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In order to dissolve a blood clot and restore the patency of a blood vessel, various treatments have been used. Direct or intravenous injection of thrombolytic agents, such as tissue plasminogen activator (tPA), urokinase(uPA), streptokinase (SK), has been used for the treatment of thrombosis. Direct injection of thrombolytic agents to the clot may increase the effectiveness of thrombolysis by enhancing the permeation of a thrombolytic agent into the blood clot. Injection velocity and methodology, such as continuous infuson and pulsed injection, would affect the thrombolytic efficiecy. In order to explore the effectivenesss of injection methods, we modeled clot dissolution numerically. Species transport equation was solved along with three dimensional momentum equations. The blood clots were modeled as prorous media. Pressure, velocity and species concentration fields were calculated by computational fluid mechanics methods. Two different thrombus models - arterial and venous thrombus - were simulated. The results showed that thrombolytic speed increased as the injection velocity increased, and intermittent injection was more efficient in dissolving clots comparing to comtinuous perfusion.

Trials of intravenous thrombolytic agents in acute stroke date back to the early 1960s. At that time, several trials of streptokinase, fibrinolysin and urokinase were performed and demonstrated either no effect or higher mortality in patients treated with thrombolysis [1, 2, 3]. Because these studies preceded CT scanning, patients with hemorrhage were not necessarily excluded. The discouraging results inhibited further acute stroke trials until the 1980 s when several reports appeared showing favorable outcomes with local intra-arterial thrombolytic therapy within a few hours of stroke onset [4,5]. These reports renewed interest in thrombolysis and led to several feasibility studies and small randomized trials of intravenous thrombolysis [6,7]. In 1995 the results of the National Institute of Neurological Disorders and Stroke (NINDS) intravenous tPA study, a multicenter, randomized, controlled trial of intravenous tPA for acute ischemic stroke, were published, demonstrating for the first time a beneficial effect of acute stroke treatment when given within three hours of onset [8] (Table 1). Open image in new window Table 1. Clinical trials of thrombolytic therapy for stroke

Some approaches to improve the thrombolytic profile of recombinant singlechain urokinase-type plasminogen activator (rsc-uPA, prourokinase) are briefly summarised below.

From the contents: Molecular Biology, Biochemistry, Physiology, and Pharmacology of the Plasminogen-Plasmin Enzyme System II: Clinical Use of Thrombolytic Agents: In Acute Myocardial Infarction Thrombolytic Treatment of Other Clinical Thromboembolic Conditions Thrombolytic Agents in Development, Biochemistry, Pharmacology, Efficacy in Animal Experiments and First Clinical Trials.The complete table of contents can be found on the Internet: http://www springer.de

Antifibrinolytic therapy constitutes an effective means to control or reduce bleeding and to limit or avoid blood transfusion in current medical practice. During the past 30 years it has been used as an established antidote in patients treated by thrombolytic agents and experiencing bleeding complications. Antifibrinolytic drugs have also been prescribed in patients developing clinical hyperfibrinolysis. However, use of these products has been limited to very specific situations involving small numbers of patients.

Acute myocardial infarction is the most common cause of death in men in the Western world. The treatment of this condition is no longer simply supportive, awaiting the complications of ischaemic injury, but has entered a new era where the mortality of acute myocardial infarction can be approximately halved by thrombolytic agents and aspirin (ISIS-2 1988), with the greatest benefit seen in those treated soon after the onset of symptoms. The lack of a reduction in mortality when thrombolytic treatment is administered late is most likely due to the fact that the prolonged coronary occlusion has resulted in such severe necrosis of the myocardium that little benefit can be derived by restoring blood flow (Reimer and Jennings 1979). Therefore any intervention that could delay the onset of tissue necrosis could buy valuable time by extending the effective temporal window for thrombolysis. Attempts to limit myocardial infarct size over the last decade with exogenous pharmacological agents have been largely unsuccessful (Hearse and Yellon 1983), prompting us and others to explore the heart’s endogenous protective mechanisms to ascertain if this route may provide us with the knowledge required to protect the myocardium from severe ischaemic injury.

Treatment of intracerebral hemorrhage (ICH) may include medical management or surgical evacuation. When bleeding is due to an arteriovenous malformation (AVM) treatment may include combined neurosurgical/neuroradiological approaches. Currently there are accepted indications for early evacuation by open craniotomy in some types of ICH. Where indicated, this approach can be expected to reduce mortality, but the effect on functional outcome is less certain. Japanese researchers have pioneered the use of endoscopic evacuation in acute stages, sometimes with local application of thrombolytic agents, but this approach needs to be tested in controlled trials with other modalities. In cases related to arteriovenous malformations, treatment can be improved by a joint neuro-radiological/neurosurgical approach.

As thrombolytic therapy developed as a potential intervention for acute ischemic stroke during the 1980s, early clinical investigation depended upon pretreatment cerebral arteriography [5]. The pathologic cerebral anatomy was first defined, and then thrombolytic therapy could be administered selectively to the site of thrombosis via the intra-arterial route [3, 6, 11]. These intra-arterial thrombolytic interventions, carried out with the benefit of computed tomographic (CT) scanning to exclude hemorrhagic stroke, demonstrated the feasibility of cerebral arterial clot lysis. Several thrombolytic agents administered in a variety of doses [3–6, 11–13] were shown to accomplish partial or complete arterial recanalization in the setting of acute cerebral embolism or thrombosis.

Several studies have proven the safety and efficaey of intravenous (IV) thrombolytic therapy in patients with acute myocardial infarction [26, 27]. Past trials of IV thrombolytic therapy in stroke patients have reported limited efficacy and a disturbing incidence of side effects [11, 14, 16]. Some researchers have indicated that these negative findings were due to poor patient selection, late therapy, and heterogenous drug administration techniques [3]. More recent trials of intra-arterial (IA) thrombolytic therapy in highly selected stroke patients have reported improved safety and efficacy [4, 13]. Because the IV administration of thrombolytic agents is logistically preferable and more widely feasible than IA infusions, it is appropriate to re-study the safety and efficacy of IV recombinant tissue plasminogen activator (rt-PA) in a select group of stroke patients.

The administration of thrombolytic agents and aspirin is now a well-established treatment package for selected patients with acute myocardial infarction [1, 2]. When successful, thrombolysis permits reperfusion of previously occluded coronary arteries, salvages ischemic myocardium, prevents left ventricular dysfunction, and enhances both early and late survival (Fig. 1). The overall incidence of complications or adverse reactions is very low, i.e., the benefit-risk ratio is favourable. Hemorrhage is the major complication, and intracranial hemorrhage is the most catastrophic form of hemorrhage following coronary artery thrombolysis. However, the results of large-scale trials show that the overall risk of stroke (of any type) is reduced after thrombolytic therapy (Table 1). In the prethrombolytic era, approximately 3% of patients with acute myocardial infarction developed a stroke either concurrently with the infarction or during the same hospitalization [3, 4]. The dominant form of stroke was a nonhemorrhagic infarct arising from thromboembolic disease, often in patients with atrial arrhythmias, or a large anterior wall infarction. The stroke rate in patients treated with thrombolytic therapy is l%–2% and nonhemorrhagic stroke remains the most common form of stroke, with a large anterior wall infarction being the major clinical correlate. The small excess of hemorrhagic strokes is usually heralded by symptoms such as nausea, vomiting, confusion, or lethargy, often progressing to coma.