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Title: Variation in the haemostatic response and thrombotic risk : interplay between haemostatic factors, platelets and monocytes
Author: Wright, Joy Rhiannon
ISNI:       0000 0004 2716 6895
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2010
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The haemostatic response comprises the interaction of coagulation factors and peripheral blood cells which play a vital role in maintaining vascular integrity. This study begins with the finding that plasma from premature MI subjects has increased endogenous thrombotic potential linked to higher levels of circulating Tissue Factor (TF), suggesting these individuals may have a hypercoagulable phenotype. This study seeks to further understand how cellular interaction, in particular platelet-monocyte interaction, modulates the haemostatic response. Throughout the study, TF and Tissue Factor Pathway Inhibitor (TFPI) were studied as representing the procoagulant and anticoagulant response, respectively. Study of the effects of activated platelets on monocytes found that whereas direct platelet or platelet-microparticle adhesion to monocytes, and release of platelet soluble mediators induced monocyte gene expression of TF, induction of TFPI was driven solely by platelet soluble mediators. Extension of these studies using gene expression microarray technology found that whereas activation of monocytes via PSGL-1 generates a pro-angiogenic expression profile, platelet soluble mediators significantly enhanced this profile, enabling monocytes to interact with ECM components involved in the wound healing environment of the thrombus, and additionally induced anti-inflammatory, and anti-atherothrombotic genes. Whether cells within a thrombus act simply as structural and secretory components, or play a more active role involving gene expression is unclear, therefore gene expression array analysis was carried out on thrombi generated in vitro. Genes demonstrating significant time-dependent increases included those encoding chemotactic proteins (IL8, CCL2, CXCL1, CXCL2), cell adhesion (ITGAV, ITGA5, ITGB1), regulation of coagulation (THBD, PLAU, SERPINE1), wound-healing (ENDG, SPP1, LAMB3), and regulatory transcription factors (FOS, EGR1, PPARG). Whereas initiation of thrombosis is driven by plasma proteins and facilitated by the platelet surface, this study provides evidence that thrombus resolution may be driven by changes in gene expression within the thrombus that regulate the haemostatic response, thrombus growth, and facilitate wound-healing. These findings could have implications for individuals at risk of plaque rupture, where variation in gene expression may affect not just the formation of an occlusive thrombus but also the rate of resolution.
Supervisor: Goodall, Alison ; Tomaszewski, Maciej Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available