thromboplastin and Brain-Ischemia

Coronavirus disease 2019 (COVID-19) is a newly emerging human infectious disease that has quickly become a worldwide threat to health, mainly causing severe acute respiratory syndrome. In addition to the widely described respiratory syndrome, COVID-19 may cause life-treating complications directly or indirectly related to this infection. Among these, thrombotic complications have emerged as an important issue in patients with COVID-19 infection, particularly in patients in intensive care units. Thrombotic complications due to COVID-19 are likely to occur due to a pro-coagulant pattern encountered in some of these patients or to a progressive endothelial thrombo-inflammatory syndrome causing microvascular disease. In the present authors' experience, from five different hospitals in Italy and the UK, imaging has proved its utility in identifying these COVID-19-related thrombotic complications, with translational clinical relevance. The aim of this review is to illustrate thromboembolic complications directly or indirectly related to COVID-19 disease. Specifically, this review will show complications related to thromboembolism due to a pro-coagulant pattern from those likely related to an endothelial thrombo-inflammatory syndrome.

Topics: Adult; Aged; Anticoagulants; Brain Ischemia; Cause of Death; Communicable Diseases, Emerging; Coronavirus Infections; COVID-19; Female; Humans; Italy; Male; Middle Aged; Pandemics; Pneumonia, Viral; Pulmonary Embolism; Radiography, Thoracic; Severe Acute Respiratory Syndrome; Survival Analysis; Thromboembolism; Thromboplastin; Tomography, X-Ray Computed

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

Topics: Acute Disease; Anticoagulants; Brain Ischemia; Drug Administration Schedule; Heparin; Humans; Injections, Subcutaneous; Randomized Controlled Trials as Topic; Thromboplastin; Time Factors; Vascular Cell Adhesion Molecule-1

Topics: Atrial Fibrillation; Brain Ischemia; Fibrinolytic Agents; Humans; Intracranial Embolism and Thrombosis; Platelet Aggregation Inhibitors; Recurrence; Thromboplastin; von Willebrand Factor

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

Abciximab, a nonselective glycoprotein IIb/IIIa inhibitor, was shown to reduce peri-interventional stroke rate in carotid stenting. We evaluated the effect of adjunct abciximab therapy on monocyte-platelet cross talk and neurological deficit in unprotected carotid stenting and compared its efficacy with distal filter protection.. Fifty patients were randomized to either standard antithrombotic therapy (n=30) consisting of aspirin, clopidogrel, and heparin or adjunct bolus (0.25 mg/kg) and 12-hour infusion (0.125 microg x kg(-1) x min(-1)) of abciximab (n=20). A third cohort of patients was stented with filter protection (n=30). Monocyte-platelet aggregate formation and monocyte tissue factor expression were determined by whole blood flow cytometry, and F1.2 generation and soluble CD40 ligand (sCD40L) were determined by immunoassay.. The incidence of peri-interventional ischemic episodes (23% versus 10%; P=0.2) and the number of de novo ischemic lesions detected by diffusion-weighted MRI (47% versus 30%; P=0.17) were not significantly different between standard antithrombotic therapy and adjunct abciximab but were reduced with filter protection (P=0.023). However, the number of transient ischemic attacks was lower (P=0.05) and the National Institutes of Health Stroke Score rapidly decreased in patients with adjunct abciximab. This clinical improvement was paralleled by a reduction in the postinterventional percentage of activated monocyte-platelet aggregates (CD62P+/CD14+; P=0.018) and the number of tissue factor-positive monocytes (TF+/CD14+; P=0.005). Both abciximab and filter protection suppressed F1.2 generation and significantly reduced sCD40L.. Abciximab limits thrombus propagation and thrombus stabilization after carotid stenting by reducing monocyte-platelet cross talk and sCD40L. Although abciximab seems inferior to filter devices in peri-interventional cerebral protection, it may be considered in patients who do not allow placement of protection devices.

Topics: Abciximab; Aged; Angioplasty; Antibodies, Monoclonal; Anticoagulants; Blood Vessel Prosthesis Implantation; Brain Ischemia; Carotid Stenosis; Cell Aggregation; Chemotherapy, Adjuvant; Cohort Studies; Female; Fibrinolytic Agents; Filtration; Hemorrhage; Humans; Immunoglobulin Fab Fragments; Ischemic Attack, Transient; Male; Monocytes; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Stents; Thromboplastin; Treatment Outcome

We studied the effect of argatroban, a new selective thrombin inhibitor, on the haemostatic system in seven patients with acute ischaemic stroke (the argatroban group). Argatroban was infused continuously at 2.5 mg/h for the first 48 h, and then 10 mg of argatroban was infused over 3 h twice a day on days 3-7. The placebo group consisted of six acute ischaemic stroke patients. As a combination therapy, intravenous administration of glycerol was also performed at the same time in five of the seven patients in the argatroban group and in four of the six patients in the placebo group. D-dimer levels were measured by a latex photometric immunoassay that allowed immediate quantitative assessment. The D-dimer levels of our 13 patients with acute ischaemic stroke were raised at the time of admission (day 1) and 69% of the values were above the 97th percentile ( > 500 ng/ml) in healthy subjects. D-dimer levels were significantly reduced in the argatroban group on days 2 and 7 after admission when compared with the placebo group (day 2: P = 0.032; day 7: P = 0.046). Thus, haemostatic activation occurred in acute ischaemic stroke was effectively blocked by argatroban.

Topics: Aged; Antithrombins; Arginine; Brain Ischemia; Double-Blind Method; Female; Fibrin Fibrinogen Degradation Products; Glycerol; Humans; Male; Middle Aged; Partial Thromboplastin Time; Pipecolic Acids; Placebos; Reference Values; Sulfonamides; Thrombin; 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

Microparticles (MPs), small membrane fragments shed from various cell types, have been implicated in thrombosis, inflammation, and endothelial dysfunction. Their involvement in subarachnoid hemorrhage (SAH) and the development of cerebral infarction and clinical deterioration caused by delayed cerebral ischemia (DCI) remain ill defined. The authors sought to quantify the magnitude of elevations in MPs, delineate the temporal dynamics of elevation, and analyze the correlation between MPs and DCI in patients with SAH.. On the day of hemorrhage and on Days 1, 3, 5, 7, and 10 after hemorrhage, peripheral blood samples were drawn from 22 patients with SAH. Plasma samples were labeled with Annexin V and CD142, CD41a, CD235a, CD146, CD66b, or von Willebrand factor (vWF) and were quantified by flow cytometry. Clinical data, including the 3-month extended Glasgow Outcome Scale (GOS-E) scores, infarction as measured on MRI at 14 days after SAH, and vasospasm as measured by transcranial Doppler ultrasonography and angiography, were collected and compared with the MP burden.. When averaged over time, all MP subtypes were elevated relative to controls. The CD235a+(erythrocyte)-, CD66b+(neutrophil)-, and vWF-associated MPs peaked on the day of hemorrhage and quickly declined. The CD142+(tissue factor [TF])-associated MPs and CD146+(endothelial cell)-associated MPs were significantly elevated throughout the study period. There was a strong negative correlation between TF-expressing and endothelial-derived MPs at Day 1 after SAH and the risk of infarction at Day 14 after SAH.. Microparticles of various subtypes are elevated following SAH; however, the temporal profile of this elevation varies by subtype. Those subtypes closely associated with thrombosis and endothelial dysfunction, for example, CD145+(TF)-associated MPs and CD146+(endothelial cell)-associated MPs, had the most durable response and demonstrated a significant negative correlation with radiographic infarction at 14 days after SAH. Levels of these MPs predict infarction as early as Day 1 post-SAH.

Topics: Adult; Brain Ischemia; Case-Control Studies; CD146 Antigen; Cell-Derived Microparticles; Cerebral Infarction; Follow-Up Studies; Glasgow Outcome Scale; Humans; Incidence; Male; Middle Aged; Retrospective Studies; Risk Factors; Subarachnoid Hemorrhage; Thromboplastin; Time Factors; Ultrasonography

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

The effects of statins on gene expression of cerebral endothelial cells (ECs) in vivo have not been investigated after stroke. We developed a rapid double immunofluorescent staining protocol with antibodies against von Willebrand factor (a marker for endothelium) and glial fibrillary acidic protein (a marker for astrocytes) for laser capture microdissection to isolate single ECs in brain tissue of the rat. Using this protocol in combination with real-time PCR, we found that stroke significantly increased mRNA levels of protease-activated receptor 1 (PAR-1) and tissue factor (TF) in ECs isolated from ischemic cerebral microvessels compared with nonischemic vessels. Treatment of embolic stroke with recombinant human tissue plasminogen activator (rht-PA) 4 h after stroke further elevated PAR-1 mRNA levels nearly 1000-fold in the core and 500-fold in the boundary above the nonstroke group 30 h after stroke, while TF mRNA levels were elevated approximately 10 fold above the nonstroke group. Furthermore, stroke significantly increased matrix metalloproteinase (MMP) 2 and 9 mRNA levels in the ischemic core and boundary regions 6 and 30 h after stroke. Treatment with rht-PA-upregulated MMP2 expression in the ischemic boundary and core. Atorvastatin completely blocked rht-PA upregulation of the above genes, when atorvastatin in combination with rht-PA was administered 4 h after stroke. Monotherapy of atorvastatin 4 h after stroke did not significantly reduce expression of genes examined in the present study. These data provide evidence that atorvastatin reduces exogenous tPA-aggravated cerebral endothelial genes that mediate thrombosis and blood-brain barrier permeability, which could contribute to the beneficial effects of statins on thrombolytic treatment of acute stroke.

Topics: Animals; Anticholesteremic Agents; Atorvastatin; Blood Coagulation; Brain; Brain Ischemia; Capillary Permeability; Down-Regulation; Endothelial Cells; Gene Expression; Heptanoic Acids; Humans; Lasers; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Microdissection; Pyrroles; Rats; Rats, Wistar; Receptor, PAR-1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thromboplastin; Tissue Plasminogen Activator

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

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

Microvascular perfusion defects occur after occlusion and reperfusion of the middle cerebral artery in examples of focal cerebral ischemia. In addition to cellular (eg, polymorphonuclear leukocyte) contributors to the focal "no-reflow" phenomenon, activation of coagulation may also play a role. We have tested a potential role of tissue factor-mediated coagulation in the microvascular perfusion defects seen after focal cerebral ischemia-reperfusion in a baboon model of reversible middle cerebral artery occlusion with the murine anti-tissue factor monoclonal antibody TF9-6B4. Tissue factor is the principal resident procoagulant substance in cerebral tissues and has a distinct perivascular distribution.. Microvascular patency in the basal ganglia after 3-hour middle cerebral artery occlusion and 1-hour reperfusion was quantified by computerized video imaging of carbon-tracer perfused tissues. Animals were randomized to receive intravenous TF9-6B4 (10 mg/kg) 10 minutes before middle cerebral artery occlusion (n = 6) or no treatment (n = 6) in an open study.. In the control animals, a significant decrease in patency was confirmed in microvessels less than 30 microns in diameter. Infusion of TF9-6B4 before middle cerebral artery occlusion produced a stable maximal level of circulating antibody within 10 minutes, which lasted the duration of ischemia and reperfusion. An increase in reflow in microvessels of all size classes occurred after TF9-6B4 infusion, which was significant in those 7.5 to 30 microns (P = .038) and 30 to 50 microns (P = .013) in diameter.. These results indicate that tissue factor-mediated events may also contribute to no-reflow in noncapillary microvessels after focal cerebral ischemia.

Topics: Animals; Antibodies, Monoclonal; Blood Coagulation Disorders; Brain Ischemia; Cerebral Arteries; Disease Models, Animal; Male; Microcirculation; Papio; Reperfusion Injury; Thromboplastin

We studied 23 patients suffering cerebral ischemia who also had laboratory evidence of either a lupus anticoagulant (LA) or an abnormal anticardiolipin antibody (ACA). Four patients had lupus or a lupus-like illness, three had drug-induced lupus, and 16 had no overt evidence of collagen-vascular disease. Cerebral ischemic events were multiple in 71% of the patients; two patients presented with multi-infarct dementia. Recognized cerebrovascular disease risk factors were present in 57% of the patients. The partial thromboplastin time was prolonged in only 35% of the patients. An LA was identified in 15 of 21 patients tested, and an elevated ACA titer was identified in 10 of 12 patients tested. Simultaneous assays for LA and ACA were discordant in eight of 10 patients tested. LA- and ACA-associated brain ischemia is often recurrent, but other risk factors for cerebrovascular disease are often present. The laboratory findings in such patients may display considerable heterogeneity.

Topics: Adult; Aged; Aged, 80 and over; Antibodies; Blood Coagulation Factors; Blood Coagulation Tests; Brain Ischemia; Cardiolipins; Female; Humans; Lupus Coagulation Inhibitor; Male; Middle Aged; Partial Thromboplastin Time; Retrospective Studies; Thromboplastin