fibrin and Cerebrovascular-Disorders

Despite advances in revascularization tools for large vessel occlusion presenting as acute ischemic stroke, a significant subset of clots remain recalcitrant to current strategies. We assessed the effectiveness of a novel thrombectomy device that was specifically designed to retrieve resistant fibrin rich clots, the geometric clot extractor (GCE; Neuravi, Galway, Ireland), in an in vitro cerebrovascular occlusion stroke model.. After introducing fibrin rich clot analogues into the middle cerebral artery of the model, we compared the rates of recanalization between GCE and Solitaire flow restoration stent retriever (SR; Medtronic, Minneapolis, Minnesota, USA; control group) cases. A maximum of three passes of each device was allowed. If the SR failed to recanalize the vessel after three passes, one pass of the GCE was allowed (rescue cases).. In a total of 26 thrombectomy cases (13 GCE, 13 SR), successful recanalization (Thrombolysis in Cerebral Infarction score of 2b or 3) was achieved 100% of the time in the GCE cases with an average of 2.13 passes per case. This rate was significantly higher compared with the Solitaire recanalization rate (7.7%, P<0.0001) with an average of three passes per case. After SR failure (in 92% of cases), successful one pass GCE rescue recanalization was achieved 66% of the time (P<0.005).. Application of the GCE in this experimental stroke model to retrieve typically recalcitrant fibrin rich clots resulted in higher successful recanalization rates than the SR.

Topics: Aged; Cerebrovascular Disorders; Device Removal; Female; Fibrin; Humans; Male; Middle Aged; Stents; Stroke; Thrombectomy; Thrombosis; Treatment Outcome

Fibrinogen and β-amyloid (Aβ) peptide independently form ordered aggregates but in combination, they form disordered structures which are resistant to fibrinolytic enzymes like plasmin and cause severity in cerebral amyloid angiopathy (CAA). A novel enzyme of 31.3 kDa has been isolated from the root of the medicinal plant Aristolochia indica that showed fibrinolytic as well as fibrin-Aβ co-aggregate destabilizing properties. This enzyme is functionally distinct from plasmin. Thrombolytic action of the enzyme was demonstrated in rat model. The potency of the plant enzyme in degrading fibrin and fibrin-plasma protein (Aβ, human serum albumin, lysozyme, transthyretin and fibronectin) co-aggregates was demonstrated by atomic force microscopy, scanning electron microscopy and confocal microscopy that showed better potency of the plant enzyme as compared to plasmin. Moreover, the plant enzyme inhibited localization of the co-aggregate inside SH-SY5Y human neuroblastoma cells and also co-aggregate induced cytotoxicity. Plasmin was inefficient in this respect. In the background of limited options for fragmentation of these co-aggregates, the plant enzyme may appear as a potential proteolytic enzyme.

Topics: Amyloid beta-Peptides; Animals; Aristolochia; Cell Line, Tumor; Cerebrovascular Disorders; Enzyme Stability; Fibrin; Fibrinolysis; Humans; Peptide Fragments; Plant Extracts; Protein Aggregates; Proteolysis; Rats; Rats, Sprague-Dawley; Thrombosis

Lp(a), a major cardiovascular risk factor, contains a specific apolipoprotein, apo(a), which by virtue of structural homology with plasminogen inhibits the formation of plasmin, the fibrinolytic enzyme. A number of clinical reports support the role of Lp(a) as a cardiovascular or cerebral risk factor, and experimental data suggest that it may contribute to atherothrombosis by inhibiting fibrinolysis.. A well-characterized model of a fibrin surface and an apo(a)-specific monoclonal antibody were used to develop a functional approach to detect pathogenic Lp(a). The assay is based on the competitive binding of Lp(a) and plasminogen for fibrin, and quantifies fibrin-bound Lp(a). High Lp(a) binding to fibrin is correlated with decreased plasmin formation. In a transversal case-control study we studied 248 individuals: 105 had a history of ischaemic cardiopathy (IC), 52 had cerebro-vascular disease (CVD) of thrombotic origin, and 91 were controls.. The remarkably high apo(a) fibrin-binding in CVD (0.268 +/- 0.15 nmol L-1) compared with IC (0.155 +/- 0.12 nmol L-1) suggests the existence of peculiar and poorly understood differences in pro- or anti-thrombotic mechanisms in either cerebral and/or coronary arteries.. Our results demonstrated that Lp(a) fibrin-binding and small Apo(a) isoforms are associated with athero-thrombotic disease.

Topics: Adult; Apolipoproteins A; Binding, Competitive; Biomarkers; Case-Control Studies; Cerebrovascular Disorders; Female; Fibrin; Fibrinolysin; Humans; Lipoprotein(a); Male; Middle Aged; Myocardial Ischemia; Plasminogen; Protein Binding; Protein Isoforms

Cerebrovascular events (CVE) in patients with prosthetic heart valves (PHV) have remained a severe and frequent complication despite oral anticoagulation with or without aspirin. We studied the possible pathophysiological involvement of platelet-derived microparticles (PMP) as a contributing factor for the increased incidence of CVE in patients with PHV.. We compared in a retrospective, case-control study the clinical outcome after the implantation of the PHV with several different independent morphological and functional methods, including simultaneous transcranial Doppler monitoring of both middle cerebral arteries, PMP detection by flow cytometry with use of platelet-specific antibodies, coagulation markers, and determination of the procoagulant activity by Russell's viper venom time, a phospholipid-dependent coagulation assay.. Eight of 26 patients with PHV had 9 CVE during 136 person-years of observation. Transcranial Doppler monitoring revealed an increased frequency of microembolic signals recorded over a 30-minute period in patients with CVE (75+/-25; median, 55; range, 27 to 248) compared with those without CVE (23+/-12; median, 7; range, 0 to 153; P<0.05) or with control subjects (0; P<0.001). Flow cytometry analysis showed increased levels of PMP in patients with compared to those without CVE (4.1+/-0.6% versus 2.4+/-0.4% of all fluorescence-positive events gated; P<0.05). Increased procoagulant activity was documented by the shortened Russell's viper venom time expressed as an increased level of platelet equivalents per microliter of plasma in patients compared with control subjects (+24.7+/-14.9%; P<0.01). Subgroup analysis revealed that patients with CVE had a higher excess of platelet equivalents per microliter of plasma than patients without CVE in relation to the controls (+68.7+/-36.7%; P<0.05). Mildly elevated thrombin-antithrombin III complexes (2.9+/-0.7; median, 2.3; normal, <2.0 microg/L) suggested incompletely suppressed thrombin formation, and fibrin generation (fibrinopeptide A) was in the upper normal range (2.1+/-0.2; median, 1.8; normal, <2.0 ng/mL), despite adequate anticoagulation (INR=3.6+/-0.1).. Our data show increased microembolic signals, platelet microparticles, and procoagulant activity in symptomatic patients with PHV and provide a potential pathophysiological explanation of CVE.

Topics: Antithrombin III; beta-Thromboglobulin; Blood Coagulation; Blood Platelets; Case-Control Studies; Cerebral Arteries; Cerebrovascular Circulation; Cerebrovascular Disorders; Female; Fibrin; Fibrinolysis; Fibrinopeptide A; Flow Cytometry; Heart Valve Prosthesis; Humans; Intracranial Embolism and Thrombosis; Male; Middle Aged; Peptide Hydrolases; Prothrombin; Prothrombin Time; Retrospective Studies; Thrombin; Ultrasonography, Doppler, Transcranial

We investigated the distribution and frequency of microthromboemboli (MTE) in acute infarcts in humans and determined whether MTE in the contralateral circulation resulted in histological changes.. Forty patients dying within the first month after unilateral infarct were investigated. Infarct etiology was determined mainly on the pathological findings. Whole brain sections from the region of maximal necrosis were stained for fibrin. Fibrin-containing MTE were transferred to a schematic drawing and counted. Sections from 20 patients without infarcts served as controls.. Infarct sections had significantly more MTE than controls. Infarcts of thrombotic (n=6) and thromboembolic (n=21) origin had more MTE than infarcts of embolic origin (n=13). Thromboembolic infarcts had the highest number of MTE within the region assumed to be the ischemic penumbra, other arterial territories, and the contralateral hemisphere. Patients with large infarcts and those with short clinical courses had a higher number of MTE. Sixteen patients had recent micronecroses in the contralateral hemisphere.. There seems to be a pattern of MTE in acute infarcts that is dependent on cause, size, and clinical duration. Our findings of contralateral micronecroses emphasize that acute infarcts may result in more widespread cerebral injury than clinically expected. Given the many variables influencing stroke and death in humans, the results have to be interpreted with caution.

Topics: Acute Disease; Aged; Autopsy; Brain; Cause of Death; Cerebral Arteries; Cerebral Infarction; Cerebrovascular Circulation; Cerebrovascular Disorders; Coloring Agents; Female; Fibrin; Humans; Intracranial Embolism and Thrombosis; Male; Necrosis

We compared the activity of a new long-half-life, fibrin-specific tissue-type plasminogen activator (TPA) variant with that of wild-type TPA in rabbit models of embolic stroke and peripheral bleeding.. In the embolic stroke model. TPA-induced clot lysis is followed by continuous monitoring of a radiolabeled clot lodged in the middle cerebral artery. Twenty-four hours after embolization and treatment with either thrombolytic agent or excipient, the brains are removed, fixed, and evaluated for cerebral hemorrhage. In a parallel template bleeding time experiment, the effects of equipotent doses of the two TPA molecules were measured.. Infusion of wild-type TPA or bolus administration of the TPA variant resulted in dose-dependent clot lysis. The TPA variant was found to be an order of magnitude more potent than wild-type TPA on a milligram-per-kilogram basis. Unlike wild-type TPA, the variant caused less systemic activation of plasminogen (P < .05) and fewer hemorrhagic transformations in this model (P < .05). The TPA variant did not extend template bleeding times.. These findings show that by combining increased fibrin specificity with decreased plasma clearance, it is possible to produce a thrombolytic agent that is more convenient and more potent than wild-tpe TPA. At the same time the significant reduction in hemorrhagic conversions may be attributable to the conservation of systemic plasminogen seen with this molecule.

Topics: alpha-2-Antiplasmin; Animals; Blood Coagulation; Cerebral Hemorrhage; Cerebrovascular Disorders; Dose-Response Relationship, Drug; Fibrin; Fibrinogen; Fibrinolysis; Half-Life; Hemorrhage; Intracranial Embolism and Thrombosis; Male; Plasminogen; Rabbits; Thrombolytic Therapy; Tissue Plasminogen Activator

Racial differences in stroke are known to exist with persons in the black race having a higher morbidity, mortality and incidence of stroke compared to whites. We evaluated coagulation factors in black and white stroke patients and compared the results between races. D-dimer was elevated more frequently in blacks than whites to a statistically significant degree. There were non-significant trends for blacks to have a positive lupus anticoagulant, low protein C and protein S, higher platelet factor 4, and hyporesponsive platelets to 10 microM epinephrine. The significance of these findings in understanding racial differences in stroke is discussed.

Topics: Aged; Antithrombin III; Black People; Blood Coagulation; Cerebrovascular Disorders; Female; Fibrin; Fibrinogen; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Factor 4; Protein C; Reference Values; White People

Plasma crosslinked fibrin polymers (XLFP) are formed as a result of in vivo hemostatic activation and are elevated in thrombotic disease. We have investigated the plasmic degradation of plasma XLFP in vitro to provide information regarding the pattern of crosslinking and the composition of degradation products. Plasma XLFP were identified by sodium dodecyl sulfate (SDS)-agarose electrophoresis and Western blotting and quantitated by gel scanning. D-dimer was measured by enzyme-linked immunosorbent assay and the results were verified by SDS-polyacrylamide gel electrophoresis and Western blotting of the digests. Complete degradation of XLFP occurred only after supplementation of plasma with plasminogen (5 U/mL) and incubation with recombinant tissue plasminogen activator (rt-PA), indicating that the normal plasma plasminogen concentration limits plasmic degradation in vitro. Gel electrophoresis showed that the principal terminal degradation products of XLDP were fragments D, DD, and E, indicating that crosslinking occurred primarily through gamma chain dimers. After adding a low concentration of thrombin to plasma in vitro, XLFP increased progressively before clotting, and the concentration correlated with the increase in the D-dimer concentration after degradation (r = .98). Plasma XLFP and D-dimer concentrations in plasmic digests were significantly elevated in patients with stroke (150 +/- 83 micrograms/mL and 88 +/- 32 micrograms/mL), myocardial infarction (217 +/- 110 micrograms/mL and 84 +/- 30 micrograms/mL), and venous thrombosis (187 +/- 80 micrograms/mL and 86 +/- 19 micrograms/mL) compared with normals (28 +/- 12 micrograms/mL and 25 +/- 7 micrograms/mL). There was a strong correlation between the plasma concentration of XLFP and the D-dimer immunoreactivity of plasma after plasmic degradation (r = .87). The results indicate that XLFP in plasma are crosslinked primarily through gamma chains and degrade to fragment DD with plasminogen activation. Also, the immunoreactivity of in vitro plasmic digests of plasma reflects the concentration of XLFP and may provide a useful indirect measure of in vivo hemostatic activation in patients with thrombotic disease.

Topics: Acute Disease; Blotting, Western; Cerebrovascular Disorders; Electrophoresis, Agar Gel; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Fibrin; Fibrinolysin; Humans; Macromolecular Substances; Molecular Weight; Reference Values; Thrombosis; Tissue Plasminogen Activator

In the spontaneously hypertensive stroke-prone rat, it is unclear whether plasminogen activator plays a role in the development of stroke. The present study was undertaken to investigate brain levels of plasminogen activator activity in spontaneously hypertensive stroke-prone rats and Wistar-Kyoto rats.. Plasminogen activator was purified from the brains of rats of both strains. The purification involved used ammonium sulfate precipitation, gel filtration, a zinc chelate-Sepharose column, and a concanavalin A-Sepharose column. Fraction I (0.15 M KCl-soluble fraction) and fraction II (2 M KCl plus 6 M urea-soluble fraction) were purified from both strains.. Total plasminogen activator activity in the original homogenates for fractions I and II derived from spontaneously hypertensive stroke-prone rats was increased to twice the level found in Wistar-Kyoto rats. The final product purified from fractions I and II in both strains of rats revealed single bands of plasminogen activator activity on enzymatic analysis with a molecular weight of 72,000. The purified product had stronger S-2288 amidolytic activity than S-2444 amidolytic activity, and it also displayed fibrin-binding ability.. The study demonstrated that there is an increased content of plasminogen activator in the brains of spontaneously hypertensive stroke-prone rats that might be related to the development of stroke.

Topics: Animals; Brain; Cerebrovascular Disorders; Electrophoresis, Polyacrylamide Gel; Fibrin; Hypertension; Male; Plasminogen Activators; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Topics: Cerebrovascular Disorders; Disseminated Intravascular Coagulation; Fibrin; Humans; Hydrolysis; Thrombin; Thrombosis

Evidence of damage to cerebral vein walls was sought in 70 cases of multiple sclerosis. Seventy control cases were also examined. The multiple sclerosis cases showed venous intramural fibrinoid deposition (7%), recent haemorrhages (17%), old haemorrhages revealed by haemosiderin deposition (30%), thrombosis (6%) and thickened veins (19%). In all, 41% of all multiple sclerosis cases showed some evidence of vein damage. Occasional control cases showed haemosiderin deposition in the brain but, unlike the multiple sclerosis cases, these were diffuse and almost entirely related to coexistent cardiovascular or cerebrovascular disease. Haemosiderin deposition was common in the substantia nigra and other pigmented nuclei in all cases. It is concluded that the cerebral vein wall in multiple sclerosis is subject to chronic inflammatory damage, which promotes haemorrhage and increased permeability, and constitutes a form of vasculitis.

Topics: Cerebral Hemorrhage; Cerebral Infarction; Cerebral Veins; Cerebrovascular Disorders; Fibrin; Hemosiderin; Humans; Intracranial Embolism and Thrombosis; Iron; Multiple Sclerosis; Vasculitis

The plasma concentrations of protein C, an anticoagulant protein, and fibrinopeptide A were measured in 37 patients with acute hemispheric stroke and in age-matched controls with nonvascular neurologic diseases. In 11 stroke patients who died within 15 days after the onset (nonsurvivors) protein C antigen concentration on admission was lower than in the control group (p less than 0.005), with a mean value of 63% of the concentrations found in the 26 survivors (p less than 0.001). The difference in protein C concentrations was not associated with different prothrombin time ratios and serum albumin concentration in survivors and nonsurvivors of stroke and was independent of the size of the cerebral lesion. Increased fibrinopeptide A concentration on admission was found in all stroke patients (p less than 0.001), but it was higher in nonsurvivors than in survivors (p less than 0.01), suggesting that lower protein C concentrations in nonsurvivors might be due to increased thrombin-dependent protein C activation. In survivors, protein C concentration was slightly but significantly higher than in controls (p less than 0.05) and was unchanged 2 months after stroke, a time when fibrinopeptide A concentrations had returned to normal. These results show that protein C is involved in the hemostatic derangement caused by stroke and provide a rationale for clinical trials evaluating the therapeutic supplementation with protein C of patients with acute ischemic stroke.

Topics: Acute Disease; Aged; Cerebrovascular Disorders; Fibrin; Fibrinopeptide A; Humans; Middle Aged; Protein C

A combined dynamic examination of 114 patients with strokes of different nature localized in the cerebral hemispheres has shown that the degree of the hemostatic changes depends on the severity of the disease and the stage of the DIC syndrome at the time of examination. Three stages of DIC have been identified: hypercoagulation, incomplete consumption coagulopathy, and marked consumption coagulopathy. Drug correction of hemostatic alterations is possible only at stages I and II. The guidelines of the drug therapy of the DIC syndrome associated with cerebral strokes are presented.

Topics: Adult; Aged; Antifibrinolytic Agents; Brain Ischemia; Cerebral Hemorrhage; Cerebral Infarction; Cerebrovascular Disorders; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Humans; Male; Middle Aged; Protease Inhibitors

Topics: Blood Coagulation; Blood Platelet Disorders; Cerebrovascular Disorders; Fibrin; Fibrinolysis; Humans; Platelet Aggregation; Risk; Thromboembolism

Cerebral vascular lesions of 26 cases in systemic lupus erythematosus during a period from 1963 to 1978 were examined histologically and the following conclusions were made: 1. The prominent vascular changes of the brain were thrombosis, fibrinoid degeneration, endothelial swelling and proliferation, arteriolosclerosis, and perivascular infiltration of inflammatory cells. 2. From clinico-pathological viewpoints, thrombosis seemed to play an important role in the development of neurological signs. In five cases, characteristic granular or homogeneous thrombi were observed in the small blood vessels including venule. Infarct without proved vascular obstruction but probably due to thrombosis was seen in four cases. The true character of the granular thrombi was not determined, either electronmicroscopically or immunohistochemically. These suggested the presence of a tendency for in situ formation of thrombus. 3. Fibrinoid degeneration seen in four cases mainly affected arterile of less than 50 micrometer in diameter in the cerebral cortex, basal ganglia, and brain stem. This change of arteriole did not play a significant role in neurological signs. 4. Endothelial swelling and proliferation of the small blood vessels were prominent in the cases with thrombosis and fibrinoid degeneration. 5. Perivascular infiltration of the inflammatory cells was observed in about one-half of the cases but its significance was not clear.

Topics: Adolescent; Adult; Blood Vessels; Brain; Brain Diseases; Cerebral Hemorrhage; Cerebral Infarction; Cerebrovascular Disorders; Child; Encephalitis; Endothelium; Female; Fibrin; Humans; Intracranial Arteriosclerosis; Intracranial Embolism and Thrombosis; Lupus Erythematosus, Systemic; Male; Middle Aged

Determination of fibrin in plasma, also containing fibrinogen, is possible by selective absorption on affinity columns prepared from highly purified fibrinogen. Desorption is complete using 1.0 M potassium bromide, pH 5.3. In addition, the cold-insoluble globulin is desorbed. Therefore, the eluate is checked on microtiter plates by the staphylococcal clumping test which selectively detects fibrin or fibrinogen. The procedure works well with simple laboratory equipment. The diagnosis of fibrinogen-fibrin complexes is demonstrated in some pathological plasmas.

Topics: Adsorption; Blood Coagulation Tests; Cerebrovascular Disorders; Chromatography, Affinity; Chromatography, Agarose; Ethanol; Female; Fibrin; Fibrinogen; Humans; Ovarian Neoplasms; Solubility; Thrombin

Paired cerebrospinal fluid (CSF) and serum samples collected from 81 of 241 patients admitted to a district psychiatric hospital during a six month period were assayed for fibrin/fibrinogen degradation products (FDP) using a haemagglutination inhibition technique. FDP were found in all serum samples. Fifteen patients (18·5%) had FDP in the CSF (range 0·7-3·75 μg/ml.) and of these 13 (87%) had associated CSF protein abnormalities and 9 (60%) were hypertensive. Mean serum FDP values were the same (4·4 μg/ml.) in patients with and without FDP in the CSF. Three patients had raised serum FDP concentrations but no FDP in the CSF. The evidence suggests that the presence of FDP in CSF indicates recent central nervous system damage. In this series the most common cause was vascular disease.

Topics: Adult; Aged; Blood Pressure; Brain Diseases; Brain Neoplasms; Cerebrospinal Fluid Proteins; Cerebrovascular Disorders; Encephalitis; Female; Fibrin; Fibrinogen; Hemagglutination Inhibition Tests; Humans; Intracranial Arteriosclerosis; Male; Middle Aged

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Brain; Cerebrovascular Disorders; Cholesterol; Fibrin; Fibrinogen; Fibrinolysis; Humans; Ischemia; Plasminogen; Triglycerides

Topics: Blood Cells; Blood Coagulation Disorders; Cell Nucleus; Cerebrovascular Disorders; Disseminated Intravascular Coagulation; Fibrin; Humans; Lung; Malaria; Male; Middle Aged; Staining and Labeling

Topics: Cerebrovascular Disorders; Chromatography; Fibrin; Fibrinogen; Fibrinolysis; Fibrinolytic Agents; Humans; Iodine Isotopes; Methods