| 1. |
- Badimon, Lina, et al.
(författare)
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Antithrombotic therapy in obesity
- 2013
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 110:4, s. 681-688
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Tidskriftsartikel (refereegranskat)abstract
- Clinical management of obese subjects to reduce their risk of suffering cardiovascular events is complex. Obese patients typically require preventive strategies, life-style modifications, and multi-drug therapy to address obesity-induced co-morbidities. Data regarding the effects of excess weight on the pharmacokinetics of most drugs is scarce as these individuals are often excluded from clinical trials. However, the physiological alterations observed in obese patients and their lower response to some antiplatelet agents and anticoagulants have suggested that dosage regimes need to be adjusted for these subjects. In this review we will briefly discuss platelet alterations that can contribute to increased thrombotic risk, analyse existing data regarding the effects of obesity on drug pharmacokinetics focusing on antiplatelet agents and anticoagulants, and we will describe the beneficial effects of weight loss on thrombosis.
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| 2. |
- Badimon, Lina, et al.
(författare)
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Atherothrombotic risk in obesity
- 2013
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Ingår i: Hämostaseologie. - 0720-9355. ; 33:4, s. 259-268
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Tidskriftsartikel (refereegranskat)abstract
- A link between obesity and coronary artery disease development has been repeatedly proposed, possibly in part due to the development of a proinflammatory and prothrombotic state in obese subjects. Adipocytes secrete numerous hormones and cytokines (adipokines) which influence gene expression and cell functions in endothelial cells, arterial smooth muscle cells, and monocytes/macrophages favouring the development of an atherosclerotic vulnerable plaque. Moreover, the release of such biologically active molecules also promotes endothelial function impairment, disturbs the haemostatic and fibrinolytic systems, and produces alterations in platelet function affecting the initiation, progression, and stabilization of thrombus formation upon atherosclerotic plaque rupture. In this review we will discuss the pathophysiological mechanisms by which obesity contributes to increase atherothrombosis paying special attention to its effects over thrombosis.
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| 3. |
- Hernández Vera, Rodrigo, et al.
(författare)
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Obesity with insulin resistance increase thrombosis in wild-type and bone marrow-transplanted Zucker Fatty rats
- 2013
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 109:2, s. 319-327
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Tidskriftsartikel (refereegranskat)abstract
- Obesity induces metabolic and inflammatory alterations that contribute to the presentation of cardiovascular events. Although obesity is a risk factor for atherosclerosis and vascular disease, its role on thrombosis has not been directly explored. Therefore, we aimed to investigate the mechanisms by which obesity affects thrombosis. Thrombus formation was monitored by real-time intravital microscopy in Zucker Fatty rats (ZF) and lean controls (ZC). Crossed bone marrow (BM) transplants between ZF and ZC were performed. Intravital microscopy showed that ZF had significantly shorter occlusion times (OTs) than ZC, reflecting a three-fold higher thrombotic risk. Transplantation of ZC-BM to ZF recipients significantly reduced thrombosis, reducing their thrombotic risk to one third of that observed in non-transplanted ZF. Wild-type ZF showed increased platelet counts and increased platelet size compared to wild-type ZC and platelet number remained unaltered after transplantation. However, ZF-BM produced a significant increase in platelet size in ZC recipients. Thrombotic risk was found to be inversely correlated with both weight and insulin levels and directly correlated to HOMA-IR, while platelet number and size were directly correlated with weight. Thus, our data shows that obesity with insulin resistance significantly increases thrombosis and that alterations in BM-derived cells significantly contribute to this prothrombotic behaviour. Importantly, the reduction of insulin resistance was associated with reduced thrombotic risk even in the presence of obesity.
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| 4. |
- Hernández Vera, Rodrigo, et al.
(författare)
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Platelets derived from the bone marrow of diabetic animals show dysregulated endoplasmic reticulum stress proteins that contribute to increased thrombosis
- 2012
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 32:9, s. 2141-2148
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Patients with diabetes mellitus have an increased risk of suffering atherothrombotic syndromes and are prone to clustering cardiovascular risk factors. However, despite their dysregulated glucose metabolism, intensive glycemic control has proven insufficient to reduce thrombotic complications. Therefore, we aimed to elucidate the determinants of thrombosis in a model of type 2 diabetes mellitus with cardiovascular risk factors clustering.METHODS AND RESULTS: Intravital microscopy was used to analyze thrombosis in vivo in Zucker diabetic fatty rats (ZD) and lean normoglycemic controls. Bone marrow (BM) transplants were performed to test the contribution of each compartment (blood or vessel wall) to thrombogenicity. ZD showed significantly increased thrombosis compared with lean normoglycemic controls. BM transplants demonstrated the key contribution of the hematopoietic compartment to increased thrombogenicity. Indeed, lean normoglycemic controls transplanted with ZD-BM showed increased thrombosis with normal glucose levels, whereas ZD transplanted with lean normoglycemic controls-BM showed reduced thrombosis despite presenting hyperglycemia. Significant alterations in megakaryopoiesis and platelet-endoplasmic reticulum stress proteins, protein disulfide isomerase and 78-kDa glucose-regulated protein, were detected in ZD, and increased tissue factor procoagulant activity was detected in plasma and whole blood of ZD.CONCLUSIONS: Our results indicate that diabetes mellitus with cardiovascular risk factor clustering favors BM production of hyperreactive platelets with altered protein disulfide isomerase and 78-kDa glucose-regulated protein expression that can contribute to increase thrombotic risk independently of blood glucose levels.
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| 5. |
- Vilahur, Gemma, et al.
(författare)
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Short-term myocardial ischemia induces cardiac modified C-reactive protein expression and proinflammatory gene (cyclo-oxygenase-2, monocyte chemoattractant protein-1, and tissue factor) upregulation in peripheral blood mononuclear cells
- 2009
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 7:3, s. 485-493
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Prompt coronary thrombus resolution, reducing time of ischemia, improves cardiac recovery. The factors triggered by ischemia that contribute to the clinical outcome are not fully known. We hypothesize that unabated inflammation due to cardiac ischemia may be a contributing factor.AIMS: As a proof-of-concept, we evaluated the effect of short-term myocardial ischemia on the local and systemic inflammatory response.METHODS: Pigs underwent either 90-min mid-left anterior descending (LAD) coronary artery balloon occlusion (infarct size 25% +/- 1% left ventricle; 29% heart function deterioration) or a sham-operation procedure. Peri-infarcted and non-ischemic cardiac tissue was obtained for histopathologic, molecular and immunohistochemical analysis of inflammatory markers [interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), modified C-reactive protein (mCRP), and human alveolar macrophage-56 (HAM-56)]. Blood (femoral vein) was withdrawn prior to myocardial infarction (MI) induction (t = 0) and at 30 and 90 min to evaluate: (i) systemic cytokine levels (IL-6, TNF-alpha, CRP); (ii) proinflammatory gene and protein expression in peripheral blood mononuclear cells (PBMCs) of tissue factor (TF), cyclo-oxygenase-2 (Cox-2), monocyte chemoattractant protein-1 (MCP-1), and CRP; and (iii) platelet activation (assessed by perfusion studies and RhoA activation).RESULTS: Short-term ischemia triggered cardiac IL-6 and TNF-alpha expression, recruitment of inflammatory cells, and mCRP expression in infiltrated macrophages (P < 0.05 vs. t = 0 and sham). PBMC mRNA and protein expression of MCP-1, Cox-2 and TF was significantly increased by ischemia, whereas no differences were detected in CRP. Ischemia increased cardiac troponin-I, IL-6 and TNF-alpha systemic levels, and was associated with higher platelet deposition and RhoA activation (P < 0.001 vs. t = 0 and sham).CONCLUSION: Short-term myocardial ischemia, even without atherosclerosis, induces an inflammatory phenotype by inducing local recruitment of macrophages and systemic activation of mononuclear cells, and renders platelets more susceptible to activation.
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