Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0028754 (obesity)
124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with ovarian cancer with clear cell histology often have venous thromboembolism (VTE) even before surgery. In view of the possible association between clear cell histology and VTE in endometrial cancer, we measured the plasma levels of thrombin-antithrombin III complex (TAT) and D-dimer (DD) in the preoperative examinations of a patient with clear cell adenocarcinoma of the endometrium. Plasma TAT and DD were both highly elevated, though the patient had no symptoms of VTE or risk factors such as obesity or diabetes mellitus. Ultrasound Doppler examination and lung perfusion scintigraphy just before surgery revealed a thrombosis in the left popliteal vein and a pulmonary embolism. After implanting an inferior vena cava filter to prevent a fatal embolism of the lung, we performed abdominal total hysterectomy, bilateral salpingo-oophorectomy, and sampling of the pelvic lymph nodes. The VTE gradually disappeared and the plasma levels of TAT and DD returned to normal after surgery. Possibly, the VTE in this patient may have been associated with the clear cell histology.
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PMID:Successful diagnosis of thromboembolism before surgery in a woman with clear cell adenocarcinoma of the endometrium. 1636 52

There is a considerable body of evidence supporting an association between hypertriglyceridaemia, a hypercoagulable state and atherothrombosis. A disorder of triglyceride metabolism is a key feature of the metabolic syndrome that increases risk of both ischaemic heart disease and type 2 diabetes approximately 3-fold. An increasing prevalence of obesity and metabolic syndrome is likely to contribute markedly to the prevalent ischaemic heart in the foreseeable future, and therefore it is crucial to understand mechanisms linking hypertriglyceridaemia and a hypercoagulable state. Activation of platelets and the coagulation cascade are intertwined. VLDL and remnant lipoprotein concentrations are often increased with the metabolic syndrome. These lipoproteins have the capacity to activate platelets and the coagulation pathway, and to support the assembly of the prothrombinase complex. VLDL also upregulates expression of the plasminogen activator inhibitor-1 gene and plasminogen activator inhibitor-1 antigen and activity, a process accompanied by platelet aggregation and clot formation. The surface membrane of activated platelets also supports the assembly and activity of the prothrombinase complex, resulting in further thrombin generation and amplification of the coagulation cascade. Fibrinolysis is also less efficient when thrombin is generated. Thrombin induces thrombin activatable fibrinolysis inhibitor. Thrombin activatable fibrinolysis inhibitor is a carboxypeptidase that cleaves the carboxylic lysine residues on fibrin, thereby abolishing the critical binding site for tPA-plasminogen decreasing plasmin formation. Thus the evidence is supportive of dysregulated coagulation, and impaired fibrinolysis with a predisposition to atherothrombosis, in conditions such as the metabolic syndrome, in which there are increased concentrations of VLDL and remnant lipoproteins. The purpose of this review is to describe the current evidence supporting a procoagulant state induced by VLDL and remnant lipoproteins. The role of these lipoprotein classes in (1) platelet activation; (2) the intrinsic coagulation cascade, and (3) clot formation and fibrinolysis is discussed.
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PMID:Effects of VLDL and remnant particles on platelets. 1687 77

Obesity and its associated metabolic complications can impair the physiologic regulation of fibrinolysis, leading to a hyper coagulable state. We aimed to assess circulating thrombin activatable fibrinolysis inhibitor (TAFI) levels in obese female patients and to test the effects of orlistat-induced weight loss on basal TAFI concentrations. Obese female outpatients age 18 and older, with a body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) of at least 30, were included into the study. Thirteen nonobese (median BMI, 22.60 kg/m(2)) age-matched females were taken as controls. Plasma TAFI levels were measured before orlistat administration and after 6 months of orlistat treatment in the obese group and only one measurement was done in the control group. Twenty-seven obese patients were recruited into the study. The median TAFI level of the control group was 124.00; this value was significantly lower than the basal TAFI level of the obese group (p < 0.001). TAFI levels after orlistat therapy were statistically significantly lower than basal TAFI levels (p < 0.001) in the obese group. Hemostatic abnormalities including TAFI alterations represent a link between obesity and vascular thrombosis. Effective interventions should be considered in improving the obesity-associated prothrombotic risk profile.
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PMID:Decrements in the thrombin activatable fibrinolysis inhibitor (TAFI) levels in association with orlistat treatment in obesity. 1695 92

Clinical examples of coagulation abnormalities may occur from single or multiple abnormailties and include both inherited and acquired defects. Risk factors that further increase clotting include obesity, recent surgery, pregnancy and cancer. Venous thrombosis is a common complication in patients with malignant diseases. The estimates of the prevalence of cancer among patients with venous thrombosis vary from 3 to 18%. Since cancer is a common disorder in the aging population, it may be responsible for a considerable proportion of all cases of thrombosis. The pathogenic mechanisms of thrombosis in the cancer patient involve a complex interaction between the tumor cell, the patient, and the hemostatic system. These include activation of the coagulation system, platelet activation, endothelial damage, indwelling venous access devices, direct effects of chemotherapy/hormonal therapy, and host inflammatory responses. Furthermore, local peritumoral activation of coagulation may have important effects on the biology of cancer. In recent years there have been many new developments in understanding basic mechanisms and optimizing clinical care of thrombosis in cancer patients. Subcutaneous low-molecular weight heparin LMWH) has replaced intravenous unfractionated heparin (UFH) for the initial treatment of thrombosis. In the search for new agents matching the "ideal" anticoagulant profile, a number of different steps in the coagulation cascade have been targeted, including direct thrombin inhibition, and inhibition of factor Xa, factor IXa, the factor VIIa-tissue factor complex and the factor Va-factor VIIIa complex. Such agents could potentially improve thrombosis magement in cancer patients.
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PMID:Cancer and venous thromboembolism. 1735 4

The contribution of obesity to the occurrence of cardiovascular events may not be wholly related to its influence on traditional risk factors. Coagulation and fibrinolysis may also influence cardiovascular risk, but the relationship of adiposity with these processes is unclear. The aim of the present study was to investigate the relationships of BMI (body mass index), waist circumference, hip circumference and WHR (waist-to-hip ratio) with VIIc (factor VII activity), plasma markers of thrombin generation [F1+2 (prothrombin fragment 1+2)], fibrin formation [SF (soluble fibrin)] and fibrin turnover (D-dimer), and PAI-1 (plasminogen activator inhibitor-1; a marker of fibrinolytic inhibitory capacity). The study cohort was 80 healthy postmenopausal women who were not diabetic, current smokers or taking hormone therapy and who had a fasting sample of blood collected. VIIc, F1+2, SF and PAI-1 were all positively correlated with BMI, waist circumference and WHR, whereas D-dimer was positively correlated with waist circumference and WHR, but not BMI. WHR was the strongest correlate of all the markers except for PAI-1, which was most closely related to BMI. Hip circumference became a negative correlate of F1+2 and D-dimer after adjusting for waist circumference. The relationships of WHR with F1+2 and SF, but not with VIIc and D-dimer, were independent of traditional risk factors. The positive association between waist circumference and markers of thrombin generation, fibrin production and fibrin turnover suggests that abdominal adiposity may contribute to atherothrombosis by activating intravascular coagulation. In contrast, a larger hip circumference appears to have a protective affect against coagulation activation.
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PMID:Relationship of waist and hip circumference with coagulation and fibrinolysis in postmenopausal women. 1760 27

It is well documented that elevated levels of PAI-1 in plasma can decrease the fibrinolytic activity in blood with an associated increased risk of thrombus formation. A diverse range of molecules including bacterial lipopolysaccharide (LPS), the inflammatory mediators tumor necrosis factor alpha (TNFalpha) and interleukins, thrombin, transforming growth factor-beta (TGF-beta), and hormones regulate the synthesis of plasma PAI-1. Therefore, it is of clinical importance to restore the fibrinolytic balance. For a drug to be effective in controlling the synthesis of PAI-1, sufficient insight into the signal transduction pathways that control its regulation is desirable, which could serve as logical targets for the development of pharmaceuticals. Some key signaling pathways have been identified with the aid of pharmacological inhibitors, involved in the up-regulation of PAI-1 in context with several diseases, including obesity, insulin resistance, diabetic nephropathy, glomulonephritis, and pulmonary fibrosis. Furthermore, independent of its inhibitory activity PAI-1 mediates interactions with vitronectin (VN) and low density lipoprotein receptor-related protein (LRP) which modifies basic cell behaviors of proliferation, migration, and attachment. Intriguingly, it has been shown that both anti-fibrinolytic and non-fibrinolytic-related functions of PAI-1 may have overlapping roles in many diseases that are poorly understood. Tailoring knock-in mice with site-specific alterations that diminish the inhibitory activity, VN-binding, and LRP-binding activity of PAI-1 are useful tools for manipulation of biochemical properties, in vivo, and evaluating therapeutics.
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PMID:Targeting plasminogen activator inhibitor-1: role in cell signaling and the biology of domain-specific knock-in mice. 1789 50

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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PMID:Obesity promotes injury induced femoral artery thrombosis in mice. 1823 95

Synchronous peri-anastomotic pseudo-aneurysms were discovered in a 65-year-old man 26 years after an aorto-bi-iliac bypass and 11 years after an ileo-femoral bypass. He was a poor surgical candidate owing to his obesity, hostile abdomen, and multiple medical comorbidities. Therefore, a novel hybrid device was designed that was part stent graft with the addition of two 6-mm Dacron limbs for anastomosis onto the superficial femoral and profunda femoris arteries. An unexpected type 2 endoleak developed through the internal iliac artery, which was thought to be occluded. This was successfully treated with a direct injection of bovine thrombin. This was an excellent outcome, and the patient made an uneventful recovery.
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PMID:A novel hybrid device for avoiding redo surgery in synchronous iliac and femoral peri-anastomotic pseudo-aneurysms. 1866 8

Obesity is associated with a high risk of cardiovascular events. Several haemostatic disturbances which could contribute to this increased risk have been described in obesity; nevertheless, the state of coagulation inhibitors has been scarcely studied in these patients. The aim of the present study was to compare activated protein C levels in obese patients and in a control group, and to evaluate the effect of weight loss. In 67 severe or morbid obese patients, an evaluation was performed at baseline and 3 months after diet. The same determinations were performed in 67 healthy volunteers with normal body weight. We also quantified the levels of protein C and prothrombin fragment 1+2. Obese patients showed significantly higher levels of activated protein C, protein C and fragment 1+2. No correlation was found between activated protein C and fragment 1+2 levels in obese patients. After three months of diet, a significant decrease in activated protein C and fragment 1+2 was observed. In conclusion, activated protein C levels are increased in obese patients, but only a minor fraction of this increase may be explained by the higher thrombin generation and C protein levels. Activated protein C levels decrease with weight loss, due in part to a thrombin generation reduction.
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PMID:Activated protein C levels in obesity and weight loss influence. 1883 18

Dabigatran etexilate is a novel, oral reversible direct thrombin inhibitor that is rapidly absorbed and converted to its active form, dabigatran. Dabigatran has been shown to be a potent, competitive, and reversible inhibitor of thrombin, inhibiting both thrombin activity and generation. Studies in healthy volunteers and in patients undergoing orthopedic surgery indicate that dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for coagulation monitoring. In healthy volunteers, peak plasma concentrations of dabigatran are reached approximately 2 hours after oral administration. The elimination half-life is 12 to 14 hours, with clearance predominantly occurring via renal excretion of unchanged drug. Dabigatran is not metabolized by cytochrome P450 isoenzymes, has no interactions with food, and also has a low potential for drug-drug interactions. The pharmacokinetic profile of dabigatran is consistent across a broad range of different patient populations and is unaffected by gender, body weight, ethnic origin, obesity, and mild-to-moderate hepatic impairment. Small differences in dabigatran pharmacokinetics associated with age are attributable to variation in renal function. Dabigatran etexilate produces a predictable pharmacodynamic effect and requires no coagulation monitoring. It has been approved in the European Union (EU) and Canada for prophylaxis of thromboembolism in patients undergoing total knee or hip arthroplasty. Ongoing clinical trials are investigating its use in the treatment of venous thromboembolism, prevention of stroke in patients with nonvalvular atrial fibrillation, and treatment of thromboembolic complications, following acute coronary syndromes.
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PMID:Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. 1969 42


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