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Experimental and Clinical Studies for Tirofiban Combined Urokinase Super-selective Intra-arterial Thrombolysis

Author: FengLei
Tutor: MaLianTing; PanLi
School: Southern Medical University,
Course: Neurosurgery
Keywords: Acute cerebral embolic model Rabbit Digital subtraction angiography Diffusion weighted imaging TTC stain Animal modelThrombolytic therapy Digital subtraction Animal model Acute cerebralischemia Tirofiban UrokinaseTirofiban Urokinase Interventional thrombolysis Intracranial aneurysm Thrombus Thrombolytic therapyVenous sinus thrombosis Endovascular treatment Thrombolytic therapy
CLC: R743
Type: PhD thesis
Year: 2012
Downloads: 192
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Abstract


The conventional wisdom is that early thrombolytic therapy has mainly taken the time window of3hours or less, designed by occlusion of the artery recanalization to restore perfusion of the ischemic area, in order to save the surviving brain tissue vitality, improve patient prognosis. Indeed, intravenous administration of recombinant tissue plasminogen activator (rtPA) as a procedure for thrombolysis is currently the only FDA-approved medical therapy for treatment of patients with acute ischemic stroke. Though intravenous thrombolytic therapy for acute stroke is now generally accepted, it has also been challenged. At the same time it also brings some of thrombolytic-related issues, such as intracranial hemorrhage, reocclusion, ischemia-reperfusion injury and other complications. Intravenous thrombolytic therapy, partial or complete recanalization rate of the internal carotid artery10%, about25%of the middle cerebral artery. Hemorrhage and vascular reocclusion is the main reason to limit thrombolytic therapy. Symptomatic hemorrhage was seen in a higher incidence (6%) of patients and severe consequences of forcing medical workers to re-examine this approach. The results confirmed the efficacy of thrombolytic therapy of acute phase again, but strict treatment time window restrictions, while filling the clinically most patients can not benefit from symptomatic hemorrhage as the biggest obstacle to therapeutic applications in acute ischemic stroke thrombolysis.PROACT clinical trials confirmed that intra-arterial thrombolytic therapy to improve prognosis and have an advantage in recanalization, but hemorrhage and reocclusion of vascular remains the major problem. In recent years, with the further understanding pathophysiology of acute cerebral ischemia, involved in the development of pharmacology and intervention radiation techniques, intervention thrombolytic managment have received increasing attention. But there are still many imperfect place need to be resolved instantly, including material selection, the treatment time window, and superselective intravascular thrombolysis drug selection, dosage, rate, etc. To establish the animal models resembling human embolic stroke is the foundation for researching the pathogenesis and therapeutic strategies about cerebral thrombosis. In recent years, along with the perpetual development of the experimental animal science, there has been made rapid progress in this field. The construction of autologogus embolic cerebral ischemia and thrombolytic therapy model may be helpful to make further study on the pathophysiologic changes and therapy improvements. DSA, MR-DWI, neurological deficit scores and TTC staining technique are successful and accurate in detecting cerebral arterial embolism, and play important roles.Platelets play an important role in acute cerebral ischemia, anti-platelet aggregation therapy is the basic measure. For reocclusion after recanalization, antiplatelet or anticoagulant therapy can be solved, but the best choice of drugs, dosage, administration time and method has been controversial.75%of cerebral emboli is a "white thrombus", that is rich in platelets and fibrin. Acute fresh platelet thrombus (white thrombus) use of anticoagulant drugs (heparin) and thrombolytic agents (urokinase) is not valid. In the cardiovascular field, there are a lot of clinical evidence-based medicine demonstrate that the GPⅡb/Ⅲa receptor antagonists are effective and safe antithrombotic in acute coronary syndrome (ACS) and percutaneous coronary intervention therapy (PCI). Platelet glycoprotein (GPⅡb/Ⅲa) receptor antagonists are a class of new antiplatelet aggregation drugs through the inhibition specific binding of fibrinogen (Fg) and GPⅡb/Ⅲa, this is the final common pathway of platelet aggregation, effectively blocking all ways to induced platelet aggregation, so as to achieve the greatest degree of anti-platelet effect. In recent years, foreign GPⅡb/Ⅲa receptor antagonist is administered alone or in combination with fibrinolytic drugs intravenously for acute cerebral ischemia to improve thrombolytic efficacy, prevent vascular reocclusion, and to reduce the thrombolytic complications. Clinical trials have shown that the GPⅡb/Ⅲa receptor antagonist no significantly increased the risk of intracranial hemorrhage in acute ischemic stroke. Even in cardiopulmonary bypass surgery, the use of tirofiban is safe.Thrombolysis is inevitable to activate the coagulation system, resulting in thrombosis reformed, incomplete brain tissue perfusion or delayed reperfusion, microcirculation disorders, and even vascular recanalization after occlusion, neurological deterioration. Studies have found that tirofiban can inhibit microcirculation thrombosis, reduce no-reflow phenomenon after thrombolysis. Intravenous Tirofiban with rt-PA enabled68%of patients with middle cerebral artery recanalization, follow-up brain tissue ischemic injury was significantly reduced, significantly improved neurological function, symptomatic hemorrhagic rate of about7%-8%in acute middle cerebral artery occlusion. Tirofiban has been used routinely in the adjuvant therapy of urokinase arterial thrombolysis and mechanical thrombectomy. A early study of use of abciximab, heparin and aspirin in the treatment of myocardial infarction patients found to improve blood flow to the infarct vascular. Speculated that the GPⅡb/Ⅲa receptor antagonist change the structure of the thrombus and make thrombosis endogenous thrombolytic, through depolymerization of platelet aggregation.In cerebrovascular disease, thromboembolism incidence of endovascular interventional management is3-10%, permanent neurological deficit is the incidence of3-5%. Thrombolysis in such patients is controversial, especially in hemorrhagic diseases, such as patients with ruptured intracranial aneurysms. Tirofiban is non-peptide small molecules, specific, short biological half-life, repeated use of less prone to immune response. And it takes effects rapidly, inhibits platelet aggregation up to96%after administered5minutes, platelet function recovery within4hours after discontinuation. Liebeskind DS, etc. had successfully treated a patient of vertebral basilar artery acute thrombosis with intravenous Tirofiban alone, which rt-PA thrombolysis was not satisfied. South Korean doctor Tae Jin Song found that thrombus was dissolved and vessel recanalized soon after intra-arterial Tirofiban, while the use of fibrinolytic drugs were not effective in carotid thrombosis restenosis after the internal carotid artery stenosis stents. Recently, it is reported cases obtained satisfactory results, which of superselective intra-arterial injection of GPⅡb/Ⅲa receptor antagonists, for acute ischemic complications during endovascular interventional treatment of rupture or rupture of the aneurysms. The above studies support the anti-thrombosis, intra-arterial injection safety of tirofiban. Intra-arterial injection of tirofiban achieved encouraging results, but the only case to explore, need further proof of the efficacy and safety.Brain-derived neurotrophic factor (BDNF), a natural protein molecules in vivo, to prevent neuronal death, is mainly produced by neurons and glial cells, an important member of neurotrophic factor. Studies have shown that after brain injury, there is a parallel initiative neuronal survival process in the resistant cells, in addition to a proactive process of programmed cell apoptosis. Brain-derived neurotrophic factor is involved in this initiative neuronal survival process. Animal studies have shown that BDNF reactivity enhancement is neuron self-protection to early ischemia and hypoxia. In cerebral ischemic injury, BDNF in the penumbra surround of infracted region, even in distant region, had a significant expression, while the BDNF expression of infarct core permanently reduced. BDNF inside of infarct border increased immunoreactivity temporarily. Demostic such reports were inconsistent, but were mostly concentrated in the peak of12-24h for BDNF expression,48h began to decline, indicating that BDNF played an important role in neuronal injury repair and regeneration. If we focus on local cerebral ischemic injury, early to take effective measures to improve the blood circulation of the ischemic area of brain, to prevent cerebral ischemia neurons continue to degeneration and necrosis, to improve endogenous BDNF expression levels has an important significance in protection of neurons after cerebral ischemic injury.At present, the GPⅡb/Ⅲa receptor antagonists in acute ischemic stroke is basically the intravenous injection, the effect on intra-arterial medication, safety, and dosage has been rarely reported at home and abroad. Tirofiban as an efficient, highly selective GPⅡb/Ⅲa receptor antagonist, a novel mechanism of action, clinical efficacy, safety, good, is a very promising therapy.This paper includes two parts. Experimental study on Tirofiban combined Urokinase selective intra-arterial thrombolysis in the middle cerebral artery occlusion was studied in part one, which including2experients:In first experiment, a middle cerebral artery occlusion (MCAO) animal model in rabbits were established with intervention technique, to provide a new model for image diagnosis and superselective intra-arterial contacting thrombolytic treatment and evaluating the technique feasibility and stability. In second experiment, efficacy and safety of Tirofiban combined Urokinase selective intra-arterial thrombolysis in the rabbit MCAO model was investigated. The recanalized rate, relative-apparent diffusion coefficient (rADC) and the neurologic function deficit score were compared among them. After24h, the animals were sacrificed and brain tissues were stained by chlorination-2,3,5-triphenyl tetrachloro and given light microscopy morphological examination. Therapeutic effects and safety of Tirofiban combined Urokinase in clinic were studied in part two, which including2trials:In first experiment, efficacy and safety of intra-arterial Tirofiban combined Urokinase was investigated when thrombus was acutely formed during electrolytic coil embolization of ruptured aneurysms. In second trial, the efficacy and risk of interventional Tirofiban and Urokinase thrombolysis for cerebral venous sinus thrombosis was studied.Objective:To establish a middle cerebral artery occlusion (MCAO) animal model in the rabbit with intervention technique, to be demonstrated by image diagnosis, given super-selective intra-arterial contacting thrombolytic treatment and evaluated the technique feasibility and stability.Methods:Autologous blood clot was cut into a0.5mm×0.4mm size with ophthalmic scalpel, which formed by lumbar puncture needle aspiration and scraping the intima of the rabbit ear artery. The rabbit was anesthetized and fixed and the proximal femoral artery of the rabbit was exposed. A microcatheter had been introduced into the internal carotid artery (ICA) under the guidance of the DSA. The rabbit autogenous arterial thrombosis were injected through the microcatheter to established the rabbit brain a middle cerebral artery occlusion model. Observed the cerebral vascular obstruction and infarction by DSA and MRI, the modified Bederson scoring for observing the.neurological deficits. Animals were sacrificed after24hours and pathological changes were observed by a light microscope and transmission electron microscope.Results:All the middle cerebral artery occlusion animal model were successful established, the animals survived24h after embolization. The position of the cerebral infarction was all located at the ipsilateral hemisphere, and the lesions situated in the parietal cortex, subcortex and basal nucleus. The mean infarction size at24h sacrifice was (44.08±5.13)%. There was statistically significant difference, mean velocity (Vm) of before MCAO compared with mean velocity (Vm) of MCAO2h later and5h later (P=0.000and P=0.000). There was no statistically significant difference between2h and5h MCAO model (P=0.908). Diffusion MRI, TTC stain and pathology showed infarction lesion site in the brain was consistentConclusion:The middle cerebral artery occlusion model (MCAO) established in rabbit by selectively intra-arterial autologous clot has the advantages of fewer Invasive, easyer survive, reliable embolization, appropriate infarct size. These study confirmed that MCAO model established with selectively intra-arterial autologus clots had a goog repeatablility and controllability, and can be used for early diagnosis of cerebral infarction and clinical thrombolysis study. Objective:To explore the efficacy and safety of intra-arterial Tirofiban Combined Urokinase Selective Intra-arterial Thrombolysis in the Middle Cerebral Artery Occlusion.Methods:The middle cerebral artery occlusion model (MCAO) was established by autologous clot in Japan male rabbits (n=60) were randomly assigned before performance into four groups. Each group was divided into two subgroups:subgroup A (n=10), subgroup B (n=5). Group Tirofiban (group T):animals received intra-arterial thrombolysis of tirofiban (5μg/kg) over a period of30min at2h after onset of MACO; Group Urokinase (group U):a intra-arterial infusion of Urokinase (20000U/kg) was given in animals over a period of30min at2h after onset of MACO; Group Tirofian+Urokinase (group T+UK):an infusion of Tirofian (3μg/kg) and Urokinase (10000U/kg) was given intra-arterially alternatively in animals over a period of30min at2h after onset of MACO; Group Control (group C):animals in group C only received an intra-arterial infusion of normal saline on the same condition. The recanalized rate, relative-apparent diffusion coefficient (rADC) and the neurologic function deficit score were compared among each subgroup A. Animals were sacrificed after24hours, the infarct volume was measured after TTC staining in10animals of each subgroup A. Pathological changes were observed by a light microscope, electron microscope and immunohistochemistry in each subgroup B.Results:The repatency rate in T+U group was90%, no hemorrhagic pathological was found. There were statistically significant differences, group T+U respectively compared with group C, group T, group UK in rADC, the neurologic function deficit score and percentage of cerebral infarction area (P=0.000,P=0.000and P=0.011; P=0.000, P=0.000and P=0.029; P=0.000,P=0.029and P=0.002). T+UK was better than other three groups, could significantly reduce brain injury and ameliorates neurological performance. Immunohistochemistry confirmed that BDNF in T+U group increased compared with group C, T and UK. Results in statistically significant difference (P=0.000, P=0.000and P=0.001). The electron microscope showed a nomal morphology of neuro, mitochondria mild swelling, cristae increase in group T+U, as well as neuronal mild degeneration, cell moderate swelling, mitochondrial moderate swelling, cristae increase, reducing the number of mitochondrial and cristae disappeared individually in group T and group U. Nuclear fast reduction, nuclear chromatin dissolution and cell structure disappearance were demonstrated in group C.Conclution:Intra-arterial combined tirofiban and urokinase thrombolysis in the rabbit middle cerebral artery occlusion model (MCAO) is better than intra-arterial single urokinase, which can promote reperfusion, decrease infarct volume, improve the microcirculation and reduce the intracerebral hemorrhage rate. Objective:To evaluate the efficacy and risk of interventional trofiban and urokinase thrombolysis for complicated thromboembolism during embolization of ruptured intracranial aneurysms with micro coil. Methods:12cases of ruptured intracranial aneurysms underwent acute thromboembolism during coil embolization, continued to complete aneurysms embolization from2010May to2011Februray in our hospital. Within1hour after thrombosis, all cases were given inventional Tirofiban and Urokinase thrombolysis combined with mechanical thrombus maceration under DSA surveillance. Angiogram was performed to assess vascular thrombolysis situation every10min, until the vascular complete or partial recanalization.Results:All are internal carotid artery system except one case of vertebral artery system.9cases achieved complete vascular recanalization after thrombolysis as confirmed on DSA studies, with negative cranial CT imagine manifestations after24h, no neurological deficits. Partial recanalization and mild neurological dysfunction was gained in1case, without intracranial hemorrhage after24h head CT check, died of myocardial infarction in recovery.1case achieved completely vascular recanalization was found the right frontal lobe hemorrhage with immediate postoperative CT scan, and paralysis of the left limbs, received conservative treatment and discharged with mild paralysis3months later.1case obtained most partial recanalization, while24h postoperative cranial CT showed cerebral infarction and cerebral edema. The patient was given decompressive craniectomy and discharged with residual right limb hemiparesis3months later.Conclusion:Intra-arterial Tirofiban and Urokinase thrombolysis is an effective and safe measure for complicated thrombosis duiring embolization of intracranial aneurysms with coil. Objective:To evaluate the efficacy and risk of interventional trofiban and urokinase thrombolysis for intracranial venous sinus thrombosis.Methods:9patients with intracranial venous sinus thrombosis were performed intravenous sinus urokinase and tirofiban thrombolysis combined with mechanical thrombus maceration from2009January to2011January.Results:After thrombolysis, symptoms and signs of8patients improved obviously and headache disappeared in7of them, but with only mild degree in other1and1died.7patients among them achieved recanalization of sinuses completely as confirmed on postprocedural DSA studies taken prior to hospital discharge, as well as normal intracranial pressure. Only1achieved recanalization of sinuses partly.Conclusion:Intravenous sinus urokinase and tirofiban thrombolysis is an effective and safe measure for potentially catastrophic intracranial dural sinus thrombosis.

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