Desmoteplase as a potential treatment for cerebral ischaemia.

INTRODUCTION: Desmoteplase is an investigational plasminogen activator found in the saliva of the vampire bat, Desmodus rotundus. It has been of scientific interest for over 25 years as it exhibits pharmacological properties that have led to the hypothesis that desmoteplase may be safer and more effective than recombinant tissue plasminogen activator (rtPA) in arterial thromboembolic disease, and in particular, acute ischaemic stroke (AIS). AREAS COVERED: In this review, the authors cover the pharmacological properties of desmoteplase, focussing on how this translates into a theoretical advantage over rtPA in AIS. The authors further present preclinical studies and clinical data on the use of desmoteplase in AIS. EXPERT OPINION: In contrast to rtPA, and despite a similar structure, desmoteplase has demonstrated high selectivity for fibrin and an absence of neurotoxicity in experimental models. Demonstrating such properties in animal models, one would have expected an ambitious clinical study future. Phase II and Phase III clinical studies in patients with AIS demonstrated an excellent safety profile with low risk of symptomatic intracranial haemorrhage compared to rtPA. However, data on clinical and radiological efficacy end points of desmoteplase in AIS are inconclusive. Further Phase III trials are currently underway and their results are eagerly awaited.

Ancillary approaches to plasminogen activators.

Acute ischemic stroke develops from an interruption in focal cerebral blood flow. In many cases, it is caused by an acute thromboembolism. Although systemic fibrinolytic therapy for acute ischemic stroke has been a significant breakthrough in the management of this disease, additional agents and methods that could improve or restore cerebral flow are necessary. Similarly to findings in acute myocardial infarction, combination pharmacotherapy has the potential to improve current thrombolytic treatment in acute ischemic stroke. In recent years, research efforts were directed toward various combination therapy with pharmacological and nonpharmacological methods. Several trials tested tissue plasminogen activator (t-PA) in combination with antiplateletes and anticoagulants. Combination of t-PA with nonpharmacological agents included sonothrombolysis (amplifying the thrombolytic effect), laser (neuro-recovery), hypothermia (cytoprotection and decreasing brain swelling), and blood flow augmentation (increasing residual flow and recruitment of collateral vessels). This paper will review ongoing clinical trials and safety of these promising combinatory treatments.

Influencia de la curva de aprendizaje y del código ictus extrahospitalario en el tratamiento trombolítico del ictus agudo / Influence of the experience and of out-of-hospital stroke code in thrombolytic treatment of acute stroke

Introducción. Se presenta la experiencia en el tratamientodel ictus isquémico con activador del plasminógeno tisularrecombinante (rt-PA) en un hospital universitario. Seevalúa la influencia de la curva de aprendizaje, individual ycolectiva, y de la activación del código ictus extrahospitalario(CIE) en las demoras hasta el inicio del tratamiento, en elnúmero de pacientes tratados y en su evolución.Método. Registro prospectivo de pacientes con ictus isquémicotratados con rt-PA entre enero de 2004 y diciembrede 2006. Análisis comparativo entre los pacientes tratadosen los 3 años del estudio y en función de la experienciadel neurólogo que aplica el tratamiento, así como en pacientestratados con o sin activación del CIE.Resultados. Se trataron 87 pacientes (66,6±13,7 años).El tiempo puerta-aguja fue de 79±21 min en 2004, 64±22 minen 2005 y 63±26 min en 2006 (p=0,003). Los neurólogoscon experiencia aplicaron el tratamiento más rápido (tiempopuerta-aguja: 62±22 frente a 75±27 min; p=0,03). La activacióndel CIE redujo el tiempo puerta-aguja (53±17 frentea 65±21 min; p=0,032) y el tiempo puerta-tomografíacomputarizada (21±10 frente a 29±24 min; p=0,016). Nohubo diferencias en la evolución de los pacientes en los distintosgrupos.Conclusión. La experiencia adquirida y la activación delCIE disminuyen las demoras intrahospitalarias, contribuyendoa aumentar el número de pacientes tratados con trombólisis.El tratamiento trombolítico es seguro y eficaz, inclusosi se aplica por neurólogos sin experiencia si se siguencriterios estrictos (AU)

Introduction. We present the experience for thrombolytictreatment using recombinant tisular plasminogenactivator (rt-PA) at a university hospital. We analyze theinfluence of individual and collective acquired experienceand of the activation of an out-of-hospital stroke code(OSC) on the delays to onset of treatment, number ofpatients treated and outcome.Method. Prospective register of patients with ischemicstroke treated with rt-PA within the period 1/2004-12/2006. Comparison of results between patients treatedduring the three years of study and based on the individualexperience of the neurologist who applies the treatmentand on the patients treated with or without activationof OSC.Results. A total of 87 patients were treated (meanage: 66.6±13.7). Door-to-needle time was 79±21 min in2004, 64±22 in 2005 and 63±26 in 2006 (p=0.003).Experienced neurologists started thrombolysis sooner(door-to-needle time: 62±22 min vs 75±27, p=0.03).Activation of the ESC reduced door-to-needle time (53±17 min vs 65±21; p=0.032) and door-to-computed tomographyscan time (21±10 min vs 29±24; p=0.016). Therewere no differences in outcome in the different groups.Conclusions. Individual and collective acquired experienceand the activation of an OSC can lower in-hospitaldelays. This contributes to increasing the number of patientseligible for thrombolysis. Thrombolytic therapy issafe and effective even when it is applied by inexperiencedneurologists if strict guidelines are followed (AU)

Vampire bats yield potent clot buster for ischemic stroke.

While tissue-type plasminogen activator (tPA) is currently the standard "clot-busting" drug used to treat patients with acute ischemic stroke, another new option for treatment is now under clinical study. Desmodus rotundus plasminogen activator (DSPA), an enzyme found in the saliva of vampire bats, may offer another therapeutic option instead of tPA, a current therapy for stroke. Animal research indicates that tPA may mediate neuronal death as well as increase systemic plasminogen consumption and fibrinogenolysis. Conversely, DSPA's activity is dependent on the presence of fibrin and therefore has not been associated with the systemic plasminogen consumption and fibrinogenolysis that potentially may occur in those receiving tPA. In animal studies, tPA was found to exhibit "inherent neurotoxic properties" not seen with DSPA. In addition, DSPA may be administered up to 9 hours after the onset of symptoms, unlike tPA, which cannot be given after 3 hours without potential risk of additional brain injury. Phase II clinical trials have demonstrated a positive result in human subjects. Phase III trials are currently under way in stroke populations.

Technology evaluation: desmoteplase, PAION/Forest.

PAION GmbH, under license from Schering AG, is developing desmoteplase, a recombinant form of the anticlotting salivary plasminogen activator of the vampire bat Desmodus rotundus (DSPAalpha-1), for the potential treatment of acute ischemic stroke. The drug is currently undergoing phase II clinical trials.

Thrombin activatable fibrinolysis inhibitor (TAFI) affects fibrinolysis in a plasminogen activator concentration-dependent manner. Study of seven plasminogen activators in an internal clot lysis model.

TAFIa was shown to attenuate fibrinolysis. In our in vitro study, we investigated how the inhibitory effect of TAFIa depended on the type and concentration of the plasminogen activator (PA). We measured PA-mediated lysis times of plasma clots under conditions of maximal TAFI activation by thrombin-thrombo-modulin in the absence and presence of potato carboxypeptidase inhibitor. Seven different PAs were compared comprising both tPA-related (tPA, TNK-tPA, DSPA), bacterial PA-related (staphylokinase and APSAC) and urokinase-related (tcu-PA and k2tu-PA) PAs. The lysis times and the retardation factor were plotted against the PA concentration. The retardation factor plots were bell-shaped. At low PA concentrations, the retardation factor was low, probably due to the limited stability of TAFIa. At intermediate PA concentrations the retardation factor was maximal (3-6 depending on the PA), with TNK-tPA, APSAC and DSPA exhibiting the strongest effect. At high PA concentrations, the retardation factor was again low, possibly due to inactivation of TAFIa by plasmin or to a complete conversion of glu-plasminogen into lys-plasminogen. Using individual plasmas with a reduced plasmin inhibitor activity (plasmin inhibitor Enschede) the bell-shaped curve of the retardation factor shifted towards lower tPA and DSPA concentrations, but the height did not decrease. In conclusion, TAFIa delays the lysis of plasma clots mediated by all the plasminogen activators tested. This delay is dependent on the type and concentration of the plasminogen activator, but not on the fibrin specificity of the plasminogen activator. Furthermore, plasmin inhibitor does not play a significant role in the inhibition of plasma clot lysis by TAFI.

Tratamiento intravenoso con activador del plasminógeno tisular en la isquemia cerebral aguda / Intravenous tissue-type plasminogen activator for the treatment of acute cerebral ischemia

FUNDAMENTO Y OBJETIVO: Se desconoce si el riesgo de transformación hemorrágica sintomática (THS) del infarto cerebral por el uso de activador del plasminógeno tisular (t-PA) en la práctica clínica es superior al observado en los ensayos clínicos. El objetivo de este estudio fue analizar la seguridad y la evolución clínica de los pacientes con isquemia cerebral aguda que recibieron tratamiento abierto con t-PA en hospitales españoles. PACIENTES Y MÉTODO: Estudio observacional y prospectivo que incluyó a 155 pacientes consecutivos con isquemia cerebral de menos de 3 h de evolución, o de menos de 6 h en ausencia de signos tempranos de infarto cerebral extenso en la tomografía computarizada (TC) craneal. Se administraron 0,9 mg/kg de t-PA intravenoso, el 10 per cent en bolo y el resto en infusión continua durante 60 min. El deterioro neurológico se cuantificó con la escala del ictus del NIH (NIHSS). Se evaluaron la THS en la TC realizada a las 24-36 h, la mortalidad y la capacidad funcional a los 3 meses. Los pacientes fueron atendidos por neurólogos expertos, y controlados en unidades de ictus. RESULTADOS: La mediana de la NIHSS al ingreso fue de 16, y el tiempo medio desde el inicio de los síntomas hasta el tratamiento, de 163 min. Se observó THS en 12 pacientes (7,7 per cent; intervalo de confianza [IC] del 95 per cent, 4,0-13,1), que fue fatal en 7 (4,5 per cent; IC del 95 per cent, 1,8-9,1). La mortalidad global a los 90 días fue del 16,8 per cent (IC del 95 per cent, 11,2-23,6). A las 24 h, el 48 per cent (IC del 95 per cent, 39,7-55,9) de los pacientes había mejorado en 4 puntos o más en la NIHSS, y el 29 per cent (IC del 95 per cent, 22,0-36,8) había mejorado en 10 puntos o más o se había recuperado. En el día 90, el 56 per cent (IC del 95 per cent, 47,9-64,1) de los pacientes era independiente. CONCLUSIONES: Este estudio demuestra que en la práctica clínica la administración intravenosa de tPA por neurólogos con experiencia, en centros españoles con unidades o equipos de ictus, es segura y se asocia a una evolución clínica favorable, comparable a la observada en los ensayos clínicos (AU)

Modulation of PAI-1 and tPA activity and thrombolytic effects of corilagin.

In this study, Charlton's and Tomihisa's methods were modified to investigate the thrombolytic effect of corilagin from the Chinese herbal plant Phyllanthus urinaria L., as well as its effect on carotid artery patency status. The activity of type 1 plasminogen activator inhibitor (PAI-1) in rat plasma or platelet-released substances and tissue-type plasminogen activator (tPA) in rat plasma was assayed by use of a chromogenic substrate. The results showed that corilagin had a dose-dependent thrombolytic effect in rats. 5 mg/kg of corilagin produced a nearly similar reperfusion rate to that of 20000 U/kg of urokinase, whereas it produced a lower reocclusion rate than urokinase. Corilagin significantly inhibited PAI-1 activity in rat plasma or platelet-released substances while it elevated plasma tPA activity, in a concentration-dependent manner. Corilagin, however, had no influence on rabbit platelet aggregation. It is indicated that corilagin inhibited PAI-1 activity and increased tPA activity, and this property of corilagin is assumed to be responsible for the thrombolytic effect. Abbreviations. PO:persistent occlusion CR:cyclic reflow PP:persistent patency PAI-1:type 1 plasminogen activator inhibitor tPA:tissue-type plasminogen activator PBS:phosphate buffer solution IC (50):50 % of inhibitory concentration PRP:platelet-rich plasma ADP:adenosine diphosphate AA:arachidonic acid PAF:platelet-activating factor

Early recovery of microvascular perfusion induced by t-PA in combination with abciximab or eptifibatide during postischemic reperfusion.

BACKGROUND: GPIIb/IIIa inhibitors abciximab and eptifibatide have been shown to inhibit platelet aggregation in ischemic heart disease. Our aim was to test the efficacy of abiciximab (Reo Pro) or eptifibatide (Integrilin) alone or in combination with plasminogen activator (t-PA) in an experimental model of ischemia reperfusion (I/R) in hamster cheek pouch microcirculation visualized by fluorescence microscopy. Hamsters were treated with saline, or abiciximab or eptifibatide or these drugs combined with t-PA infused intravenously 10 minutes before ischemia and through reperfusion. We measured the microvessel diameter changes, the arteriolar red blood cell (RBC) velocity, the increase in permeability, the perfused capillary length (PCL), and the platelet and leukocyte adhesion on microvessels. RESULTS: I/R elicited large increases in the platelet and leukocyte adhesion and a decrease in microvascular perfusion. These responses were significantly attenuated by abiciximab or eptifibatide (PCL:70 and 65% at 5-10 mins of reperfusion and 85 and 87% at 30 mins of reperfusion, respectively, p < 0.001) while t-PA combined with abiciximab or eptifibatide, was more effective and microvascular perfusion recovered immediately after postischemic reperfusion. CONCLUSIONS: Platelets are crucial in I/R injury, as shown by the treatment with abicixmab or eptifibatide, which decreased platelet aggregation in microvessels, and also decreased leukocyte adhesion in venules. Arterial vasoconstriction, decreased arterial RBC velocity and alterations in the endothelial barrier with increased permeability delayed the complete restoration of blood flow, while t-PA combined with inhibition of platelet aggregation speeded up the capillary perfusion after reperfusion.

Various problems during long-term percutaneous cardiopulmonary support.

A 54-year-old man with a left ventricular free wall rupture following acute anterior myocardial infarction underwent a repair surgery with percutaneous cardiopulmonary support (PCPS). During surgery and postoperatively, PCPS provided sufficient support flow. The patient was successfully weaned from PCPS on the 15th postoperative day and discharged subsequently. In the management of cardiac rupture patients, PCPS has the merit of preventing rupture progression and the advantage of recovery of pulmonary function. However, there are several problems to solve. The support effectiveness and recovery of the patient's heart should be carefully evaluated. Effective left heart decompression also needs to be established. Heparin-coated circuits still need proper anticoagulation treatment to prevent thrombus formation especially while support flow is low. A circuit construction that allows easier maintenance and safer exchange of oxygenators and pump heads is suggested. Ischemia of the cannulated leg should be prevented by femoral artery perfusion.

[Isolation and properties of a novel fibrinolytic enzyme from an earth worm].

A novel fibrinolytic enzyme is isolated from one species of Pheretima by means of homogenizing, extracting with an extractive agent, precipitating with ammunonium sulfate, ultrafiltration and chromatography. The enzyme consists of a single chain with an M. W. of 22,000. It can not only dissolve human thrombi and fibrin directly and strongly, but also activate human plasminogen. The enzyme shows little toxic and side effects in animal tests. The activity, purity and etraction-rate of the enzyme in this report are all very high.

Inhibitory effect of a novel orally active GP IIb/IIIa inhibitor, SC-54684A on intimal thickening in the guinea pig femoral artery.

The inhibitory effect of a novel orally active platelet membrane glycoprotein receptor complex IIb/IIIa (GP IIb/IIIa) inhibitor, SC-54684A is studied on intimal thickening in the guinea pig femoral artery. A segment of the femoral artery was occluded by a platelet-rich thrombus induced by photochemical reaction between systemically administered Rose Bengal and transluminal green light which causes endothelial injury followed by platelet adhesion and aggregation at the site of photochemical reaction. Three weeks after successful thrombolysis by tissue-type plasminogen activator, intimal thickening occurred at the irradiated site. SC-54684A (30 mg/kg), administered 2 h before photochemical reaction, significantly (P < 0.05) prolonged the time to occlusion of the femoral artery; in this respect aspirin (100 mg/kg) was ineffective. A combination of SC-54684A and recombinant tissue-type plasminogen activator (rt-PA) increased the frequency of reopening and significantly (P < 0.05) prolonged the duration of reflow compared with rt-PA alone. Further, SC-54684A administered orally twice a day for 3 weeks significantly (P < 0.05) inhibited intimal thickening but aspirin, administered orally once a day for 3 weeks, was ineffective. Scanning electron microscopy revealed extensive platelet adhesion and aggregation on the denuded vessel walls in the untreated group 24 h after successful thrombolysis. In separate experiments, SC-54684A markedly inhibited platelet aggregation ex-vivo. Inhibition of platelet adhesion and aggregation at the site of endothelial injury by SC-54684A (via GPIIb/IIIa inhibition) may account for its inhibitory effect on intimal thickening.

[The antithrombotic and thrombolytic activity of a plasminogen activator isolated from a monolayer cell culture]. / Antitromboticheskaia i tromboliticheskaia aktivnost' aktivatora plazminogena, vydelennogo iz kletok monosloinoi kul'tury.

Plasminogen activator has been isolated from the culture of pig kidney cells by gel-filtration on Sephadex G-75. The plasminogen activator (181.9 MU/200 g body weight) protected the animals against thrombosis hazard in case of provocation by thromboplastin and exerted a thrombolytic effect in case of thrombus appearance.

Evaluation of the combination of a tissue-type plasminogen activator, SUN9216, and a thromboxane A2 receptor antagonist, vapiprost, in a rat middle cerebral artery thrombosis model.

BACKGROUND AND PURPOSE: We aimed to evaluate a modified tissue-type plasminogen activator, SUN9216, and the combination of SUN9216 and a thromboxane A2 receptor antagonist, vapiprost, in a rat middle cerebral artery thrombosis model. METHODS: Under anesthesia, the left middle cerebral artery was observed under an operation microscope without cutting the dura mater via a subtemporal craniotomy. Photoillumination (wave length, 540 nm) was applied to the middle cerebral artery, and then rose bengal (20 mg/kg) was administered intravenously. The reopening of the middle cerebral artery by SUN9216, injected 30 minutes after middle cerebral artery occlusion, was observed under an operation microscope for a 60-minute observation period. Twenty-four hours after the operation, sections of the cerebrum were stained with triphenyltetrazolium chloride, and the area of cerebral infarction was analyzed by a computer. RESULTS: The combination of SUN9216 and vapiprost caused reopening of the middle cerebral artery in 58.8% of the rats, which was a greater percentage than that achieved with SUN9216 alone (31.6%). In contrast, saline did not cause reopening of the middle cerebral artery during the 60-minute observation period. The area of cerebral infarction in rats reperfused with SUN9216 was significantly reduced compared with that in the control group. The infarction area in rats treated with the combination of SUN9216 and vapiprost was reduced compared with that in rats treated with SUN9216 alone; this was the case whether or not the occlusion was reperfused. There was a significant correlation between the time of reopening of the middle cerebral artery and area of cerebral infarction. CONCLUSIONS: A single injection of SUN9216 was effective in recanalizing the vessel and reducing the area of cerebral infarction.

[The thrombolytic activity of acylated activator complexes of plasmin-streptokinase with different rates of reactivation]. / Tromboliticheskaia aktivnost' atsilirovannykh aktivatornykh kompleksov plazmin--streptokinaza s razlichnymi skorostiami reaktivatsii.

In the experiments on guinea-pigs with venous thrombosis there were studied the fibrin- and thrombolytic effects of streptokinase, the plasmin-streptokinase complex and the acylated derivatives of the complex with various rates of reactivation. It was established that the acylated derivatives of the plasmin-streptokinase complex possess greater stability in the blood flow and lead to more prolonged stimulation of fibrinolysis at less magnitude of its systemic activation. Due to this the acylated derivatives of the plasmin-streptokinase complex produce less pronounced fibrinogenolysis. In connection with a high affinity to fibrin their thrombolytic action does not depend on the systemic activation of fibrinolysis.

Complementary modes of action of tissue-type plasminogen activator and pro-urokinase by which their synergistic effect on clot lysis may be explained.

Tissue plasminogen activator (t-PA) and/or pro-urokinase (pro-UK) induced lysis of standard 125I-fibrin clots suspended in plasma was studied. Doses were kept below the concentration at which a nonspecific effect was seen, i.e., where fibrinogenolysis and major plasminogen consumption were observed. Small amounts of t-PA potentiated clot lysis by pro-UK by attenuating the lag phase characteristic of pro-UK, and causing a much earlier transition to the rapid phase of lysis. Similar promotion of the fibrinolytic effect of pro-UK was obtained when clots were pretreated with UK or with a little plasmin (less than 1% clot lysis). Promotion by plasmin was nullified by a subsequent treatment of the clot with carboxypeptidase B, indicating that the plasmin effect was related to the exposure of carboxy terminal lysine residues on fibrin. These lysine termini, absent in undegraded fibrin, are known to be essential for the high affinity binding of plasminogen to fibrin. In contrast, clot lysis by t-PA was unaffected by plasmin pretreatment and little affected by carboxypeptidase B treatment of the fibrin substrate. Therefore, plasminogen bound to lysine termini on fibrin, although found to be essential for pro-UK, did not appear to serve as a substrate for t-PA. Selective activation of fibrin bound plasminogen has been attributed to the conformational change in Glu-plasminogen that occurs as a result of binding. The present findings suggest that this conformational change occurs when plasminogen is bound to a terminal lysine but not to an internal lysine. Plasminogen bound to the latter site on fibrin was activated by t-PA and therefore is involved in the ternary complex. This initiates lysis of the undegraded clot and exposes the plasminogen binding sites required by pro-UK. By their complementary activation of fibrin bound plasminogen, t-PA followed by pro-UK induces efficient and synergistic fibrinolysis, whereas each is relatively inefficient when used alone.

A comparative study of the efficacy and specificity of tissue plasminogen activator and pro-urokinase: demonstration of synergism and of different thresholds of non-selectivity.

Clot lysis and non-specific plasminogen activation in human plasma by tissue tissue plasminogen activator (t-PA) and/or pro-urokinase (pro-UK) were studied. The fibrinolytic activity of pro-UK was expressed as latent units, i.e. measured after activation with plasmin on a fibrin plate against the reference standard. The t-PA unitage was assigned on a weight basis of a similar equivalence of 100,000 IU/mg. To simplify comparison, both activators were expressed in IU (1 IU = approximately 10 ng). At low concentration (1-50 IU/ml), t-PA induced more effective and more linear clot lysis, whereas pro-UK induced lysis was preceded by a lag phase. The two activators were equivalently effective at higher concentrations and saturated at the same lysis rate. Clots made from platelet rich plasma or whole blood were more responsive to lysis by pro-UK but not t-PA than corresponding platelet poor clots. At very low concentrations (2.5-5 IU/ml) of t-PA combined with moderate concentrations (25-50 IU/ml) of pro-UK, a synergistic effect on clot lysis, which was fibrin-specific, was observed. Plasminogen and fibrinogen and the appearance of plasmin-inhibitor complexes in plasma were measured after incubation with either activator with and without a clot present. Non-specific plasminogen activation occurred above a certain concentration of either activator but was found at lower concentrations of t-PA than pro-UK. In the absence of a clot, plasmin generation occurred with t-PA at about 30% of the concentration at which pro-UK induced a corresponding effect. It is concluded that there are important differences in the fibrinolytic and clot selective properties of t-PA and pro-UK, and that some of these properties may be complementary resulting in a fibrin specific, synergistic fibrinolytic effect.

New approaches to thrombolytic therapy.

Tissue-type plasminogen activator (t-PA), purified from the culture fluid of a stable human melanoma cell line, is a serine protease, different from urokinase, with a molecular weight of about 70,000. It is composed of one polypeptide chain, which is converted to a two-chain molecule by limited plasmic action. Activation of plasminogen to plasmin occurs by cleavage of the Arg 560-Val 561 peptide bond. Kinetic analysis has shown that the activation obeys Michaelis-Menten kinetics and that the presence of fibrin strikingly enhances the activation rate by increasing the affinity of plasminogen for fibrin-bound t-PA. The directed action of plasmin toward fibrin in vivo, might be explained by the low Michaelis constant in the presence of fibrin (0.16 microM), which allows efficient plasminogen activation on a fibrin clot, while its high value in the absence of fibrin (65 microM) prevents efficient activation in plasma. Plasmin formed on the fibrin surface would then be protected from rapid inactivation by alpha 2-antiplasmin. An important consequence of this molecular model for physiological fibrinolysis is that specific thrombolysis is only expected with the use of a specific plasminogen activator, which confines activation to the fibrin surface. Studies on the thrombolytic properties of purified t-PA in various animal species and in humans have revealed a higher specific thrombolytic activity than urokinase. Thrombolysis could be achieved without causing significant plasminogen activation, alpha 2-antiplasmin consumption, or fibrinogen breakdown. Alternatively, pro-urokinase, the zymogen precursor of urokinase, also displays a certain degree of fibrin specificity. Its mechanism of action and potential therapeutic value remain to be established.

[Fibrinolytic and thrombolytic properties of a plasminogen activator isolated from the culture broth of calf kidney cells]. / Fibrinoliticheskie i tromboliticheskie svoistva aktivatora plazminogena, vydelennogo iz kul'tural'noi zhidkosti kletok pochki teliat.

Plasminogen activator isolated from cultural liquid of calf renal cells is an enzyme having a fibrinolytic action in vitro and in vivo, provoking a demonstrable thrombolytic effect, which depends on the drug dose, thrombus size and animal's body weight.

[Plasminogen activator from a kidney cell culture]. / Aktivator plazminogena iz kul'tury kletok pochki.

Plasminogen activator (PA) isolated from kidney's cells culture (doses 10 to 5000 IE/kg) induced lysis of experimental thrombi. Lysis time decreased from 214 to 23 min after PA infusion in doses 10 to 700 IE/kg, further doses decrease from 700 to 5000IE/kg does not accelerate lysis time of thrombi. PA infusion in doses mentioned increases the activator activity of plasma and euglobulin lysis time, but does not change the fibrinolytic activity, antiplasmin content and fibrinogen concentration.