Tissue-specific hemostasis in mice

Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 5.53). 12/2005; 25(11):2273-81. DOI: 10.1161/01.ATV.0000183884.06371.52
Source: PubMed

ABSTRACT 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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    • "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.
    Chemistry & Biology 07/2014; 21(8). DOI:10.1016/j.chembiol.2014.05.016 · 6.59 Impact Factor
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    • "Thrombosis plays a critical role in the development of cardiovascular diseases (Sturm 2004) and may be caused by the upregulation of the procoagulant pathway, or the downregulation of anticoagulant and fibrinolytic pathways (Mackman 2005). Thrombotic risk has been associated with genetic variation in these three pathways (Grant 2003; Williams and Bray 2001). "
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    ABSTRACT: Susceptibility to thrombosis varies in human populations as well as many in inbred mouse strains. The objective of this study was to characterize the genetic control of thrombotic risk on three chromosomes. Previously, utilizing a tail-bleeding/rebleeding assay as a surrogate of hemostasis and thrombosis function, three mouse chromosome substitution strains (CSS) (B6-Chr5(A/J), Chr11(A/J), Chr17(A/J)) were identified (Hmtb1, Hmtb2, Hmtb3). The tail-bleeding/rebleeding assay is widely used and distinguishes mice with genetic defects in blood clot formation or dissolution. In the present study, quantitative trait locus (QTL) analysis revealed a significant locus for rebleeding (clot stability) time (time between cessation of initial bleeding and start of the second bleeding) on chromosome 5, suggestive loci for bleeding time (time between start of bleeding and cessation of bleeding) also on chromosomes 5, and two suggestive loci for clot stability on chromosome 17 and one on chromosome 11. The three CSS and the parent A/J had elevated clot stability time. There was no interaction of genes on chromosome 11 with genes on chromosome 5 or chromosome 17. On chromosome 17, twenty-three candidate genes were identified in synteny with previously identified loci for thrombotic risk on human chromosome 18. Thus, we have identified new QTLs and candidate genes not previously known to influence thrombotic risk.
    Mammalian Genome 10/2008; 19(6):406-12. DOI:10.1007/s00335-008-9122-0 · 2.88 Impact Factor
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    • "Inappropriate activation of the coagulation pathways, however, can promote intravascular thrombosis (Chu 2006; Mackman 2005). The blood coagulation cascade is composed of intrinsic and extrinsic pathways. "
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    ABSTRACT: Epidemiology studies have linked exposure to pollutant particles to increased cardiovascular mortality and morbidity, but the mechanisms remain unknown. We tested the hypothesis that the ultrafine fraction of ambient pollutant particles would cause endothelial cell dysfunction. We profiled gene expression of human pulmonary artery endothelial cells (HPAEC) exposed to ultrafine particles (UFPs; 100 microg/mL) from Chapel Hill, North Carolina, or vehicle for 4 hr with Affymetrix HG U133 Plus 2.0 chips (n = 4 each). We found 320 up-regulated genes and 106 down-regulated genes (p < 0.01, 5% false discovery rate). We noted up-regulation of genes related to coagulation [tissue factor (F3) and coagulation factor II receptor-like 2 (F2RL2)] and differential regulation of genes related to F3 signaling (FOS, JUN, and NFKBIA). Results of quantitative polymerase chain reaction show a significant up-regulation of F3 after 10 and 100 microg/mLUFP exposures. Additionally, the water-soluble fractions of UFPs were sufficient to induce the expression of F3, F2RL2, and heme oxygenase 1 (HMOX1). Treatment of HPAEC with UFPs for 16 hr increased the release of interleukin (IL)-6 and IL-8. Pretreatment of HPAEC with a blocking antibody against F3 attenuated IL-6 and IL-8 release by 30 and 70%, respectively. Using gene profiling, we discovered that UFPs may induce vascular endothelial cells to express genes related to clotting. These results indicate that PM may cause adverse cardiovascular health effects by activating coagulation-inflammation circuitry.
    Environmental Health Perspectives 04/2007; 115(4):535-40. DOI:10.1289/ehp.9556 · 7.03 Impact Factor
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