Intraventricular administration of recombinant tissue plasminogen activator for intraventricular hemorrhage in the newborn

Intraventricular hemorrhage remains associated with high mortality and morbidity. Its most serious complication is posthemorrhagic hydrocephalus caused by multiple small blood clots obstructing the arachnoid villi. We treated three newborn infants (one term, two preterm) with posthemorrhagic hydrocephalus using recombinant tissue plasminogen activator, a thrombolytic agent, injected into the ventricles with a spinal needle. Sufficient fibrinolysis was achieved in these preterm patients. They all survived, and shunt surgery was only required in one. No adverse reactions or side effects have occurred. Intraventricular fibrinolysis with tissue plasminogen activator seems to be safe and effective for the treatment of intraventricular hemorrhage. However, controlled studies are needed for assessing treatment efficiency.     

Peroxynitrite inactivates tissue plasminogen activator

Tissue plasminogen activator (tPA) has a prominent role in physiological fibrinolysis in vivo. Thrombosis has been associated with clinical scenarios (e.g., atherosclerotic disease) known to involve local decreases in tPA activity with concomitant formation of reactive nitrogen species such as peroxynitrite (OONO(-)), a molecule formed from nitric oxide and superoxide. We hypothesized that exposure of tPA to OONO(-) would result in a decrease in tPA activity. OONO(-) was generated with 3-morpholinosydnonimine (SIN-1), a molecule that produces both nitric oxide and superoxide. Recombinant tPA was incubated at 37 degrees C for 60 min with 0 microM SIN-1; 100 microM SIN-1; 100 microM SIN-1 and 4000 U/mL recombinant human superoxide dismutase; or 4000 U/mL recombinant human superoxide dismutase (n = 8 separate reactions per condition). Changes in tPA activity were assessed by addition of tPA samples to tissue factor-exposed human plasma and measuring clot fibrinolysis with a thrombelastograph. Exposure to SIN-1 resulted in a decrease in tPA-mediated fibrinolysis (<1% activity of tPA not exposed to SIN-1) that was significantly (P < 0.001) different from the other three conditions. There were no significant differences between the other conditions. We conclude that tPA is inhibited by OONO(-), and that OONO(-) may have a role in clinical thrombotic scenarios. IMPLICATIONS: Tissue plasminogen activator (tPA) has a prominent role in fibrinolysis in vivo. Thrombosis has been associated with clinical scenarios involving decreases in tPA activity with concomitant formation of the oxidant peroxynitrite. We determined that peroxynitrite decreased tPA activity via thrombelastography. Peroxynitrite-mediated tPA inactivation may have a role in thrombotic states.     

Efficacy and safety of tissue plasminogen activator

Simple aspiration to remove acute intracerebral hematomas has been thwarted by the solidity of the clot. Urokinase, a first generation fibrinolytic agent, has been used to liquefy such clots with some success. Therefore, tissue plasminogen activator (t-PA), a second generation fibrinolytic drug that may be safer and more effective, was studied to evaluate its ability to lyse clot in vitro and its reactivity in the brain and subarachnoid space. t-PA seems to cause partial clot lysis in small dosages (3750 units/70-cc clot) and in a short time (15 minutes). It seems to perfuse through the clot when injected in one place. It does not cause inflammation or bleeding when injected into the rat brain, but indeed seems to promote resorption of blood when the two are injected together. It does not cause aseptic meningitis when injected into the cisterna magna of rabbits. t-PA may prove to be an important adjuvant to the stereotactic aspiration of intracerebral hematomas. It may be particularly helpful in lysing these clots to make possible more gentle aspiration, removing the risk to surrounding brain of strong vacuum.     

Hemorrhagic upper extremity complications from tissue plasminogen activator

Five patients, ages 63 to 79, had hemorrhagic complications involving the upper extremity from fibrinolytic therapy using intravenous tissue plasminogen activator (tPA) for acute myocardial infarction. The hemorrhages varied in severity. Three patients were treated for superficial hematomas, one with a deep subcutaneous hematoma producing skin necrosis, and one compartment syndrome with posterior interosseous nerve palsy and marked intramuscular bleeding. tPA is currently being used in the treatment of acute myocardial infarction and acute nonhemorrhagic stroke. Caution should be used particularly for IV sites, central lines, arterial catheterization, and pneumatic tourniquets, to avoid upper extremity hemorrhage.     

Intrapleural tissue plasminogen activator for complicated pleural effusions

BACKGROUND: This study is aimed at evaluating the safety and efficacy of intrapleural tissue plasminogen activator (TPA) for complicated pleural effusions, including posttraumatic hemothorax. METHODS: Data were retrospectively collected from hospitalized patients over a 4-year period (1999-2003) who were treated with intrapleural TPA after failing drainage by tube thoracostomy. Pre- and post-TPA imaging studies were reviewed and scored by a blinded radiologist. RESULTS: Forty-one consecutive patients with 42 effusions were identified with the following indications: 6 traumatic hemothoraces (14%), 22 loculated pleural effusions (52%), 2 line-associated hemothoraces (5%), and 12 empyemas (29%). Nine patients (22%) required operative drainage including two with posttraumatic hemothoraces. All patients managed nonoperatively demonstrated radiographic improvement after TPA administration. One patient (2.4%) developed hematuria, requiring transfusion. No trauma patient required TPA-related blood transfusion and no deaths were attributable to TPA therapy. CONCLUSION: Intrapleural TPA administration appears safe for use in complicated pleural effusions and may decrease the need for operative intervention.     

Randomized trial of intra-arterial recombinant tissue plasminogen activator, intravenous recombinant tissue plasminogen activator and intra-arterial streptokinase in peripheral arterial thrombolysis

Sixty patients were recruited into a randomized parallel group comparison of three thrombolytic regimens for acute or subacute peripheral arterial thrombosis. There were no significant differences in age, duration of history, length of occlusion or presence of neurosensory deficit between the groups. Initially successful lysis was significantly greater with intra-arterial (IA) recombinant tissue plasminogen activator (rt-PA) than with either streptokinase (Sk) (P less than 0.04) or intravenous (IV) rt-PA (P less than 0.01). The duration of therapy varied from a median of 35 h with IA rt-PA to 40 h with Sk (P greater than 0.5). The median (confidence interval) increase in ankle:brachial pressure index following IA rt-PA of 0.57 (0.33-0.82) was significantly higher than for either Sk of 0.24 (0-0.57) or for IV rt-PA of 0.18 (0-0.41). Limb salvage at 30 days was achieved in 80, 60 and 45 per cent respectively for IA rt-PA, Sk and IV rt-PA. Haemorrhagic complications occurred in six patients following Sk and in 13 following IV rt-PA; only one minor haemorrhage occurred following a catheter perforation in a patient who received IA rt-PA (P less than 0.05). IA rt-PA provides a more effective, safer fibrinolytic regimen than conventional therapy with Sk. IV rt-PA has not been as successful and carries a significantly higher risk of haemorrhagic complications.     

Abnormal levels of urokinase plasminogen activator protein and tissue plasminogen activator activity in human aortic aneurysms.

OBJECTIVE: To measure the concentrations and activities of plasminogen activators and plasminogen activator inhibitors in human abdominal aneurysms. DESIGN: Laboratory study. SETTING: University hospital, Sweden. MATERIAL: Biopsy specimens from 12 abdominal aortic aneurysms and 8 normal aortas (controls). INTRERVENTIONS: Tissues were homogenised and eluted. The supernatants were assayed for antigens of tissue and urokinase plasminogen activator and plasminogen activator inhibitor 1 and 2. The activities of tissue plasminogen activator and plasminogen activator inhibitor-1 were assayed by ELISA. Frozen sections were immunostained for tissue and urokinase plasminogen activators and for plasminogen activator inhibitor-1. MAIN OUTCOME MEASURES: Concentrations and activities of these activators and inhibitors. RESULTS: The concentration of urokinase plasminogen activator antigen was higher in aneurysmal walls than in normal aortas; it was detected immunohistochemically in aneurysmal but not in normal aortas. The concentration (and the detection immunohistochemically) of tissue plasminogen activator was equal in aneurysmal and normal aortas, but its activity was reduced in the aneurysmal wall. Plasminogen activator inhibitor-1 did not differ significantly between the groups. CONCLUSIONS: Urokinase plasminogen activator may be responsible for the digestion of the media of the aorta and the development of an aneurysm. Reduced activity of tissue plasminogen activator may be responsible for thrombosis in the aneurysm.     

Intracisternal recombinant tissue plasminogen activator after aneurysmal subarachnoid hemorrhage

Fifteen patients undergoing surgery within 48 hours of aneurysm rupture were administered recombinant tissue plasminogen activator (rt-PA) directly into the basal subarachnoid cisterns after minimal surgical clot removal and aneurysm clipping. Preoperatively, 13 patients had diffuse or localized thick subarachnoid blood clots on computerized tomography (CT), and two had diffuse thin clots. The rt-PA was given as a single intraoperative injection of 7.5 mg (one patient), 10 mg (nine patients), or 15 mg (five patients). Postoperative cisternal drainage was employed in three patients. All patients except one demonstrated partial to complete cisternal clot clearance on CT scans within 24 hours after surgery. The patient who showed no clot reduction was the only patient in this series to develop symptomatic vasospasm and was the only fatality, dying 8 days after rupture. No vasospasm was seen on follow-up cerebral angiography in six of the 14 responding patients, and mild-to-moderate arterial narrowing was seen in at least one major cerebral artery in the remaining eight patients. Severe angiographic vasospasm was not seen, although the patient who died did not undergo repeat angiography. There was one major complication early in the series which seemed clearly related to treatment, and that was a large extradural hematoma occurring within several hours of craniotomy. Intrathecal fibrinolytic treatment appears effective in clearing subarachnoid clot and reducing vasospasm, and may be associated with acceptable risks if given to patients with large-volume subarachnoid hemorrhages at high risk for severe vasospasm.     

Experimental adhesion prophylaxis with recombinant tissue plasminogen activator.

The deposition of fibrin in the peritoneal cavity leads to fibrous adhesion formation. Recombinant tissue plasminogen activator (rtPA), delivered locally, was investigated as a method of preventing adhesion formation. Six standardised areas of peritoneal ischaemia were formed in each of 36 male Wistar rats randomised to three intraperitoneal treatments: (A) no treatment control; (B) carboxymethylcellulose gel; (C) rtPA-carboxymethylcellulose gel combination. At 1 week all animals underwent relaparotomy and the number of ischaemic sites with an adhesion counted by an independent observer. rtPA-treated animals formed fewer adhesions compared with gel alone or controls (median number of adhesions 1.5 versus 2.5 versus 5, P < 0.001, ANOVA). Intraperitoneal rtPA in a slow-release formulation is able to reduce adhesion formation significantly in an animal model and may prove to have clinical benefit.     

Recombinant tissue plasminogen activator infusion for hemodialysis catheter clearance

Hemodialysis (HD) catheter occlusion is a common cause of poor blood flow and inadequate dialysis. In order to address this problem in our pediatric dialysis unit, we elected to use short (2-h) infusions of low-dose recombinant tissue plasminogen activator (rtPA) for thrombolysis of occluded catheters. Catheters meeting diagnostic criteria for thrombosis were infused with 2.5 mg rtPA in 25 ml 0.9 normal saline over 2 h prior to dialysis. Retrospective data collection was carried out to assess the success of this procedure. Variables assessed included blood flow (Qb), transmembrane pressure (TMP) and venous pressure (VP) before and after rtPA infusion. Seven catheter thromboses in six patients were successfully treated with rtPA; there were significant improvements in Qb ( p <0.01), TMP ( p <0.01), and VP ( p <0.02). At 32 weeks after rtPA therapy, Kaplan-Meier survival analysis showed a 60% probability of primary catheter patency. At the end of the study, 85% of catheters had adequate function as defined by a Qb >200 ml/min. No adverse events were observed. Low-dose rtPA infusion is safe and effective for catheter thrombolysis in outpatient pediatric HD patients. It may serve as an alternative method of administration to local instillation and may be used to restore patency before resorting to surgical revisions.     

坐骨神经损伤脊髓神经元退变与组织型纤溶酶原激活物及其抑制物表达的关系研究

目的 探讨坐骨神经离断后脊髓内组织型纤溶酶原激活物(tissue plasminogen activator,tPA)及其抑制物纤溶酶原激活物抑制物1(type-1 plasminogen activator inhibitor,PAI-1)、神经丝氨酸蛋白酶抑制剂(neuroserpin,NSP)的表达与神经元退变的关系.方法 将56只雄性SD大鼠随机分为实验组和对照组.对实验组大鼠行坐骨神经离断术,于术后各时间点取材伤侧脊髓L4～6节段,经Nissl染色后,运用透射电镜观察神经元退变及死亡情况;运用免疫组化染色和半定量RT-PCR检测tPA、PAI-1及NSP的表达变化.结果 坐骨神经离断术后7d,伤侧相应脊髓节段前角外侧核神经元存活率显著下降,术后21 d神经元存活率为61.6％.电镜观察显示,术后7d开始,脊髓前角可见处于不同凋亡阶段的神经元及神经胶质细胞,术后14 d开始脊髓后角也可见少数凋亡样变的神经元及胶质细胞.免疫组化结果显示,坐骨神经损伤后ld,伤侧脊髓Ⅴ～Ⅸ板层内tPA表达水平开始上调(P＜0.05),第7天时达到高峰后下降,至术后21 d仍未恢复正常水平(P＞0.05);PAI-1则在正常脊髓及损伤后脊髓均未能检测到.半定量RT-PCR结果显示,tPA的mRNA变化趋势与蛋白表达基本相同,略早于后者;NSP的mRNA术后1d内迅速上调,随后2周都处于较高水平,21 d才基本回复正常.结论 坐骨神经离断后同侧相应脊髓节段近50％的前角运动神经元死亡可能与损伤刺激脊髓灰质内神经元和小胶质细胞合成、释放tPA增加有关,同时损伤也促使tPA抑制物NSP表达上调,后者可能发挥神经保护作用.     

Treatment of catheter-related bacteremia with tissue plasminogen activator antibiotic locks

This retrospective study was completed to investigate the effectiveness of tissue plasminogen activator (TPA) antibiotic locks (ABL) along with systemic antibiotics (AB) to clear catheter-related bacteremia (CRB) in children on chronic hemodialysis. There were 76 CRBs in 37 children. CRBs were successfully cleared with AB/ABL in 63/76 (83%) cases. Ten of 76 (13%) CRBs were symptomatic at 48 h of treatment. These were seven polymicrobial, two gram-negative, and one Candida CRB. 13/76 (17%) episodes required catheter exchange, and all were wire-guided exchanges. TPA-ABL/AB cleared gram-positive and gram-negative CRBs significantly better than polymicrobial CRBs (p < 0.01). The infection-free survival and the rate of recurrence at 45 days was not statistically different between the TPA-ABL/AB group and the catheter-exchange group. If CRB was symptomatic at 48 h of treatment, recurrence at 6 weeks was more frequent with persistent use of TPA-ABL/AB (p < 0.05). There were no episodes of metastatic infections, catheter malfunction from occlusion, or catheter breakdown during the course of TPA-ABL treatments. In conclusion, TPA-ABL can be safely and effectively used in the management of CRB, increasing the probability of catheter survival and preserving the vascular access site. With the exception of polymicrobial CRB, there is no disadvantage in using TPA-ABL/AB over catheter exchange, as the infection-free survival and the rate of recurrence are comparable.