thromboplastin and Stroke

The term microparticle (MP) identifies a heterogeneous population of vesicles playing a relevant role in the pathogenesis of vascular diseases, cancer and metabolic diseases such as diabetes mellitus. MPs are released by virtually all cell types by shedding during cell growth, proliferation, activation, apoptosis or senescence processes. MPs, in particular platelet- and endothelial-derived MPs (PMPs and EMPs), are increased in a wide range of thrombotic disorders, with an interesting relationship between their levels and disease pathophysiology, activity or progression. EMP plasma levels have been associated with several cardiovascular diseases and risk factors. PMPs are also shown to be involved in the progressive formation of atherosclerotic plaque and development of arterial thrombosis, especially in diabetic patients. Indeed, diabetes is characterised by an increased procoagulant state and by a hyperreactive platelet phenotype, with enhanced adhesion, aggregation, and activation. Elevated MP levels, such as TF+ MPs, have been shown to be one of the procoagulant determinants in patients with type 2 diabetes mellitus. Atherosclerotic plaque constitutes an opulent source of sequestered MPs, called "plaque" MPs. Otherwise, circulating MPs represent a TF reservoir, named "blood-borne" TF, challenging the dogma that TF is a constitutive protein expressed in minute amounts. "Blood-borne" TF is mainly harboured by PMPs, and it can be trapped within the developing thrombus. MP detection and enumeration by polychromatic flow cytometry (PFC) have opened interesting perspectives in clinical settings, particularly for the evaluation of MP numbers and phenotypes as independent marker of cardiovascular risk, disease and outcome in diabetic patients.

Topics: Acute Coronary Syndrome; Atherosclerosis; Biomarkers; Blood Platelets; Cardiovascular Diseases; Cell-Derived Microparticles; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Endothelial Cells; Humans; Plaque, Atherosclerotic; Risk Factors; Stroke; Thromboplastin

Tissue factor is the primary initiator of the coagulation cascade. Formation of the TF:FVIIa complex activates both FX and FIX, with subsequent thrombin generation, fibrin deposition and activation of platelets. In addition to playing important role in hemostasis and thrombosis, TF and downstream coagulation proteases can mediate intracellular signaling via activation of protease-activated receptors (PARs). Maintaining hemostasis in the brain is of utmost importance: bleeding or thrombosis within this organ can lead to significant morbidity and mortality. Both TF and PARs are widely expressed within the CNS, with TF expressed predominantly by astrocytes and PARs expressed in multiple cell types including astrocytes, neurons, microglia and oligodendrocytes [1-4]. PARs activation can result in either neuronal survival or death and link the coagulation system with the inflammatory response. In this brief review we summarize the contribution of the coagulation system to brain hemostasis as well as to the pathophysiology of stroke and multiple sclerosis.

Topics: Animals; Astrocytes; Autoimmunity; Blood Coagulation; Brain; Hemorrhage; Hemostasis; Humans; Inflammation; Multiple Sclerosis; Stroke; Thromboplastin

An enhanced risk of cardiovascular mortality has been observed after pneumonia. Epidemiological studies have shown that respiratory tract infections are associated with an increased risk of thrombotic-related vascular disease such as myocardial infarction, ischemic stroke and venous thrombosis. Myocardial infarction and stroke have been detected essentially in the early phase of the disease (i.e. within 48 h from hospital admission), with an incidence ranging from as low as 1% to as high as 11%. Age, previous cardiovascular events and high pneumonia severity index were independent predictors of myocardial infarction; clinical predictors of stroke were not identified. Deep venous thrombosis and pulmonary embolism may also occur after pneumonia but incidence and clinical predictors must be defined. The biological plausibility of such an association may be deduced by experimental and clinical studies, showing that lung infection is complicated by platelet aggregation and clotting system activation, as documented by up-regulation of tissue factor and down-regulation of activated protein C. The effect of antithrombotic drugs has been examined in experimental and clinical studies but results are still inconclusive.

Topics: Age Factors; Anticoagulants; Blood Coagulation; Clinical Trials as Topic; Fibrinolytic Agents; Humans; Myocardial Infarction; Patient Admission; Platelet Aggregation; Pneumonia; Protein C; Research Design; Stroke; Thromboplastin; Thrombosis; Treatment Outcome; Vascular Diseases

Anticoagulants are effective at preventing and treating thrombosis, but can cause bleeding. For decades, vitamin K antagonists (VKAs) have been the only available oral anticoagulants. The development of non-VKA oral anticoagulants (NOACs), which inhibit either factor Xa or thrombin stoichiometrically, has provided alternatives to VKAs for several indications. The results of recent large-scale randomised controlled trials comparing NOACs with VKAs for the prevention of stroke in patients with non-valvular atrial fibrillation (AF) have produced some unexpected results. As a group, NOACs showed similar efficacy as warfarin, but a reduced risk of major bleeding. The reduction in bleeding with NOACs was greatest with intracranial hemorrhage. In contrast, the relative risk of gastro-intestinal bleeding was increased with some NOACs. In this review, we explore the potential mechanisms as well as the implications of these organ-specific bleeding patterns.

Topics: Anticoagulants; Atrial Fibrillation; Blood Coagulation Factors; Endothelium, Vascular; Factor Xa Inhibitors; Gastrointestinal Hemorrhage; Hemorrhage; Humans; International Normalized Ratio; Intestinal Absorption; Intracranial Hemorrhages; Organ Specificity; Randomized Controlled Trials as Topic; Stroke; Thrombophilia; Thromboplastin; Vitamin K; Warfarin

Topics: Animals; Antithrombin III; Blood Coagulation; Brain; Cerebral Hemorrhage; Disease Models, Animal; Epoprostenol; Hemostasis; Humans; Microcirculation; Nitric Oxide; Plasminogen Activator Inhibitor 1; Protease Nexins; Stroke; Thrombomodulin; Thromboplastin; Thrombosis; Tissue Plasminogen Activator

The interaction of coagulation factors with the perivascular environment affects the development of disease in ways that extend beyond their traditional roles in the acute hemostatic cascade. Key molecular players of the coagulation cascade like tissue factor, thrombin, and fibrinogen are epidemiologically and mechanistically linked with diseases with an inflammatory component. Moreover, the identification of novel molecular mechanisms linking coagulation and inflammation has highlighted factors of the coagulation cascade as new targets for therapeutic intervention in a wide range of inflammatory human diseases. In particular, a proinflammatory role for fibrinogen has been reported in vascular wall disease, stroke, spinal cord injury, brain trauma, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, bacterial infection, colitis, lung and kidney fibrosis, Duchenne muscular dystrophy, and several types of cancer. Genetic and pharmacologic studies have unraveled pivotal roles for fibrinogen in determining the extent of local or systemic inflammation. As cellular and molecular mechanisms for fibrinogen functions in tissues are identified, the role of fibrinogen is evolving from a marker of vascular rapture to a multi-faceted signaling molecule with a wide spectrum of functions that can tip the balance between hemostasis and thrombosis, coagulation and fibrosis, protection from infection and extensive inflammation, and eventually life and death. This review will discuss some of the main molecular links between coagulation and inflammation and will focus on the role of fibrinogen in inflammatory disease highlighting its unique structural properties, cellular targets, and signal transduction pathways that make it a potent proinflammatory mediator and a potential therapeutic target.

Topics: Alzheimer Disease; Animals; Arthritis, Rheumatoid; Bacterial Infections; Blood Coagulation; Brain Injuries; Colitis; Fibrinogen; Humans; Inflammation; Kidney Diseases; Multiple Sclerosis; Muscular Dystrophy, Duchenne; Neoplasms; Pulmonary Fibrosis; Spinal Cord Injuries; Stroke; Thrombin; Thromboplastin; Vascular Diseases

The exposure of tissue factor (TF) to blood flow is the initial step in the coagulation process and plays an important role in thrombogenesis. We investigated the role of genetic polymorphisms and haplotypes of the TF gene in the risk of ischemic vascular disease.. Four hundred and twenty-two Italian patients with juvenile myocardial infarction (MI) and 434 controls, 808 US cases with MI and 1005 controls, 267 Italian cases with juvenile ischemic stroke and 209 controls and 148 German cases with juvenile ischemic stroke and 191 controls were studied. rs1361600, rs3917629 (rs3354 in the US population), rs1324214 and rs3917639 Tag single nucleotide polymorphisms were genotyped. Additionally, a meta-analysis of all previous studies on TF loci and the risk of ischemic coronary disease (ICD) was performed.. After multivariable analysis none of the SNPs, major SNP haplotypes or haplotype-pairs showed any consistent association with MI. Pooled meta-analysis of six studies also suggested that TF polymorphisms are not associated with CHD. A significant, independent association between SNP rs1324214 (C/T) and juvenile stroke was found in Italian and German populations (OR for TT homozygotes = 0.47, 95% CI 0.24-0.92, in combined analysis). Pooled analysis also showed a significant association for haplotype H3 (OR = 0.76, 95% CI 0.57-1.00) and haplotype-pair H3-H3 (OR = 0.43, 95% CI 0.20-0.92).. TF genetic variations were associated with the risk of ischemic stroke at young age, but did not affect ischemic coronary disease.

Topics: Adult; Case-Control Studies; Female; Genetic Variation; Haplotypes; Homozygote; Humans; Interleukin-1beta; Ischemia; Italy; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Risk; Stroke; Thromboplastin

The evidence gathered in clinical trials of low molecular weight heparins (LMWHs) or with unfractionated heparin (UH) given subcutaneously at low or medium doses to patients with acute stroke cannot be extrapolated to the insufficiently tested effects of intravenous, weight-adjusted UH. Recent small studies have provided encouraging results but are potentially confounded and deserve confirmation in larger randomized controlled trials. In accordance with the current understanding of the biology of acute ischemic stroke and the pharmacology of UH, the new randomized controlled trials on heparin should give appropriate credit to the importance of a short therapeutic window, adequate dose adjustment of the drug, intravenous administration, and close monitoring of biological effects. UH is an orphan drug and only an academic driven trial would be able to face such an enterprise. Meanwhile, recommendations against the value of "early" anticoagulation with full dose of weight adjusted UH in the setting of acute ischemic stroke are not based on direct evidence but on extrapolations.

Topics: Acute Disease; Anticoagulants; Brain Ischemia; Fibrinolytic Agents; Heparin; Humans; Stroke; Thromboplastin

Atrial fibrillation (AF) is the commonest sustained cardiac arrhythmia, which confers a high risk of mortality and morbidity from stroke and thromboembolism. The precise mechanisms by which AF causes thromboembolism and subsequent cerebrovascular events have attracted much research interest, and are yet to be fully elucidated. Nonetheless, it is well recognised that AF fulfils Virchow's triad for thrombogenesis, with abnormal flow conditions with loss of atrial contractility and an irregularly irregular cardiac output, (i. e. flow abnormalities), as well as structural heart disease with endocardial damage (i. e. abnormal vessel wall) and abnormalities in platelet and haemostatic variables (i. e. abnormal blood constituents). This review is to summarise the evidence so far for the role of coagulation and fibrinolytic components, platelets and inflammation (that is blood constituents) in the generation of the prothrombotic state in AF, with particular focus on the endothelium and AF.

Topics: Atrial Fibrillation; Cyclic GMP; Endothelium, Vascular; Fibrinolysis; Hemostasis; Humans; Nitric Oxide; Stroke; Thromboembolism; Thromboplastin; von Willebrand Factor

Thrombus formation on a disrupted atherosclerotic plaque is a threatening event that leads to vessel occlusion and acute ischemia. In this current perspective, we present evidence for apoptosis as a major determinant of the thrombogenicity of the plaque lipid core and a potential contributor to plaque erosion and associated thrombosis. Moreover, apoptosis may directly affect blood thrombogenicity through the release of apoptotic cells and microparticles into the bloodstream.

Topics: Angina, Unstable; Animals; Apoptosis; Arteriosclerosis; Blood Coagulation; Embolism; Humans; Inflammation; Myocardial Infarction; Phosphatidylserines; Stroke; Thromboplastin; Thrombosis

Cancer and stroke, which are known to be associated with one another, are the most common causes of death in the elderly. However, the pathomechanisms that lead to stroke in cancer patients are not well known. Circulating extracellular vesicles (EVs) play a role in cancer-associated thrombosis and tumor progression. Therefore, we hypothesized that cancer cell-derived EVs cause cancer-related coagulopathy resulting in ischemic stroke.. Serum levels of D-dimer and EVs expressing markers for cancer cells (epithelial cell adhesion molecule [CD326]), tissue factor (TF [CD142]), endothelial cells (CD31+CD42b-), and platelets (CD62P) were measured using flow cytometry in (a) 155 patients with ischemic stroke and active cancer (116 - cancer-related, 39 - conventional stroke mechanisms), (b) 25 patients with ischemic stroke without cancer, (c) 32 cancer patients without stroke, and (d) 101 healthy subjects.. The levels of cancer cell-derived EVs correlated with the levels of D-dimer and TF+ EVs. The levels of cancer cell-derived EVs (CD326+ and CD326+CD142+) were higher in cancer-related stroke than in other groups (P<0.05 in all the cases). Path analysis showed that cancer cell-derived EVs are related to stroke via coagulopathy as measured by D-dimer levels. Poor correlation was observed between TF+ EV and D-dimer, and path analysis demonstrated that cancer cell-derived EVs may cause cancer-related coagulopathy independent of the levels of TF+ EVs.. Our findings suggest that cancer cell-derived EVs mediate coagulopathy resulting in ischemic stroke via TF-independent mechanisms.

Topics: Aged; Disseminated Intravascular Coagulation; Extracellular Vesicles; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Neoplasms; Stroke; Thromboplastin

Tissue factor (TF) expression is increased in inflammatory atherosclerotic plaques and has been related to their thrombogenicity. Blood-borne TF has been also demonstrated to contribute to thrombogenesis. However, few studies have evaluated the association of circulating levels of TF with stroke. We investigated the association of baseline circulating levels of TF with stroke events occurred in the European Prospective Investigation into Cancer and Nutrition-Italy cohort.. Using a nested case-cohort design, a center-stratified random sample of 839 subjects (66% women; age range, 35-71 years) was selected as subcohort and compared with 292 strokes in a mean follow-up of 9 years. Blood samples were collected at baseline in citrate, plasma was stored in liquid nitrogen and TF was measured by ELISA (IMUBIND, TF ELISA, Instrumentation Laboratory, Milan, Italy). The odd ratios and 95% confidence intervals, adjusted by relevant confounders (covariates of TF) and stratified by center, were estimated by a Cox regression model using Prentice method.. Individuals in the highest compared with the lowest quartile of TF plasma levels had significantly increased risk of stroke (odds ratioIVvsI quartile, 2.01; 95% confidence interval, 1.25-3.23). The association was independent from several potential confounders (odds ratioIVvsI quartile, 1.91; 95% confidence interval, 1.15-3.19). No differences were observed between men and women. The increase in risk was restricted to ischemic strokes (odds ratioIVvsI quartile, 2.13; 95% confidence interval, 1.10-4.12; fully adjusted model), whereas high levels of TF were not associated with the risk of hemorrhagic stroke (odds ratioIVvsI quartile, 1.12; 95% confidence interval, 0.49-2.55; fully adjusted model).. Our data provide evidence that elevated levels of circulating TF are potential risk factors for ischemic strokes.

Topics: Adult; Aged; Brain Ischemia; Female; Follow-Up Studies; Humans; Intracranial Hemorrhages; Italy; Male; Middle Aged; Prospective Studies; Risk Factors; Stroke; Thromboplastin

Stroke is the third leading cause of death and an important cause of longterm disability. Up to 10% of stroke patients is younger than 45 years old. In the present study we measured and compared TF and TFPI concentrations in 50 ischemic stroke patients up to the age of fifty and in 30 control subjects matched for age. TF concentration was significantly higher in ischemic stroke patients, TFPI concentration did not differ compared to controls. No relationship was established between TF and TFPI in relation to clinical subtypes of stroke, sex, smoking, plasma cholesterol level, hypertension, previous stroke.

Topics: Adult; Biomarkers; Female; Humans; Lipoproteins; Male; Middle Aged; Risk Factors; Stroke; Thromboplastin

Tissue factor (TF) and activated factor XI (FXIa) have been associated with acute coronary syndrome, ischemic stroke and venous thromboembolism. Their predictive value in stable coronary artery disease (CAD) is unclear. We investigated whether active TF and FXIa were associated with clinical outcomes in CAD patients in long-term observation.. In 124 stable patients with multivessel CAD, we assessed the presence of circulating, active TF and FXIa by measuring a response of thrombin generation to respective inhibitory antibodies. We recorded the composite endpoint of myocardial infarction (MI), stroke, systemic thromboembolism and cardiovascular death during follow-up (median 106 months, interquartile range 95-119).. Circulating FXIa and active TF were detected in 40% and 20.8% of the 120 patients (aged 65.0 [57.0-70.3] years, men, 78.3%), who completed follow-up. The composite endpoint occurred more frequently in patients with detectable active TF and FXIa present at baseline (hazard ratio [HR] 4.02, 95% confidence interval [CI] 2.26-7.17, p < 0.001 and HR 6.21, 95% CI 3.40-11.40, p < 0.001, respectively). On multivariate analysis FXIa, but not active TF, was an independent predictor of the composite endpoint, as well as MI, stroke/systemic thromboembolism, and cardiovascular death, when analyzed separately.. To our knowledge, this study is the first to show that circulating FXIa predicts arterial thromboembolic events in advanced CAD, supporting a growing interest in FXIa inhibitors as novel antithrombotic agents.

Topics: Aged; Blood Coagulation Tests; Coronary Artery Disease; Factor IX; Factor XIa; Female; Humans; Male; Middle Aged; Myocardial Infarction; Risk Factors; Stroke; Thromboembolism; Thromboplastin

Smoking increases the risk of atherothrombotic events. Tissue factor (TF) mainly expressed on monocytes plays an important role in thrombosis and atherosclerosis. Metabolic syndrome (MetS) is being increasingly recognized as a major atherothrombotic risk factor, but the effects of smoking on monocyte TF activity (MTFA), carotid atherosclerosis estimated on carotid intima-media thickness (CIMT), and long-term prognosis in MetS remain unclear.Methods and Results:A total of 301 MetS patients lacking any known cardiovascular disease were prospectively investigated and classified into 4 groups according to smoking status at entry and at 12 months as follows: never smokers, past smokers, quitters, and persistent smokers. Peripheral blood mononuclear cells (PBMC) were isolated, and MTFA was measured using a coagulation assay. Linear trends for higher baseline MTFA and CIMT were observed among persistent smokers, quitters, and past smokers compared with never smokers. At 12 months, MTFA and CIMT decreased in never and past smokers and quitters but increased in persistent smokers. Six acute myocardial infarctions and 8 strokes occurred during a median follow-up of 66.0 months. Persistent smoking was associated with an increased risk of events (P<0.001).. Smoking is associated with upregulated MTFA and progression of CIMT, which may be related to the risk of atherothrombotic events in MetS patients.

Topics: Aged; Carotid Artery Diseases; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Monocytes; Myocardial Infarction; Prognosis; Smoking; Stroke; Thromboplastin

Hypertension is a well known risk factor for thrombotic events such as myocardial infarction and stroke. Platelets express tissue factor (TF), the key activator of blood coagulation and thrombus formation. The number of TF-positive platelets increases in pathological conditions characterized by thrombotic complications but whether this occurs in hypertension is unknown. Here we investigated whether platelet TF expression is increased in a hypertensive status through a mechanism acting on megakaryocytes; the phenomenon could be modulated by antihypertensive drug as captopril; angiotensin (AngII) influences platelet TF expression.. Spontaneously hypertensive stroke prone (SHRSP) rats received standard diet (StD) or a Japanese high-salt permissive diet (JpD). After 3 weeks, JpD animals were randomized to receive captopril or vehicle. Normotensive Wistar Kyoto (WKY) rats were used as controls. Cell-associated TF expression and activity were analyzed by flow cytometry and calibrated automated thrombogram, respectively.. Hypertensive StD-SHRSP showed an increased number of TF-positive platelets compared with normotensive WKY. After JpD administration, SHRSP developed severe hypertension and renal damage; the number of TF-positive megakaryocytes significantly increased compared with StD-SHRSP resulting in a higher number of TF-positive platelets with a faster kinetic of thrombin generation. These effects were reverted by captopril. Ex-vivo stimulation of platelets, isolated from normotensive WKY and from healthy individuals, with AngII induced a concentration-dependent increase of surface-associated TF expression.. The current study shows for the first time that in hypertension the number of TF-positive megakaryocytes increases thus releasing in the circulation more platelets carrying a functionally active TF. AngII stimulates platelets to express TF.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Megakaryocytes; Random Allocation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stroke; Thromboplastin

The impact of thrombolysis with recombinant tissue plasminogen activator (rtPA) on blood coagulation in acute ischemic stroke (AIS) patients is not completely understood. We studied the effect of thrombolysis on the thrombin generation (TG) profile as well as coagulant activity of activated factors IX (FIXa), XI (FXIa) and tissue factor (TF) in AIS patients. In a case-control study, TG parameters as well as FIXa, FXIa and TF levels were assessed in 95 AIS patients, including individuals receiving rtPA treatment within 4.5 h since AIS onset (n = 71, 74.7%) and those ineligible for thrombolysis (n = 24, 25.3%). Blood samples were collected at baseline and after 24 h since admission. The two groups were similar with regard to demographics and clinical factors. In thrombolysed patients, all TG parameters measured after 24 h were markedly decreased, with strongest impact on lag time (LT), when compared with the baseline values (81.3% longer LT, p < 0.0001), as well as when compared to the non-thrombolysed group (86% longer LT, p = 0.002). In non-thrombolysed AIS patients the TG remained unaltered. Logistic regression adjusted for potential confounders showed that high baseline ETP value (the top quartile) was solely predicted by the presence of circulating FIXa, whereas after 24 h FXIa predicted high ETP in the subgroup of thrombolysed and in all AIS patients. Thrombolysis in AIS patients markedly attenuates the TG. Elevated FXIa contributes to thrombin formation capacity after 24 h, highlighting a role of this factor in the regulation of blood coagulation in AIS.

Topics: Aged; Aged, 80 and over; Blood Coagulation; Brain Ischemia; Case-Control Studies; Factor IXa; Factor XIa; Female; Humans; Male; Stroke; Thrombin; Thrombolytic Therapy; Thromboplastin; Tissue Plasminogen Activator

Background Although the role of microparticles was recently implicated in stroke pathophysiology, the association between microparticles and inflammation is still not fully understood. The aim of this cohort study of 66 patients was to assess a relation between haemostatic factors, C-reactive protein and clinical outcome of ischaemic stroke. Methods Plasma microparticles procoagulant activity, concentrations of tissue factor-bearing microparticles, tissue factor and tissue factor pathway inhibitor in ischaemic stroke patients were determined with enzyme-linked immunosorbent assays at the time of initial diagnosis, along with serum C-reactive protein concentrations. Patients were divided into two groups depending on their C-reactive protein concentrations (C-reactive protein <3 mg/L; n = 28 vs. C-reactive protein ≥3 mg/L; n = 38). The analysed clinical outcome measures included the National Institutes of Health Stroke Scale and the Barthel Index. Results The two C-reactive protein groups did not differ significantly in terms of microparticles procoagulant activities, tissue factor-bearing microparticles, tissue factor and tissue factor pathway inhibitor concentrations. A significant correlation was observed between tissue factor pathway inhibitor and National Institutes of Health Stroke Scale score at admission ( R = 0.3, P = 0.03). Patients with C-reactive protein ≥3 mg/L presented with significantly higher National Institutes of Health Stroke Scale scores (median, 9.00 vs. 5.50, P = 0.002) and lower Barthel Index scores (median, 20.00 vs. 65.00, P = 0.002) than individuals with C-reactive protein <3 mg/L. The C-reactive protein concentrations correlated positively with National Institutes of Health Stroke Scale scores ( R = 0.3, P = 0.02) and inversely with Barthel Index scores ( R = - 0.4, P = 0.002). Conclusions Altogether, these findings imply that haemostatic parameters (microparticles, tissue factor-bearing microparticles, tissue factor, tissue factor pathway inhibitor) do not account for elevated C-reactive protein concentrations in ischaemic stroke patients.

Topics: Aged; Biomarkers; Brain Ischemia; C-Reactive Protein; Cell-Derived Microparticles; Cohort Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lipoproteins; Male; Middle Aged; Patient Outcome Assessment; Protein Binding; Severity of Illness Index; Stroke; Thromboplastin

Stroke is an important cause of death and disability throughout the world. Microparticles play a cardinal role in vascular hemostasis. The primary aim of this study was to evaluate the procoagulant activity of microparticles and levels of tissue-factor-bearing microparticles (MPs-TF), tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with acute ischaemic stroke.. Seventy-three patients with a diagnosis of acute ischaemic stroke were included. Venous blood samples were drawn on the first day and the seventh day after stroke onset. Plasma microparticles, MPs-TF, TF and TFPI were determined by enzyme-linked immunosorbent assay. Assessment variables were timing of blood collection, type of stroke treatment, presence or absence of diabetes mellitus and hypertension, and scores on the National Institutes of Health Stroke Scale together with scores on the modified Rankin Scale.. Whilst MPs-TF and TFPI levels of stroke subjects were significantly higher (median, 1.63 vs. 0.73 pg/ml; median, 114.26 vs. 78.60 ng/ml, respectively), TF levels in the plasma of stroke patients were significantly lower (median, 82.27 vs. 97.80 pg/ml) than those of healthy individuals. Lower levels of TF were detected in patients with severe stroke in comparison with patients with mild stroke. Moreover, the data also showed that in stroke patients not treated with alteplase the activity of microparticles was significantly higher 1 week after diagnosis in comparison with the activity at the time of diagnosis.. Our findings suggest that patients with acute ischaemic stroke have increased generation of MPs-TF. Nevertheless, further studies are needed in order to confirm such inference.

Topics: Aged; Aged, 80 and over; Brain Ischemia; Cell-Derived Microparticles; Female; Humans; Lipoproteins; Male; Middle Aged; Stroke; Thromboplastin; United States

The role played by hemostasis in the pathogenesis of ischemic strokes is still controversial. The activated partial thromboplastin time (APTT) measures the time necessary to generate fibrin from initiation of the intrinsic pathway. In the present study, we looked for a possible association of ischemic strokes with the shortened APTT.. The study population consisted of 154 patients with acute ischemic strokes who had been admitted from December 2013 to December 2014 to the Department of Neurology, Chiayi Chang Gung Memorial Hospital, and 71 control subjects with no history of stroke.. In a univariate risk analysis, shortened APTT was associated with an odds ratio (OR) for acute ischemic strokes of up to 1.86 (95% confidence interval [CI], 1.06-3.29, P = .031). In a multivariate analysis using a logistic regression model including age, sex, hypertension, diabetes mellitus, and shortened APTT, shortened APTT was still found to significantly add to the risk of ischemic stroke (OR = 2.12 with 95% CI, 1.13-3.98, P = .020). Shortened APTT was also associated significantly with neurological worsening (OR = 3.72 with 95% CI 1.03-13.5, P = .046). As for stroke severity, shortened APTT was associated with an OR for moderate/severe stroke of up to 3.42 (95% CI, 1.53-7.61, P = .003).. Shortened APTT is a prevalent and independent risk factor for ischemic stroke, stroke severity, and neurological worsening after acute stroke.

Topics: Adult; Aged; Aged, 80 and over; Brain Ischemia; Female; Humans; Lipoproteins; Male; Middle Aged; Nervous System Diseases; Partial Thromboplastin Time; Retrospective Studies; Stroke; Thromboplastin; Time Factors

This study aimed to simultaneously observe the expression of mononuclear cells (Mo) and plasma tissue factor (TF) in patients with ischemic cardiocerebrovascular diseases during the stage of acute onset and after the following three weeks and three months for exploration of the clinical implications concerned.. MoTF mRNA and plasma TF antigen (TFAg) from 76 patients with acute myocardial infarction (AMI) together with 46 patients with acute ischemic stroke (AIS) and 61 healthy controls were quantitated respectively through RT-PCR and ELISA.. Compared with the results in the control group, the level of MoTFmRNA and plasma TF in the other groups increased simultaneously and dramatically in the acute stage, which showed a good correlation among the groups (P<0.01), especially in AIS group. The quantitative data showed that both MoTF mRNA and plasma TF remained higher than that of the control group (P<0.01 and P<0.05) after three weeks from the acute onset. It was after three months that the content of MoTF mRNA, in spite of its relatively high level (P<0.05), began to decline in AMI and AIS groups. In this stage the level of MoTFmRNA in AIS group was lower than that in the acute onset stage (P<0.05), while the reduction of plasma TF in AMI and AIS groups was not significantly different from that of the control group (P>0.05). However, the reduced level of plasma TF was still different from that in the acute onset stage (P<0.05).. The simultaneous increase of the level of peripheral MoTF mRNA and plasma TF in the acute onset stage of ischemic cardiocerebrovascular diseases shows a good correlation and suggests the up-regulation of MoTF mRNA's expression participates in the maintenance and expansion of thrombotic formation. Dynamic monitoring of MoTF mRNA and plasma TF at different time points after acute onset has important clinical implications for prevention and treatment of arterial thrombotic diseases.

Topics: Adult; Aged; Aged, 80 and over; Cerebrovascular Disorders; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Myocardial Infarction; Reverse Transcriptase Polymerase Chain Reaction; Stroke; Thromboplastin

We identified a male Polish patient with a very rare minor homozygous GG genotype of the tissue factor (TF) +5466A>G polymorphism, who within two months experienced a transient ischemic attack (TIA) and ischemic stroke of unknown origin associated with the presence of patent foramen ovale below 40 years of age. A relationship between the TF +5466GG genotype and cerebrovascular thromboembolic events could be explained by detectable coagulant TF activity determined in a clotting assay and increased immunoreactive TF levels detected in plasma 5 years after the previous TIA and stroke. Given the role of TF-induced pathway in blood coagulation, it might be speculated that the TF +5466A>G polymorphism, especially in the homozygous GG form, predisposes to increased risk of cerebrovascular ischemic events. There is a need to conduct a prospective study on the effect of TF +5466A>G polymorphism on the risk of cryptogenic stroke.

Topics: Adult; Brain Ischemia; Homozygote; Humans; Ischemic Attack, Transient; Male; Mutation; Polymorphism, Genetic; Stroke; Thromboplastin

We investigated fibrin network permeability and fibrinolysis in the acute and convalescent phase of ischemic stroke.. 20 patients with a mean age of 74 years were studied in the acute (day 1) and convalescent phase (day 60) of ischemic stroke. 23 healthy individuals (controls) were also investigated. Fibrin formation in the samples was triggered by addition of tissue factor (1 pmol/L) and washed frozen-thawed platelets obtained from a healthy donor. The permeability constant (K(s)), which reflects fibrin network permeability, was then calculated from liquid flow measurements. A global assay newly developed in our group was also employed to determine the balance between fibrin formation ("Coagulation profile"; Cp) and fibrin degradation ("Fibrinolysis profile"; Fp) in the same samples. We also measured PAI-1 antigen and fibrinogen concentrations in plasma.. As compared to controls, the stroke patients had lower Ks (lower fibrin network permeability) both on day 1 and on day 60 (p < 0.01 and p < 0.05, respectively). Fibrinolysis, assessed by Fp, was reduced on both day 1 and day 60 (p < 0.001, compared to controls), and PAI-1 concentrations were increased (p < 0.01 for both, compared to controls). Fibrin formation capacity in plasma (i.e. Cp) was increased in the acute phase (p < 0.05) but not in the convalescence, as compared to controls.. The combination of a proneness to form a tighter fibrin network and impaired fibrinolysis is a feature of ischemic stroke that is present in both the acute and convalescent phase of the disease.

Topics: Aged; Aged, 80 and over; Biomarkers; Blood Coagulation Tests; Blood Platelets; Brain Ischemia; Case-Control Studies; Female; Fibrin; Fibrinogen; Fibrinolysis; Humans; Male; Middle Aged; Permeability; Plasminogen Activator Inhibitor 1; Stroke; Sweden; Thromboplastin; Time Factors

Topics: Biomarkers; Blood Coagulation Tests; Blood Platelets; Brain Ischemia; Fibrin; Fibrinolysis; Humans; Permeability; Predictive Value of Tests; Stroke; Thromboplastin; Time Factors

Elevated factor (F)XI is associated with an increased risk for ischemic stroke. Activated FXI (FXIa) and tissue factor (TF) have not been studied following stroke. The aim of the current study was to evaluate circulating FXIa and TF in patients with prior cerebrovascular events.. We studied 241 patients, including 162 after ischemic stroke and 79 after transient ischemic attack (TIA), recruited 6 months to 4 years (median, 36 months) after the events. Plasma TF and FXIa activity following the index event were determined in clotting assays by measuring the response to inhibitory monoclonal antibodies.. Active TF was detected in 25 (10.4%) of the patients, while FXIa activity (median, 37.5 [IQR 397] pM) was found in 64 (26.7%) of the patients (p<0.01). The prevalence of active TF and FXIa was higher in subjects with previous stroke compared with those with a history of TIA (13% vs 5.1%, p=0.05, and 34% vs 11.4%, p<0.0001, respectively). Patients with circulating FXIa were younger and had higher fibrinogen and interleukin-6 compared to the remainder. Patients with detectable TF or FXIa activity had higher NIHSS score, higher modified Rankin scale and lower Barthel Index than the remaining subjects (all p<0.05).. Circulating active TF and FXIa can occur in patients with cerebrovascular ischemic events ≥6 months after the events. The presence of these factors is associated with worse functional outcomes, which highlights the role of persistent hypercoagulable state in cerebrovascular disease.

Topics: Adult; Age Factors; Blood Coagulation Tests; Brain Ischemia; Factor XIa; Female; Fibrinogen; Humans; Interleukin-6; Ischemic Attack, Transient; Male; Middle Aged; Predictive Value of Tests; Prognosis; Stroke; Thrombophilia; Thromboplastin; Young Adult

We investigated the neuroprotective effects of fasudil's active metabolite, hydroxyfasudil, a Rho-kinase inhibitor, in a rat stroke model in which endothelial damage and subsequent thrombotic occlusion were selectively induced in perforating arteries. By examining the effects on the endothelial damage/dysfunction, we thought to explore the mechanism of Rho-kinase inhibitors. Hydroxyfasudil (10mg/kg, i.p., once daily for 3 days) significantly improved neurological functions and reduced the size of the infarct area produced by internal carotid artery injection of sodium laurate in a rat cerebral microthrombosis model. Treatment with fasudil or hydroxyfasudil concentration-dependently inhibited tumor necrosis factor alpha-induced tissue factor expression on the surface of cultured human umbilical vein endothelial cells. They also inhibited thrombin-induced endothelial hyperpermeability. The present findings suggest that hydroxyfasudil is efficacious in preventing brain damage associated with cerebral ischemia, and is partially responsible for fasudil's cytoprotective potential. The results also suggest that the therapeutic benefits against ischemic injury of Rho-kinase inhibitors are attributed, at least in part, to activity upon endothelial damage/dysfunction.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Brain; Brain Ischemia; Capillary Permeability; Cells, Cultured; Disease Models, Animal; Endothelium; Enzyme Inhibitors; Humans; In Vitro Techniques; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; Stroke; Thromboplastin; Tumor Necrosis Factor-alpha; Umbilical Veins

Topics: Administration, Oral; Blood Coagulation; Blood Coagulation Tests; Clinical Chemistry Tests; Fibrinolytic Agents; Hemorrhage; Humans; International Normalized Ratio; Safety; Stroke; Thrombin; Thromboplastin; Venous Thrombosis

More than 80% of cerebrovascular events are ischemic and largely thromboembolic by nature. We evaluated whether plasma factor composition and thrombin generation dynamics might be a contributor to the thrombotic phenotype of ischemic cerebrovascular events.. We studied (1) 100 patients with acute ischemic stroke (n=50) or transient ischemic attack (TIA) (n=50) within the first 24 hours from symptom onset, and (2) 100 individuals 1 to 4 years following ischemic stroke (n=50) or TIA (n=50). The tissue factor pathway to thrombin generation was simulated with a mathematical model using plasma levels of clotting factors (F)II, V, VII, VIII, IX, X, antithrombin and free tissue factor pathway inhibitor (TFPI).. The plasma levels of free TFPI, FII, FVIII, and FX were higher, while antithrombin was lower, in the acute patients compared to the previous event group (all p≤0.02). Thrombin generation during acute events was enhanced, with an 11% faster maximum rate, a 15% higher maximum level and a 26% larger total production (all p<0.01). The increased thrombin generation in acute patients was determined by higher FII and lower antithrombin, while increased free TFPI mediated this effect. When the groups are classified by etiology, all stroke sub-types except cardioembolic have increased TFPI and decreased AT and total thrombin produced.. Augmented thrombin generation in acute stroke/TIA is to some extent determined by altered plasma levels of coagulation factors.

Topics: Adult; Blood Coagulation Factor Inhibitors; Blood Coagulation Factors; Female; Humans; Ischemic Attack, Transient; Lipoproteins; Male; Middle Aged; Stroke; Thrombin; Thromboplastin

Topics: Adult; Brain Ischemia; Female; Humans; Male; Polymorphism, Genetic; Predictive Value of Tests; Risk Factors; Stroke; Thromboplastin

Severely stenotic, symptomatic carotid atheromas are associated with a high risk of stroke in the short term. Although carotid endarterectomy is effective in reducing this stroke risk, it is frequently not applied within the time window for significant benefit. We investigated the effect of peroxisome proliferator-activated receptor (PPAR) -alpha and -gamma ligands in acutely modifying tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in unstable carotid atheromas.. During a 3-year period, 64 patients who had experienced a transient ischemic attack or stroke with good recovery within 6 weeks before surgery and 12 asymptomatic patients with a >70% carotid stenosis were recruited. The expression of PPAR-alpha and -gamma was investigated in endarterectomy samples. The effects of the PPAR-alpha and -gamma ligands fenofibrate and rosiglitazone were investigated in cell culture experiments. Targeted biopsy specimens from endarterectomy samples (n=48) were incubated with medication for 4 days. TF and TFPI were assessed by immunohistochemistry, Western blot analysis, flow cytometry, and activity assays.. PPAR-gamma1 but not -alpha was downregulated in atheromas removed from patients with recent symptoms and no evidence of diabetes. Fenofibrate but not rosiglitazone impaired the induction of TF in human endothelial cells and reduced resting levels of TF activity in vascular smooth muscle cells. Rosiglitazone but not fenofibrate increased TFPI secretion from human endothelial cells. Both fenofibrate (100+/-18.7% to 56.6+/-8.8%, P=0.005; 0.2664+/-0.0696 to 0.1771+/-0.0310, P=0.02) and rosiglitazone (100+/-22% to 88.3+/-20%, P=0.02; 0.3113+/-0.0729 to 0.2287+/-0.0415, P=0.04) reduced TF expression and activity, respectively, in atheroma biopsy specimens. A low expression of TFPI was found in atheroma biopsy specimens with little evidence of TFPI activity.. This study suggests that both PPAR-alpha and -gamma ligands have beneficial effects in acutely reducing TF in unstable carotid atheromas.

Topics: Aged; Aged, 80 and over; Carotid Stenosis; Female; Fenofibrate; Humans; Ischemic Attack, Transient; Ligands; Lipoproteins; Male; Middle Aged; Peroxisome Proliferator-Activated Receptors; PPAR alpha; PPAR gamma; Rosiglitazone; Signal Transduction; Stroke; Thiazolidinediones; Thromboplastin

Alterations in blood coagulation may explain the poorer neurological outcome with diabetes mellitus and hyperglycemia after acute ischemic stroke. We studied the relationships between diabetes mellitus, hyperglycemia, whole blood tissue factor procoagulant activity (TF-PCA) and plasma factorVIIa (FVIIa) in ten patients with type 2 diabetes mellitus and 11 non-diabetic patients at baseline and 6, 12, 24, and 48 hours (h) after presentation for acute stroke. In addition, we examined plasma prothrombin fragment 1+2 (F1.2) and thrombin-antithrombin complexes (TAT) as markers of thrombin generation. Stroke severity, assessed by National Institute of Health Stroke Scale (NIHSS), was similar at baseline (p=0.26) but worse in diabetic (8.20+/-4.3) than nondiabetic patients (2.67+/-2.1, p=0.023) at 48 h. At presentation, diabetic patients had higher FVIIa (p=0.004) and lower TF-PCA (p=0.027) than non-diabetic patients but both were higher than in normal control subjects. FVIIa levels remained higher in diabetic patients at 6, 12 and 24 h after stroke. In diabetic patients, FVIIa (r=0.40, p=0.02) and TF-PCA (r=0.50, p=0.02) correlated with blood glucose; and, FVIIa correlated with plasma F1.2 (r=0.34, p=0.002) and TAT levels (r=0.62, p<0.0001). In non-diabetic patients, TF-PCA, but not FVIIa, correlated with F1.2 (r=0.402, p=0.010) and TAT (r=0.39, p=0.011). Combining both groups, NIHSS scores were positively related to FVIIa levels (r=0.50, p=0.021) and inversely related to TF-PCA levels (r=-0.498, p=0.02). Acute ischemic stroke patients with diabetes and hyperglycemia have a more intense procoagulant state compared with nondiabetic patients. This is related to glucose levels and provides a potential mechanism for the observed worse prognosis in such patients after acute stroke.

Topics: Aged; Aged, 80 and over; Biomarkers; Case-Control Studies; Diabetes Complications; Diabetes Mellitus, Type 2; Factor VIIa; Female; Humans; Hyperglycemia; Male; Middle Aged; Prognosis; Severity of Illness Index; Stroke; Thrombophilia; Thromboplastin

Cigarette smoking is associated with an increased risk to develop myocardial infarction and ischemic stroke. However, the mechanisms responsible for these effects are still poorly understood.. To investigate whether nicotine, the major component of cigarette smoking, and its main metabolite, cotinine, might induce a pro-thrombotic state via stimulation of tissue factor (TF) expression in two cell population widely represented in the arterial wall such as endothelial cells (ECs), and smooth muscle cells (SMCs).. Incubation of ECs and SMCs with nicotine and cotinine induced TF expression in both cell types in a dose-dependent fashion, exerting its effect at the transcriptional level, as demonstrated by semiquantitative and by real-time PCR. Nicotine- and cotinine-induced TF expression was mediated by the activation of the transcription factor, nuclear factor-kappa B (NF-kappaB), as demonstrated by electrophoretic mobility shift assay and by the suppression of TF expression by the NF-kappaB inhibitor, pyrrolidine dithio carbamate ammonium.. These data indicate that nicotine and cotinine exert direct effects on ECs and SMCs, shifting them toward a pro-thrombotic state via induction of TF expression. These effects on cells of the vessel wall might explain, at least in part, the deleterious cardiovascular consequences of cigarette smoking.

Topics: Animals; Base Sequence; Cells, Cultured; Cotinine; DNA, Complementary; Endothelium, Vascular; Gene Expression; Humans; Muscle, Smooth, Vascular; Myocardial Infarction; NF-kappa B; Nicotine; Rabbits; Risk Factors; RNA, Messenger; Smoking; Stroke; Thromboplastin; Thrombosis; Transcription, Genetic

There is no biological marker that can accurately predict the prognosis after an acute ischaemic stroke. The main objective of this study was to evaluate the prognostic value of tissue factor (thromboplastin) levels in first ischaemic stroke.. This was a prospective study of all patients with first ischaemic stroke conducted from October 2003 to February 2004. Plasma for tissue factor levels was kept at -80 degrees Celsius and was analysed at the end of the study period by an independent person. The activities of daily living (ADL) were assessed by using the Barthel index (BI) on admission and at one month after the stroke onset. Any death or recurrent events were recorded.. 50 patients were recruited into the study. The median tissue factor level was 184.5 +/- 97.3 pg/ml. Only age (p-value is 0.027) and middle cerebral artery (MCA) infarcts (p-value is 0.038) were found to be significant independent predictors for severe disability at one month with BI equal to or less than 9. There was no correlation of tissue factor level with BI at one month post-stroke (r equals -0.028, p-value is 0.846) and there was also no significant relationship between levels of tissue factor and recurrent events (p-value is 0.41).. There is no correlation between tissue factor levels with acute ischaemic stroke outcome.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Brain Ischemia; Female; Humans; Male; Middle Aged; Prognosis; Prospective Studies; Stroke; Thromboplastin

To explore the role of the the tissue factor (TF) pathway in ischemic stroke. We measured blood concentrations of markers of the TF pathway [TF antigen, free tissue factor pathway inhibitor antigen (TFPIf) and activity (TFPIac), and activated factor VII (FVIIa)] within 7 days (acute phase) and after 3-6 months (convalescence) in 150 patients with first-ever ischemic stroke and 150 community controls. During the acute phase, TF antigen and TFPIf were not significantly altered but TFPIac was increased (mean 1.27 versus 1.13 U/ml, P = 0.04) and FVIIa was decreased in cases compared with controls (mean 43.3 versus 57.9 mU/ml, P = 0.0004). After adjusting for baseline differences between cases and controls, increasing quartiles of TFPIf were independently associated with reduced odds of stroke, and reducing quartiles of FVIIa and increasing quartiles of TFPIac with increased odds of stroke. During the convalescent phase, FVIIa and TFPIac returned to normal but TF antigen and TFPIf were significantly decreased compared with controls [median TF antigen, 110 (follow-up) versus 155 pg/ml (controls), P = 0.0008; median TFPIf, 15.5 (follow-up) versus 23.3 ng/ml (controls), P = 0.002]. Alterations of blood concentrations of TF pathway markers are common in patients with acute ischemic stroke. The mechanisms are unclear but may relate to enhanced formation of TF-FVIIa complexes and upregulation and release of TFPI during the acute phase, and ongoing consumption of TF antigen and TFPIf during the chronic phase as the atherosclerotic plaque heals.

Topics: Aged; Biomarkers; Brain Ischemia; Cohort Studies; Female; Humans; Male; Stroke; Thromboplastin; Time Factors

To investigate the role of interleukin-1beta (IL-1beta) gene polymorphisms as a link between inflammation, coagulation, and risk of ischemic vascular disease at young age.. A total of 406 patients with myocardial infarction (MI) at young age, frequency-matched for age, sex, and recruitment center, with 419 healthy population-based controls and 134 patients with ischemic stroke at young age, matched by age and sex, with 134 healthy population-based controls, were studied. Subjects carrying the TT genotype of the -511C/T IL-1beta polymorphism showed a decreased risk of MI (odds ratio [OR], 0.36; 95% CI, 0.20 to 0.64) and stroke (OR, 0.32; 95% CI, 0.13 to 0.81) after adjustment for conventional risk factors. In both studies, the T allele showed a codominant effect (P=0.0020 in MI; P=0.021 in stroke). Mononuclear cells from volunteers carrying the T allele showed a decreased release of IL-1beta and a decreased expression of tissue factor after stimulation with lipopolysaccharide compared with CC homozygotes. The presence of a monoclonal antibody against IL-1beta during cell stimulation resulted in a marked reduction of tissue factor activity expression.. -511C/T IL-1beta gene polymorphism affects the risk of MI and ischemic stroke at young age and the response of mononuclear cells to inflammatory stimulation.

Topics: Adolescent; Adult; Child; Child, Preschool; Cytosine; Female; Genetic Predisposition to Disease; Humans; Infant; Interleukin-1; Leukocytes, Mononuclear; Linkage Disequilibrium; Lipopolysaccharides; Male; Myocardial Infarction; Polymorphism, Genetic; Promoter Regions, Genetic; Risk Factors; Stroke; Thromboplastin; Thymine

It is widely recognized that thrombosis is the major event in the evolution of acute myocardial infarction (AMI) and acute ischemic stroke (AIS). But the contribution of coagulation factors to the development of ischemic arterial diseases is still not clearly established. The goal of this study was to establish the possible relationship between coagulation factors as well as anticoagulant and the onset of AMI and AIS. The study population consisted of 69 patients with AMI and 71 with AIS as well as 50 age-matched healthy volunteers. Compared with the control group, plasma tissue factor (TF) and tissue factor pathway inhibitor (TFPI) activities and both TF and TFPI antigens were significantly higher in the AMI group; plasma TF activity and antigen in AIS group were significantly increased, but the activity and antigen of plasma TFPI were significantly decreased in the AIS group. Plasma FVII coagulation (FVII:C) activity was markedly higher in patients with AIS, but not statistically different to the control in patients with AMI. FVIII coagulation (FVIII:C) activity was remarkably higher in patients with AMI but slightly lower than the control in patients with AIS. In the AMI and AIS groups, prothrombin activity and clottable fibrinogen were significantly higher and plasma antithrombin III activity was remarkably lower than the control. The results suggested that during the onset of AMI and AIS, the initiation of TF pathway would be associated with the thrombotic events and that the blood be in hypercoagulable state. But the changes of FVII:C, TFPI and FVIII:C in AMI are different from those in AIS.

Topics: Acute Disease; Aged; Aged, 80 and over; Biomarkers; Blood Coagulation; Case-Control Studies; Coronary Thrombosis; Female; Humans; Intracranial Thrombosis; Male; Middle Aged; Myocardial Infarction; Stroke; Thromboplastin

Activated platelets are implicated in the development of premature arterial vascular diseases, in particular ischemic stroke. Since elevated cytosolic [Ca(2+)](i) is an integrative marker of platelet activation, we determined the generation of Ca(2+) signal in stimulated platelets from 26 young patients recuperating from stroke, 20 patients with symptomatic peripheral arterial disease, and 56 healthy volunteers. Even in the presence of aspirin, the platelets from various individuals showed highly different thrombin-induced Ca(2+) responses. On average, the thrombin-induced Ca(2+) response was increased for platelets from either patient group in comparison to the controls (P <0.04). Relatively more stroke patients had high-responsive platelets (27%, 7/26) than patients with peripheral arterial disease (10%, 2/20) or healthy subjects (4%, 2/56). The average prothrombinase activities of platelets from patients and controls were similar, but 3 out of 6 patients with increased thrombin-induced Ca(2+) responses also exhibited high prothrombinase activity. In a follow-up study, the subject-dependent thrombin-induced Ca(2+) response was found to correlate strongly with the platelet response to protease-activated receptor 1 (PAR1) agonist (r = 0.91), but was not linked to the Pl(A1/2) polymorphism. It is concluded that a significant part of young patients with stroke have platelets with hyperactivity toward thrombin, which is not normalised by aspirin treatment. Furthermore, the subject-dependent variation in thrombin-induced signalling is likely to involve PAR1-mediated platelet activation.

Topics: Adult; Base Sequence; Blood Platelets; Calcium Signaling; Case-Control Studies; DNA; Female; Humans; In Vitro Techniques; Integrin alpha2; Integrin beta3; Male; Middle Aged; Peripheral Vascular Diseases; Platelet Activation; Polymorphism, Genetic; Receptor, PAR-1; Receptors, Thrombin; Stroke; Thrombin; Thromboplastin

Activated monocytes may contribute to the pathogenesis of ischemic stroke. We tested the hypothesis that release products and procoagulant activity of monocytes are increased in acute ischemic stroke. In patients on days 1, 3 and 7 after ischemic stroke and in age- and sex-matched healthy control subjects, we assessed plasma levels of interleukin 8 (IL-8) and neopterin (enzyme linked immunosorbent assay, ELISA) and investigated superoxidanion release (ferricytochrome C reduction), procoagulant activity (one-stage clotting assay) and tissue factor (TF) gene transcription (reverse transcriptase polymerase chain reaction) by monocytes. As compared to control subjects (n=23), IL-8 levels were increased on day 1 after stroke (n=22; p=0.005) and remained elevated on days 3 and 7. Neopterin levels were elevated on days 3 and 7 (p<0.05, respectively) but not on day 1. Neopterin and IL-8 were not correlated with monocyte counts. Superoxid anion production by stimulated and unstimulated monocytes was not different between groups. TF mRNA could neither be detected in monocytes from patients investigated within 12 h after ischemia (n=12) nor in control subjects (n=10) and procoagulant activity of cells was similar in both groups. Our results indicate increased monocyte activation after ischemic stroke although not all activation parameters were elevated. We found no support for the hypothesis that circulating monocytes express TF and possess increased procoagulant activity. Elevated IL-8 may contribute to stroke pathophysiology by activating polymorphonuclear leukocyte (PMNL) activation early after ischemia.

Topics: Acute Disease; Aged; Blood Coagulation; Brain; Brain Ischemia; Female; Gene Expression; Humans; Interleukin-8; Leukocyte Count; Male; Middle Aged; Monocytes; Neopterin; RNA, Messenger; Stroke; Superoxides; Thromboplastin; Transcription, Genetic

Hemostasis factors may influence the pathophysiology of stroke. The role of brain hemostasis in ischemic hypertensive brain injury is not known. We studied ischemic injury in spontaneously hypertensive rats in relation to cerebrovascular fibrin deposition and activity of different hemostasis factors in brain microcirculation. In spontaneously hypertensive rats subjected to transient middle cerebral artery occlusion versus normotensive Wistar-Kyoto (W-K) rats, infarct and edema volumes were increased by 6.1-fold (P < 0.001) and 5.8-fold (P < 0.001), respectively, the cerebral blood flow (CBF) reduced during middle cerebral artery occlusion (MCAO) by 55% (P < 0.01), motor neurologic score increased by 6.9-fold (P < 0.01), and cerebrovascular fibrin deposition increased by 6.8-fold (P < 0.01). Under basal conditions, brain capillary protein C activation and tissue plasminogen activator activity were reduced in spontaneously hypertensive rats compared with Wistar-Kyoto rats by 11.8-fold (P < 0.001) and 5.1-fold (P < 0.001), respectively, and the plasminogen activator inhibitor-1 antigen and tissue factor activity were increased by 154-fold (P < 0.00001) and 74% (P < 0.01), respectively. We suggest that hypertension reduces antithrombotic mechanisms in brain microcirculation, which may enhance cerebrovascular fibrin deposition and microvascular obstructions during transient focal cerebral ischemia, which results in greater neuronal injury.

Topics: Animals; Blood Gas Analysis; Brain Ischemia; Capillaries; Cerebrovascular Circulation; Disease Models, Animal; Endothelium, Vascular; Fibrin; Fibrinolysis; Gene Expression; Hemostasis; Hypertension; Intracranial Thrombosis; Male; Microscopy, Electron; Neurologic Examination; Plasminogen Activator Inhibitor 1; Protein C; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Stroke; Thromboplastin