Publications by authors named "Audrey Cleuren"

17 Publications

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Illustrated State-of-the-Art Capsules of the ISTH 2020 Congress.

Res Pract Thromb Haemost 2021 Jul 16;5(5):e12532. Epub 2021 Jul 16.

Transfusion Medicine NHS Blood and Transplant (London) and Barts Health NHS Trust London UK.

This year's Congress of the International Society of Thrombosis and Haemostasis (ISTH) was hosted virtually from Philadelphia July 17-21, 2021. The conference, now held annually, highlighted cutting-edge advances in basic, population and clinical sciences of relevance to the Society. Despite being held virtually, the 2021 congress was of the same scope and quality as an annual meeting held in person. An added feature of the program is that talks streamed at the designated times will then be available on-line for asynchronous viewing. The program included 77 State of the Art (SOA) talks, thematically grouped in 28 sessions, given by internationally recognized leaders in the field. The SOA speakers were invited to prepare brief illustrated reviews of their talks that were peer reviewed and are included in this article. The topics, across the main scientific themes of the congress, include Arterial Thromboembolism, Coagulation and Natural Anticoagulants, COVID-19 and Coagulation, Diagnostics and Omics, Fibrinogen, Fibrinolysis and Proteolysis, Hemophilia and Rare Bleeding Disorders, Hemostasis in Cancer, Inflammation and Immunity, Pediatrics, Platelet Disorders, von Willebrand Disease and Thrombotic Angiopathies, Platelets and Megakaryocytes, Vascular Biology, Venous Thromboembolism and Women's Health. These illustrated capsules highlight the major scientific advances with potential to impact clinical practice. Readers are invited to take advantage of the excellent educational resource provided by these illustrated capsules. They are also encouraged to use the image in social media to draw attention to the high quality and impact of the science presented at the congress.
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http://dx.doi.org/10.1002/rth2.12532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285574PMC
July 2021

Tissue factor pathway inhibitor is required for cerebrovascular development in mice.

Blood 2021 01;137(2):258-268

Versiti Blood Research Institute, Milwaukee, WI.

Tissue factor pathway inhibitor (TFPI) inhibits proteases in the blood coagulation cascade that lead to the production of thrombin, including prothrombinase (factor Xa [FXa]/FVa), the catalytic complex that directly generates thrombin. Thus, TFPI and FV are directly linked in regulating the procoagulant response. Studies using knockout mice indicate that TFPI and FV are necessary for embryogenesis, but their contributions to vascular development are unclear. We performed extensive histological analyses of Tfpi-/- and Tfpi-/-F5-/- mouse embryos to investigate the importance of the interplay between TFPI and FV in regulating hemostasis and vascular development during embryogenesis. We observed normal tissue development throughout Tfpi-/- embryos, except in the central nervous system (CNS). The CNS displayed stunted brain growth, delayed development of the meninges, and severe vascular pathology characterized by the formation of glomeruloid bodies surrounding areas of cellular death, fibrin deposition, and hemorrhage. Removing FV from Tfpi-/- embryos completely ameliorated their brain pathology, suggesting that TFPI dampens FV-dependent procoagulant activity in a manner that modulates cerebrovascular development. Thus, we have identified a previously unrecognized role for TFPI activity within the CNS. This TFPI activity likely diminishes an effect of excess thrombin activity on signaling pathways that control cerebral vascular development.
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http://dx.doi.org/10.1182/blood.2020006054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820871PMC
January 2021

Glomerular endothelial cells and podocytes can express CD80 in patients with minimal change disease during relapse.

Pediatr Nephrol 2020 10 12;35(10):1887-1896. Epub 2020 May 12.

Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, USA.

Background: Urinary CD80 has emerged as potential biomarker in idiopathic nephrotic syndrome (INS). However, its cellular source remains controversial. The aim of the study was to assess whether CD80 is truly expressed by glomerular cells in INS patients during relapse and in the LPS mouse model of podocyte injury.

Methods: The presence of CD80 in glomeruli was evaluated by combining immunostaining, immunogold labeling, and in situ hybridization techniques.

Results: CD80 was present along the surface of glomerular endothelial cells (GEC) and rarely in podocytes in six of nine minimal change disease (MCD) patients in relapse, two of eleven patients with focal segmental glomerulosclerosis in relapse, and absent in controls. In mice, CD80 was upregulated at mRNA and protein level in GEC and podocytes, in a similar pattern to that seen in MCD patients.

Conclusions: Glomerular endothelial cells and podocytes can express CD80 in patients with MCD during relapse. A better understanding of the role of CD80 in glomerular cells may provide further insights into the mechanisms of proteinuria in INS.
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http://dx.doi.org/10.1007/s00467-020-04541-3DOI Listing
October 2020

Thrombo-Inflammation in Cardiovascular Disease: An Expert Consensus Document from the Third Maastricht Consensus Conference on Thrombosis.

Thromb Haemost 2020 Apr 14;120(4):538-564. Epub 2020 Apr 14.

Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; Haemostasis Research Unit, University College London, London, United Kingdom.

Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism.
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http://dx.doi.org/10.1055/s-0040-1708035DOI Listing
April 2020

Differential roles of factors IX and XI in murine placenta and hemostasis under conditions of low tissue factor.

Blood Adv 2020 01;4(1):207-216

UNC Blood Research Center, Division of Hematology and Oncology, Department of Medicine, and.

The intrinsic tenase complex (FIXa-FVIIIa) of the intrinsic coagulation pathway and, to a lesser extent, thrombin-mediated activation of FXI, are necessary to amplify tissue factor (TF)-FVIIa-initiated thrombin generation. In this study, we determined the contribution of murine FIX and FXI to TF-dependent thrombin generation in vitro. We further investigated TF-dependent FIX activation in mice and the contribution of this pathway to hemostasis. Thrombin generation was decreased in FIX- but not in FXI-deficient mouse plasma. Furthermore, injection of TF increased levels of FIXa-antithrombin complexes in both wild-type and FXI-/- mice. Genetic studies were used to determine the effect of complete deficiencies of either FIX or FXI on the survival of mice expressing low levels of TF. Low-TF;FIX-/y male mice were born at the expected frequency, but none survived to wean. In contrast, low-TF;FXI-/- mice were generated at the expected frequency at wean and had a 6-month survival equivalent to that of low-TF mice. Surprisingly, a deficiency of FXI, but not FIX, exacerbated the size of blood pools in low-TF placentas and led to acute hemorrhage and death of some pregnant dams. Our data indicate that FIX, but not FXI, is essential for survival of low-TF mice after birth. This finding suggests that TF-FVIIa-mediated activation of FIX plays a critical role in murine hemostasis. In contrast, FXI deficiency, but not FIX deficiency, exacerbated blood pooling in low-TF placentas, indicating a tissue-specific requirement for FXI in the murine placenta under conditions of low TF.
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http://dx.doi.org/10.1182/bloodadvances.2019000921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960463PMC
January 2020

The in vivo endothelial cell translatome is highly heterogeneous across vascular beds.

Proc Natl Acad Sci U S A 2019 11 11;116(47):23618-23624. Epub 2019 Nov 11.

Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109;

Endothelial cells (ECs) are highly specialized across vascular beds. However, given their interspersed anatomic distribution, comprehensive characterization of the molecular basis for this heterogeneity in vivo has been limited. By applying endothelial-specific translating ribosome affinity purification (EC-TRAP) combined with high-throughput RNA sequencing analysis, we identified pan EC-enriched genes and tissue-specific EC transcripts, which include both established markers and genes previously unappreciated for their presence in ECs. In addition, EC-TRAP limits changes in gene expression after EC isolation and in vitro expansion, as well as rapid vascular bed-specific shifts in EC gene expression profiles as a result of the enzymatic tissue dissociation required to generate single-cell suspensions for fluorescence-activated cell sorting or single-cell RNA sequencing analysis. Comparison of our EC-TRAP with published single-cell RNA sequencing data further demonstrates considerably greater sensitivity of EC-TRAP for the detection of low abundant transcripts. Application of EC-TRAP to examine the in vivo host response to lipopolysaccharide (LPS) revealed the induction of gene expression programs associated with a native defense response, with marked differences across vascular beds. Furthermore, comparative analysis of whole-tissue and TRAP-selected mRNAs identified LPS-induced differences that would not have been detected by whole-tissue analysis alone. Together, these data provide a resource for the analysis of EC-specific gene expression programs across heterogeneous vascular beds under both physiologic and pathologic conditions.
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http://dx.doi.org/10.1073/pnas.1912409116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876253PMC
November 2019

Expression of factor V by resident macrophages boosts host defense in the peritoneal cavity.

J Exp Med 2019 06 2;216(6):1291-1300. Epub 2019 May 2.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO

Macrophages resident in different organs express distinct genes, but understanding how this diversity fits into tissue-specific features is limited. Here, we show that selective expression of coagulation factor V (FV) by resident peritoneal macrophages in mice promotes bacterial clearance in the peritoneal cavity and serves to facilitate the well-known but poorly understood "macrophage disappearance reaction." Intravital imaging revealed that resident macrophages were nonadherent in peritoneal fluid during homeostasis. Bacterial entry into the peritoneum acutely induced macrophage adherence and associated bacterial phagocytosis. However, optimal control of bacterial expansion in the peritoneum also required expression of FV by the macrophages to form local clots that effectively brought macrophages and bacteria in proximity and out of the fluid phase. Thus, acute cellular adhesion and resident macrophage-induced coagulation operate independently and cooperatively to meet the challenges of a unique, open tissue environment. These events collectively account for the macrophage disappearance reaction in the peritoneal cavity.
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http://dx.doi.org/10.1084/jem.20182024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547866PMC
June 2019

Whole exome sequencing of ENU-induced thrombosis modifier mutations in the mouse.

PLoS Genet 2018 09 6;14(9):e1007658. Epub 2018 Sep 6.

Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.

Although the Factor V Leiden (FVL) gene variant is the most prevalent genetic risk factor for venous thrombosis, only 10% of FVL carriers will experience such an event in their lifetime. To identify potential FVL modifier genes contributing to this incomplete penetrance, we took advantage of a perinatal synthetic lethal thrombosis phenotype in mice homozygous for FVL (F5L/L) and haploinsufficient for tissue factor pathway inhibitor (Tfpi+/-) to perform a sensitized dominant ENU mutagenesis screen. Linkage analysis conducted in the 3 largest pedigrees generated from the surviving F5L/L Tfpi+/- mice ('rescues') using ENU-induced coding variants as genetic markers was unsuccessful in identifying major suppressor loci. Whole exome sequencing was applied to DNA from 107 rescue mice to identify candidate genes enriched for ENU mutations. A total of 3,481 potentially deleterious candidate ENU variants were identified in 2,984 genes. After correcting for gene size and multiple testing, Arl6ip5 was identified as the most enriched gene, though not reaching genome-wide significance. Evaluation of CRISPR/Cas9 induced loss of function in the top 6 genes failed to demonstrate a clear rescue phenotype. However, a maternally inherited (not ENU-induced) de novo mutation (Plcb4R335Q) exhibited significant co-segregation with the rescue phenotype (p = 0.003) in the corresponding pedigree. Thrombosis suppression by heterozygous Plcb4 loss of function was confirmed through analysis of an independent, CRISPR/Cas9-induced Plcb4 mutation (p = 0.01).
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http://dx.doi.org/10.1371/journal.pgen.1007658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143275PMC
September 2018

Sensitized mutagenesis screen in Factor V Leiden mice identifies thrombosis suppressor loci.

Proc Natl Acad Sci U S A 2017 09 21;114(36):9659-9664. Epub 2017 Aug 21.

Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109;

Factor V Leiden ( ) is a common genetic risk factor for venous thromboembolism in humans. We conducted a sensitized -ethyl--nitrosourea (ENU) mutagenesis screen for dominant thrombosuppressor genes based on perinatal lethal thrombosis in mice homozygous for ( ) and haploinsufficient for tissue factor pathway inhibitor ( ). deficiency enhanced the survival of mice, demonstrating that lethality is genetically suppressible. ENU-mutagenized males and females were crossed to generate 6,729 progeny, with 98 offspring surviving until weaning. Sixteen lines, referred to as "modifier of Factor 5 Leiden ()," exhibited transmission of a putative thrombosuppressor to subsequent generations. Linkage analysis in identified a chromosome 3 locus containing the tissue factor gene (). Although no ENU-induced mutation was identified, haploinsufficiency for ( ) suppressed lethality. Whole-exome sequencing in identified an gene point mutation (p.R258G) as the sole candidate. Inheritance of this variant is associated with suppression of lethality ( = 1.7 × 10), suggesting that is thrombosuppressive. CRISPR/Cas9 experiments to generate an independent knockin/knockout demonstrated that haploinsufficiency is lethal, supporting a hypomorphic or gain-of-function mechanism of action for Our findings identify and the axis as key regulators in determining thrombosis balance in the setting of and also suggest a role for in this process.
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http://dx.doi.org/10.1073/pnas.1705762114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594664PMC
September 2017

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

PLoS One 2015 15;10(7):e0131859. Epub 2015 Jul 15.

Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.

Background: Obesity is associated with a hypercoagulable state and increased risk for thrombotic cardiovascular events.

Objective: Establish the onset and reversibility of the hypercoagulable state during the development and regression of nutritionally-induced obesity in mice, and its relation to transcriptional changes and clearance rates of coagulation factors as well as its relation to changes in metabolic and inflammatory parameters.

Methods: Male C57BL/6J mice were fed a low fat (10% kcal as fat; LFD) or high fat diet (45% kcal as fat; HFD) for 2, 4, 8 or 16 weeks. To study the effects of weight loss, mice were fed the HFD for 16 weeks and switched to the LFD for 1, 2 or 4 weeks. For each time point analyses of plasma and hepatic mRNA levels of coagulation factors were performed after overnight fasting, as well as measurements of circulating metabolic and inflammatory parameters. Furthermore, in vivo clearance rates of human factor (F) VII, FVIII and FIX proteins were determined after 2 weeks of HFD-feeding.

Results: HFD feeding gradually increased the body and liver weight, which was accompanied by a significant increase in plasma glucose levels from 8 weeks onwards, while insulin levels were affected after 16 weeks. Besides a transient rise in cytokine levels at 2 weeks after starting the HFD, no significant effect on inflammation markers was present. Increased plasma levels of fibrinogen, FII, FVII, FVIII, FIX, FXI and FXII were observed in mice on a HFD for 2 weeks, which in general persisted throughout the 16 weeks of HFD-feeding. Interestingly, with the exception of FXI the effects on plasma coagulation levels were not paralleled by changes in relative transcript levels in the liver, nor by decreased clearance rates. Switching from HFD to LFD reversed the HFD-induced procoagulant shift in plasma, again not coinciding with transcriptional modulation.

Conclusions: Changes in dietary fat content rapidly alter the mouse plasma coagulation profile, thereby preceding plasma metabolic changes, which cannot be explained by changes in relative expression of coagulation factors or decreased clearance rates.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131859PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503443PMC
April 2016

Murine coagulation factor VIII is synthesized in endothelial cells.

Blood 2014 Jun 9;123(24):3697-705. Epub 2014 Apr 9.

Howard Hughes Medical Institute, Chevy Chase, MD; and Departments of Internal Medicine, Human Genetics, and Pediatrics, University of Michigan, Ann Arbor, MI.

The primary cellular source of factor VIII (FVIII) biosynthesis is controversial, with contradictory evidence supporting an endothelial or hepatocyte origin. LMAN1 is a cargo receptor in the early secretory pathway that is responsible for the efficient secretion of factor V (FV) and FVIII to the plasma. Lman1 mutations result in combined deficiency of FV and FVIII, with levels of both factors reduced to ~10% to 15% of normal in human patients. We generated Lman1 conditional knockout mice to characterize the FVIII secretion profiles of endothelial cells and hepatocytes. We demonstrate that endothelial cells are the primary biosynthetic source of murine FVIII and that hepatocytes make no significant contribution to the plasma FVIII pool. Utilizing RiboTag mice and polyribosome immunoprecipitation, we performed endothelial cell-specific messenger RNA isolation and quantitative polymerase chain reaction analyses to confirm that endothelial cells highly express F8 and to explore the heterogeneity of F8 expression in different vascular beds. We demonstrate that endothelial cells from multiple, but not all, tissues contribute to the plasma FVIII pool in the mouse.
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http://dx.doi.org/10.1182/blood-2014-02-554501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055920PMC
June 2014

Regulation of the F11, Klkb1, Cyp4v3 gene cluster in livers of metabolically challenged mice.

PLoS One 2013 16;8(9):e74637. Epub 2013 Sep 16.

Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands ; Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands.

Single nucleotide polymorphisms (SNPs) in a 4q35.2 locus that harbors the coagulation factor XI (F11), prekallikrein (KLKB1), and a cytochrome P450 family member (CYP4V2) genes are associated with deep venous thrombosis (DVT). These SNPs exert their effect on DVT by modifying the circulating levels of FXI. However, SNPs associated with DVT were not necessarily all in F11, but also in KLKB1 and CYP4V2. Here, we searched for evidence for common regulatory elements within the 4q35.2 locus, outside the F11 gene, that might control FXI plasma levels and/or DVT risk. To this end, we investigated the regulation of the orthologous mouse gene cluster under several metabolic conditions that impact mouse hepatic F11 transcription. In livers of mice in which HNF4α, a key transcription factor controlling F11, was ablated, or reduced by siRNA, a strong decrease in hepatic F11 transcript levels was observed that correlated with Cyp4v3 (mouse orthologue of CYP4V2), but not by Klkb1 levels. Estrogens induced hepatic F11 and Cyp4v3, but not Klkb1 transcript levels, whereas thyroid hormone strongly induced hepatic F11 transcript levels, and reduced Cyp4v3, leaving Klkb1 levels unaffected. Mice fed a high-fat diet also had elevated F11 transcription, markedly paralleled by an induction of Klkb1 and Cyp4v3 expression. We conclude that within the mouse F11, Klkb1, Cyp4v3 gene cluster, F11 and Cyp4v3 frequently display striking parallel transcriptional responses suggesting the presence of shared regulatory elements.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0074637PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774739PMC
May 2014

Short-term ethinyl estradiol treatment suppresses inferior caval vein thrombosis in obese mice.

Thromb Haemost 2009 Nov;102(5):993-1000

Center for Molecular and Vascular Biology, KU Leuven,3000 Leuven, Belgium.

Obesity and oral estrogens are independent risk factors for venous thrombosis, and their combined effect is stronger than the sum of the isolated factors. It was the objective of this study to investigate the interaction between obesity and estrogens at the level of venous thrombotic tendency, coagulation and inflammation in a mouse model. Female C57Bl/6J mice were fed a standard fat diet (SFD) or a high fat diet (HFD) to induce nutritional obesity. After 14 weeks, while maintaining their diet, mice were orally treated eight days with 1 microg ethinylestradiol or vehicle (n=25 per group), and subsequently subjected to an inferior caval vein (ICV) thrombosis model. The ICV thrombosis model resulted in an increased thrombus weight in vehicle-treated HFD mice (3.0 +/- 0.7 mg) compared to vehicle-treated SFD mice (1.4 +/- 0.4 mg; p=0.064). Surprisingly, estrogens reduced thrombus weight, which was significant for the HFD group (0.8 +/- 0.5 mg; p=0.013). As compared to SFD feeding, HFD feeding significantly increased plasma levels of coagulation factor VIII, combined factor II/VII/X (p < 0.001), and plasminogen activator inhibitor-1 (p=0.009), causing a prothrombotic shift of the coagulation profile. Estrogens had no significant effects on this profile with either diet, whereas serum amyloid A and hepatic inflammatory cytokines were minimally affected. The synergistic effect of obesity and estrogens on the venous thrombotic risk in women could not be translated into the mouse context. Short-term ethinylestradiol administration in a mouse ICV thrombosis model counteracts the prothrombotic phenotype associated with nutritionally induced obesity, despite a comparable activated plasma coagulation profile in estrogen-treated and untreated obese mice.
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http://dx.doi.org/10.1160/TH09-03-0169DOI Listing
November 2009

Obesity promotes injury induced femoral artery thrombosis in mice.

Thromb Res 2008 29;122(4):549-55. Epub 2008 Jan 29.

Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.

An FeCl(3) induced femoral arterial thrombosis model was applied to lean (47+/-1.4 g) and obese (64+/-1.7 g) mice (Swiss genetic background) in order to study the relation between obesity and thrombotic risk. As compared to lean mice, obese mice showed a significantly shorter occlusion time (9.9+/-1.0 min versus 13+/-0.5 min; p=0.04) and lower total blood flow (37+/-7.3% versus 69+/-6.7%; p=0.008). A significant negative correlation was observed between body weight and both occlusion time (r=-0.57; p=0.014) and blood flow (r=-0.57; p=0.028). Analysis of the coagulation profile revealed significantly higher levels of plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex, Factor V activity and combined Factors II/VII/X activity, and moderately elevated Factor VIII activity in obese mice. The degree of arterial damage and the thrombus extension were, however, not significantly different. A significant positive correlation was observed between body weight and either PAI-1 (r=0.63; p=0.003), Factors II/VII/X levels (r=0.80; p<0.0001) or Factor V levels (r=0.65; p=0.003). Thus, this injury induced femoral artery thrombosis model in mice establishes experimentally a correlation between obesity and prothrombotic tendency.
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http://dx.doi.org/10.1016/j.thromres.2007.12.017DOI Listing
November 2008

Factor V Leiden mutation is associated with enhanced arterial thrombotic tendency in lean but not in obese mice.

Thromb Haemost 2007 Oct;98(4):858-63

Center for Molecular and Vascular Biology, KU Leuven, Campus Gasthuisberg, O & N 1, Herestraat 49, Box 911, 3000 Leuven, Belgium.

The homozygous factor V Leiden mutation is associated with enhanced venous thrombotic risk. Obesity is a major risk factor for development of thrombotic cardiovascular disease. It was the objective of this study to investigate whether obesity affects the thrombotic risk associated with the mutation. Male mice with homozygous factor V Leiden mutation (Arg 504 to Gln) (FVQ/Q) and corresponding wild-type (WT) mice were kept on a standard fat diet (SFD) or high fat diet (HFD) for 14 weeks, and femoral artery thrombosis was induced by FeCl3 treatment. As compared to SFD, HFD feeding for 14 weeks resulted in significantly higher body weight and fat mass associated with adipocyte hypertrophy, which were, however, similar for both genotypes. In the FeCl3-induced arterial thrombosis model, FVQ/Q mice kept on SFD had a 40% shorter occlusion time (p = 0.015) and 40% lower blood flow (p = 0.03), as compared to WT mice. However, on HFD the occlusion time and blood flow were not significantly different for both genotypes. This finding could not be explained by differential changes of coagulation factors in either genotype fed on SFD or HFD. In conclusion, on SFD, but not on HFD, the factor V Leiden mutation is associated with enhanced thrombotic tendency after FeCl3 injury of the femoral artery, suggesting that in this model obesity rescues the increased thrombotic risk associated with the factor V Leiden mutation.
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October 2007

Transgenic mouse models of venous thrombosis: fulfilling the expectations?

Semin Thromb Hemost 2007 Sep;33(6):610-6

Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands.

During the last 15 years, transgenic mice have been generated that carry defective and/or mutant alleles of the natural anticoagulant pathways and display a spontaneous thrombotic phenotype. With the generation of these mouse lines, better opportunities became available for investigating both existing and novel risk factors for venous thrombosis. In addition, these models could serve as a tool for evaluating novel antithrombotic strategies. This review summarizes these mouse models and evaluates whether they have fulfilled the expectations.
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http://dx.doi.org/10.1055/s-2007-985758DOI Listing
September 2007
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