells. Like PAR1, protease activated receptor 2 (PAR2) has also been found to play a critical role in breast cancer cell migration and invasion. Thus, TF plays a very crucial role in breast cancer progression. This review focuses on the role of TF in breast cancer progression based on the evidences available. Better understanding the role of TF in breast cancer will provide considerable clinical benefits associated with breast cancer treatment.
    Full-text · Article · Sep 2015
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    • "Genetic studies with knockout mice have been performed to study the role of coagulation proteins and pathway specific responses. However, genetically null mice for TF, factor VII (FVII), factor X (FX), and prothrombin are not viable, making many studies challenging (Mackman, 2005). Therefore, we sought to utilize a set of matched anticoagulant agents to inhibit various human clotting proteins and further clarify the role of these individual proteins in clot formation in human blood. "
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    ABSTRACT: Coordinated enzymatic reactions regulate blood clot generation. To explore the contributions of various coagulation enzymes in this process, we utilized a panel of aptamers against factors VIIa, IXa, Xa, and prothrombin. Each aptamer dose-dependently inhibited clot formation, yet none was able to completely impede this process in highly procoagulant settings. However, several combinations of two aptamers synergistically impaired clot formation. One extremely potent aptamer combination was able to maintain human blood fluidity even during extracorporeal circulation, a highly procoagulant setting encountered during cardiopulmonary bypass surgery. Moreover, this aptamer cocktail could be rapidly reversed with antidotes to restore normal hemostasis, indicating that even highly potent aptamer combinations can be rapidly controlled. These studies highlight the potential utility of using sets of aptamers to probe the functions of proteins in molecular pathways for research and therapeutic ends.
    Full-text · Article · Jul 2014 · Chemistry & Biology
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    • "Endothelial cells (ECs) in different tissues and organs exhibit molecular heterogeneity in normal physiology to address tissue-specific needs [1], [2]. This EC specialization includes highly variable characteristics with respect to degree of permeability, response to vascular endothelial growth factors, synthesis of hemostasis mediators, and leukocyte recruitment/expression of cluster differentiation (CD) antigens [2]–[5]. Rather than being fixed at birth, ECs retain a high degree of plasticity, altering their properties in response to the needs of the organism and based on microenvironmental changes. "
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    ABSTRACT: Structural and gene expression changes in the microvasculature of the human choroid occur during normal aging and age-related macular degeneration (AMD). In this study, we sought to determine the impact of aging and AMD on expression of the endothelial cell glycoprotein CD34. Sections from 58 human donor eyes were categorized as either young (under age 40), age-matched controls (> age 60 without AMD), or AMD affected (>age 60 with early AMD, geographic atrophy, or choroidal neovascularization). Dual labeling of sections with Ulex europaeus agglutinin-I lectin (UEA-I) and CD34 antibodies was performed, and the percentage of capillaries labeled with UEA-I but negative for anti-CD34 was determined. In addition, published databases of mouse and human retinal pigment epithelium-choroid were evaluated and CD34 expression compared between young and old eyes. Immunohistochemical studies revealed that while CD34 and UEA-I were colocalized in young eyes, there was variable loss of CD34 immunoreactivity in older donor eyes. While differences between normal aging and AMD were not significant, the percentage of CD34 negative capillaries in old eyes, compared to young eyes, was highly significant (p = 3.8×10(-6)). Endothelial cells in neovascular membranes were invariably CD34 positive. Published databases show either a significant decrease in Cd34 (mouse) or a trend toward decreased CD34 (human) in aging. These findings suggest that UEA-I and endogenous alkaline phosphatase activity are more consistent markers of aging endothelial cells in the choroid, and suggest a possible mechanism for the increased inflammatory milieu in the aging choroid.
    Full-text · Article · Jan 2014 · PLoS ONE
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