Arterial occlusion

Thrombolytic Enzymes. Although atherosclerosis and the accompanying vascular wall defects are ultimately responsible for such diseases as acute pulmonary embolism, arterial occlusion, and myocardial infarction, the lack of blood flow caused by a fibrin clot directly results in tissue injury and in the clinical symptoms of these devastating diseases (54). Thrombolytic enzyme therapy removes the fibrin clot by dissolution, and has shown promise in the treatment of a number of thrombo-occlusive diseases (60). 

Indications for treatment with streptokinase include acute occlusion of arteries, deep vein thrombosis, and pulmonary embolism. Streptokinase therapy in coronary thrombosis, which is the usual cause of myocardial infarction (54,71,72), has proved to be valuable. In this frequently fatal condition, the enzyme is adrninistered intravenously at a dose of 1.5 million units over 60 min, or given by intracoronary infusion at a 20,000- to 50,000-unit bolus dose followed by 2000 to 4000 units/min for 60 min therapy must be instituted as soon as practicable after the diagnosis of heart attack is made. For deep vein thrombosis, pulmonary embolism, or arterial occlusion, streptokinase is infused at a loading dose of 250,000 units given over 30 min, followed by a maintenance dose of 100,000 units over a 60-min period. 

Many serious health problems result from abnormally located blood clots heart attacks (clots in coronary arteries), pulmonary embolism (clots in the lungs), and peripheral arterial occlusion and deep vein thrombosis (clots in the limbs). Each year heart attacks alone afflict over a million people in the United States, and almost half of them die as a result. 

At the other extreme are those acute stroke patients who have no visible arterial occlusion whatsoever, presumably because their infarcts were due to lesions in small arteries that cannot be imaged, or because an embolus in a large proximal artery has broken up spontaneously. Several smdies (again using catheter angiography rather than CTA) have shown that such patients generally enjoy relatively favorable outcomes. 

Slivka A, Murphy E, Horrocks L. Cerebral edema after temporary and permanent middle cerebral artery occlusion in the rat. Stroke 1995 26 1061-1065. 

Lin W, Celik A, Derdeyn C, An H, Lee Y, Videen T, Qstergaard L, Powers WJ. Quantitative measurements of cerebral blood flow in patients with unilateral carotid artery occlusion a PET and MR study. J Magn Reson Imaging 2001 14 659-667. 

Endo H, Inoue T, Ogasawara K, Fukuda T, Kanbara Y, Qgawa A. Quantitative assessment of cerebral hemodynamics using perfusion-weighted MRI in patients with major cerebral artery occlusive disease comparison with positron emission tomography. Stroke 2006 37 388-392. 

Ischemic stroke has numerous causes. Cerebral infarction may result from large artery atherosclerosis, cardiac embolism, small artery lipohyalinosis, cryptogenic embolism, or, more rarely, from other diverse conditions such as arterial dissection, infective endocarditis, and sickle cell disease. Arterial occlusion is the cause of at least 80% of acute cerebral infarctions. " ... 

Decreased cerebral blood flow, resulting from acute arterial occlusion, reduces oxygen and glucose delivery to brain tissue with subsequent lactic acid production, blood-brain barrier breakdown, inflammation, sodium and calcium pump dysfunction, glutamate release, intracellular calcium influx, free-radical generation, and finally membrane and nucleic acid breakdown and cell death. The degree of cerebral blood flow reduction following arterial occlusion is not uniform. Tissue at the... 

Preclinical studies have suggested that early thrombolysis, within 3.5 hours of arterial occlusion, resulted in neurological improvement with an acceptable risk of secondary central nervous system hemorrhage. ... 

Middle Cerebral Artery Occlusion and the PROACT Trial The safety and efficacy of lAT in the anterior circulation have been evaluated in two randomized, multicenter, placebo-controlled trials. In the Prolyse in Acute Cerebral Thromboembolism (PROACT) 1 and 11 trials, patients with proximal MCA (Ml or M2 segment) occlusions within 6 hours of symptom onset were treated with recombinant prourokinase (r-pro-UK) or placebo. ... 

Internal Carotid Artery Occlusion Acute stroke due to a distal ICA T (T = terminus) occlusion carry a much worse prognosis than MCA occlusions. In a recent analysis of 24 consecutive patients (median NIHSS 19) presenting with T occlusions of the ICA who were treated by lAT using urokinase at an average of 237 minutes from symptom onset, only four patients (16.6%) had a favorable outcome at 3 months. Partial recanalization of the intracranial ICA was achieved in 15 (63%), of the MCA in 4 (17%), and of the ACA in 8 patients (33%). Complete recanalization did not occur. The presence of good leptomeningeal collaterals and age <60 years were the only predictors of a favorable clinical outcome. New treatment strategies, such as the combination of IV rt-PA and lAT, or the use of new mechanical devices may improve the outcome in these patients. 

Lindsberg and Mattle ° recently analyzed published case series reporting on the outcome of basilar artery occlusion (BAO) after lAT or IV thrombolysis. In 420 BAO patients treated with IV thrombolysis (76) and lAT (344), death or dependency was equally common 78% (59 of 76) and 76% (260 of 344). Recanalization was achieved more frequently with lAT (225 of 344 65%) than with IV thrombolysis (40 of 76 53% p = 0.05), but survival rates after IV thrombolysis (38 of 76 50%) and lAT (154 of 344 45%) were equal (p = 0.48). A total of 24% of patients treated with lAT and 22% treated with IV thrombolysis reached good outcomes (p = 0.82). Without recanalization, the likelihood of achieving a good outcome was close to nil (2%). The authors conclude that recanalization occurs in more than half of BAO patients treated with lAT or IV thrombolysis, and 45-55% of survivors regain functional independence. They advised that hospitals not equipped for lAT should consider setting up IV thrombolysis protocols for BAO since the effect of IVT did not appear to be much different from the effect of lAT. 

Direct Fibrinolytics Alfimeprase is a recombinant tmncated form of fibrolase, a fibrinolytic zinc metalloproteinase isolated from the venom of the Southern copperhead snake. It degrades fibrin directly and achieves thrombolysis independent of plasmin formation. This may result in faster recanalization and a decreased risk of hemorrhagic conversion. The initial data on the safety and efficacy of alfimeprase in peripheral arterial occlusion disease appeared very promising, but recent communication from the sponsor revealed that the phase III trials of the drug in peripheral arterial disease and catheter obstruction (NAPA-2 and SONOMA-2) failed to meet their primary and key secondary endpoints of revascularization. A trial for I AT in acute stroke (CARNEROS-1) is planned to begin soon. 

The efficacy of IV thrombolysis in patients with moderate-to-severe strokes due to proximal arterial occlusions is restricted by several factors, including the relatively short therapeutic window, poor recanalization rates as the clot burden increases, restrictive eligibility criteria, and the risk of intracerebral hemorrhage. Endovascular techniques improve the rates of recanalization in this patient population, and appear to increase the likelihood of a good functional outcome. Intravenous thrombolysis... 

Yu W, Binder D, Foster-Barber A, Malek R, Smith WS, Higashida RT. Endovascular embolectomy of acute basilar artery occlusion. Neurology 2003 61 1421-1423. 

Sussman BJ, Fitch TS. Thrombolysis with lihrinolysin in cerebral arterial occlusion. J Am Med Assoc 1958 167 1705-1709. 

Zaidat OO, Suarez Jl, Santillan C, Sunshine JL, Tarr RW, Paras VH, Selman WR, Landis DM. Response to intra-arterial and combined intravenous and intra-arterial thrombolytic therapy in patients with distal internal carotid artery occlusion. Stroke 2002 33 1821-1826. 

Lindsberg PJ, Mattie HP. Therapy of basilar artery occlusion a systematic analysis comparing intra-arterial and intravenous thrombolysis. Stroke 2006 37 922-928. 

Eckert B, Koch C, Thomalla G, Roether J, Zeumer H. Acute basilar artery occlusion treated with combined intravenous Abciximab and intra-arterial tissue plasminogen activator report of 3 cases. Stroke 2002 33 1424-1427. 

Bergui M, Stura G, Daniele D, Cerrato P, Berardino M, Bradac GB. Mechanical thrombolysis in ischemic stroke attributable to basilar artery occlusion as first-line treatment. Stroke 2006 37 145-150. 

Veznedaroglu E, Levy El. Endovascular management of acute symptomatic intracranial arterial occlusion. Neurosurgery 2006 59 S242-S250. 

Jovin TG, Gupta R, Uchino K, Jungreis CA, Wechsler LR, Hammer MD, Tayal A, Horowitz MB. Emergent stenting of extracranial internal carotid artery occlusion in acute stroke has a high revascularization rate. Stroke 2005 36 2426-2430. 

Izumi Y Roussel S, Pinard E, Seylaz J. Reduction of infarct volume by magnesium after middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab 1991 11 1025-1030. 

Corbett D, Hamilton M, Colboume F. Persistent neuroprotection with prolonged postischemic h3fpothermia in adult rats subjected to transient middle cerebral artery occlusion. Exp Neurol 2000 163 200-206. 

Weinstein PR, Anderson GG, Telles DA. Results of h3fperbaric oxygen therapy during temporary middle cerebral artery occlusion in unanesthetized cats. Neurosurgery 1987 20 518-524. 

The timing of CEA after ischemic stroke has been a controversial issue. In 1969, the Joint Study of Extracranial Arterial Occlusion reported 42% mortality after CEA in patients with neurological deficits of less than 2 weeks duration, compared with 5% mortality in patients with more than 2 weeks of symptoms. Early evidence also demonstrated an increased risk of intracerebral hemorrhage after early CEA in patients with acute stroke. This led to the conclusion that most complications occurred with early surgical intervention, and resulted in a traditional 4-6 week delay for CEA after an acute stroke. In retrospect, however, there were major problems with patient selection in these earlier reports. Many of the patients... 

Blaisdell WE, Clauss RH, Galbraith JG, Imparato AM, Wylie EJ. Joint study of extracranial arterial occlusion. IV. A review of surgical considerations. JAMA 1969 209 1889 1895. 

Straub S, Junghans U, Jovanovic V, Wittsack HJ, Seitz RJ, Siebler M. Systemic thrombolysis with recombinant tissue plasminogen activator and tirofiban in acute middle cerebral artery occlusion. Stroke 2004 35 705-709. 

KawaiN, Keep RE, Betz AL. Effects of hyperglycemia on cerebral blood flow and edema formation after carotid artery occlusion in Fischer 344 rats. Acta Neurochir Suppl 1997 70 34-36. 

Kiening KL. Schneider GH, Unterherg AE, Lanksch WR. Effect of tromethamine (THAM) on infarct volume following permanent middle cerebral artery occlusion in rats. Acta Neurochir 1997 70 188-190. 

The proposal that NO or its reactant products mediate toxicity in the brain remains controversial in part because of the use of non-selective agents such as those listed above that block NO formation in neuronal, glial, and vascular compartments. Nevertheless, a major area of research has been into the potential role of NO in neuronal excitotoxicity. Functional deficits following cerebral ischaemia are consistently reduced by blockers of NOS and in mutant mice deficient in NOS activity, infarct volumes were significantly smaller one to three days after cerebral artery occlusion, and the neurological deficits were less than those in normal mice. Changes in blood flow or vascular anatomy did not account for these differences. By contrast, infarct size in the mutant became larger... 

Lagiou, P. et al., Flavonoid classes and risk of peripheral arterial occlusive disease a case-control study in Greece, Eur. J. Clin. Nutr., 60, 214, 2006. 

Maroko, P.R., Kjeksus, J.K., Sobel, B.E., Watanabe, T., Covell, J.W., Ross, J., Jr and Braunwald, E. (1971). Factors influencing infarct size following experimental coronary artery occlusions. Circulation 43, 67-82. 

Martz, D., Rayos, G., Schielke, G.P. and Betz, A.L. (1989). Allopurinol and dimethylthiourea reduce brain infarction following middle cerebral artery occlusion in rats. Stroke 20, 488-494. 

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