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

To study the thrombolytic effect of tissue plasminogen activator (t-PA) on cerebral emboli, we characterized cerebral embolization in stroke-prone spontaneously hypertensive rats (SHRSPs) and Wistar Kyoto rats (WKYs). [125I]Fibrin clot particles (20-100 microns diameter) were injected twice at an interval of 90 min into the left internal carotid artery of WKYs and SHRSPs. After each injection, spontaneous embolus dissolution was monitored with a gamma-ray detector placed on the head of the embolic rats. Embolus dissolution was spontaneously generated in 15 min after the injection of fibrin clots. In WKYs, 21% and 42% of the clots were dissolved 30 and 90 min after the second embolization, respectively. On the other hand, the spontaneous embolus dissolution in SHRSPs was significantly lower than that of WKYs, indicating that the endogenous fibrinolytic ability of SHRSPs is less potent than that of normotensive rats. The intravenous administration of t-PA at doses of 75, 250 and 750 micrograms/kg caused a dose-dependent embolus dissolution in SHRSPs. Furthermore, systematically applied t-PA produced embolus dissolution without causing systemic plasminogen activation, fibrinogen breakdown or bleeding. In conclusion, the intravenous administration of t-PA produces selective embolus dissolution without systemic fibrino(geno)lysis in a cerebral embolic SHRSP.
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PMID:Fibrinolytic effect of tissue plasminogen activator on cerebral embolism in stroke-prone spontaneously hypertensive rats. 181 26

A 49-year-old man had for 30 years suffered from severe recurrent thromboembolism with leg-vein thrombosis, pulmonary emboli, mesenteric infarction, cerebrovascular accident, cerebral vein thrombosis, portal vein thrombosis and femoral artery occlusion requiring leg amputation. In addition to moderately increased clotting activation with single-fold positive demonstration of fibrin monomers and a D-dimer concentration of 1 mg/l platelet aggregation was increased and could not be influenced by aspirin, 300 mg daily. Despite aspirin there were recurrent transitory attacks of cerebral ischaemia. Fibrin monomers were threefold positive and D-dimer concentration was increased to 4 mg/l (elevated clotting activation). Ticlopidine administration (250 mg daily) reduced adenosine diphosphate-induced platelet aggregation by 30% without effect on collagen-induced platelet aggregation. In parallel to these changes the patient's general condition clearly improved: fibrin monomers were no longer demonstrated and the D-dimer level fell to 0.5 mg/l.
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PMID:[Recurrent thromboembolism due to increased acetylsalicylic acid-resistant platelet aggregation]. 188 75

In a randomized, single-blind study, 30 patients with acute ischemic stroke were treated with either low-molecular weight dextran and mannitol alone (group A, mean age, 63.3 +/- 11.8 years, n = 15) or in combination with the viper venom enzyme ancrod (group B, mean age, 67.9 +/- 7.6 years, n = 15). Lowering of plasma fibrinogen levels to 100-130 mg/dL with ancrod resulted in a significant reduction of the apparent blood viscosity, ie, of 37% at a shear rate of 0.03 s-1, compared with only 7% in group A. Fibrin degradation products increased considerably from 3.1 +/- 0.4 to 154.3 +/- 31.6 mg/L on day 3, while plasminogen decreased from 98.2% +/- 2.0% to 79.8% +/- 2.9% in group B. Global coagulation and platelet function tests were not influenced by either treatment. Neurological score improved by 1.1 arbitrary units (AU) in group A and by 2.6 AU in group B. Five patients in group A and two in group B died during the first two weeks. This preliminary study indicated a slightly better outcome in the ancrod treated patients. The beneficial effect may be due to the anticoagulative and fibrinolytic activity of ancrod rather than its effect on blood viscosity.
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PMID:Controlled trial of ancrod in ischemic stroke. 619 6

Fibrin-platelet microembolism in cortical branches distal to stenosis of the middle cerebral artery was directly visualized in a patient with transient ischemic attacks (TIA) and was histopathologically confirmed. Cerebral microembolism may produce TIA in patients with stenosis of the middle cerebral artery and may influence the success of the extracranial-intracranial bypass operation in treatment of these patients.
Stroke
PMID:Embolism distal to stenosis of the middle cerebral artery. 723 69

Clinical experience suggests that thrombolytic-induced bleeding is associated with systemic activation of the thrombolytic system. Using fibrin specific variants of tissue-type plasminogen activator (t-PA) and making use of the apparent fibrin specificity of streptokinase (SK) in the rabbit we tested the hypothesis that minimizing systemic plasmin production and fibrinogenolysis will decrease hemorrhages in models of peripheral bleeding and embolic stroke. t-PA consumed 51% of the available fibrinogen; caused cerebral bleeds and increased peripheral bleeding time. Fibrin-specific variants of t-PA depleted less than 20% of the fibrinogen and did not cause peripheral or cerebral bleeding. However, an equipotent dose of SK converted only 12% of the available fibrinogen but increased bleeding time and caused hemorrhagic conversion in 75% of embolic stroke model animals treated. The data suggest that bleeding associated with tissue-type plasminogen activators is linked to systemic plasmin generation and subsequent fibrinogenolysis. This hypothesis does not explain the mechanism(s) of SK-induced bleeding.
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PMID:Limiting systemic plasminogenolysis reduces the bleeding potential for tissue-type plasminogen activators but not for streptokinase. 882 86

Although the arterial tree is exposed to increased pressure in hypertensive patients, paradoxically, the complications of hypertension (heart attacks, stroke) are mainly thrombotic rather than hemorrhagic. Patients with left ventricular (LV) hypertrophy are at high risk of the complications of hypertension. We performed a cross-sectional study of 178 patients attending a hypertension clinic in a city center teaching hospital, and measured plasma levels of the soluble adhesion molecule P-selectin (associated with platelet activity/function and atherosclerosis), the von Willebrand factor (vWf; a marker of endothelial dysfunction), fibrin D-dimer (an index of thrombogenesis), plasminogen activator inhibitor (PAI, an index of fibrinolysis), lipoprotein(a) (Lp(a), associated with thrombogenesis and atherogenesis) and hemorheological indexes (fibrinogen, hematocrit, plasma viscosity, hemoglobin) in patients with essential hypertension, in whom the LV mass and LV mass index were determined using echocardiography. The 178 patients (86 men, mean age 54 +/- 15 years) were compared with 47 normotensive healthy controls (aged 56 +/- 20 years). Hypertensive patients had higher P-selectin, PAI, vWf, fibrin D-dimer, Lp(a), plasma fibrinogen, and plasma viscosity when compared with controls. Black hypertensive patients had higher Lp(a) levels and LV septal and posterior wall thickness on echocardiography, but lower plasma PAI levels. Patients with LV hypertrophy (defined as a LV mass index > 134 g/m2 in men or > 110 g/m2 in women) had higher plasma fibrinogen compared with those without LV hypertrophy. Systolic blood pressures were significantly correlated to age, plasma viscosity, plasma fibrinogen, and vWf. Diastolic blood pressures were significantly correlated with age and plasma fibrinogen. Fibrinogen levels were correlated with LV mass, LV mass index, left atrial size, plasma viscosity, and vWf. Fibrin D-dimer levels were significantly correlated with vWf and fibrinogen levels. Thus, hypertensive patients have high plasma fibrinogen levels, thrombogenesis, and impaired fibrinolysis (as indicated by high D-dimer and PAI levels, respectively), platelet activation (raised soluble P-selectin), and endothelial dysfunction (high vWF). The high plasma fibrinogen levels were related to blood pressures, LV mass index (and LV hypertrophy), and left atrial size. These abnormalities in hemorheologic factors and markers of thrombogenesis and endothelial function may act synergistically to increase the risk of thrombogenesis and atherosclerosis in hypertensive patients.
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PMID:Relation of endothelium, thrombogenesis, and hemorheology in systemic hypertension to ethnicity and left ventricular hypertrophy. 941 37

A single base substitution (C-->T) in exon II of the Bbeta fibrinogen gene resulting in an Arg14-->Cys replacement was identified in a young woman with a history of recurrent thrombotic stroke. The patient's plasma showed prolongation of the thrombin and Reptilase times, and plasma fibrinogen, which was low when determined by chronometric assay (Clauss technique) was normal by clot weight. Dysfibrinogenaemia associated with the same mutation was identified in eight family members including two siblings with a history of venous and arterial thrombosis. Fibrin monomer polymerization with thrombin, Reptilase and Agkistrodon contortrix contortrix venom was defective. Polymerization studies revealed a reduced rate of polymerization compared with normal plasma, which improved on cooling from 37 degrees C to 20 degrees C. Plasma viscosity in the affected individuals was normal. Flow cytometric analysis of platelets from the proband and another affected member showed no increase in surface bound fibrinogen. Euglobulin clot lysis time was normal. The same point mutation has been described previously in individuals with thrombosis. This family adds further to the genotype-phenotype correlation of the dysfibrinogenaemias and provides strong evidence for a genuine association of fibrinogen BbetaArg14Cys with thrombosis. The mechanism underlying a causal relationship with the increased incidence of thrombosis remains obscure but a review of related dysfibrinogens suggests that the addition of a free thiol group rather than the loss of the thrombin cleavage site may be important.
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PMID:Fibrinogen Bbeta14 Arg-->Cys: further evidence for a role in thrombosis. 1069 65

Cardiopulmonary bypass (CPB) is routinely utilized to provide circulatory support during cardiac surgical procedures. The morbidity of CPB has been significantly reduced since its introduction 50 years ago; however, cerebral injury remains a potentially serious consequence of otherwise successful surgery. The risk of stroke postoperatively is approximately 1-5%. Incidence rates for neurocognitive deficit, however, vary markedly depending on the detection method, although typically it is reported in at least 50% of patients. The aetiology of this cerebral injury remains open to debate, although evidence shows that ischaemia secondary to microembolism may be the principal factor. Emboli originate from bubbles of air, atheroemboli released on aortic manipulation and thromboemboli generated as a result of haemostatic activation. Significant generation of thrombin occurs during CPB resulting in fibrin formation, although the trigger of this activation is not fully understood. Rather than originating from contact activation as previously thought, the primary trigger may be via the activated factor VII/tissue factor pathway of coagulation, with an additional role of contact activation in amplification of coagulation as well as the fibrinolytic response to CPB. Haemostatic activation is inhibited with systemic heparin therapy. The relationship between haemostatic activation and emboli formation during CPB is not known. Interventions to reduce cerebral injury in the context of cardiac surgery depend, in large part, on the minimization of emboli. This review investigates cerebral injury after cardiac surgery and evidence showing that microembolism is the principal causative agent. Fibrin emboli are postulated to be an important source of cerebral embolism. The mechanism of haemostatic activation during CPB is therefore also discussed.
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PMID:Alterations to haemostasis following cardiopulmonary bypass and the relationship of these changes to neurocognitive morbidity. 1173 60

Elevated levels of tissue-type plasminogen activator antigen (tPA), fibrinogen, and fibrin D-dimer predict coronary artery disease (CAD) events and stroke. These factors, possibly in association with insulin resistance, may be important in families in which CAD has become clinically apparent at a premature age. From 125 patients with angiographically confirmed, premature CAD, 175 healthy male relatives (age </=65 years) were identified. One hundred seventy-five healthy volunteers of similar age and without any family history of CAD were recruited. There were no differences between relatives and controls in terms of conventional CAD risk factors, cigarette smoking, alcohol consumption, or cardiorespiratory fitness. Estimated insulin resistance and plasminogen activator inhibitor 1 levels were not increased in relatives. Fibrin D-dimer, tPA, and fibrinogen levels were elevated in relatives compared with controls, 55 (52 to 58) ng/mL versus 49 (45 to 53) ng/mL, P<0.01, for D-dimer; 8.0 (7.5 to 8.6) ng/mL versus 5.6 (5.2 to 6.1) ng/mL, P<0.001, for tPA; and 3.0 (2.9 to 3.1) g/L versus 2.8 (2.7 to 2.9) g/L, P<0.05, for fibrinogen. These differences remained after adjustment for correlates, including fibrinogen, age for D-dimer, and features of the insulin resistance syndrome for tPA. tPA and D-dimer levels are elevated in the healthy, male, first-degree relatives of patients with premature CAD. This association is independent of potential confounding factors.
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PMID:Tissue plasminogen activator, fibrin D-dimer, and insulin resistance in the relatives of patients with premature coronary artery disease. 1195 Jul 14

Fibrinogen is far more important as a risk factor for acute cardiovascular syndromes than generally recognized. Evidence from a recent metaanalysis (including 22 studies of 63,736 subjects and 5,717 events [1] suggests that the risk for myocardial infarction and stroke almost doubles if the fibrinogen level exceeds 3.03 g/l (measured according to Clauss) with an odds ratio of 1.99 and a 95% confidence interval of 1.85-2.13. The predictive value of fibrinogen levels equally applies to men and women, young and old, primary and secondary prevention. Repeated fibrinogen measurements are particularly helpful with emphasis on high risk patients: concentrations of the upper tertile indicate a 92% higher risk of impending acute cardiovascular syndromes, as evidenced by a metaanalysis evaluating five prospective studies with 9,639 participants and 671 events [1]. Together with other risk factors such as hypertension, hypercholesterolemia, or diabetes, the risk of fatal and nonfatal acute cardiovascular syndromes may further increase by 6-12- fold, while fibrinogen remains an independent risk factor for both cardiac and extracardiac atherothrombotic complications, as well as for iatrogenic complications like restenosis following PTCA or stenting. Fibrin(ogen) and his effector thrombin substantially determine the extent and outcome of atherothrombotic complications, because they are the molecules linking the mutually dependent events of atherogenesis, coagulation/fibrinolysis, rheology/vasotonus, and inflammation. Interventional studies on fibrinolytic and defibrinating substances, as well as GpIIb/IIIa-inhibitors for treatment of acute cardiovascular syndromes have confirmed the benefit of fibrinogen reduction and extended the experimental evidence for the relevance of fibrin(ogen) in the pathogenesis of these syndromes. Accordingly, the preventive use of fibrates leading to moderate reductions in plasma cholesterol and fibrinogen diminished significantly the rate of reinfarction. The emerging possibilities from a more than 50% fibrinogen reduction (by studies using H.E.L.P. apheresis) strengthened the therapeutic concept to free the blood from all risk factors-as effective as it can be-in order to achieve an optimal plaque regression, since changes in the blood composition strongly affect the fragility and stability of the atherosclerotic plaques.
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PMID:[Fibrinogen and atherothrombosis: vulnerable plaque or vulnerable patient?]. 1456 94


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