Thrombolytic therapy in modern neurosurgery

Rozhchenko L.V.

Polenov Russian Neurosurgical Institute

Developing thrombosis is one of the main causes of rather spread diseases cardiovascular system. Thrombus formation leads to impairment or complete block of blood flow. Plasmin causes lysis of intravascular clots. This trypsin of the -like enzyme catalyzes fibrinolysis with subsequent formation of soluble substances. It results in restoration of blood flow. Plasmin is the most effective link of the fibrinolytic system. It is formed due to activation of plasminogen, being its predecessor.

Both plasminogen activation and coagulation are characterized by two mechanisms: external and internal (fig.1.). A leading internal mechanism is triggered by the same factors, which initiate blood coagulation. In particular, it is factor XIIa, interacting with prekallikrein and high-molecular kininogen (HMK) of plasma and activating plasminogen [1]. This basic mechanism of fibrinolysis ensures activation of plasmin not immediately after blood coagulation, but simultaneously with it. It is a "closed-cycle" mechanism, as the first formed amounts of kallikrein and plasmin cause proteolysis of factor XII by splitting off fragments, which accelerate transformation of prekallikrein into kallikrein. It is worth mentioning, that though components of the kallikrein-kininogen system have an auxiliary function in blood coagulation, they play one of the main parts in a humoral mechanism of fibrinolysis. An external mechanism of activation depends on tissue plasminogen activator (tPA), which is synthesized in endothelial cells, covering vessels. Secretion of tPA is a continuous process. Its enhancement is watched in response to various stimuli, among which one can enumerate thrombin, some hormones and drugs (epinephrine, vasopressin and its analogues, nicotinic acid), stress, shock, tissue hypoxia, surgical trauma. Plasminogen and tPA have close affinity to fibrin. When fibrin appears, plasminogen and its activator bind with it, forming a triple complex (fibrin- plasminogen-tPA), whose constituents are located so that to provide effective activation of plasminogen. Thus, plasmin is formed just on the surface of fibrin, subjected to further proteolytic degradation. The second natural activator of plasminogen is a urokinase-type activator, synthesized by renal epithelium, which has no affinity to fibrin in contrast to a tissue activator. Plasminogen activation takes place on specific receptors on the surface of endothelial cells and some formed elements of blood, directly participating in thrombus formation. In a normal state a level of plasma urokinase is several times higher, than that of tPA. An important role of a urokinase-type activator in healing of damaged endothelium has been reported [6].

Plasmin, formed under the influence of plasminogen activators, is an active short-life enzyme (a period of half-life in blood flow is 0.1 s), which causes proteolysis not only of fibrin, but also of fibrinogen, coagulation factors V, VII and other plasma proteins. Plasmin activity is controlled by some inhibitors; the main of them is quick-acting a-antiplasmin, asynthesized in the liver. It forms inactive complex with free plasmin, circulating in blood. Plasmin, formed on fibrin or cells' surface, is protected from an effect of a-antiplasmin. It is necessary to pay attention to a2-macroglobulin and an inhibitor of C1-esterase among other substances, inhibiting fibrinolysis and possessing a much weaker effect. The latter inhibits factor XIIa, kallikrein and partially plasmin, i.e. it blocks internal fibrinolysis. The second mechanism, limiting fibrinolysis, is inhibition of plasminogen activators. An inhibitor of plasminogen activator of an endothelial type (PAI-1) is the most important component from the physiologic point of view. This inhibitor inactivates both tissue- and urokinase-type activators and is synthesized in endothelial cells, thrombocytes and monocytes. Its secretion can be enhanced due to an effect of a tissue-type plasminogen activator, thrombin, cytokines, mediating inflammation, and bacterial endotoxins. Besides an enzymatic fibrinolytic system there is a system of non-enzymatic fibrinolysis. It is dependent on complex combinations of heparin with hormones and coagulation system components (heparin-antithrombin III-epinephrine complex is the most active one). Non-enzymatic fibrinolysis is of peculiar importance for preservation of a liquid state of blood and prevention of thrombi formation in stress situations, as it turns epinephrine from a risk factor into an anticoagulative system component. Non-enzymatic fibrinolysis is not inhibited by antiplasmins and, functions under physiologic conditions, balancing subclinical shifts of the homeostasis system.

Pharmacologic dilution of blood clots can be achieved with the help of intravenous or intra-arterial infusion of plasminogen activators (fig.2.) [3, 55]. Today there are five generations of plasminogen activators. They differ from each other in their composition and origin. However, their activating effect is conditioned by proteolysis of one and the same peptide bond of plasminogen. All plasminogen activators have the same principle of action. Nevertheless, various types of activators are characterized by different sorption ability, which determines recognition and binding of an activator with a traumatic lesion zone. The first and second generations include natural activators of plasminogen. Urokinase and streptokinase are representatives of the first generation, having no evident affinity to fibrin. They cause powerful systemic activation of plasminogen in contrast to its tissue activator and prourokinase, possessing marked affinity to fibrin and activating plasminogen only on a clot surface. Development of technology of recombinant DNA and improvement of methods of chemical synthesis of biomacromolecules allowed to obtain a great number of new derivatives, which differed from natural activators and were ascribed to the third generation. Modified urokinase-fibrinogen has a more marked thrombolytic effect in comparison with urokinase, prolonged stay in blood flow and a weak impact on fibrinolysis systemic activation. Reteplasa, lanoteplasa, E6010 are mutant forms of tissue plasminogen activator, characterized by prolonged stay in blood flow and a higher thrombolytic effect against a background of lesser exhaustion of hemostatic blood proteins. Saruplasa is a mutant form of prourokinase with more powerful catalytic activity. Mutant plasminogen, in contrast to natural plasminogen, is transformed into plasmin by thrombin. Chimerical activators of plasminogen were received with the help of genetic engineering. Creation of such derivatives is based on binding a catalytic portion of plasminogen activators, which ensures plasmin formation, with protein molecule fragments, capable of recog-nizing a thrombosis zone. It should be proteins, promoting binding and accumulation of such an agent in this zone. The first type of chimerical molecules consists of fragments of monoclonal antibodies to fibrin and prourokinase with low molecular mass. Activation of a urokinase activator in this biomolecule is dependent on thrombin; thus, this chimerical form is specific in relation to fresh thrombi. The second type of chimerical activators is represented by fragments of monoclonal antibodies to fibrin, which are bound to a tissue activator of plasminogen. Modelling of thrombosis in monkeys showed, that this chimerical protein had caused more effective thrombolysis in comparison with plasminogen tissue activator and prourokinase. Chimerical derivatives of the third type consist of parts of tissue plasminogen activator and a catalytic part of urokinase. They ensure effective thrombolysis in lower doses, than those of natural activators. As for chimerical derivatives of the fourth type, P-selectin and annexin V are used as a part, capable of recognition. P-selectin is a protein, synthesized by endothelium and thrombocytes; it provides thrombocyte adhesion and accelerates thrombus formation. Annexin V targets a plasminogen activator at thrombus thanks to it ability to bind with membranes of activated thrombocytes. A catalytic part is represented by fragments of tissue plasminogen activator and prourokinase. Practically, these chimeras are not inhibited by PAI-1. Appearance of a great number of chimerical derivatives raises a problem of their use in reality. Possible limiting factors are high cost of their production and necessity of profound immunologic estimation of these chimeras as absolutely new biological molecules. Plasminogen activators of the fourth generation were received by means of combining methods of biological and chemical synthesis. Thrombolytic compounds of the fifth generation presuppose combined administration of various plasminogen activators with a complementary mechanism of action and different pharmacokinetic profile. It results in reliable achievement of effective thrombolysis in vitro [4, 5]. For example, let us dwell on use of tPA as a thrombolysis trigger and urokinase-fibrinogen covalent conjugate as a means, supporting a thrombolytic effect, which it possesses thanks to its prolonged stay in blood flow. Study on a model of venous thrombosis in dogs was indicative of a quick and significant effect in moderate exhaustion of hemostatic blood proteins [4]. This derivative consists of small doses of the above components, which are 4-20 times lower, than those used in monotherapy. It can give considerable reduction of thrombolytic therapy cost, limiting its spread.

At present there are four plasminogen activators, allowed for use or being in the process of clinical trials. They are streptokinase, urokinase or a two-chain urokinase type of plasminogen activator, prourokinase or a recombinant one-chain urokinase type of plasminogen activator and a recombinant tissue activator of plasminogen (reteplasa) [3, 4].

E.I. Chasov was the first physician in the world, who succeeded in use of a thrombolytic preparation for coronary thrombolysis in 1975 [6]. Thrombolytic therapy is not a rare phenomenon in modern neurosurgery table 1.

Table 1.

Use of thrombolytic therapy in neurosurgical practice

Indications Contraindications
  • Lysis of subarachnoid clots after cerebral aneurysm rupture for prevention of vasospasm and hydrocephalus
  • Treatment of intraoperative thromboembolic complications in endovascular interventions
  • Treatment of acute thrombosis of cerebral arteries and sinuses (in combination with surgical treatment)
  • Treatment of intracerebral and intraventricular hypertensive and traumatic hematomas in adults and children
  • Internal hemorrhages
  • Stroke, suffered during previous 6 months
  • Hemorrhagic diathesis
  • Acute traumas of the spinal cord, thorax or abdomen
  • Gastrointestinal, gynecologic or urologic hemorrhages during previous three months
  • Severe pericarditis
  • Marked diabetic retinopathy
  • Hepatocirrhosis with varicosis of esophagus veins
  • Arterial hypertension of more than 180/110 mm Hg

Multiple reports on intrathecal fibrinolysis in patients with aneurysmal subarachnoid hemorrhages confirm efficacy of such therapy in prevention of vasospasm [23, 48, 49, 53, 71]. Coagulation of blood from aneurysm results in disorders both of liquor circulation and a process of eliminating blood from a subarachnoid space. Biologically active substances, formed in destruction of blood cells, maintain vasospasm. A natural process of eliminating blood and products of its disintegration from liquor lasts from 20 days up to 1.5-2 months. As complete removal of blood clots from basal cisterns during an intervention is impossible, it is both physiologic and expedient to use postoperative intrathecal irrigation of thrombolytic drugs, allowing to eliminate blood from a subarachnoid space during 1-2 days [51, 59, 71].

Research in coagulating and fibrinolytic activity of liquor and plasma, carried our in patients with vasospasm after aneurysm rupture, was indicative of an increase of PAI-1 concentration. It is conditioned by impaired vascular permeability and activation of its secretion by endothelial cells, thrombocytes, fibroblasts. It results in deceleration of clots solubility in basal cisterns and vasospasm progression [37]. A high level of PAI-1 in liquor can be an important marker of vasospasm development and progression. Besides, there is a persistent increase of thrombin-antithrombin III complex in liquor of patients with developing vasospasm [19]. A high level of PAI-1 in liquor can be an important marker of vasospasm development and progression. Besides, there is a persistent increase of thrombin-antithrombin III complex in liquor of patients with developing vasospasm [38], secondary release of serotonin, arachidonic acid, a factor of thrombocyte aggregation [12], leading to vasospasm progression [23, 59].

Zabramski M. et al. [71] ţwere the first to report successful use of tPA in 10 patients with aneurysm rupture (the IIIrd and IVth stages according to Hunt and Hess). They were operated on the 1st-3rd day after hemorrhage. The authors administered tPA in a dose of 1.5 mg (three intracisternal injections of 0.5 mg each every 8 hours). Complete lysis of blood clots in basal cisterns was watched in a day after operation. There were no complications. It resulted in a lesser degree of vasospasm in 9 out of 10 patients.

Kodama et al. [43] made an analysis of the results of subarachnoid use of urokinase in combination with ascorbic acid after aneurysm clipping. Prolonged intracisternal infusion of urokinase was carried out in 217 patients (the IIIrd group according to Fischer's scale). It was done during 2-18 days (9.9 days on the average). Doses of urokinase and ascorbic acid were 120 IU/ml and 4 mg/ml respectively; a rate of infusion was 30 ml/h. Yoshida M. [43] was the first to use irrigation of urokinase into a subarachnoid space with the purpose of vasospasm prevention. The first intrathecal administration of ascorbic acid was performed by Omoto T. [43] in 1978. This thrombolytic mixture reduced the rate of vasospasm and hemorrhagic complications up to 3.7% and 1.9% respectively.

In 1994 Usui M. et al. [67] informed about 111 patients, operated during 48 hours since the moment of aneurysm rupture. They were subject to thrombolytic therapy in a postoperative period. Prolonged intracisternal irrigation of urokinase in a dose of 60 000 IU in 500ml of saline (120 IU/ml administered at a rate of 21 ml/h during 7 days) was used in 60 of them; 22 patients were treated with endolumbar administration of tPA in a dose of 0.042-1.0 mg, prescribed in a day after aneurysm clipping; 29 patients represented a control group. The authors demonstrated efficacy of intrathecal thrombolytic therapy in eliminating blood clots from basal cisterns and Sylvius sulcus and reducing a degree of vasospasm severity (the rate of vasospasm in a control group, in urokinase and tPa groups was 50%, 22.9% and 11.8% respectively). If thrombolysis is started in 24 hours after an operation, it results in reduction of a risk of possible intracranial hemorrhages up to 0.9%.

Kawada et al. [44] analyzed the results of intracisternal use of tPA in patients with intracranial aneurysms, whose necks were embolized with cellulose acetate during the first three days after hemorrhage. A single dose of tPA (1-2 mg) was administered through lumbar drainage immediately after an operation. There were no hemorrhagic complications; the vasospasm rate was equal to 13%.

Reports on intraoperative bolus administration of tPA are indicative of a higher risk of hemorrhagic complications, reaching 13%. Findlay J. et al. [23], studied 15 patients, who underwent operations for aneurysms (the IIIrd degree according to Hunt and Hess). Intraoperative administration of 10 mg of tPA into basal cisterns was made after aneurysm clipping. According to CT findings, there was complete elimination of blood clots from a subarachnoid space within 24 hours after an operation. Moderate vasospasm, was observed in 5 patients (33%); there were no cases with severe vasospasm.

Some experimental studies of the last five years were devoted to combined use of thrombolytic preparations and substances, being their potential assistants [15]. Experimental randomized study, carried out in monkeys by Kim C.J. et al., [42] demonstrated efficacy of vasospasm prevention by simultaneous injection of tPA and BQ-123, being an antagonist of endothelin receptor. A role of potential vasoconstrictive peptides or the so-called endothelins, in vasospasm pathogenesis is well-known. A-endothelin receptors mediate vasoconstriction and B-endothelin receptors are vasodilation mediators [38, 48]. Endothelin-1 leaves endothelium in response to direct stimulation by free hemoglobin and induces vasospasm through A-endothelin receptors. Combined use of BQ-123 selective antagonist of these receptors (10 mg/day) and tPA (1 mg three times every 12 hours after hemorrhage) during 7 days allowed to achieve complete elimination of blood clots from a subarachnoid space and a twofold decrease of vasospasm in comparison with a control group.

Kajimoto Y. et al. [40] carried out experimental study in dogs, estimating simultaneous administration of urokinase in a dose of 120 IU/ml at a rate of 4 ml/h and plasminogen in a dose of 90 IU/ml. Taking into account, that plasminogen concentration in liquor is ten times lower than in plasma even after hemorrhage, it can be a limiting factor in clot lysis. The authors came to a conclusion, that preliminary administration of exogenous plasminogen led to improvement of lytic properties of urokinase and, as a result, dose reduction. It is a very important information, as fibrinolytic preparations have a dose-dependent effect and increase of a dose is associated with higher probability of intracranial hemorrhage [24, 53, 71]. Besides, the authors proved, that thrombolytic drugs, administered into a subarachnoid space, did not penetrate into blood flow. Thus, there was no activation of systemic fibrinolysis.

Blocking of basal subarachnoid spaces by blood clots after aneurysm rupture leads to impaired liquor absorption, persistent increase of intracranial pressure and liquorodynamic disorders during the first week after hemorrhage [23]. Brinker T. et al. [10] studied an effect of intrathecal fibrinolysis on hydrocephalus development. They used a single dose of tPA (3 mg), administered in 24 hours after experimental hemorrhage. In comparison with cats, receiving no treatment, animals, treated with tPA, had smaller resistance to liquor resorption; a size of the ventricular system was practically normal. Thus, fibrinolytic preparations can accelerate elimination of blood from a subarachnoid space and restore liquor circulation. It has a positive effect on a vasospasm course and hydrocephalus. Hansen A. et al. [33] discovered a high level of PAI-1 in liquor (94 pg/ml) of some patients with acute hydrocephalus, treated with tPA. It is known, that increase of PAI-1 level results in inhibition of fibrinolysis in liquor and a more marked adhesive process in basal cisterns [23, 53, 59]. Detection of a high level of PAI-1 in liquor after hemorrhage is an important prognostic sign of developing chronic hydrocephalus, whose prevention demands administration of higher doses of thrombolytic preparations [33].

Nieuwkamp D. J. [52] analyzed the results of treatment of 343 patients with severe cerebroventricular hemorrhage (cases with primary ventricular hemorrhages were not taken into account). Intraventricular hematomas, as complications of aneurysmal sunarachnoid hemorrhages, were present in 1/3 of patients. In hypertensive intracerebral hemorrhages outflow of blood into ventricles was observed in 70-85% of cases. The rate of fatal outcomes in conservative treatment was equal to 78%. Mortality in external ventricular drainage and its combination with fibrinolytic therapy was 58% and 6% respectively. As for invalidism, the indices were as follows: conservative treatment - 90%, external ventricular drainage - 89%, its combination with fibrinolytic therapy - 34%. These data show, that elimination of intraventricular clots with the help of thrombolytic therapy gives considerable improvement of treatment results. Fear of hemorrhagic complications, developing after thrombolytic therapy, turned out to be groundless. According to CT findings, increase of hematoma volume 16 hours after infusion was watched only in one of 49 patients, receiving tPA (2%).

Use of thrombolytic preparations for minimizing a traumatic effect of intracerebral hematoma removal is justified. Stereotactic removal of intracerebral hematomas with subsequent administration of prourokinase is an alternative to an open intervention, as it is characterized by a minimum risk of recurrent hemorrhages. Its good clinical effect and quick regress of neurologic symptoms are proved by a number of authors [2, 7, 57]. There are reports on single use of 5 mg of tPA for treatment of traumatic intraventricular hematomas, complicated by occlusive hydrocephalus [26].

Endovascular operations in neurosurgery are becoming more and more popular. They are connected with a risk of immediate and delayed thromboembolic and ischemic complications, conditioned by technical aspects. According to Qureshi A.I. et al. [55], a risk of thromboembolic complications in diagnostic angiography and endovascular occlusions with detachable spirals was 1-2.6% and 8.2% (127 out of 1547 patients) respectively. A risk of thromboembolism in endovascular occlusion with a balloon reached 11-19%. The rate of ischemic disorders due to thrombo-embolism, embolizing agents and vasospasm in embolization of arterio-venous malformations was 21% (213 out of 1011 patients). Treatment of thromboembolic complications is often carried out with selective intraarterial administration of thrombolytic preparations. Administration of 500 000 units of urokinase in the form of prolonged intraarterial infusion, supplemented by mechanical fragmentation of clots or angioplasty in case of delayed efficacy of pharmacological recanalization, turned out to be successful. Prourokinase in a dose of 6-9 mg is used successfully for intraarterial thrombolysis too [41]. Bolus intravenous administration of heparin in a dose of 70 IU/kg, preceding use of thrombolytic preparations, proved to be effective. A heparin dose should be tested from the point of view of a number of APTTs; it should not be 1.5-2 times higher than control indices. Post-thrombolytic use of heparin prevents reocclusion of arteries. However, one should be very careful, when high doses of heparin and tPA are administered simultaneously with the purpose of reducing a risk of hemorrhagic complications, as heparin possesses a direct stimulating effect on tPA activity, resulting in conformation changes in tPA and its transformation into a form, which is more available for interaction with plasminogen [46].

Cronqvist M. (1998) [18] ţdescribes his strategy of treatment and clinical outcomes of 19 (5.4%) thromboembolic complications, watched in embolization of 352 intracranial aneurysms. Immediate fibrinolytic therapy was used in all these cases. Thromboembolic complications took place during an operation in 18 patients and during an hour after it in one case. Urokinase in a dose of 150-200 000 IU was administered at a rate of 20 000 IU/min during 30-60 min. Complete recanalization was achieved in 10 patients (53%), partial - in 9 cases (47%). Complete and partial recanalization was watched respectively in 9 and 5 patients out of 14 cases (74%) with good results. Zeumer H. [72] informs about the rate of recanalization of acute arterial thrombosis, arising during endovascular operations, equal to 96%. As for other authors, this rate is as follows: Barnwell S.L. [9] - 77%, ╠ţri F. [50] - 45%, Hacke W. [31] - 44%, Sazaki O. [59] observed complete or partial recanalization in 74% of patients. Complications of fibrinolytic therapy were typical of 3 cases; two of them had repeated aneurysm rupture (they were subject to embolization in a hemorrhagic period of aneurysm); one patient developed hematoma in an ischemic focus. In order to avoid such complications, fibrinolytic drugs should be used only in case of complete exclusion of aneurysm from blood flow [14, 68].

The rate of thrombolytic complications in angioplasty of stenosed major cerebral vessels varies from 4.3% up to 5.9% [55] They are conditioned by migration of intima scraps or thrombi, formed on damaged intima of a widened artery, into blood flow. It is known, that secretion of tissue coagulation factors begins within 24 hour after endothelium damage; an increased level of thrombin is watched after 72 hours. Damaged epithelium and synthesis and secretion of plasminogen activators and PAI-1 are restored in 2 and 4 weeks respectively [16]. Thrombosis of cerebral arteries, developing after angioplasty, is to be treated with thrombolytic preparations. Local fibrinolysis is indicated in case of postoperative thrombosis of ICA with floating clots, spreading up to the skull base. It is contraindicated in patients with marked disorders of consciousness and thrombosis, involving lenticulostrial arteries [40]. In such cases intraarterial administration of thrombolytic drugs should be started at an extremely early stage (1.5-2 hours). According to Komiyama H. et al. [45], diagnosis of complications should be immediately followed by administration of 5.2 mg tPA in 10 ml of saline and 5000 IU of heparin via a diagnostic catheter, placed in an embolic area. The authors recommend prophylactic admi-nist-ration of tPA at the stage of preparation for angioplasty.

Recent studies show, that systemic activation of PAI-1 in plasma after balloon angioplasty or its initial high level are a favorable prognostic factor in restenosis prevention [16]. On the contrary, reduction of thrombin-antithrombin III complex in plasma after tPA infusion and subsequent increase of its concentration above the initial level can be a prognostic factor, indicative of a risk of rethrombosis after successful recanalization.

Use of tPA in acute ischemic stroke within 3 hours from the moment of its onset was permitted in 1996. Since that time there appeared a lot of reports, devoted to the results of treatment. Jahar R. [39] Jahar R. administered urokinase to 26 patients with acute ischemic stroke within 6 hours from its onset. Good results were obtained in 14 patients. Complete or partial recanalization of thrombosed artery and intracranial hemorrhage were observed in 11 and 10 out of 26 cases respectively. Three patients with intracranial hemorrhage died. Recanalization of thrombosed arteries promoted achievement of good results. Alberts M. J. [8] studied 100 patients with ischemic stroke, who received tPA within 3 hours since its onset. He came to the conclusion, that thrombolytic preparations should be regarded as a new strategy in stroke treatment [8]. Intracranial hemorrhages as complications of thrombolysis were watched by the author in 9% of patients (3% of them died). According to Del Zoppo G.L., [19] successful recanalization of cerebral arteries after intraarterial administration of urokinase and alteplasa took place in 21-72% of cases. Wardlaw [68] reported 46.8% of good outcomes in 3435 patients with acute ischemic stroke, who got tPA within 3 hours since its onset. Intracranial hemorrhages were watched in 6.2 % of observations; 1.8% of patients died; 29% of cases became invalids. Qureshi A. I. [57] described 8 patients, who underwent intraarterial superselective tPA thrombolysis (40 mg) within 1-8 hours since the disease onset. A marked improvement was present in a half of patients; 2 cases had intracranial hemorrhage.

Ekseth K. et al. [21] informed about successful treatment of three patients with severe thrombosis of dural sinuses with the help of open thromboectomy, supplemented by local thrombolysis (8 mg of tPA). All patients returned to their usual way of life, though, according to existing data, mortality in sinus thrombosis is as high as 49%. Neurologic deterioration, a failure of adequate anticoagulant treatment and intensive care are indications for thromboectomy and local thrombolytic therapy.

Fray J.L. [24] ˝reported 12 patients with thrombosis of upper sagittal, transverse and sigmoid sinuses, watched from the first up to the 40th day since its onset and treated with long-term intradural administration of tPa in a dose of 1-2 mg/h. An average dose was equal to 46 mg (23-123 mg), administered during 29 hours. Sinus patency was restored completely in 9 out of 12 patients; hemorrhagic complications were watched in 3 cases (hematoma was evacuated in one of them). Horowits M. [36] described 13 patients, who were treated successfully with intradural urokinase infusion. Despite presence of brain infarction before infusion in 5 patients (they were hemorrhagic in 4 cases), long-term administration of thrombolytic preparations gave good clinical results in 10 out of 12 observations.

Even a simple enumeration of neurosurgical diseases, which can be treated with thrombolytic preparations, makes one think about unrealized possibilities. There is no doubt, that preparations for immediate coping with thromboembolic complications of intravascular interventions, watched in 5.4-21% of cases, are worth using. Possible selective intraarterial administration of thrombolytic drugs via an operating catheter allows to use average doses, i.e. 500 000-1 000 000 IU of urokinase, 6-9 mg of prourokinase and 5-20 mg of tPA in combination with bolus administration of 5000-7000 IU of heparin. Thanks to thrombolytic drugs, reduction of the rate of ischemic strokes, watched during minimum invasive operations in case of development of thromboembolic complications, reaches 50-90%.

One should pay attention to the fact, that doses, used for intathecal lysis of subarachnoid intracerebral and intraventricular clots, are much lower (0.33-1.5 mg of tPA and up to 60 000 IU of urokinase). It is explained by a considerably longer half-life of thrombolutic preparations in liquor in comparison with blood (tPA lives in blood flow during 5-8 minutes; as for liquor, this figure is equal to 3 hours). Absence of systemic hemorrhagic complications, a small rate of intracranial hemorrhages (0.9-2%) against a background of a marked clinical effect prove, that this trend is very promising. Mortality in acute thrombosis of dural sinuses is equal to 49%. Long-tern intradural infusion of rather high doses of tPA (8-120 mg) results in restoration of sinus patency in 75-80% of cases; the rate of hemorrhagic complications is about 20%. Reports on use of thrombolytic preparations in acute ischemic strokes, caused by thrombosis and severe stenosis of major cerebral vessels, are less optimistic. However, one should take into account imperfect organization of emegency care, rendered to this category of patients. Today it is hardly possible to imagine a situation, when a period of time, passing between a patient's admission to a specialized hospital, his angiographic examination and the moment of the disease onset and beginning of thrombolytic therapy, is not more than 3 hours. Intravenous use of high doses of fibrinolytic drugs (more than 40 mg of tPA, 1500 000 IU of urokinase or streptokinase) leads to recanalization of thrombosed arteries and improvement of treatment results in 42-47% of cases; intracranial hemorrhages occur in 9-38% of observations, every third episode is fatal.

Summarizing the above-mentioned information, one can say, that thrombolytic preparations as a natural biological protective system are sure to occupy an important place in neurosurgical practice of the nearest future. Further and more precise determination of indications and necessary therapeutic doses, use of thrombolytic mixtures with the purpose of achieving lower cost of thrombolytic therapy, will allow to ensure less traumatic and more successful treatment of some serious complications of neurosurgical diseases.

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