rt-PA Infusion Research Articles

A Novel Platelet-Rich Arterial Thrombosis Model in Rabbits: Simple, Reproducible, and Dynamic Real-Time Measurement by Using Double-Opposing Inverted-Sutures Model

Though numerous animal thrombosis models have been introduced, an easy, reliable, and reproducible arterial thrombosis model remains a continuing challenge prior to a thrombolytic study. In an effort to evaluate the efficiency of various recombinant thrombolytic agents with specific affinity to activated platelets in vivo, we developed a novel double-opposing inverted-sutures model to create a platelet-rich thrombus in the femoral artery of rabbits. The arteriotomy was done semicircumferentially, and variously sized microsurgical sutures were introduced intraluminally in a double-opposing inverted manner. The animals were divided into three groups according to the double-opposing inverted-sutures used: Group 1 with 10-0 nylon ( n=6), Group 2 with 9-0 nylon ( n=6), and Group 3 with 8-0 nylon ( n=22). The superficial epigastric branch was cannulated with a thin polyethylene (PE) tube for intraarterial administration of the studied thrombolytic agent. The blood flow was continuously measured with a real-time ultrasonic flow meter. Within 2 h of installation of the sutures, there was no thrombus formation in either Group 1 or 2. In Group 3, the thrombosis rate was 91% (20 of 22) under a steady baseline flow (with an average of 12.23±2.40 ml/min). It was highly statistically significant with a P-value of .0000743 using Fisher's Exact Test. The averaged time to thrombosis was 21.8±9.8 min. The ultrasonic flow meter to record the dynamic real-time measurement of blood flow was a guideline for thrombus formation or dissolution, which was correlated with the morphological findings of stenotic status of the vessel detected by the Doppler sonography. The components of the thrombus were proven to be platelet-rich predominant by histological examination via hematoxylin and eosin (H&E) stain and transmission electron microscopy (TEM). To confirm that the double-opposing inverted-sutures model would be useful for a study of thrombolytic agents, we evaluated the effects of recombinant tissue-type plasminogen activator (rt-PA) and streptokinase-human plasminogen (SK-HPlg). The average time to thrombolysis post rt-PA infusion was 16.0±8.2 min and that of SK-HPlg was 79.6±23.1, which were similar to the previous reports. In conclusion, the novel double-opposing inverted-sutures (8-0 nylon) model provides a simple, reliable, and reproducible platelet-rich arterial thrombosis model with noninvasive and dynamic real-time measurement. It may be applied in assessing the efficiency of the recombinant thrombolytic agents and offers many advantages of an arterial platelet-rich in vivo thrombosis model.

No Influence of Acute Hypertriglyceridemia on Plasma t-PA in Healthy Male Volunteers

Dietary effects on liver blood flow may have biased the previously observed effects of hypertriglyceridemia on systemic tissue-type plasminogen activator (t-PA) concentrations. Therefore, in this study the effects of hypertriglyceridemia on plasma t-PA were determined by inducing hypertriglyceridemia with an intravenous fat emulsion (Intralipid) infusion. In a randomised crossover fashion, eight healthy male volunteers received Intralipid 10% (1.5 ml/min) or 0.9% saline for 2 h and 45 min. After 2 h of infusion, t-PA antigen, t-PA activity, t-PA/plasminogen activator inhibitor (PAI-1) complex, and PAI-1 activity were determined. Concomitantly, the effects of Intralipid t-PA clearance were determined from steady-state t-PA antigen concentrations of a 45-min recombinant tissue-type plasminogen activator (rt-PA) infusion (31.25 μg/min). Liver blood flow was assessed from steady-state concentrations of a continuous sorbitol infusion. Differences between treatments were calculated using the prevalue as the covariate. No significant differences were observed in mean±S.D. endogenous concentrations of t-PA antigen, 4.5±0.9/4.1±0.9 ng/ml (Intralipid vs. saline infusion; difference of 0.3 ng/ml, 95% confidence interval, CI: −0.2, 0.8); t-PA activity, 0.69±0.21/0.68±0.21 U/ml (difference of 0.04 U/ml, CI: −0.17, 0.25); t-PA/PAI-1 complex, 2.0±1.3/1.6±1.0 ng/ml (difference of 0.1 ng/ml, CI: −0.8, 0.6); and PAI-1 activity, 7.3±5.1/7.1±5.1 U/ml (difference of 0.26 U/ml, CI: −3.7, 4.3). Mean t-PA clearance and liver blood flow were unaffected by the Intralipid infusion. These results indicate that acute hypertriglyceridemia does not alter plasma fibrinolytic parameters in healthy male volunteers.

Treatment of Hemodialysis Catheter–associated Fibrin Sheaths by rt-PA Infusion: Critical Analysis of 124 Procedures

To prospectively evaluate the efficacy of a low-dose, 3-hour infusion of recombinant tissue plasminogen activator (rt-PA) for the treatment of hemodialysis catheter (HDC)-associated fibrin sheaths. This report expands the authors' experience with this technique over that previously reported. Fifty-five patients with end-stage renal disease (38 women, 17 men) undergoing catheter-directed hemodialysis treatment were evaluated for 124 episodes of HDC dysfunction. This patient group had a mean age of 57 years and an age range of 23-92 years. Radiographic contrast studies and/or clinical evaluation were consistent with the presence of a fibrin sheath on the arterial and/or venous port in all cases. Each patient underwent a thrombolytic infusion consisting of 2.5 mg rt-PA in 50 mL normal saline at 17 mL/h (3-hour infusion) per port. All infusions were performed in the interventional radiology recovery room on an outpatient basis. Patients were followed prospectively for technical success, complications, catheter patency, and long-term outcome. The technical success rate, defined as return of effortless manual aspiration and infusion capability from both ports followed by at least one successful dialysis session, was 91%. No patient was excluded from rt-PA therapy because of contraindications, and the procedure-related complication rate was zero percent. A Kaplan-Meier survival analysis yielded primary patency rates at 30, 60, 90, and 120 days of 0.55, 0.36, 0.25, and 0.15 (SE <.10), respectively; secondary patency rates at 60, 120, 180, and 240 days were 0.70, 0.46, 0.30, and 0.27 (SE <.10), respectively (P < 001). At the end of the study period, all 52 surviving patients continued to undergo catheter-directed hemodialysis and 34 (65%) were using the same catheter present at the time of entrance into the study. Of the 18 patients (35%) requiring catheter exchange, 16 (89%) did for persistent malfunction after rt-PA therapy, one (5.5%) for infection, and one (5.5%) for a fractured hub. Thrombolytic therapy with use of a 2.5-mg rt-PA infusion through each port over a 3-hour period would appear to be a safe method for treating HDC-associated fibrin sheaths. Immediate return of catheter function is achieved in most patients, obviating more invasive techniques. Primary patency rates are relatively short, but catheters that fail can be retreated, resulting in secondary patency rates that are substantial and significantly improved.

Successful intraarterial recombinant tissue plasminogen activator therapy for acute embolic occlusion of the superior mesenteric artery

While there have been multiple reports of catheter-directed thrombolysis with streptokinase or urokinase for thromboembolic occlusion of the superior mesenteric artery (SMA), there has been only one previous report describing SMA thrombolysis using tissue plasminogen activator (rt-PA). We present a case of acute embolic occlusion of the SMA initially diagnosed by CT and then successfully treated with selective infusion of rt-PA.

Transcatheter Intraarterial Infusion of rt-PA for Acute Lower Limb Ischemia: Results and Complications

To determine the success and complication rates of intraarterial recombinant tissue-type plasminogen activator (rt-PA) infusion for the treatment of acute lower extremity artery and bypass graft occlusions. The results of 74 limbs in 70 patients (mean age, 66 y) treated with catheter-directed rt-PA infusion for the treatment of acute lower extremity ischemia were retrospectively evaluated. The group included 42 bypass grafts and 32 native arteries. All limbs were viable at presentation. The mean duration of symptoms was 11.9 days. rt-PA was infused for a mean of 27.9 hours for a mean total dose of 38.7 mg. Initial infusion rates of 3-6 mg/h were lowered to a preferred rate of 1.5 mg/h. Thrombolytic success was defined as 95% thrombolysis of an occluded segment with return of antegrade flow. Major bleeding complications were defined as any hemorrhagic event leading to surgery, extended or unexpected hospitalization, transfusion, death, intracranial hemorrhage, or a decrease in hemoglobin of 5 g/dL or in hematocrit of 15%. Thirty-day mortality and amputation rates were calculated. Patient characteristics and infusion parameters were evaluated as to whether they contributed to thrombolytic success or major bleeding events. Thrombolytic success was achieved in 64 limbs (86%). Major bleeding complications occurred in 33 (47%) patients. In 22 of these patients, bleeding occurred at a vascular puncture site, whereas remote bleeding occurred in seven patients. Remote bleeding complications included two retroperitoneal hematomas, two rectus sheath hematomas, one lower gastrointestinal hemorrhage, one episode of hemoptysis, and one dehiscence of a femoral-popliteal bypass graft revision. No parameters were found to be predictive of thrombolytic success, whereas a negative history of smoking, increasing duration of infusion, and a low preprocedural ankle-brachial index (ABI) were found to be associated with major hemorrhagic events. Four patients (6%) underwent amputation and one patient (1%) died, resulting in a 30-day amputation-free survival rate of 93%. Catheter-directed rt-PA infusion is effective in achieving thrombolysis. Despite a significant number of bleeding complications, 30-day mortality and amputation rates were favorable. Nonetheless, complication rates related to bleeding were not trivial and further evaluation with use of variable dosing regimens is indicated.

Pharmacokinetic Properties of a Novel Tissue-Type Plasminogen Activator Pamiteplase After Single Intravenous Administration to Rats, Dogs, and Monkeys

The pharmacokinetics of pamiteplase and recombinant tissue-type plasminogen activator (rt-PA) in rats, dogs, and monkeys were examined using a newly developed enzyme-linked immunosorbent assay (ELISA). Plasma concentrations after intravenous administration of pamiteplase to rats declined in a triphasic manner. Plasma concentrations after intravenous administration of pamiteplase to dogs or monkeys declined in a biphasic manner. The area under the plasma concentration–time curve from zero to infinity (AUC 0→∞) in rats and dogs increased with increasing dose. The half-life and mean residence time of pamiteplase in rats, dogs, and monkeys were shown to be longer than those of rt-PA. Total clearance (CL total) of pamiteplase was only 7–16% that of rt-PAs, suggesting that concentrations of pamiteplase in plasma were higher and more continuous than those of rt-PA in these experimental animals. The data suggest that a bolus administration of pamiteplase shows the same thrombolytic activity as continuous infusion of rt-PA in experimentally induced thrombosis in rats and dogs. The pharmacokinetic parameters distribution volume at the steady state and CL total calculated by immunoreactive concentration after administration of pamiteplase to rats, dogs, and monkeys show high correlation with body weights ( r 2=.7728 and .9039).

Protocol violations in community-based rTPA stroke treatment are associated with symptomatic intracerebral hemorrhage.

Recombinant tissue plasminogen activator (rTPA) is an established treatment for acute ischemic stroke. The rate and type of protocol violations in rTPA use and their effect on patient outcomes in this setting are not well understood. The objective of this study was to examine associations between protocol violations and outcomes in community-based rTPA use. We reviewed medical records of stroke patients treated with rTPA in 10 acute-care hospitals in Indianapolis from July 1996 to February 1998 and assessed complications and outcome. Retrospective National Institute of Health Stroke Scale (on admission and discharge), Canadian Neurological Scale, and length of hospital stay were calculated. Appropriate use of rTPA was determined by the National Institute of Neurological Disorders and Stroke (NINDS) protocol. Fifty patients (mean age, 66 years; 76% white; 56% men) were treated by general neurologists (70%), stroke neurologists (24%), or emergency physicians (6%). Mean times to hospital arrival, brain CT, and start of rTPA infusion were 44, 86, and 141 minutes, respectively. In-hospital mortality rate was 10% (4 intracerebral hemorrhage [ICH], 1 cardiogenic shock). Complications were more frequent among patients with protocol violations (n=8) compared with those without all hemorrhages (75% versus 10%, P:<0.001), symptomatic ICH (38% versus 5%, P:<0.02), and ICH attributable to rTPA, occurring within 36 hours (38% versus 2.4%, P:<0.01), respectively. NINDS protocol violations are relatively common and are associated with symptomatic cerebral and systemic hemorrhages. When the NINDS protocol is strictly followed, hemorrhage rates in community-based rTPA use are similar to those in the NINDS trial.

Hemodialysis Catheter-associated Fibrin Sheaths: Treatment with a Low-Dose rt-PA Infusion

To prospectively evaluate the efficacy of a low-dose, 3-hour recombinant tissue plasminogen activator (rt-PA) infusion for the treatment of hemodialysis catheter (HDC)-associated fibrin sheaths. Seventeen patients with end-stage renal disease (female, n = 11; male, n = 6), who were undergoing catheter-directed hemodialysis, were evaluated for 28 episodes of HDC dysfunction. This patient group ranged in age from 25 to 92 years (mean, 57 years). Radiographic contrast and/or clinical evaluation were consistent with the presence of a fibrin sheath on either the arterial and/or venous port in all cases. Patients subsequently underwent a thrombolytic infusion consisting of 2.5 mg rt-PA in 50 mL normal saline at a rate of 17 mL/h (3-hour infusion) per port. All infusions were performed in the interventional radiology recovery room, on an outpatient basis. Patients were followed-up prospectively for technical success, complications, catheter patency, and long-term outcome. The immediate technical success rate, defined as return of manual aspiration and infusion capabilities to both ports, was 100%. No potential patients required exclusion from thrombolytic therapy secondary to contraindications, and no procedure-related complications occurred. The arithmetic mean and median catheter patency at the end of the study was 41 and 25 days, respectively (range, 1-116 days). A Kaplan-Meier survival analysis yielded a 30-, 60-, and 90-day probability of patency of 0.67, 0.61, and 0.51, respectively. At the end of the study period, all 17 patients remained on catheter-directed hemodialysis and 13 (76%) were utilizing the same catheter present at the time of entrance into the study. Thrombolytic therapy utilizing a 2.5-mg rt-PA infusion through each port during a 3-hour period would appear to be a safe, efficient method for treating HDC-associated fibrin sheaths. Three-month patency rates are comparable to those reported for other methods of restoring function to HDC catheters, including new catheter placement, catheter exchange over a guide wire, thrombolytic infusions with urokinase, and percutaneous fibrin sheath stripping.

Effect of thrombolysis on the dynamics of infarct evolution after clot embolism of middle cerebral artery in mice.

Reversible focal ischemia may lead to delayed tissue injury despite primary restoration of blood flow and metabolism. The authors investigated whether such delayed changes also occur after thrombolytic treatment of thromboembolic stroke. Clot embolism of the middle cerebral artery (MCA) was produced in C57/B16J mice by intracarotid injection of heterologous clots. One hour after embolism, one group was treated with intracarotid infusion of rt-PA (10 mg/kg). The untreated control group received an equal amount of vehicle. Just before onset of treatment and after 1, 3. 6, and 24 hours, animals were frozen in situ and cerebral blood flow (CBF), cerebral protein synthesis (CPS), ATP content, and DNA fragmentations (TUNEL) were imaged on cryostat sections using double tracer autoradiography. bioluminescence, and immunohistochemical techniques, respectively. In untreated animals (n = 20), CPS was suppressed in approximately 68% of hemispheric transsection at 1 hour after embolization. The ATP depleted area was smaller (approximately 58%), but between 6 and 24 hours it merged with that of CPS suppression. TUNEL-positive neurons became visible between 6 and 24 hours exclusively in regions with ATP depletion. rt-PA-induced thrombolysis (n = 20) led to the gradual improvement of blood flow. At 24 hours. ATP depletion was fully reversed and the CPS suppression area declined to approximately 16% of hemispheric transsection. Despite progressive metabolic recovery, large numbers of neurons became TUNEL-positive and animals died between 24 and 48 hours. Thrombolysis after clot embolism restores metabolic activity including protein synthesis, but the therapeutic benefit is limited by secondary injury that requires additional treatment to improve final outcome.

Thrombolytic Therapy with Use of Alteplase (rt-PA) in Peripheral Arterial Occlusive Disease: Review of the Clinical Literature

The clinical literature describing the use of alteplase in the treatment of peripheral arterial occlusive (PAO) disease is reviewed. The literature database was acquired by a MEDLINE search using the Boolean keyword string: tissue plasminogen activator and/or rt-PA and peripheral not animal. A review was performed to identify the dose range of alteplase, technique of infusion, use of anticoagulation, clinical success rates, and risk of complications. Forty-six clinical studies were identified. There are few prospective, randomized clinical trials and a lack of standardized protocols and endpoints. Use of catheter-directed infusions of recombinant tissue plasminogen activator (rt-PA) may be beneficial versus surgery in the initial management of acute limb ischemia (< 14 days) and in reducing the magnitude of subsequent surgical or percutaneous revascularization. For patients with chronic limb ischemia (> 14 days), irreversible acute limb ischemia, or advanced diabetic arteriopathy, catheter-directed infusion of rt-PA or other plasminogen activators may be unsuitable. The risk of adverse bleeding appears related to the overall dose and duration of infusion. These risks appear similar to those of urokinase. The role of heparin in increasing adverse bleeding during rt-PA therapy is unclear. There is no generally accepted dose or technique for administering catheter-directed thrombolysis using alteplase; however, several studies have demonstrated its clinical safety and efficacy. Formal studies will be required to determine the optimal dose, technique of infusion, the role of anticoagulation, and complication rates when alteplase is used for PAO disease.

Images in cardiovascular medicine. Evolution of rapid middle cerebral artery recanalization during intravenous thrombolysis for acute ischemic stroke.

Intravenous recombinant tissue plasminogen activator (rtPA) is thought to benefit patients with acute ischemic stroke by producing early reperfusion.1 Transcranial Doppler (TCD) is a noninvasive method that can monitor the recanalization process in real time when occlusion occurs in the proximal intracranial vessels. We present our findings during rtPA infusion in a 56-year-old man with acute ischemic stroke to illustrate the time course of changes that occur in a middle cerebral artery (MCA) stem occlusion treated by intravenous thrombolysis. We used a 2-MHz portable unit (Multigon 500 mol/L) with a pulse-wave transducer mounted on a head frame (Marc 500, Spencer Technologies) …

Successful Treatment of Right Heart Thromboemboli With IV Recombinant Tissue-Type Plasminogen Activator During Continuous Echocardiographic Monitoring: A Case Series Report

Echocardiographic detection of right heart thromboemboli (RHTE) during pulmonary embolism (PE) shows an uncommon but life-threatening event. The treatment of this condition is not well established. The aim of our study is to evaluate the efficacy and safety of recombinant tissue-type plasminogen activator (rt-PA) in treating RHTE. We performed a transthoracic echocardiogram within (mean +/- SD) 120+/-45 min from onset of symptoms on 30 consecutive patients with proven massive PE. Seven patients (23%) showed RHTE, four patients (57%) had cardiogenic shock; and all patients showed echocardiographic features of acute cor pulmonale. The seven patients with RHTE received an IV infusion of 100 mg rt-PA over a period of 2 h with continuous echocardiographic monitoring. We observed complete RHTE lysis at 45 to 60 min from the onset of rt-PA infusion and significant reductions at 2 h in the following: 14% in right ventricle (RV) end-diastolic diameter (reduction, 40.8 to 35 mm; p < 0.01); 12% in RV/left ventricular ratio (reduction, 0.83 to 0.73; p < 0.01); and 17% in tricuspid regurgitant flow velocity (reduction, 3.5 to 2.9 m/s; p < 0.01). The interventricular septal and RV wall motions improved. An excellent clinical outcome was achieved rapidly in all patients. No adverse events were recorded. We demonstrated the rapid, effective, and safe action of rt-PA in RHTE resolution and an improvement in pulmonary perfusion. Our data confirm the important role of an early, systematic echocardiographic approach in order to detect RHTE quickly in patients with suspected massive PE.

Effect of time of 7E3 administration on rt-PA-induced reperfusion: study in a canine model of thrombus-based occlusion–reperfusion

Chimeric version of the murine monoclonal antibody, 7E3 has been proposed for the early restoration of coronary artery patency during thrombolytic therapy. We determined the optimal time for administration of 7E3 during recombinant tissue plasminogen activator (rt-PA)-induced thrombolysis using a canine model of coronary artery thrombosis. After 30 min of thrombotic occlusion, microspheres were injected to assess regional myocardial blood flow, followed by a 90-min rt-PA infusion. Dogs were randomized to three groups wherein 7E3 (0.8 mg kg −1, i.v.) was administered either 5 min before rt-PA (Group I), at the first evidence of thrombolysis (Group II), or after the completion of rt-PA infusion (Group III). Hemodynamic parameters were monitored for 6 h after which infarct size was estimated. Time to occlusion/reperfusion was similar in all groups. In the rt-PA alone group, 78% arteries reoccluded after 60 min of reperfusion. The incidence of reocclusion was lower in Groups II (25%, P=0.04) and III (0%, P<0.01). All arteries (100%) were patent at the end of the protocol in Group III vs 50% remaining patent in Group I ( P=0.01). Arterial patency was maintained longer in Group III (301 min, n=10), compared with Groups I (124 min, n=5) and II (124 min, n=6). Arterial flow was greater in Group III (82%) compared with Groups I (27%) and II (35%) ( P<0.01). Regional myocardial blood flow and infarct size were similar in all groups. The data indicate that the time of administration of 7E3 in conjunction with rt-PA-induced thrombolysis influences patency status. The experimental results suggest that in the absence of aspirin and heparin, optimal thrombolysis is obtained when 7E3 is administered after the completion of rt-PA infusion regimen.

Percutaneous catheter and guidewire fragmentation with local administration of recombinant tissue plasminogen activator as a treatment for massive pulmonary embolism.

The purpose of this article is to report four patients with massive pulmonary embolism treated with percutaneous catheter and guidewire fragmentation and local administration of recombinant tissue plasminogen activator (r-TPA). Four patients with massive pulmonary embolism initially underwent pulmonary angiography. Thrombus fragmentation was performed with both standard angiographic guidewires and catheters followed by local infusion of 41-200 mg of r-TPA. Pulmonary angiography was repeated after treatment. All patients survived with improvement in their clinical status and eventual discharge from hospital. Angiography in all patients post treatment demonstrated improvement in pulmonary perfusion (mean Miller score before treatment 22.5; mean Miller score after treatment 5.75). No patient had a significant complication. Mechanical fragmentation of the thrombus followed by local infusion of r-TPA was an effective treatment for massive pulmonary embolism in these four patients with no significant complications.

Fibrinolyse intraventrikulärer Hämatome mit rt-PA

Intraventricular administration of recombinant tissue plasminogen activator (rt-PA) is an experimental therapy to hasten the lysis of intraventricular hemorrhages. We report nine patients (7 male, 2 female, mean age 64a) with intracerebral hematoma with ventricular extension who were treated with intraventricular infusion of rt-PA (2-32 mg, mean dose 17 mg). In two patients, clinically significant bleeding complications were associated with the fibrinolytic therapy. In one of these patients, fibrinolytic therapy was stopped. Other complications could not be observed. In eight of all nine patients, a rapid and extensive reduction of the amount of intraventricular blood occurred. A persistent shunt became necessary in two patients. We conclude, that intraventricular fibrinolysis probably leads to a faster clearance of intraventricular blood. Despite of fibrinolytic treatment, a permanent shunt becomes necessary in some cases. Intraventricular fibrinolysis is a potentially hazardous therapy with the risks of bleeding complications and infection.

Local recombinant tissue plasminogen activator (rt‐PA) thrombolytic therapy in microvascular surgery

Vascular thrombosis remains a dreaded complication of any microvascular procedure, be it composite tissue transfer or replantation of amputated limbs or parts. Despite the tremendous advances in microvascular-related technologies and the accumulated surgical skills, failures caused by occlusion of anastomosed vessels remain a continuous source of frustration to all microsurgeons alike. Several anticoagulation and antiplatelet protocols have been proposed to be used in conjunction with microvascular surgery. More recently, thrombolytic drugs such as urokinase, streptokinase, and thrombolysin have been introduced, yet their systemic effect on hemostasis remains an undesirable side effect. We present our experience with local intra-arterial, intravenous, and soft-tissue injection of recombinant tissue plasminogen activator rt-PA in replantation surgery in three consecutive patients. Arterial thrombi are managed by intra-arterial rt-PA infusion with the catheter placed proximal to the arterial anastomosis. Venous thrombi are best lysed by infusing rt-PA in an engorged vein of the replanted limb. In replanted digits, direct intravenous infusion is not possible. In such situations, injection of rt-PA in the pulp soft tissues may result in successful salvage. We believe this agent also has a role in microvascular composite tissue transfer in preventing free flap failures as well as in salvaging failing flaps. © 1999 Wiley-Liss, Inc. MICROSURGERY 19:265–271 1999

Local recombinant tissue plasminogen activator (rt-PA) thrombolytic therapy in microvascular surgery

Vascular thrombosis remains a dreaded complication of any microvascular procedure, be it composite tissue transfer or replantation of amputated limbs or parts. Despite the tremendous advances in microvascular-related technologies and the accumulated surgical skills, failures caused by occlusion of anastomosed vessels remain a continuous source of frustration to all microsurgeons alike. Several anticoagulation and antiplatelet protocols have been proposed to be used in conjunction with microvascular surgery. More recently, thrombolytic drugs such as urokinase, streptokinase, and thrombolysin have been introduced, yet their systemic effect on hemostasis remains an undesirable side effect. We present our experience with local intra-arterial, intravenous, and soft-tissue injection of recombinant tissue plasminogen activator rt-PA in replantation surgery in three consecutive patients. Arterial thrombi are managed by intra-arterial rt-PA infusion with the catheter placed proximal to the arterial anastomosis. Venous thrombi are best lysed by infusing rt-PA in an engorged vein of the replanted limb. In replanted digits, direct intravenous infusion is not possible. In such situations, injection of rt-PA in the pulp soft tissues may result in successful salvage. We believe this agent also has a role in microvascular composite tissue transfer in preventing free flap failures as well as in salvaging failing flaps.

Low molecular weight heparin as an adjunct to thrombolysis for acute myocardial infarction: the FATIMA study

ObjectiveTo investigate the feasibility of fixed dose, weight adjusted subcutaneous low molecular weight heparin (LMWH), with monitoring of anti-Xa levels and assessment of coronary patency rates after three to five...

Tetranectin levels in patients with acute myocardial infarction and their alterations during thrombolytic treatment.

Tetranectin (TN), a new regulator of fibrinolysis, was studied in the plasma of 60 patients with acute myocardial infarction (AMI) and 30 healthy subjects (HS), in relation to D-dimer (DD) and alpha 2-plasmin inhibitor (alpha 2-PI), to investigate its possible involvement in the pathophysiology of AMI. Thirty patients underwent thrombolytic treatment with fibrin-specific plasminogen activator (rt-PA) (group A); the other 30 patients, according to the exclusion criteria, were conventionally treated (group B). Twenty of the thrombolysized patients established early recanalization (subgroup A1), while 10 failed to respond to thrombolytic treatment (subgroup A2). Median (interquartile range), baseline plasma TN levels were lower in AMI patients compared to HS [8.27 (2.75) mg/L versus 12.1 (0.55) mg/L, P < 10(-6)]. In subgroup A1, TN increased at the end of rt-PA infusion and returned to the baseline levels 12 h later. A positive association between DD and TN release (3 h level minus baseline level) was found (rs = 0.48, P = 0.03) in subgroup A1. No significant alterations of TN levels were observed during therapy in subgroup A2 and group B. TN, DD and alpha 2-PI concentrations in group B remained relatively constant during the study period. This study provides evidence of a significant decrease of TN levels in AMI patients compared to healthy subjects and of a remarkable difference in the evolution of TN levels during thrombolytic treatment with rt-PA between recanalized and non-recanalized AMI patients. Thus, an involvement of TN in the formation and dissolution of fibrin clot in AMI patients is worthy of further investigation.

Clopidogrel enhancement of rt-PA thrombolysis in a thrombo-embolic model of cerebral ischemia in rats

Summary Objective: The effects of postembolic treatment with clopidogrel — a thienopyridine derivative and inhibitor of platelet aggregation — alone and in combination with rt-PA were investigated in a thromboembolic model of monofocal cerebral ischemia in rats. Methods: After injection of a single in vitro prefabricated fibrin-rich autologous macroclot (400 μm × 4 mm) into the internal carotid artery of Sprague Dawley rats, the animals were assigned to one of four intravenous treatment groups: (1) continuous saline infusion over 45 min starting 60 min after embolization (control); (2) rt-PA as a continuous infusion at 6 mg/kg for 45 min starting 60 min after embolization; (3) clopidogrel at 20 mg/kg immediately after embolization followed by a continuous saline infusion for 45 min starting 60 min after injection; (4) rt-PA as in group 2 plus clopidogrel as in group 3. Results: Embolization produced occlusions of the ipsilateral middle cerebral artery or the internal carotid artery at the origin of the middle cerebral artery. Occlusions were stable in the control group. Administration of rt-PA at a thrombolytic threshold dose together with clopidogrel resulted in a recanalization of the middle cerebral artery as demonstrated by angiographic control immediately after treatment. Recanalization was associated with a decrease in the neurological deficit (30% vs control) and in the subcortical and total infarct volumes (18 and 25%) at 24 h albeit the differences did not attain significance. No gross intracranial hemorrhages were observed following clopidogrel/rt-PA coadministration. Postembolic treatment with clopidogrel alone tended to reduce infarct volume and to improve neurological outcome. Tail transection bleeding time was prolonged in the clopidogrel group (4.7-fold) and in both rt-PA-treated groups (> 9-fold). Ex vivo platelet aggregation was inhibited by clopidogrel treatment but not by rt-PA infusion. Conclusions: These data provide evidence for the first time that rt-PA thrombolysis after ischemic stroke can be enhanced by adjunctive postembolic antiplatelet therapy. This effect was not accompanied by gross intracranial hemorrhages.