Understanding the biological mechanisms underlying acquired risk factors for venous thrombosis : studies in mice

Over the years, a number of acquired risk factors for venous thrombosis have been identified in large epidemiological studies. We aimed to identify the biological mechanisms by which acquired risk factors like female hormones, thyroid hormone and obesity result in a hypercoagulable state and increased risk for venous thrombosis, since these are currently poorly understood. As these risk factors are all, to a certain extent, able to interfere with liver metabolism we hypothesized that they modulate hepatic transcription of coagulation genes, either directly via nuclear hormone receptors and hormone response elements in target genes (female hormones and thyroid hormone), or indirectly as a result of altered liver homeostasis (obesity). To study these hypotheses, we used an in vivo approach, which not only gives the opportunity to study the risk factor-mediated transcriptional modulation of coagulation genes, but also allowed us to study the relation between transcriptional changes on the one hand and plasma protein levels and a thrombotic tendency on the other. The data presented in this thesis clearly demonstrate that modulation of hepatic coagulation gene transcription is a key mechanism by which acquired risk factors for venous thrombosis impact the hemostatic balance.Nederlandse HartstichtingUBL - phd migration 201

Understanding the biological mechanisms underlying acquired risk factors for venous thrombosis : studies in mice

Over the years, a number of acquired risk factors for venous thrombosis have been identified in large epidemiological studies. We aimed to identify the biological mechanisms by which acquired risk factors like female hormones, thyroid hormone and obesity result in a hypercoagulable state and increased risk for venous thrombosis, since these are currently poorly understood. As these risk factors are all, to a certain extent, able to interfere with liver metabolism we hypothesized that they modulate hepatic transcription of coagulation genes, either directly via nuclear hormone receptors and hormone response elements in target genes (female hormones and thyroid hormone), or indirectly as a result of altered liver homeostasis (obesity). To study these hypotheses, we used an in vivo approach, which not only gives the opportunity to study the risk factor-mediated transcriptional modulation of coagulation genes, but also allowed us to study the relation between transcriptional changes on the one hand and plasma protein levels and a thrombotic tendency on the other. The data presented in this thesis clearly demonstrate that modulation of hepatic coagulation gene transcription is a key mechanism by which acquired risk factors for venous thrombosis impact the hemostatic balance

Metabolic regulation of mouse liver F11 gene transcription and its relation to KLKB1 and CYP4V3 control

Thrombosis and Hemostasi

Progestins posses poor anti-estrogenic activity on murine hepatic coagulation gene transcription despite evident anti-estrogenic activity on uterine tissue

Thrombosis and Hemostasi

Long-term estrogen treatment of mice with a prothrombotic phenotype induces sustained increases in thrombin generation without affecting tissue fibrin deposition

Thrombosis and Hemostasi

Early death of factor v leiden hemizygous mice: a fatal absence of wild type FV anticoagulant function

Thrombosis and Hemostasi

Early death of factor v leiden hemizygous mice: a fatal absence of wild type FV anticoagulant function

Thrombosis and Hemostasi

17 alpha-Ethinylestradiol rapidly alters transcript levels of murine coagulation genes via estrogen receptor alpha

Background: Oral estrogen use is associated with changes in plasma levels of many coagulation proteins. Objective: To gain more insight into the underlying mechanism of estrogen-induced changes in coagulation. Methods: Ovariectomized female mice were used to study the impact of oral 17 alpha-ethinylestradiol (EE) on plasma coagulation, hepatic coagulation gene transcript levels, and dependence on estrogen receptor (ER) alpha and ER beta. Results: Ten days of oral EE treatment resulted in significantly reduced plasma activity levels of factor (F)VIII, FXII, combined FII/FVII/FX and antithrombin, whereas FIX activity significantly increased. Regarding hepatic transcript levels, oral EE caused significant decreases in fibrinogen-gamma, FII, FV, FVII, FX, FXII, antithrombin, protein C, protein Z, protein Z inhibitor and heparin cofactor II mRNA levels, whereas FXI levels significantly increased and transcript levels of FVIII, FIX, protein S and alpha(2)-antiplasmin remained unaffected. All EE-induced coagulation-related changes were neutralized by coadministration of the non-specific ER antagonist ICI182780. In addition, ER alpha-deficient mice lacked the EE-induced changes in plasma coagulation and hepatic transcript profile, whereas ER beta-deficient mice responded similarly to non-deficient littermate controls. A crucial role for the ER was further demonstrated by its rapid effects on transcription, within 2.5-5 h after EE administration, suggesting a short chain of events leading to its final effects. Conclusions: Oral EE administration has a broad impact on the mouse coagulation profile at the level of both plasma and hepatic mRNA levels. The effects on transcription are rapidly induced, mostly downregulatory, and principally mediated by ER alpha.Thrombosis and Hemostasi

Changes in Dietary Fat Content Rapidly Alters the Mouse Plasma Coagulation Profile without Affecting Relative Transcript Levels of Coagulation Factors

Thrombosis and Hemostasi

Regulation of the F11, Klkb1, Cyp4v3 Gene Cluster in Livers of Metabolically Challenged Mice

Thrombosis and Hemostasi