Expression of exogenous tissue factor pathway inhibitor in vivo suppresses thrombus formation in injured rabbit carotid arteries.
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OBJECTIVES: The aim of the present study was to test the hypothesis that retrovirus-mediated in vivo tissue factor pathway inhibitor (TFPI) gene transfer to the arterial wall would efficiently inhibit thrombosis without causing significant changes in systemic hemostatic variables. BACKGROUND: Acute coronary syndromes (unstable angina and acute myocardial infarction) are usually caused by atherosclerotic plaque rupture, with consequent activation of the coagulation cascade and circulating platelets. Tissue factor (TF) exposure represents an early event in this pathophysiologic sequence, leading to activation of the extrinsic coagulation pathway and thrombin formation. Tissue factor pathway inhibitor is a naturally occurring inhibitor of the extrinsic pathway. METHODS: In the present study, the gene coding for rabbit TFPI was inserted in a retroviral vector under control of a tetracycline-inducible promoter. Replication-defective, infectious, recombinant retroviruses were used to transfect rabbit carotid arteries with either TFPI or a reporter gene--green fluorescent protein (GFP). RESULTS: Retroviral-mediated arterial gene transfer of TFPI resulted in potent inhibition of intravascular thrombus formation in stenotic and injured rabbit carotid arteries, whereas transfection of the contralateral carotid artery with GFP had no effect on thrombosis. No significant changes in systemic hemostatic variables (prothrombin time and partial thromboplastin time) were observed when thrombosis was inhibited. CONCLUSIONS: These data suggest that retroviral-mediated transfection of the arterial wall with TFPI might represent an attractive approach for the treatment of thrombotic disorders. (+info)
Combined therapeutic approach of intra-arterial thrombolysis and carotid endarterectomy in selected patients with acute thrombotic carotid occlusion.
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PURPOSE: The feasibility and clinical outcome of intra-arterial thrombolysis followed by carotid endarterectomy (CEA) for acute thrombotic occlusion of the internal carotid artery (ICA) were evaluated. METHODS: Intra-arterial thrombolysis and CEA were performed in four patients with acute thrombotic ICA occlusion. Computed tomography scans, cerebral angiograms, and the severity of carotid plaques were examined, and the patients' clinical outcome was evaluated. RESULTS: All 4 patients had severe hemiparesis; 3 patients were alert, and 1 patient was lethargic at the time of hospital admission. New lesions were not shown by means of the initial computed tomography scan. ICA occlusion was indicated in all four patients by means of cerebral angiograms; in three patients, middle cerebral artery occlusion was noted. Collateral circulation was manifested in all patients. Partial recanalization of the occluded ICA was obtained in all patients. Two patients with severe residual ICA stenosis underwent an emergency CEA soon after thrombolysis; the other two patients were treated by means of CEA in the subacute or chromic stage. Plaque rupture and intraplaque hemorrhage were seen in all four patients. All four patients recovered completely, and restenosis of the ICA was not shown by means of follow-up angiograms. CONCLUSION: Intra-arterial thrombolysis followed by CEA may be an effective therapeutic approach for treating acute thrombotic ICA occlusion. The optimal timing of CEA remains controversial. (+info)
Carotid compression tonography. Correlation with bilateral carotid arteriography in the diagnosis of extracranial carotid occlusive disease.
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One hundred twenty two patients ahd carotid compression tonography (CCT) followed by bilateral carotid arteriogaraphy. Inthe group (82 patients) which was felt to have significant occlusive disease of internal carotid at the level of carotid bifurcation (smaller than 50 percent stenosis), the CCT showed a 92 per cent correlation with arteriography. Of the group (48 patients) that underwent endarterectomy, there was a 94 per cent correlation with CCT testing. In 40 patients, with normal arteriogram or with less than 50 percent stenotic lesions on arteriography, there was a larger number (25% of patients with a CCT test which appeared to indicate decreased flow. Various reasons for this are discussed. The high correlation of the CCT test and carotid arteriography in the patients with surgically amenable lesions would suggest that the CCT test is a good noninvasive screening technique for the detection of significant occlusive disease of the extracranialcarotid vascular system. (+info)
Stoke in the young: a four-year study, 1968 to 1972.
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Twenty-six patients under 20 years of age having cerebrovascular disease were studied from 1968 to 1972. Common risk factors such as hypertension, diabetes mellitus, hyperlipidemia and heart disease were not present. Angiographical study showed a variety of abnormalities. No consistent defect was present. There was a high incidence of pyrexia and convulsions in the early stages of stroke and it appears possible that some form of arteritis might have been important in the production of the cerebral infarction. (+info)
Characterization of a mouse model for thrombomodulin deficiency.
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Mutations in the gene encoding thrombomodulin (TM), a thrombin regulator, are suspected risk factors for venous and arterial thrombotic disease. We have previously described the generation of TM(Pro/Pro) mice carrying a TM gene mutation that disrupts the TM-dependent activation of protein C. Here, it is shown that inbred C57BL/6J TM(Pro/Pro) mice exhibit a hypercoagulable state and an increased susceptibility to thrombosis and sepsis. Platelet thrombus growth after FeCl(3)-induced acute endothelial injury was accelerated in mutant mice. Vascular stasis after permanent ligation of the carotid artery precipitated thrombosis in mutant but not in normal mice. Mutant mice showed increased mortality after exposure to high doses of endotoxin and demonstrated altered cytokine production in response to low-dose endotoxin. The severity of the hypercoagulable state and chronic microvascular thrombosis caused by the TM(Pro) mutation is profoundly influenced by mouse strain-specific genetic differences between C57BL/6 and 129SvPas mice. These data demonstrate that in mice, TM is a physiologically relevant regulator of platelet- and coagulation-driven large-vessel thrombosis and modifies the response to endotoxin-induced inflammation. The phenotypic penetrance of the TM(Pro) mutation is determined by as-yet-uncharacterized genetic modifiers of thrombosis other than TM. (+info)
Spontaneous thrombosis of intracavernous internal carotid artery aneurysm and parent artery occlusion in patients with positive balloon test occlusion--two case reports.
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Two patients with giant intracavernous internal carotid artery (ICA) aneurysms were intolerant to balloon test occlusion of the ICA, and later developed spontaneous thrombosis of the aneurysm and the parent ICA without ischemic sequelae. Case 1: A 60-year-old female with a giant right intracavernous ICA aneurysm presented with right abducens nerve paresis. An unsuccessful extracranial-to-intracranial bypass graft operation was complicated by transient postoperative ophthalmoplegia. The patient did not tolerate balloon test occlusion of the right ICA after attempted bypass surgery, and was treated conservatively. The patient presented with acute onset of headache 3 years later. Case 2: A 50-year-old female with a giant right intracavernous ICA aneurysm presented with right abducens nerve paresis. The patient was managed conservatively after a positive balloon test occlusion of the right ICA. The patient suffered transient hypopituitarism and acute onset of headache 2 years later. Spontaneous thrombosis of the aneurysms and occlusion of the parent ICA were found in both patients. Neither had major hemispheric infarcts, but the first patient had asymptomatic infarcts, which were presumed to be thromboembolic in nature. Patients with intracavernous ICA aneurysms who have positive balloon test occlusions appear to develop tolerance to spontaneous and gradual occlusion of the ICA without significant sequelae. However, these patients have an increased risk of developing embolic infarctions. The role for anticoagulation and repeat hemodynamic tests remains unclear. (+info)
Recombinant annexin II modulates impaired fibrinolytic activity in vitro and in rat carotid artery.
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Fibrinolytic activity has been reported to be decreased in atherosclerosis. Recently, annexin II was identified as a coreceptor on endothelial cells for plasminogen and tissue plasminogen activator. In this study, we examined whether recombinant annexin II (rAN II) protein can modulate fibrinolytic activity on vascular endothelium in vitro and in vivo. The effect of rAN II on human umbilical vein endothelial cells (HUVECs) was measured. Addition of a fluorescent plasmin substrate revealed that HUVECs treated with rAN II exhibited significantly more plasmin generation than those treated with BSA. Moreover, rAN II treatment of HUVECs restored plasmin generation impaired by plasminogen activator inhibitor-1 or homocysteine pretreatment. In a rat carotid artery thrombus model, the patency of thrombosed carotid arteries was significantly enhanced by rAN II injection, in contrast to BSA injection, without systemic blood coagulation dysregulation. We found that rAN II enhanced plasmin generation on vascular endothelium in vitro and reduced thrombus formation in vivo, and concluded that enhancement of endothelial fibrinolytic activity by annexin II could modulate the hypercoagulable state of atherosclerosis. Further study of rAN II in vitro and in vivo may lead to the establishment of novel therapeutic approaches to thrombogenic vascular disease. (+info)
Clinical and sonographic patterns of tandem internal carotid artery/middle cerebral artery occlusion in tissue plasminogen activator-treated patients.
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BACKGROUND AND PURPOSE: The National Institutes of Health Stroke Scale (NIHSS) is predictive of thrombus presence but has limited ability to identify occlusion location in the anterior circulation. We describe clinical and sonographic patterns that are associated with tandem internal carotid artery (ICA) and middle cerebral artery (MCA) occlusions. METHODS: Consecutive acute ischemic stroke patients receiving intravenous tissue plasminogen activator (TPA) were studied. Pretreatment NIHSS scores and bedside transcranial Doppler (TCD) were obtained for all patients. RESULTS: A total of 95 patients treated with intravenous TPA at 132+/-60 minutes from stroke onset were studied. On TCD, 48 had isolated MCA occlusion (mean NIHSS 16.8+/-5.8, median 17, range 5 to 28); and 16 had tandem ICA/MCA occlusion (mean NIHSS 18.8+/-5.8, median 22, range 8 to 29; P=NS). In the MCA occlusion and tandem ICA/MCA occlusion groups, 19% and 11%, respectively, had NIHSS scores <12 points. Compared with the NIHSS scores in patients with hemiplegia, forced gaze deviation, and complete neglect, the lower NIHSS scores were attributable to partial arm and/or leg paresis, gaze preference, and partial neglect. In those patients, TCD showed > or =2 major collateral channels and low-resistance flow at the M1 origin, suggesting perfusion of perforating arteries. Although TCD cannot differentiate between high-grade ICA stenosis or occlusion, collateral flow patterns and stenotic signals at the terminal ICA differentiated tandem lesions from isolated MCA occlusion (P<0.01). CONCLUSIONS: Tandem ICA/MCA occlusion was found on TCD in 17% of TPA-treated patients. NIHSS scores were similar in patients with isolated MCA and tandem occlusions. Lower NIHSS scores were seen in patients with a higher number of major collateral flow channels and higher Thrombolysis in Brain Ischemia (TIBI) flow grades at the MCA origin. (+info)