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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue plasminogen (plgn) activator (tPA) modulates neuronal death in models of stroke, excitotoxicity, and oxidative stress. Amyloid-beta (Abeta) appears central to Alzheimer's disease and is neurotoxic to neurons in vitro. Here, we evaluate tPA effects on Abeta toxicity. We report that tPA alone had no effect on Abeta toxicity. However, in combination with plgn, tPA reduced Abeta toxicity in a robust fashion. Moreover, the combined tPA and plgn treatment markedly inhibited Abeta accumulation. The addition of phenylmethylsulfonyl fluoride, a serine protease inhibitor, to a sample of tPA, plgn, and Abeta resulted in a marked reduction of Abeta degradation. We interpret the actions of tPA and plgn within the context of the ability of plasmin to degrade Abeta.
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PMID:Tissue plasminogen activator requires plasminogen to modulate amyloid-beta neurotoxicity and deposition. 1103 7

To clarify the sequence of alterations in the thrombotic and fibrinolytic systems after acute brain infarction, we prospectively examined sequential changes in coagulatory markers in 38 patients suffering from cardioembolic infarcts (CEI), 41 patients with atherothrombotic infarcts (ATI), 58 patients with lacunar infarcts (LI), and 32 age-matched controls. The plasma level of thrombin-antithrombin III complex (TAT), fibrinopeptide A (FpA), D-dimer, fibrin degradation products-E (FDP-E), fibrinogen, alpha2-plasmin inhibitor-plasmin complex (PIC), and percent activity of antithrombin III (AT-III) were measured within 48 h, at 1 week, and at 3 weeks after the stroke onset. Significantly elevated levels of TAT and FpA, which are both markers of thrombin formation, were observed in CEI patients, and these elevated levels were associated with increasing D-dimer levels for 3 weeks (P<0.0001). D-Dimer in CEI patients was significantly elevated compared to control, LI and ATI levels within 48 h (P<0.001). Percent activity of AT-III was significantly decreased in CEI patients for 3 weeks compared to this activity in controls, LI and ATI (P<0.001). TAT and FpA also increased significantly within 48 h in ATI subjects and declined thereafter. A significant elevation of FDP-E (P<0.001) and D-dimer (P<0.05, P<0.01) was detected in parallel with increasing fibrinogen for 3 weeks. However, there was no significant depletion of percent activity of AT-III in ATI. In LI subjects, no significant elevation of TAT, D-dimer or FDP-E were observed within 1 week. PIC increased significantly in three subtypes of brain infarcts, but did not differ significantly among the three subtypes for 3 weeks. An accurate assessment of sequential alterations in thrombotic and fibrinolytic markers in the acute stage of brain infarct should contribute to the clinical diagnosis of brain infarct subtype. Alterations in these markers in response to activation of the coagulatory system are attributable to the different pathogenesis of ischemic stroke.
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PMID:Activation of thrombosis and fibrinolysis following brain infarction. 1109 16

Reperfusion injury is defined as the enhancement of the damage that occurs in ischaemic cells during the reperfusion period. Cellular damage to the brain occurs not only during the ischaemic period, but also during the reperfusion period. Such injury occurs when blood flow is restored to heart, brain or other tissue after flow has been blocked. Several mechanisms appear to play a role in the generation of reperfusion injury. To a greater or lesser extent, most involve neutrophils. The infiltration of neutrophils into the previously ischaemic area has been implicated as playing major role following reperfusion. Microscopic examination of tissue has shown a direct correlation between the duration of oxygen deprivation with the amount of damage, and the extent of activated neutrophil recruitment. Activated neutrophils are responsible for the release of serine proteases, which directly lead to tissue damage. Activated neutrophils also contain a newly assembled enzyme that produces tissue damaging free radicals. However, a preliminary and necessary step is to attach the activated neutrophil on to the lining of the blood vessels, a process requiring proteolytic activity. Administration of a drug that prevents neutrophil transmigration would reduce reperfusion injury. SuperGen is developing a drug, LEX 032, with a unique spectrum of activities, including the ability to inhibit binding of neutrophils to the vascular surface by blocking this proteolytic activity. In addition, this drug inhibits free radical production by neutrophils, and inhibits the activity of released serine proteases. Therefore, LEX 032 is expected to prevent or minimise neutrophil mediated reperfusion injury. Blockade of all three destructive inflammatory responses should limit the amount of damaged tissue and save viable tissue. A drug with these capabilities might find use in the treatment of myocardial infarction, shock-resuscitation, replantation surgery, frostbite, burns and organ transplantation. Since LEX 032 has no inhibitory activity against thrombin and plasmin, it represents an ideal drug for use in the treatment of ischaemic stroke. Recently, data have been published demonstrating that ischaemic stroke patients given the thrombolytic drug tPA were at least 30% more likely to have minimal or no disability at three months, as measured by outcome scales, when compared to placebo-treated patients. Presumably, this action was because of the hastening of brain reperfusion, and may have been limited due to reperfusion injury. The FDA approved the use of tPA for the limited treatment of acute ischaemic stroke. Since LEX 032 has been shown to limit neutrophil mediated reperfusion damage, it may find use either alone, to ameliorate damage occurring spontaneously during ischaemic stroke, or in combination therapy with tPA to reduce reperfusion injury secondary to thrombolytic therapy. This unique approach may have broad therapeutic potential in the treatment of neutrophil mediated diseases since, unlike a monoclonal antibody for example, it is independent of the specific adhesion molecule(s). These diseases include inflammatory diseases which are, at least in part, caused or exacerbated by excessive neutrophil proteases, such as acute pancreatitis, arthritis, allograft rejection, sepsis, meningitis, acute pulmonary inflammation, psoriasis and damage caused by burns. This is in addition to reperfusion-related diseases such as myocardial infarction, stroke, shock-resuscitation, replantation surgery, frostbite, burns and organ transplantation.
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PMID:LEX 032: a novel recombinant human protein for the treatment of ischaemic reperfusion injury. 1113 33

The relationship between systemic infection or inflammation and an increased risk of thrombotic diseases has recently raised renewed interest. In order to determine the mechanisms underlying this relationship, we determined plasma levels of coagulation/fibrinolysis markers and platelet function in patients with acute thrombotic stroke (<24 h after onset) prior to treatment, and compared the results between cases with elevated and normal C-reactive protein (CRP) levels and controls. Plasma levels of thrombin-antithrombin complex (TAT), plasmin-antiplasmin complex, and D-dimer were significantly higher in patients with elevated CRP levels than in those with normal CRP levels and controls (P<0.005). Platelet aggregation induced by 1 and 10 microM ADP was significantly higher in patients with elevated CRP levels than those with normal CRP levels (P<0.05). These findings suggest that activation of the coagulation/fibrinolysis system and platelet function may be in part related to stroke onset in patients with increased CRP levels.
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PMID:Activated coagulation/fibrinolysis system and platelet function in acute thrombotic stroke patients with increased C-reactive protein levels. 1168 Apr 14

To determine the presence of a 'hypercoagulable state' as assessed by indices of thrombin and plasmin generation and of the amount of fibrin that is lysed, in patients with stable coronary, cerebral and peripheral arterial disease a population-based cross-sectional study was performed. From a population-based cohort comprising 7983 men and women aged 55 years and over, we randomly selected 127 subjects with a history of myocardial infarction, 124 with a history of stroke and/or transient ischemic attack, 131 patients with peripheral arterial disease and 263 control subjects in the same age group without arterial disease. Subjects using anticoagulant drugs were not selected. F1+2, TAT, and PAP were not associated with a history of cardiovascular events, nor with peripheral arterial disease. In contrast, positive associations were found for D-Dimer. Mean D-Dimer level was 40 microg/l (95% CI 35, 44) in control subjects; 53 microg/l (47, 61) in those with a history of myocardial infarction and 51 microg/l (45, 58) in those with a history of stroke and or transient ischemic attack. D-Dimer increased gradually with increasing severity of peripheral atherosclerosis; a decrease in ankle/arm systolic blood pressure ratio of 0.1 was associated with an increase in D-Dimer of 3.9 microg/l (p<0.01). This was more pronounced in subjects with higher F1+2, TAT and PAP concentration. In conclusion, the markers of onset of coagulation F1+2, TAT and PAP are not associated with the presence of arterial disease, but increased levels of these markers are necessary for the positive association between D-Dimer and arterial disease.
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PMID:Activation products of the haemostatic system in coronary, cerebrovascular and peripheral arterial disease. 1124 39

In the absence of arterial recanalization, thrombolytic agents induce a dose-related extension of focal cerebral ischemic injury (FII) in experimental animals. However, FII is smaller in mice lacking alpha(2)-antiplasmin (alpha(2)-AP), the physiologic inhibitor of plasmin, suggesting its depletion might reduce FII in the absence of reperfusion. Therefore, the effect of human plasmin (Pli), human miniplasmin (mPli), and an Fab fragment neutralizing murine alpha(2)-AP (Fab-4H9) on FII after middle cerebral artery (MCA) ligation was studied in mice and in hamsters. In BALB/c mice, the median FII after 24 hours was 28 microL (range, 20-34) (n = 10) with saline and 23 microL (range, 17-26) (n = 9) with a single bolus of 0.07 mg Pli, given after MCA ligation (P =.010), which reduced alpha(2)-AP to 44% and fibrinogen from 0.75 to 0.44 g/L. FII was 20 microL (range, 13-26) (n = 6, P =.025) with 0.2 mg mPli and was 24 microL (range, 20-27) (n = 6, P =.020) with 1.7 mg Fab-4H9. Neuronal atrophy and reduction of laminin immunoreactivity were comparably observed in the infarct area after saline and Pli. In hamsters, a single bolus injection of 1 mg Pli, after MCA ligation, depleted alpha(2)-AP and fibrinogen and reduced FII at 24 hours from 20 microL (range, 9.9-38) (n = 6) to 7.0 microL (range, 0.44-31) (n = 7, P =.032). Thus, reduction of circulating alpha(2)-AP, with a single bolus of plasmin or of a neutralizing antibody fragment, significantly reduced FII after MCA ligation in mouse and hamster models, suggesting that, provided these observations can be extrapolated to human beings, transient depletion of circulating alpha(2)-AP might reduce ischemic stroke in the absence of reperfusion.
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PMID:Depletion of circulating alpha(2)-antiplasmin by intravenous plasmin or immunoneutralization reduces focal cerebral ischemic injury in the absence of arterial recanalization. 1134 34

Tissue plasminogen activator (tPA) has a critical role in fibrinolysis, converting plasminogen into active protease plasmin. Because intravenous tPA has only limited effectiveness as acute stroke therapy, enhancement of endogenous tPA represents a potential alternative to stroke treatment. Adenoviral-mediated gene transfer was used to enhance production of tPA in bovine brain capillary endothelial cells (BEC). Antigen and activity levels of tPA and plasminogen activator inhibitor-1 (PAI-1) in media from BEC infected with AdCMVtPA were analyzed. Conditioned media were analyzed for thrombomodulin, the integral membrane antithrombotic molecule that co-activates protein C. BEC infected with AdCMVtPA demonstrated enhanced expression of tPA antigen (40.2 +/- 0.4 ng/mL vs 1.1 +/- 1.5 ng/mL [p<0.001] and 0.3 +/- 0.5 ng/mL [p<0.0001], respectively) and increased tPA enzymatic activity (27.4 +/- 5.7 IU/mL vs 8.3 +/- 1.7 IU/mL [p<0.05] and 13.3 +/- 3.2 IU/mL [p<0.05], respectively) compared to BEC infected with the control adenovirus (Adl327) or uninfected BEC. There was a moderate increase in PAI-1 protein 4 days after transfection with AdCMVtPA, and the integral membrane protein thrombomodulin was released into media by transfected BEC. These results demonstrate that adenoviral-mediated delivery in vitro of the human tPA gene resulted in high levels of expression of tPA in BEC. Transient overexpression of tPA by gene transfer might be a useful strategy to protect against thrombotic occlusion during the period of risk of acute stroke.
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PMID:Adenoviral-mediated transfer of tissue plasminogen activator gene into brain capillary endothelial cells in vitro. 1157 Jun 62

Ancrod is a purified fraction of venom from the Malayan pit viper, Calloselasma rhodostoma, currently under investigation for treatment of ischemic stroke. The therapeutic effect is ascribed to a lowering of plasma fibrinogen. Thirty-two healthy volunteers received subcutaneous ancrod at doses of 1.0, 1.5 and 2.0 IU/kg body weight or placebo. Blood samples were drawn before the injection and at various time points until 96 h after the injection. Ancrod leads to the formation of desAA-fibrin, which serves as cofactor in tissue plasminogen activator activity (tPA)-induced plasminogen activation. Unchanged concentrations of prothrombin fragment F1.2 and thrombin-antithrombin complex (TAT) indicate that fibrin formation occurs independent of thrombin. Plasmin generation is independent of an increase in tPA activity or changes in plasminogen activator inhibitor-1 (PAI-1) concentration in plasma. Subcutaneous injection of ancrod leads to a generalized fibrino(geno)lytic response caused solely by providing tPA with soluble fibrin as its cofactor in plasminogen activation. Maximal plasmin activity is present 12 h after subcutaneous injection.
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PMID:Plasminogen activation without changes in tPA and PAI-1 in response to subcutaneous administration of ancrod. 1175 54

Ischaemic and haemorrhagic stroke may cause haemostatic abnormalities, apart from concomitant brain damage. In this study, some blood coagulation and fibrinolysis parameters were investigated in 30 patients with ischaemic stroke (atherothrombotic) and 30 with haemorrhagic (20 with intracerebral and 10 with subarachnoid haemorrhage) stroke. The following parameters were determined within the first 24h after stroke: prothrombin time (PT%). activated partial thromboplastin time (aPTT). fibrinogen, activity of FVII, antithrombin. plasmin inhibitor (PI) and fibrin D-dimer. Significant decreases in PT%, FVII activity and antithrombin as well as an increase in fibrinogen and D-dimer were noticed in ischaemic stroke and in both groups of patients with haemorrhagic stroke. PI levels were significantly lower in subarachnoid haemorrhage patients compared with those in controls and those in both the intracerebral haemorrhage and the ischaemic stroke patients. With the exception of this difference, there were no other differences between ischaemic stroke and the two types of haemorrhagic stroke. This could indicate that haemostatic abnormalities are a consequence of brain damage rather than primary haemostatic activation during thrombosis and/or bleeding in the acute phase of stroke. A decrease in the plasmin inhibitor could suggest excessive fibrinolysis in subarachnoid haemorrhage.
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PMID:Blood coagulation and fibrinolysis in acute ischaemic and haemorrhagic (intracerebral and subarachnoid haemorrhage) stroke: does decreased plasmin inhibitor indicate increased fibrinolysis in subarachnoid haemorrhage compared to other types of stroke? 1208 38

Plasminogen activators (PA) are unique agents that are currently applied as thrombolytic therapy to achieve rapid vascular reperfusion. Regimens of PA plus anticoagulants and antiplatelet drugs have attained a high degree of sophistication and predictable rates of positive clinical outcomes for acute myocardial infarction (MI), ischemic stroke, pulmonary embolism (PE), deep vein thrombosis (DVT), and thrombosed catheters. Included in the repertoire are newly approved mutants of tissue plasminogen activator (TPA), which have biochemical advantages that allow for bolus administration. Yet, despite tremendous effort devoted to enormous trials to establish the clinical efficacy of these agents in acute MI, mortality results are not superior to those with native TPA or streptokinase (SK). Furthermore, all PAs have the potential for hemorrhagic complication, most critically intracranial hemorrhage (ICH), occurring in 0.9% of patients treated with native or mutant TPA. It is possible that a limit of clinical effectiveness has been reached, beyond which more potent PAs do not achieve greater benefit without a serious increase in risk of bleeding. A breakthrough is possible, however, if the risk of ICH could be avoided. One solution is the application of the direct-acting thrombolytic enzyme, plasmin. While intravenous plasmin is not effective when administered systemically, regional infusion to a thrombus induces local thrombolysis. Unlike the PAs, plasmin treatment should not cause hemorrhage from vascular trauma sites, as it is neutralized by antiplasmin in the blood. Animal studies are fully consistent with this approach, which offers potential for achieving a truly regional thrombolytic treatment.
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PMID:Towards safer thrombolytic therapy. 1212 83


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