Gene/Protein Disease Symptom Drug Enzyme Compound
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The development of thromboses is one of the most common causes of morbidity and mortality in the Western world. The perturbation of haemostasis is the central event in the pathogenesis of all thromboses. Most patients with thromboses have no recognisable associated haemostatic disorders. However, some patients do manifest hereditary hypercoagulable states, which contribute to the development of thromboses as well as other clinical manifestations, such as miscarriages and foetal complications. The major determinants of thrombosis include both environmental influences and genetic factors. Transient or long-lasting environmental influences may play important roles in arterial and venous thromboses. Haemostatic perturbance may also be genetically determined and exert a life-long influence. Specific mutations of genes predisposed to thrombosis, such as deficiency of antithrombin, protein C, or protein S, are found in relatively small number of families. In the absence of genetic deficiencies, thrombosis occurs in the older population, largely within the context of marked environmental influences (such as surgery, obesity, and malignancy). In contrast, familial thrombosis, associated with gene mutation, is associated with a younger age. The general importance of gene polymorphism was established after the recognition of activated protein C resistance (APCR) due to gene polymorphism G1691A in factor V (Factor V Leiden). This single gene defect increases the risk of venous thrombosis, without interaction with other genetic or environmental risk factors. The development of APCR led to many other investigations of gene polymorphism, such as prothrombin 20210, thrombomodulin, factors in the coagulation and fibrinolytic system, glycoproteins of platelet membranes, as well as polymorphism C677T of methylene tetrahydrofolate reductase. The number of potential genetic risk factors for occlusive thrombotic disease has increased significantly. Most of these gene polymorphisms increase the risk of venous thrombosis but there is no strong evidence of their influence as far as arterial thrombosis is concerned.
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PMID:[Role of gene polymorphism in development of thromboses]. 1679 67

Babassu is the popular name of Orbignya phalerata Mart. (Arecaceae). The mesocarp flour obtained from their fruits has been used in Brazil as medicine in the treatment of pains, constipation, obesity, leukemia, rheumatism, ulcerations, tumors, inflammations and venous diseases. The effect of the chronic oral treatment with aqueous extract of babassu mesocarp (500mg/kgday) on the number of platelets, the prothrombin time (PT), the activated partial thromboplastin time (aPTT), the nitric oxide (NO) production and the carrageenin-induced thrombosis was evaluated, using C57Bl/6 mice. The chronic oral treatment with babassu mesocarp induced an anti-thrombotic effect. There was a 88.9% reduction in the necrosis of the tail. This effect seems to be related to an increase in the ability of the macrophage to produce NO and to a slow coagulation process associated to an increase of 12.0 and 13.9% in PT and aPTT, respectively. However, the anti-thrombotic effect seems to be not related to alterations in the number of platelets. It is possible to conclude that the oral treatment with babassu mesocarp has a significant anti-thrombotic effect, which could justify the popular use of babassu mesocarp in the treatment of venous diseases. Meanwhile, this study suggests a potential use of babassu mesocarp as a prophylactic agent to avoid thrombosis events.
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PMID:Anti-thrombotic effect of chronic oral treatment with Orbignya phalerata Mart. 1714 96

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

In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), body weight, height and body mass index (BMI) were evaluated as risk factors. Additionally, the joint effect of obesity together with oral contraceptive use and prothrombotic mutations on the risk of venous thrombosis were analysed. Three-thousand eight-hundred and thirty-four patients with a first venous thrombosis and 4683 control subjects were included, all non-pregnant and without active malignancies. Relative to those with a normal BMI (<25 kg/m(2)), overweight (BMI > or = 25 and BMI < 30 kg/m(2)) increased the risk of venous thrombosis 1.7-fold [odds ratio (OR)(adj(age and sex)) 1.70, 95% confidence interval (CI) 1.55-1.87] and obesity (BMI > or = 30 kg/m(2)) 2.4-fold (OR(adj) 2.44, 95% CI 2.15-2.78). An increase in body weight and body height also individually increased thrombotic risk. Obese women who used oral contraceptives had a 24-fold higher thrombotic risk (OR(adj) 23.78, 95% CI 13.35-42.34) than women with a normal BMI who did not use oral contraceptives. Relative to non-carriers of normal BMI, the joint effect of factor V Leiden and obesity led to a 7.9-fold increased risk (OR(adj) 7.86, 95% CI 4.70-13.15); for prothrombin 20210A this was a 6.6-fold increased risk (OR(adj) 6.58, 95% CI 2.31-18.69). Body height, weight and obesity increase the risk of venous thrombosis, especially obesity in women using oral contraceptives.
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PMID:Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. 1789 5

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

It has been reported that obesity may be associated with activated protein C resistance, which could increase the thrombotic risk in these patients. The aim of our study was to evaluate this parameter in obese patients and controls, as well as the effect of weight loss on this parameter. In 63 severely or morbidly obese patients and in 65 healthy volunteers, an anthropometric and analytical evaluation (activated protein C resistance and prothrombin fragment F1 + 2) was performed at baseline and after 3 months of diet. Obese patients showed higher levels of F1 + 2 than controls, whereas activated protein C sensitivity ratios showed no differences. After weight loss, prothrombin fragment F1 + 2 was reduced, but no differences were found in activated protein C sensitivity. We did not find an activated protein C-resistant phenotype in obese subjects.
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PMID:Obesity and activated protein C resistance. 1912 84

A 59-year-old woman was admitted to our hospital for the treatment of an acute anterior myocardial infarction. She had a history of uncontrolled diabetes mellitus, hypertension, hyperlipidemia, obesity, and smoking. Coronary angiography revealed 90% stenosis with spontaneous dissection in the proximal portion of the left anterior descending artery. At this time, heparin was initiated for the first time. Although direct stenting (Be-stent, 3.0-18 mm) was performed for the culprit lesion, coronary dissection occurred at the left main trunk and additional stenting (Multi Link ZETA stent 3.5-15mm) was performed for the left main trunk. Soon after stenting, repetitive stent thrombosis occurred. Aspiration of the thrombus using an aspiration catheter was ineffective and repetitive angioplasty and intraaortic balloon pumping were required. Although we used 17,000 units of unfractionated heparin during the intervention, the activated coagulation time (ACT) was not prolonged (157 seconds). In the coronary care unit, the ACT and activated partial prothrombin time (aPTT) were not prolonged despite the use of large amounts of heparin (69,000 units in 2 days). Protein-S, protein-C, and hepaplastin testing were within normal limits and heparin-platelet factor IV complex antibody was not detected. In the acute phase, a decrease in the antithrombin III activity (65%) was noted and with administration of argatroban, prolongation of the aPTT was achieved. In the chronic phase, the decrease in antithrombin III activity and heparin resistance had improved spontaneously. It is important to recognize the existence of transient decreases in antithrombin III activity in the acute phase of myocardial infarction.
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PMID:A case of acute myocardial infarction with repetitive stent thrombosis during emergent percutaneous coronary intervention. Transient decrease in antithrombin III activity and heparin resistance. 1924 51

Pulmonary embolus (PE) is not an uncommon cause of sudden death, and forensic pathologists are not unaccustomed to being the first to diagnose a PE in a patient, since they are often fatal. Forensic pathologists are also familiar with the known risk factors for development of PEs, including advanced age, use of oral contraceptives, smoking, obesity, a sedimentary lifestyle, postsurgery or postinjury, pregnancy, certain malignancies, factor V Leiden and prothrombin mutations, and anticardiolipin antibodies. It has recently been shown in the clinical literature that antipsychotic medications are associated with an increased risk of thromboembolic events. Clozapine, a close relative of olanzapine, has been implicated as an independent risk factor for developing a PE. Four cases have been published within the last 2 years questioning whether olanzapine may also be associated with an increased risk for PE. We report 6 cases from the Bexar County Medical Examiner's Office, occurring between 1998 and 2005 where olanzapine may have been a risk factor in the development of, and death from, PE.
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PMID:Olanzapine: a new risk factor for pulmonary embolus? 2151 77

Thrombophilia can be broadly defined as an increased tendency toward hypercoagulability and venous thrombosis. There are several defined risk factors for thrombosis, and these are generally distinguished as either acquired or congenital, although sometimes this distinction is blurred because of interrelationships. Congenital risk factors include deficiencies or defects in natural anticoagulants, such as antithrombin, Protein C and Protein S, and genetic polymorphisms such as prothrombin G20210A and cleavage-resistant forms of factor V (in particular factor V Leiden), that lead to a condition commonly known as activated protein C resistance. Acquired risk factors include antiphospholipid antibodies, detected as lupus anticoagulants and/or anticardiolipin antibodies and/or anti-beta-2-glycoprotein-I antibodies. High levels of clotting factors, dysfibrinogenemia, hyperhomocysteinemia, prolonged immobilization, increasing age, surgery, trauma, cancer, obesity, poor nutrition, pregnancy, oral contraceptives, and hormone replacement therapy comprise just some of the other risk factors. Each of these elements constitutes a component of increased risk, which is compounded when concomitant. There is ongoing debate regarding relative and compound risks, the value of laboratory screening, whom and when to screen for these markers, which tests and methodologies to use, and the form and duration of therapeutic management. The current article explores several important issues primarily from a scientific perspective and predominantly related to laboratory testing. Many of these issues appear to be simply overlooked by some clinicians managing patients with thromboses. In brief, although there is potential significance in testing for various thrombophilia-associated markers, this value is limited and greatly diminishes when inappropriately applied. The application of excessive or inappropriate thrombophilia testing is of particular concern, and the net effect of current worldwide testing trends is likely to be more detrimental than beneficial. In short, it is likely that current generalized testing is simply doing more harm than good, and thus that ordering practice requires scrutiny.
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PMID:Laboratory investigation of thrombophilia: the good, the bad, and the ugly. 2001 36

The F5 G1691A (Factor V Leiden) and F2 G20210A (prothrombin) mutations are linked to an increase in the incidence rate of venous thromboembolism (VTE), but their effects are highly variable. We investigated whether the effects of smoking and obesity might explain this variability. In a case-cohort study including the participants of the Danish Diet, Cancer and Health study, we computed incidence rates and Cox proportional hazard ratios for VTE in individuals with and without the mutations, categorized by weight and tobacco consumption. The sole effect of heavy smoking was 128 extra VTE events per 100,000 person years in individuals with the F5 G1691A mutation versus 59 in individuals without. The sole effect of obesity was 222 extra VTE events per 100,000 person years in individuals with the F5 G1691A mutation, versus 103 in individuals without this mutation; and 705 extra VTE events per 100,000 person years in individuals with the F2 G20210A mutation versus 107 in individuals without this mutation. The F5 G1691A and F2 G20210A mutations conferred increased susceptibility to the unfavourable effects of smoking and obesity on the risk for VTE. Thus, individuals with genetic risk factors for VTE might benefit from maintaining a healthy lifestyle.
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PMID:Genetic susceptibility, smoking, obesity and risk of venous thromboembolism. 2014 80


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