Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of hypothyroidism on haemostasis is controversial; both hypocoagulable and hypercoagulable states have been reported. Hypothyroidism has been associated with atherosclerosis; a hypercoagulable state in addition might represent a risk factor for thromboembolic disease. The aim of the present study was to investigate the markers of endogenous coagulation and vascular endothelial cell function and to evaluate the relationship between serum lipid profile, thyroid hormones and haemostatic parameters in hypothyroid patients. We investigated various haemostatic parameters in 20 patients with hypothyroidism and compared them with 20 euthyroid controls. The relationship between serum thyroid hormones and the haemostatic parameters was examined. The plasma levels of fibrinogen, AT III and PAI-1 were significantly increased in hypothyroid patients compared with the control group, whereas factors VIII and X activity was decreased. We showed that free T3 levels correlated with factor IX activity. Free T4, FT3 and TSH did not correlate with fibrinogen, vWF, AT III, t-PA, or PAI-1. aPTT correlated inversely with t-PA activity and positively with protein C activity. Anti-Tg correlated inversely with FV. There was a positive correlation between triglycerides and protein C. Protein S correlated inversely with high density lipoprotein cholesterol. We found a hypofibrinolytic state in patients with hypothyroidism. Our results suggest that the risk of developing thrombosis and ultimately myocardial infarction via high PAI-1 levels may be increased in patients with hypothyroidism, a result in line with recent epidemiological data. However, thyroid hormones may play a role at different levels of the complex haemostatic system.
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PMID:Blood coagulation and fibrinolytic activity in hypothyroidism. 1266 86

Thromboangiitis obliterans (TAO) and antiphospholipid syndrome (APS) share the clinical characteristics of arterial thrombosis and recurrent thrombophlebitis. Although the association of anticardiolipin antibodies (aCLa) and TAO has been previously recognized, the prevalence and the clinical impact of this association remains unclear. aCLa were measured by double ELISA in patients with TAO (n = 47), premature atherosclerosis (pASO) (n=48) and otherwise healthy individuals (n = 48). Antibody status was then compared to clinical presentation and outcomes in patients meeting the diagnostic criteria for TAO. The prevalence of aCLa was significantly higher in patients with TAO (36%) compared to either pASO (8%; p = 0.01) or healthy individuals (2%; p < 0.001). Patients with TAO and a high antibody titer tended to be younger and suffer a significantly higher rate of major amputations compared to those without the antibody (100% versus 17%; p = 0.003). Clinical features of TAO not significantly altered by the presence of aCLa included upper limb involvement, digital necrosis, superficial thrombophlebitis (or deep venous thrombosis). Protein C, protein S, and anti-thrombin III were normal in all individuals. TAO is associated with an increased prevalence of aCLa. The presence of a high antibody titer in these patients is associated with increased morbidity, including major limb amputation. In patients meeting the diagnostic criteria for TAO, screening for aCLa should be considered. Although attractive, the efficacy of chronic anticoagulation in this setting remains to be proven.
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PMID:Antiphospholipid antibodies in thromboangiitis obliterans. 1271 Aug 39

Platelets play a major role in thrombosis and hemostasis by binding the sub-endothelial matrix at sites of injury, but also participate in vascular pathologies such as atherosclerosis. Recently, junctional proteins like PECAM-I and JAM-family members have been recovered from platelets, therefore we examined what other junctional molecules may be present in platelets. We observed immunoreactivity for APC (147 kD), beta-catenin (92 kD), E-cadherin (120 and 84 kD) and occludin (70-85 kD) by western blotting. Additionally, beta-catenin, pan-reactive cadherins, E-cadherin and occludin were seen to partition with the triton insoluble cytoskeleton in platelets. These proteins were also found in a megakaryocyte (platelet precursor) line, MEG-01. Our data suggest that conventional junctional molecules are expressed in platelets and could possibly participate in aggregation, clot formation and wound healing.
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PMID:Expression of junctional proteins in human platelets. 1285 Aug 34

Activated protein C (APC) serves as an 'on demand' anticoagulant. Defects in the APC anticoagulant pathway are underlying risk factors for the development of venous and arterial thrombosis. APC has recently been shown to significantly reduce mortality in patients with severe sepsis, presumably by virtue of its ability to down-regulate coagulation as well as inflammation. Our objective was to develop an assay that, for the first time, permits rapid detection of plasma APC. This assay will expedite studies of APC in a variety of vascular disease states including sepsis, severe atherosclerosis, diabetes, and vasculitis. By generating a highly APC-specific monoclonal antibody (HAPC 1555), we have developed an assay that, for the first time, allows rapid detection of plasma APC. The Kd measured for the interaction between APC and HAPC 1555 based on BIAcore studies and binding to immobilized HAPC on microtiter plates is 6.2 +/- 0.9 and 8.8 +/- 1.0 nmol L(-1), respectively. The interaction between HAPC 1555 and APC is Ca2+-dependent, with a Ca2+ concentration of 313 +/- 48 micro mol L(-1) required for half maximal binding. HAPC 1555 interferes with APC-mediated inactivation of factor (F)Va in the presence and absence of phospholipids, suggesting that HAPC 1555 binds to the FVa binding domain of APC. When HAPC 1555 was used in an APC enzyme capture assay, therapeutic APC levels could be measured in 1.5 h, and physiologic levels of APC could be detected between 3 and 19 h. APC levels were also shown to vary markedly in patients with severe sepsis. The rapidity of our APC assay makes APC detection in patients practical clinically. This assay will expedite studies of APC in a variety of vascular disease states including sepsis, severe atherosclerosis, diabetes, and vasculitis.
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PMID:A monoclonal antibody against activated protein C allows rapid detection of activated protein C in plasma and reveals a calcium ion dependent epitope involved in factor Va inactivation. 1499 20

Systemic infection by various pathogens interacts with the endothelium and may result in altered coagulation, vasculitis and atherosclerosis. Endothelium plays a role in the initiation and regulation of both coagulation and fibrinolysis. Exposure of endothelial cells may lead to rapid activation of coagulation via tissue factor (TF) expression and the loss of anticoagulant properties by impairment of antithrombin III, TF pathway inhibitor (TFPI) and the protein C system. Endothelial-derived plasminogen activator inhibitor (PAI) is essential for the regulation of fibrinolysis and impaired endothelial function leads to imbalance in fibrinolysis, resulting in a procoagulant state. The interaction between inflammation and coagulation, soluble adhesion molecules and circulation endothelial cells is important in the pathogenesis of an unbalanced haemostatic system. Rather than being a unidirectional relationship, the interaction between inflammation and coagulation appears to be significant. In the crosstalk, the endothelium is playing a pivotal role.
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PMID:Infections and endothelial cells. 1452 5

Many risk factors for cardiovascular disease generate superoxide in the blood vessels and thereby impair endothelial function. To emphasize the critical role of oxygen radicals, this is a 'radical view' of those risk factors. It will be useful to organize risk factors into a 'superfamily', with consideration of mediators, mechanisms, and target organs. Studies are summarized which suggest that, in parallel with the impairment of endothelial vasomotor function, the thrombin/thrombomodulin/activated protein C anticoagulant mechanism, which requires endothelial thrombomodulin, is also impaired by atherosclerosis and improves during regression of atherosclerosis. Impairment of the anticoagulant mechanism may contribute to thrombosis in atherosclerotic arteries, and improvement of the anticoagulant mechanism during regression of atherosclerosis may reduce the risk of cardiovascular events.
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PMID:Mikamo Lecture: a radical view on the 'superfamily' of cardiovascular risk factors. 1457 9

Postmenopausal hormone replacement therapy (HRT), such as estrogen with a progestin (E+P), is associated with an increased risk of myocardial infarction (MI), stroke, and venous thrombosis. Subgroups of susceptible women for these clinical outcomes have not been clearly identified, although women with a prior history of venous thrombosis and women with factor V Leiden are at higher risk of venous thrombosis on HRT than others. Effects of HRT on atherosclerosis, coagulation, and inflammation have been investigated, and might improve our understanding of the pathogenesis of this drug effect. In 2 trials E+P did not alter the progression of coronary atherosclerosis, while in a third trial unopposed estradiol retarded atherosclerosis progression in the carotid arteries. HRT is associated with an increase in high-sensitivity C-reactive protein (CRP), an inflammation marker associated with arterial disease risk, and an increase in activated protein C resistance, the biochemical defect associated with factor V Leiden. Given recent data, the only current indication for E+P is the short-term treatment of symptoms of estrogen deficiency, such as hot flashes. Testing for coagulation disorders or inflammatory factors, such as factor V Leiden or CRP, for use in decision-making about HRT use would be premature in unselected patients. Further research is needed to identify pathophysiological mechanisms of vascular harm from these hormones.
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PMID:Hormone therapies and vascular outcomes: who is at risk? 1476 Feb 20

Resistance to activated protein C (APC) has been demonstrated to be a risk factor for venous thromboembolism, but it is not known whether this phenotype is consistent over time. We reinvestigated 2580 subjects from the Vicenza Thrombophilia and Atherosclerosis (VITA) Project to evaluate the prevalence of a consistent APC resistance phenotype in the population. Among the 433 subjects with an APC resistance at first visit, the phenotype was confirmed in all the 74 factor V (FV) Leiden carriers and in 124 of 359 FV Leiden negative subjects (34%). The prevalence of a confirmed phenotype, not associated with FV Leiden, was 4.8% in our population. In a subgroup of subjects previously investigated for heritability of the APC resistance, we confirmed the APC resistance phenotype in seven of 39 (17.9%) subjects with an APC resistant sibling but only in 20 of 408 (4.9%) subjects without a sibling with the same phenotype (P = 0.005). Among the 124 FV Leiden negative subjects with a persistent APC resistance phenotype, 40 (32%) had a plasma factor VIII coagulant activity level above 150 IU/dl and eight (6.4%) were carriers of the G20210A prothrombin allele. APC resistance not due to FV Leiden is a frequent and consistent phenotype in the general population, with a possibly strong genetic influence.
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PMID:Intraindividual consistency of the activated protein C resistance phenotype. 1525 14

Intravascular fibrin deposition is believed to play an important role in the development of intimal hyperplasia, which is a hallmark of several human vascular disorders, including atherosclerosis and restenosis after balloon angioplasty. Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor or tissue- and urinary-type plasminogen activator, plays a key role in fibrin homeostasis by controlling plasmin formation. PAI-1 may also modulate vascular pathology via alternative pathways, such as inhibiting activated protein C and altering interactions between vascular smooth muscle cells and the extracellular matrix. The diverse functional profile of PAI-1 likely accounts for the variation observed in its impact on intimal hyperplasia in different disease models. This review examines recent studies addressing the vascular function of PAI-1, and those assessing the role of fibrin as a downstream mediator of PAI-1's effects.
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PMID:Plasminogen activator inhibitor 1, fibrin, and the vascular response to injury. 1526 92

The role of genetic susceptibility to coronary artery disease (CAD) seems to be quite important in young patients. In the last years the attention has been focused on polymorphisms influencing some biological functions (coagulation and fibrinolysis, platelets, vascular function, lipid metabolism, inflammation). The study of prothrombotic polymorphisms has kindled a deep interest. The role of atherosclerosis and thrombosis is different in the different ages. In all the studies we examined, the polymorphism G20210A in the prothrombin gene was associated with an increased risk of acute myocardial infarction (AMI) in young people, especially when other risk factors were present. Contradictory results have been found in the studies on Factor V Leiden: according to many authors the activated protein C resistance (APCR) is associated with an increased risk of AMI only in smokers, above all if women. On the other hand, some polymorphisms of the Factor VII gene seem to be protective. Young AMI could be also caused by a reduction of the fibrinolytic activity, as it was found when the allele 4G in the promoter of plasminogen activator inhibitor (PAI) gene is present. The attention has also been focused on the effects of variations in genes that influence platelet functions. According to a metanalysis of studies published up to 1999, there is no association between the polymorphism PlA1/A2 of the GP IIIa gene and young AMI, whereas there is doubt about the role of the polymorphism in the GP IIb e GP Ib genes. Moreover, it seems to be present an association with the polymorphisms in the thrombopoietin gene (C4830A and A5713G). Also the role of some genes coding for proteins influencing the vascular functions has been valued. Few studies were performed on genetics of the renin-angiotensin-aldosterone system and the results are insufficient and contradictory, such as those about the association between the polymorphism G894T in the eNOS gene or the polymorphism C677T in the MTHFR gene and young AMI. Genes coding for proteins involved in the lipid metabolism have been closely examined. Many polymorphisms were discovered in the Apo B gene: the variant C-516T was found to be associated with increased LDL levels, whereas the results about the association between this and other polymorphisms in the same gene (I/D of LAL sequence, PvuII, MspI, Asp4311Ser) and young AMI are discordant. On the other hand, the variant e4 of the ApoE gene was associated with an increased risk of AMI at young age in many works. In the last years, a particular interest has kindled the study of the relationship between inflammation, atherosclerosis and CAD. Even if the studies performed are few, it was found an association between young AMI and polymorphism C-260T in the CD14 gene, between coronarics atherosclerosis and polymorphism A516C in the E Selectin gene or polymorphisms Leu125Val and Ser563Asn in the PECAM1 gene.
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PMID:Genetic risk factors in myocardial infarction at young age. 1528 79


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