Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcium antagonists have been shown to be superior over other antihypertensive drugs to prevent stroke. Because this cannot be fully attributed to blood pressure lowering effects, other mechanisms seem to play a role. Previously we found in patients with subarachnoid hemorrhage that nimodipine enhances fibrinolytic activity. The purpose of this systematic review was to investigate the fibrinolytic effect of calcium antagonists in general, especially in patients with hypertension. We systematically studied the entire PUBMED and EMBASE database with the search terms 'calcium antagonist' combined with 'fibrinolysis', '(euglobulin) clot lysis time' (ECLT), 'tissue plasminogen activator' (tPA), or 'plasminogen activator inhibitor' (PAI). Twenty-six prospective studies were identified and 22 manuscripts were included (802 investigated individuals). The results show that calcium antagonists significantly increase fibrinolysis as shown by a reduction of the ECLT standardized mean differences (SMD) -0.58 (95% confidence interval (CI) -1.05 to -0.11)) and an increase of tPA activity (SMD 0.73 (95% CI 0.25 to 1.21)). This increase of fibrinolysis is apparently caused by an increase of the tPA antigen level (SMD 0.16 (95% CI -0.05 to 0.37)) and a decrease of the plasminogen activator inhibitor-1 antigen antigen (SMD -0.36 (95% CI -0.74 to 0.02)). A sensitivity analysis showed that dihydropyridines, but not phenylalkylamines, exert a fibrinolytic effect. This fibrinolytic effect is not only seen in patients with subarachnoid hemorrhage but also in hypertensive patients. In conclusions, calcium antagonists increase fibrinolytic activity. This may add to the beneficial pharmacological effect of calcium antagonists to prevent ischemic events in patients with hypertension and subarachnoid hemorrhage.
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PMID:Dihydropyridine calcium antagonists increase fibrinolytic activity: a systematic review. 1719 Oct 79

High plasma levels of homocysteine (Hcy) may predispose to ischemic stroke (IS), but results of previous studies have been conflicting. We decided to determine in IS patients whether their Hcy levels are elevated, whether levels vary at different time points following stroke, whether levels are associated with stroke severity, outcome, recurrence, etiology, infarct volume, or risk factors, and whether levels are correlated with hemostatic factors or C-reactive protein values. We measured plasma Hcy levels in 102 consecutive IS patients on admission and at 1 week, 1 month, and 3 months after stroke and once in 102 control subjects. Hemostatic factors were measured in 55 patients. Compared with controls, plasma Hcy levels in patients were significantly lower on admission but not at later time points, with levels increasing by week and remaining at this level for 3 months. Hcy levels showed a positive correlation with age and a negative correlation with Mini-Mental State Examination (MMSE) scores. Plasma Hcy levels inversely correlated with plasminogen activator inhibitor type-1. Decreased Hcy levels on admission may reflect the strength of the acute-phase response rather than a pathogenetic event. The negative correlation between Hcy levels and MMSE scores is more probably age-related than stroke-related.
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PMID:Serial measurements of plasma homocysteine levels in early and late phases of ischemic stroke. 1759 5

Epidemiological studies have linked levels of particulate matter (PM) in ambient air to cardiovascular mortality and hospitalizations for myocardial infarction (MI) and stroke. Thrombus formation plays a primary role in potentiating acute cardiovascular events, and this study was undertaken to determine whether pulmonary exposure to PM alters hemostasis. PM was collected from the Chapel Hill, NC airshed and was administered to mice by intratracheal instillation at a dose previously shown to exacerbate myocardial ischemia-reperfusion injury. Twenty-four hours after exposure, an increase occurred in the number of circulating platelets and plasma concentrations of fibrinogen and soluble P-selectin. The concentration of tissue factor pathway inhibitor (TFPI) in plasma was decreased, whereas the plasma concentration of plasminogen activator inhibitor (PAI-1) was increased. Consistent with these observations, bleeding time from a tail-tip transection was shortened. These results provide evidence that PM exposure alters hemostasis in otherwise healthy animals and may thereby promote clot formation and impede clot resolution in susceptible individuals. The results also establish definite hemostatic endpoints that can be used to further investigate the effects of dose and particle characteristics on the toxicity of ambient particles.
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PMID:Effect of ambient particulate matter exposure on hemostasis. 1754 51

This study investigated the hypothesis that the insertion/deletion (4G/5G) polymorphism of the plasminogen activator inhibitor type-1 gene affects the risk for ischemic stroke, since results concerning this association have been controversial. We therefore performed a meta-analysis of published data regarding this issue. A comprehensive electronic search was carried out until January 2006. The analysis was performed using random-effects models and meta-regression. Eighteen eligible studies were retrieved (15 case-control studies and three cohort studies). The case-control studies included 3104 cases and 4870 control individuals concerning the contrast of 4G/4G versus remaining genotypes. The 4G pooled allele frequencies in cases and controls were 54.21 and 54.75%, respectively. Overall, the per-allele odds ratio of the 4G allele was 0.98 (95% confidence interval, 0.858-1.121). Regarding genotypes, we derived nonsignificant odds ratios in all contrasts. The subanalysis including the three studies with a prospective design in the 4G/4G versus 5G/5G contrast derived a significant result (relative risk, 0.523; 95% confidence interval, 0.353-0.775), but the estimated effect size was insignificant when cohort and case-control studies were analyzed together (relative risk, 0.848; 95% confidence interval, 0.662-1.087). We failed to demonstrate a significant association between the 4G/5G polymorphism and ischemic stroke under basal conditions. Determination of plasminogen activator inhibitor type-1 function seems of much higher clinical value than determination of the 4G/5G polymorphism. The effect of this genotype on risk of ischemic stroke in acute stressful diseases and the role of cohort studies in genetic epidemiology, however, warrant further investigation.
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PMID:Plasminogen activator inhibitor-1 4G/5G polymorphism and risk of ischemic stroke: a meta-analysis. 1758 26

Thrombophilia-hypofibrinolysis may play an important role in rare premature (< or = age 45 years) arterial occlusive events in atherothrombotic cardiovascular (ATCVD) disease, particularly in normolipidemic patients. Whether thrombophilia-hypofibrinolysis contributed to ATCVD < or = age 45 years was assessed in 78 men and 40 women with 230 ATCVD events (myocardial infarction (MI) [n = 60], coronary artery bypass graft [CABG, n = 33], angioplasty [n = 52], chronic angina [n = 41], ischemic stroke [n = 11], transient ischemic attack [TIA, n = 24], claudication [n = 9]). Cases were compared with healthy normal adult controls (44 men and 76 women). In men, the Factor V Leiden mutation was present in 6/63 (10%) cases versus 0/44 (0%) controls (P = 0.042), Factor VIII was high (>150%) in 16/60 (27%) cases versus 1/42 (2%) controls (P = 0.001), Factor XI was high (>150%) in 9/57 (16%) cases versus 0/42 (0%) controls (P = 0.009), and plasminogen activator inhibitor activity (PAI-Fx) was high (>21.1 U/mL) in 15/63 (24%) cases versus 3/43 (7%) controls (P = 0.023). In women, protein C was low (<73%) in 4/26 (15%) cases versus 0/74 (0%) controls (P = 0.004), and free protein S was low (<66%) in 5/27 (19%) cases versus 2/74 (3%) controls (P = 0.014). In women, Factor XI was high (>150%) in 3/27 (11%) cases versus 1/74 (1%) controls (P = 0.057), and the lupus anticoagulant was present in 9/32 (28%) cases versus 2/51 (4%) controls (P = 0.002). In patients with ATCVD < or = age 45 years, thrombophilias (Factor V Leiden, Factor VIII, Factor XI, protein C and S deficiency, lupus anticoagulant) and hypofibrinolysis (PAI-Fx, Lp[a]) may promote arterial thrombosis, which is synergistic with atherosclerotic endothelial injury.
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PMID:Thrombophilia-hypofibrinolysis and atherothrombotic cardiovascular disease < or = age 45 years. 1765 28

To investigate whether the 4G/5G polymorphism of plasminogen activator inhibitor type 1 (PAI-1) and the -7351 C/T polymorphism of tissue-type plasminogen activator (t-PA) are associated with ischemic stroke, we conducted a case-control study of 190 hospital cases of first-ever ischemic stroke and 185 community-based controls. Our findings do not indicate any association between the PAI-1 or t-PA polymorphisms and risk of stroke. Adding our PAI-1 results to previous studies in a meta-analysis indicated a strong association between this polymorphism and ischemic stroke (P = .0002), with no publication bias but with extreme heterogeneity. There was evidence of stroke association with the PAI-1 4G/5G locus. Strong heterogeneity indicates the need to address other issues, including association with particular stroke subtypes or linkage disequilibrium (LD) with another causative allele. The results also sound a cautionary note that varying LD structure across populations may obscure the relationship with a causative locus, and that future meta-analyses need to look beyond a simple pooled estimate.
J Stroke Cerebrovasc Dis
PMID:The PAI-1 4G/5G gene polymorphism and ischemic stroke: an association study and meta-analysis. 1768 14

Hyperhomocystinemia linked to B-vitamin deficiency is prevalent and associated with increased risk for stroke. While in vitro studies suggest homocysteine directly injures vascular endothelial thrombomodulin (TM), inhibits vonWillebrand factor (vWF) synthesis, and blocks tissue plasminogen activator (t-PA) receptor binding, these mechanisms and their reversibility by vitamin therapy are not established in humans. We investigated the effects of high-dose B-vitamin therapy on endogenous fibrinolysis and endothelial injury markers by randomizing 50 nonvitamin users with prior ischemic stroke to 3 months of treatment with multivitamins either containing folate (5 mg), B6 (100 mg), and B12 (1 mg), or lacking these components. Fasting before noon and post-methionine load plasma total homocysteine (tHcy), t-PA antigen levels, t-PA and plasminogen activator inhibitor (PAI) activities, total vWF antigen, and TM levels were measured before and after vitamin therapy. The primary analysis between treatment groups across time revealed no significant changes (P > .1) for any hematologic variables. However, within-groups analysis showed reductions of 23% in plasma TM (P < .005) and 27% in fasting tHcy levels (P < .0001) and a paradoxical 30% rise in vWF antigen levels (P < .05) after high-dose B-vitamin, treatment with no changes in controls. Pooled data revealed a significant and reproducible 20% to 28% decline in plasma t-PA activity after methionine load (n = 49, P < .02). Our findings demonstrate methionine load lowers plasma t-PA activity by a plasminogen activator inhibitor (PAI-1) independent mechanism that is not attenuated by 3 months of high-dose B-vitamin treatment. While not improving endogenous fibrinolysis profiles, these results provide initial evidence that B-vitamin treatment may selectively alter markers of vascular endothelial injury after stroke.
J Stroke Cerebrovasc Dis
PMID:Effects of vitamin therapy on plasma total homocysteine, endothelial injury markers, and fibrinolysis in stroke patients. 1790 48

South Africa is experiencing a rapid urbanization of its African population characterized by a demographic, nutrition, lifestyle, and health transition. The resultant high prevalence of high cardiovascular disease, in particular of stroke, is of concern. In this narrative review it is suggested that, together with hypertension, changes in the hemostatic system may be one of the major contributors to stroke in this population. It is further suggested that these changes are related to increased fat and animal protein intakes, decreased intakes of total carbohydrate and dietary fiber, as well as persistent suboptimal micronutrient intakes of Africans in transition. The effects of this nutrition transition on plasma fibrinogen, fibrin network structures, plasminogen activator inhibitor 1 activity levels and some other clotting and fibrinolytic factors are discussed. It is concluded that despite indications of present protective mechanisms against the development of coronary heart disease (CHD) in this population the observed changes in diet and hemostatic profiles may eventually lead to a high prevalence of both stroke and CHD in urban black South Africans. It is further suggested that timely nutritional interventions and research of effects thereof on the hemostatic system are urgently needed.
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PMID:Nutrition and hemostasis: a focus on urbanization in South Africa. 1808 Feb 41

Single-gene disorders explain only a minority of stroke cases. Stroke represents a complex trait, which is usually assumed to be polygenic. On this topic, the role of a wide number of candidate genes has been investigated in stroke through association studies, with controversial results. Therefore, it is difficult for the clinician to establish the validity and the level of clinical applicability of the previously reported associations between genetic factors and stroke. This review is an update and an extensive analysis of the more recent association studies conducted in stroke. We evaluated a number of studies on several candidate genes (including F5, F2, FGA/FGB/FGG, F7, F13A1, vWF, F12, SERPINE1, ITGB3/PLA1/PLA2/ITGA2B, ITGA2, GP1BA, ACE, AGT, NOS3, APOE, LPL, PON1, PDE4D, ALOX5AP, MTHFR, MTR, and CBS), providing a final panel of genes and molecular variants. We categorized this panel in relation to the degree of association with stroke, supported by the results of meta-analyses and case-control studies. Our findings could represent a useful tool to address further molecular investigations and to realize more detailed meta-analyses.
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PMID:Genetic polymorphisms for the study of multifactorial stroke. 1842 1

The fibrinolytic system includes a broad spectrum of proteolytic enzymes with physiological and pathophysiological functions in several processes, such as haemostatic balance, tissue remodeling, tumor invasion, angiogenesis and reproduction. The main enzyme of the plasminogen activator system is plasmin, which is responsible for the degradation of fibrin into soluble degradation products. The activation of plasminogen into plasmin is mediated by two types of activators, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). The activity of both is regulated by specific plasminogen activator inhibitors (PAIs). There are 3 types of PAIs described so far but the most important fibrinolytic inhibitor in vivo is PAI type 1 (PAI-1). Among others, the presence of metabolic syndrome and the -675 4G/5G promoter polymorphism are known to be modulators of PAI-1 levels. Besides their fibrinolytic profile, plasmin and plasminogen activators are implicated in tissue proliferation and cellular adhesion, as they can proteolytically degrade the extracellular matrix and regulate the activation of both growth factors and matrix metalloproteinases. By all these means, the fibrinolytic system is also involved in physiological processes, and in pathological situations such as thrombosis, arteriosclerosis, endometriosis and cancer. PAI 1 has been studied in different settings with thrombotic pathophysiology, such as coronary artery disease and ischaemic stroke. Controversial results have been published and concerns about study designs or presence of confounders have been claimed to be responsible of them. Recently, its involvement in adverse thrombotic events related to the modern drug-eluting coronary stents has renewed the interest of its study. PAI-1 also plays an important role in signal transduction, cell adherence, and migration. Indeed, studies of several types of cancers, including breast cancer, have shown that increased uPA and PAI-1 levels are associated with aggressive tumor behavior and poor prognosis. Endometriosis is defined by the presence of endometrial glands and stroma outside the uterus with marked ability to attach and invade the peritoneum. It is one of the most frequent benign gynecological diseases that affect women with pelvic pain or infertility during their reproductive age. Immune system disorders, genetic predisposition, altered peritoneal environment and endometrial alterations are believed to increase the susceptibility to endometriosis. The plasminogen activator system may be involved in this process, where local extracellular proteolysis plays a crucial role. Altered expression of several components of the fibrinolytic system in both eutopic and ectopic endometrium and peritoneal fluid of women with the disease has been implicated not only in the onset, but also in the progression of the endometriotic lesions.
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PMID:Fibrinolysis: the key to new pathogenetic mechanisms. 1847


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