Dose Of TPA Research Articles

Tigliane metabolites in Hyles frass after feeding experiments with TPA and Euphorbia cyparissias

Within the genus Hyles, Euphorbia feeding appears to have evolved twice independently, in H. euphorbiae but also in H. nicaea, a species which had not been studied for its detoxification processes before. Euphorbia is known to contain toxic secondary metabolites, including diterpene esters, preventing most herbivores from feeding on them. We investigated the metabolisation of the standard phorbol ester Phorbol 12-myristate 13-acetate (TPA) and the diterpenes contained in Euphorbia cyparissias by the two species Hyles euphorbiae and Hyles nicaea (subspecies nicaea). For the first time, we report (1) The gut disposition of Hyles n. nicaea for this standard phorbol ester, which is commonly used in cancer and tumour research and (2) The disposition of the food plant tiglinaes of Euphorbia cyparissias after gut passage in both species and (3) Tigliane metabolites in the frass of TPA and of E. cyparissias feeding larvae. For both species around 5–25% of the TPA dose was recovered in the frass of the larvae, along with the metabolites phorbol and phorbol-13-acetate in very small amounts and traces. While the amounts of phorbol found did not differ much between the species frass, phorbol-13-acetate could be found in higher amounts in Hyles n. nicaea frass, indicating a difference in metabolisation. Moreover, enzymatic hydrolysis of TPA to phorbol-13-acetate and phorbol are postulated not to be the main metabolisation pathway, seeing that the amounts found only represent a small fraction of the TPA dose consumed.

Variability of fibrinolytic activity in pregnant patients exposed to tissue plasminogen activator: an in vitro study utilizing rotational thromboelastometry

BackgroundThe investigation into the variability of fibrinolysis in obstetric patients is notably limited despite its relevance to postpartum hemorrhage. We investigate an in vitro model of fibrinolysis measured by rotational thromboelastrometry (ROTEM) in maternal blood samples with lysis stimulated by tissue plasminogen activator (tPA). MethodsWritten informed consent was obtained from 19 patients at term pregnancy during admission to the labor and delivery unit. Patients who were taking medication affecting coagulation were excluded. Tissue plasminogen activator was added to whole blood samples to a final concentration of 100 or 220 ng/mL prior to ROTEM testing. ResultsThe addition of tPA produced high intra-individual fibrinolytic variability for clot firmness and lysis parameters. Patients responded differently to each tPA dose ranging from clot lysis within the range of 0 ng/mL tPA group to complete clot lysis. The coefficient of variation (CV) values for the 220 ng/mL tPA group were: EXTEM MCF 0.510, EXTEM LI30 1.601, FIBTEM MCF 0.349, FIBTEM LI30 2.097. CV values for the 100 ng/mL tPA group were: EXTEM MCF 0.144, EXTEM LI30 1.038, FIBTEM MCF 0.096, FIBTEM LI30 1.238. ConclusionWe demonstrate a wide range of fibrinolytic response in the obstetric population to exogeneous tPA. We found subgroups of patients that were very responsive to tPA and insensitive to tPA. This study represents a preliminary exploration into classifying the obstetric fibrinolytic phenotypes. Further research will integrate relevant coagulation factors to establish a predictive model for testing susceptibility to lysis that can be applied at the point of care.

Low‐dose tissue plasminogen activator is safe and effective in treating major intracardiac thrombosis in liver transplant recipients

AbstractBackgroundMajor intracardiac thrombosis is an uncommon event during liver transplantation and has a high mortality rate. Given concerns for hemorrhage in liver transplantation with higher doses, low‐dose tissue plasminogen activator has been proposed as a treatment that rapidly leads to localized clot lysis and resolution of right ventricular failure.MethodsThis is a retrospective study using a prospectively collected database at the University of California at Los Angeles of liver transplant recipients from 2004‐2021. Adult patients who received tissue plasminogen activator for intracardiac thrombosis detected on transesophageal echocardiography were included.ResultsOut of 3236 liver transplants from 2016 to 2021, 11 liver transplant recipients were treated with intravenous low‐dose tissue plasminogen activator for major intracardiac thrombosis. The TPA dose range was 1–2.5 mg with three patients receiving more than one dose. All patients had severe hemodynamic instability. 90.9% of patients had right ventricular failure and 63.6% had cardiac arrest. After administration of low‐dose tissue plasminogen activator, 100% of patients had clinical improvement, clot resolution, and intraoperative survival, with 91% survival at 6 months post‐transplant. Adverse events included two patients with abdominal bleeding requiring re‐exploration and three patients having new intracranial hemorrhage which self‐resolved.ConclusionsLow dose tissue plasminogen activator was effective in treating major intracardiac thrombosis in our group of patients. Major complications included a limited number of hemorrhagic events.

Abstract 16163: Low Dose Alteplase for Treatment of Pacemaker Lead Associated Thrombosis

Multiple previously published case reports highlighted the thromboembolic risks associated with permanent transvenous pacemaker leads. Even though mostly clinically silent, pacemaker lead associated thrombosis has been linked to fatal outcomes via pulmonary or paradoxical embolism in the case of large mobile RA or RV thrombi formation. There is a lack of consensus on the optimal strategy for managing this condition. Oral and IV anticoagulation, thrombolysis, surgical and percutaneous thrombectomy have been attempted previously with mixed results. A 72 year old gentleman with a history of CAD requiring PCI, paroxysmal atrial fibrillation, and AV node ablation with subsequent biventricular pacemaker implant was admitted to our hospital with a few weeks of worsening dyspnea, now present at rest. Surface echocardiogram showed multiple mobile echo densities in the right ventricle and right atrium, attached to the pacemaker leads, confirmed by TEE, most likely thrombi. The venous duplex was positive for right lower extremity DVT. Bilateral pulmonary emboli with mild right-sided heart strain were noted on CTA chest. The patient was initially treated with IV unfractionated heparin. We subsequently decided to start low-dose tPA infusion for 24 hrs, similar to current off-label protocols for mechanical prosthetic valves or bioprosthetic valve thrombosis. After an initial IV bolus of 5 mg, 1 mg/hour of alteplase was continued for 24 hours. Our team has decided to use percutaneous thrombectomy as a last resort.Follow-up ECHO immediately post tPA infusion showed complete thrombi resolution. The patient was asymptomatic at this point. He was discharged the following day on Lovenox and Coumadin. To our knowledge, this is the first case demonstrating complete resolution of pacemaker lead-associated thrombi by using a 24 hr low dose tPA infusion in addition to IV anticoagulation. This can be entertained as a simple conservative initial strategy in stable patients with pacemaker lead/catheter-associated intracardiac thrombi.

Effect of race/ethnicity on arterial recanalization following intravenous thrombolysis in acute ischemic stroke patients

IntroductionSeveral reports have identified that clinical outcomes such as death or disability in acute ischemic stroke (AIS) patients following intravenous (IV) tissue plasminogen activator (tPA) treatment can vary according to race and ethnicities. We determined the effect of race/ethnicity on rates of arterial recanalization in AIS patients with large vessel occlusion (LVO) after IV tPA. MethodsWe analyzed 234 patients with LVO detected on computed tomographic angiography (CTA) who received IV tPA and subsequently underwent angiography for potential thrombectomy. The primary occlusion sites on CTA and digital subtracted angiography (DSA) were compared and a score was given to the level of recanalization with values ranging from 1 (complete recanalization), 2 (partial recanalization), or 3 (no recanalization).The effect of race/ethnicity were assessed for predicting vessel recanalization using the covariates of age, gender, time since stroke onset, tPA dose received, NIHSS (National Institute of Health Stroke Scale) score at baseline, and location of the occlusion, using logistic regression analysis. ResultsFive patients (2.1%) were Hispanic or Latino, 8 (3.4%) Asian, 24 (10.3%) African American, and 197 (84.2%) White. A total of 50% had a distal ICA/proximal M1 occlusion, 20% distal M1 occlusion, and 16% single M2 occlusion. At the primary occlusion site, 44 (18.8%) had complete recanalization on post IV tPA angiogram, 17 (7.3%) had partial recanalization, and 165 (70.5%) had no recanalization. We did not find any association between race/ethnicity and vessel recanalization post IV tPA (Nonwhite combined [OR=1.49, p=0.351]; Asian [OR=1.460, p=0.650]; African American [OR=1.508, p=0.415]; White [OR=0.672, p=0.351]; ethnicity (Hispanic or Latino) [OR= 1.008, p=0.374]); Occlusion location (OR=0.189, p<0.001). Final TICI scores and mRS at 90 days were similar among the different groups. ConclusionApproximately 19% of patients had complete recanalization after IV tPA, but race and ethnicity did not seem to have an effect on arterial recanalization. Arterial recanalization was only affected by location of occlusion.

Case report: Intra arterial thrombolysis with iv line can save an acutely ischemic limb

Case report: Intra arterial thrombolysis with iv line can save an acutely ischemic limb

Tissue plasminogen activator with prolonged dwell time effectively evacuates pleural effusions

ObjectivesFibrinolytic therapy can be effective for management of complex pleural effusions. Tissue plasminogen activator (tPA, 10 mg) and deoxyribonuclease (DNAse) every 12 h with a dwell time of one hour is a common strategy based on published data. We used a simpler protocol of tPA (4 mg) without DNAse but with a longer dwell time of 12 h, repeated daily. We reviewed our results.MethodsCharts were reviewed and demographics, clinical data and treatment information were abstracted. Outcomes were assessed based on radiographic findings and need for surgery.ResultsTwo hundred and fifteen effusions in 207 patients (8 bilateral) were identified. 85% were either infectious or malignant. Two hundred and forty nine chest tubes were used: 84% were 10 Fr or 12 Fr and 7% were PleurX®. Five hundred and thirty one doses of tPA were given. The median number of doses per effusion was 2 (range 1–10), and 84% of effusions were treated with three or fewer doses. There were no significant bleeding complications. Median time to chest tube removal was 6 days (range 1 to 98, IQR 4 to 10). Drainage was considered complete for 78% of effusions, while 6% required decortication.ConclusionsLow dose tPA daily with a 12 h dwell time may be as effective as the standard regimen of tPA and DNAse twice daily with one hour dwell. For most patients only three doses were required, and small pigtail catheters were sufficient. This regimen uses less medication and is logistically much easier than the current standard.

Clinical efficacy and safety of ultrasound-assisted thrombolysis vs. standard catheter-directed thrombolysis in patients with acute pulmonary embolism: A study level meta-analysis of clinical trials.

AimTo compare the clinical efficacy of ultrasound-assisted thrombolysis (USAT) vs. standard catheter-directed thrombolysis (SCDT) in patients with acute pulmonary embolism (aPE).MethodsThis study analyzed the clinical outcomes of patients with non-low-risk aPE who received USAT or SCDT. The primary outcomes were all-cause death, total bleeding, and major bleeding. Secondary outcomes included pulmonary thrombotic load score (Miller), improvement in right ventricular-to-left ventricular ratio (RV/LV), dose and duration of the thrombolytic drug tissue plasminogen activator (tPA), length of stay (LOS) in the ICU, and total LOS in the hospital.ResultsA total of seven articles and 451 patients were included in this study. 241 patients were in the USAT group and 210 patients were in the SCDT group. There were no significant differences in all-cause mortality, total bleeding, and major bleeding between the two groups. Miller scores for pulmonary thrombus also showed no difference between the two groups, but pulmonary artery systolic pressure (PASP) was lower in the SCDT group after-treatment. The reduction of RV/LV from baseline was more pronounced in the SCDT group than in the USAT group (OR: −0.14, 95%CI: −0.20 to 0.07, P < 0.0001, I2 = 0%). Total dose of tPA and duration of infusion in the USAT group were lower than those in the SCDT group, but there was no significant statistical difference. LOS in the ICU was similar between the two groups, while LOS in the hospital was lower in the SCDT group.ConclusionThis study did not detect any differences in all-cause mortality, total bleeding, and major bleeding between non-low-risk aPE patients treated with USAT or SCDT. Improvement in right ventricular function was better in the SCDT group, and hospital LOS was lower in the SCDT group.

Hemothorax With White-Out Lung After Intrapleural Tissue Plasminogen Activator and Deoxyribonuclease Therapy in a Patient With Complicated Parapneumonic Effusion

Tissue plasminogen activator (tPA) and recombinant deoxyribonuclease (DNase ) are used in treating pleural infection due to their mucolytic activity by effectively reducing pleural fluid viscosity. The combination of tPA and DNase has attracted considerable interest as an alternative to surgical intervention for treating complicated parapneumonic effusion in high-risk patients who are not good candidates for surgery. However, intrapleural hemorrhage has been reported as a villainous outcome in a few cases which needs to be considered as a differential diagnosis with sudden clinical deterioration after the therapy. Here, we report the case of a patient who presented with pneumonia and later developed a large right complicated parapneumonic pleural effusion. A chest tube was placed with drainage of fluid while tPA and DNase were also considered as an additional treatment module. Following the first dose of DNase and tPA, the patient developed hypoxemia with hypotension and was found to have rapid development of white-out right hemothorax.

Selective Sphingosine 1-Phosphate Receptor 1 Modulation Augments Thrombolysis of Low-Dose Tissue Plasminogen Activator Following Cerebrovascular Thrombosis.

BackgroundResults from our recent study demonstrate that sphingosine-1-phosphate receptor 1 (S1PR1) modulation improves microvascular hemodynamics after cerebrovascular thrombosis. This study was to determine the microvascular hemodynamic effects of a sub-thrombolytic dose of tPA combined with a selective S1PR1 modulator ozanimod in a mouse model of cerebrovascular thrombosis.MethodsMicrovascular circulation in mice was monitored in vivo by two-photon microscopy. Thrombosis was induced in cortical arterioles by laser irradiation. Arteriolar flow velocity was measured by line-scanning following plasma-labeling with fluorescein-dextran.ResultsLaser‐induced thrombosis led to a persistent reduction of flow velocity in cortical arterioles. Sub-thrombolytic dose of tPA along with vehicle control did not improve the flow velocity in cortical arterioles following thrombosis. In contrast, a sub-thrombolytic dose of tPA along with ozanimod dramatically restored flow velocity in cortical arterioles following thrombosis. Ozanimod did not affect coagulation and bleeding time. Notably, ozanimod reduced thrombus volume without altering microvascular lumen diameter. In addition, ozanimod reduced leukocyte components within the thrombus.ConclusionsThese findings demonstrate that the thrombolytic effect of a sub-thrombolytic dose of tPA is markedly enhanced by S1PR1 modulation, implying that S1PR1 modulation may improve the therapeutic benefit of low-dose tPA in patients with acute ischemic stroke.

Efficacy of standardizing fibrinolytic therapy for parapneumonic effusion.

BackgroundWhile chest tube placement with pleural fibrinolytic medication is the established treatment of pediatric empyema, treatment failure is reported in up to 20% of these children.ObjectiveStandardizing fibrinolytic administration among interventional radiology (IR) physicians to improve patient outcomes in pediatric parapneumonic effusion.Materials and methodsWe introduced a hospital-wide clinical pathway for parapneumonic effusion (1–2 mg tissue plasminogen activator [tPA] twice daily based on pleural US grade); we then collected prospective data for IR treatment May 2017 through February 2020. These data included demographics, co-morbidities, pediatric intensive care unit (PICU) admission, pleural US grade, culture results, daily tPA dose average, twice-daily dose days, skipped dose days, pleural therapy days, need for chest CT/a second IR procedure/surgical drainage, and length of stay. We compared the prospective data to historical controls with IR treatment from January 2013 to April 2017.ResultsSixty-three children and young adults were treated after clinical pathway implementation. IR referrals increased (P = 0.02) and included higher co-morbidities (P = 0.005) and more PICU patients (P = 0.05). Mean doses per day increased from 1.5 to 1.9 (P < 0.001), twice-daily dose days increased from 38% to 79% (P < 0.001) and median pleural therapy days decreased from 3.5 days to 2.5 days (P = 0.001). No IR patients needed surgical intervention. No statistical differences were observed for gender/age/weight, US grade, need for a second IR procedure or length of stay. US grade correlated with greater positive cultures, need for chest CT/second IR procedure, and pleural therapy days.ConclusionInterventional radiology physician standardization improved on a clinical pathway for fibrinolysis of parapneumonic effusion. Despite higher patient complexity, pleural therapy duration decreased. There were no chest tube failures needing surgical drainage.

Alteplase Dose Assessment for Pleural infection Therapy (ADAPT) Study-2: Use of 2.5mg alteplase as a starting intrapleural dose.

Intrapleural tissue plasminogen activator/deoxyribonuclease (tPA/DNase) therapy is increasingly used in pleural infection. Bleeding risks and costs associated with tPA remain the clinical concerns. Our dose de-escalation series aims to establish the lowest effective dosing regimen for tPA/DNase. This study assesses the intrapleural use of 2.5mg tPA/5mg DNase for pleural infection. Consecutive patients with pleural infection treated with a starting regime of 2.5mg tPA/5mg DNase were included from two centres in Australia and UK. Escalation of tPA dose was permitted if clinical response was inadequate. Sixty-nine patients (mean age 61.0 years) received intrapleural 2.5mg tPA/5mg DNase. Most (88.4%) were treated successfully and discharged from hospital without surgery by 90 days. Patients received a median of 5 [interquartile range [IQR]=3-6] doses of tPA/DNase. Total amount of tPA used per patient was 12.5mg [median, IQR=7.5-15.0]. Seventeen patients required dose escalation of tPA; most (n= 12) for attempted drainage of distant non-communicating locule(s). Treatment success was corroborated by clearance of pleural opacities on radiographs (from median 27.0% [IQR=17.1-44.5] to 11.0% [IQR=6.4-23.3] of hemithorax, p< 0.0001), increased pleural fluid drainage (1.98 L [median, IQR=1.38-2.68] over 72 h following commencement of tPA/DNase) and reduction of serum C-reactive protein level (by 45.0% [IQR=39.3-77.0] from baseline at day 5, p< 0.0001). Two patients required surgery. Six patients with significant comorbidities (e.g., advanced cancer) had ongoing infection when palliated and died. Two patients experienced self-limiting pleural bleeding and received blood transfusion. A starting intrapleural regime of 2.5mg tPA/5mg DNase, with up-titration if needed, can be effective and deserves further exploration.

Clinical use of tissue plasminogen activator for systemic thrombolysis in dogs and cats

IntroductionSystemic administration of tissue plasminogen activator (tPA) is seldomly reported in dogs and cats. AnimalsClient-owned animals receiving tPA (2010–2020). Materials and methodsMedical records of dogs and cats receiving tPA for distant known/suspected thrombus were reviewed. Fourteen dog visits (24 injections) and five cat visits (six injections) were included. ResultsCanine known/suspected thrombus included pulmonary thromboembolism (n=6), intracardiac thrombus (n=4), aortic thrombus (n=1), cranial vena cava thrombus (n=2), and femoral and iliac veins thrombus (n=1). Various canine primary diseases were represented, but open-heart surgery was the most common cause. Median time between diagnosis/suspicion of thrombus and tPA injection was 24.5 h (range, 3–150 h). Mean total tPA dose was 1.0±0.78 mg/kg.Clinical improvement occurred in 93% of dogs. Non-fatal complications were reported in 14% of dogs. Dogs’ survival to discharge was 78.6% without identifiable non-survivor characteristics. Feline known/suspected thrombus included unilateral feline aortic thromboembolism (FATE) (n=2), bilateral FATE (n=2), and right renal artery thrombus. Feline primary diseases included cardiomyopathy (n=5). Median time between diagnosis/suspicion of thrombus and tPA injection was 4 h (range, 2–17 h) and median total tPA dose was 1.0 mg/kg (range, 0.6–1.4 mg/kg).Clinical improvement occurred during 40% of the visits. All cats (n=3) with acute kidney injury (AKI) at admission developed worsening AKI and reperfusion injury. Of the remaining two visits, one developed a non-fatal AKI. Cats’ survival to discharge was 40%. ConclusionsSystemic thrombolysis with tPA seems to be effective and safe in dogs. More investigation is needed in cats.

Retrospective Evaluation of Intrapleural Tissue Plasminogen Activator With or Without Dornase Alfa for the Treatment of Traumatic Retained Hemothorax: A 6-Year Experience.

Intrapleural fibrinolytic instillation is second-line treatment for retained hemothorax. Dornase alfa (DNase) has demonstrated efficacy in parapneumonic effusion, but the lack of deoxyribonucleoproteins limits direct extrapolation to traumatic retained hemothorax treatment. This study evaluated the effectiveness of intrapleural tissue plasminogen activator (tPA) with and without DNase in the treatment of retained traumatic hemothorax. This retrospective cohort study included patients aged 16 years and older admitted to a level 1 trauma center from January 2013 through July 2019 with retained hemothorax and one or more intrapleural tPA instillations. Exclusion criteria were tPA for other indications or concomitant empyema. The primary endpoint was treatment failure defined as the need for operative intervention. Fifty patients were included (tPA alone: 28; tPA with DNase: 22). Baseline characteristics were similar between groups, including time to diagnosis (6.5 [interquartile range (IQR), 4-15.5] days vs 6 [IQR, 6.3-10.8] days, P = 0.52). Median tPA dose per treatment (6 [IQR, 6-6.4] mg vs 10 [IQR, 8.4-10] mg, P < 0.001) and cumulative tPA (18 [IQR, 6.5-24] mg vs 30 [IQR, 29.5-40], P < 0.001) dose were significantly lower in the tPA alone group. Treatment failure was similar between groups. Chest tube output, retained hemothorax reduction, and bleeding incidences were similar between groups. Multivariate logistic regression demonstrated no significant risk factors for treatment failure. Dornase alfa added to tPA may not reduce the need for operation to treat retained hemothorax. Further studies should be directed at optimal tPA dose determination and economic impact of inappropriate DNase use.

Abstract WP56: 2021 Comparison Of International Stroke Guidelines For Acute Ischemic Stroke

Background: Many countries/regions have formal Acute Ischemic Stroke (AIS) management guidelines. Variations between guidelines may showcase differences in demographic epidemiology and practice that correspond to the regional or national priorities. Methods: We systemically searched for guideline recommendations on AIS management published between January 1, 2004, and August 20, 2021. With only the latest guideline for each country selected, 11 guidelines from countries/regions of the world were identified and reviewed: United States (2018), Japan (2013), Europe (2018), Australia (2012), Brazil (2012), China (2019), Korea (2019), Canada (2018), India (2011), South Africa (2010), and Malaysia (2006). Results: Urgent imaging guidelines, such as CT or MRI, for initial evaluation are similar across countries; nevertheless, initial intravascular imaging guidelines greatly differ. Of the eleven countries reviewed, the majority recommend a standard tPA dose of 0.9mg/kg, while Japan and China recommend a lower tPA dose of 0.6mg/kg in select patients. While time to initiation of aspirin (ASA) post IV thrombolysis is widely accepted, consensus on the appropriate ASA dose, and possible addition of other antiplatelet therapies does not exist. Mechanical thrombectomy is overall endorsed within 6 hours or between 6-16 hours of symptom onset with causative occlusion, but countries such China and Canada have found validity extending the timeframe to 24hrs and beyond, using imaging modality recommendations. Inpatient management of nutrition, DVT prophylaxis, and rehabilitation differ between the various guidelines. Conclusion: Variations between guidelines exist that highlights those components with a lack of an evidence-based consensus. With further international collaboration, reconciliation of guidelines between countries or regions may be achievable.

Multiphysics Modelling and Simulation of Thrombolysis via Activated Platelet-Targeted Nanomedicine

PurposeThis study establishes a multiphysics simulation platform for both conventional and targeted thrombolysis using tissue plasminogen activator (tPA). Based on our computational results, the effects of therapeutic parameters on the dynamics of thrombolysis and the risk of side effects are investigated.MethodsThe model extends our previously developed one-dimensional(1D) mathematical models for fibrinolysis by incorporating targeted thrombolysis. It consists of two parts: (i) a coupled mathematical model of systemic pharmacokinetics (PK) and pharmacodynamics (PD) and local PD in a 1D occluded artery, and (ii) a mechanistic model for a targeted thrombolytic system via activated platelet-targeted tPA-loaded nanovesicles (tPA-NV), with model parameters derived from our in vitro experiments. A total of 16 therapeutic scenarios are simulated by varying the clot location and composition as well as the dosing regimen with free tPA or tPA-NV.ResultsOur simulation results indicate that tPA-NV offers several advantages over free tPA for thrombolysis. It reduces systemic exposure of tPA, thereby minimising the risk of bleeding complications. Simulations with different tPA-NV doses reveal that tPA-NV at 10% of the recommended dose can be as effective as the standard regimen with the full recommended dose of free tPA, demonstrating the potential of our tPA-NV as a new thrombolytic strategy with a reduced tPA dose. Moreover, faster recanalisation can be achieved with tPA-NV, especially for platelet-rich(or fibrin-poor) clots.ConclusionsOur simulation platform for thrombolysis with well-tuned model parameters can be used to evaluate and optimise treatment regimens of existing and new thrombolytic therapies via benefit/risk assessment under various therapeutic scenarios.

An international survey on the use of intrapleural tissue plasminogen activator/DNase therapy for pleural infection.

IntroductionIntrapleural tissue plasminogen activator (tPA) combined with human recombinant DNase (DNase) could be an effective alternative to surgery in managing pleural infection, as demonstrated in the Multi-centre Intrapleural Sepsis Trial (MIST)-2. However, the optimal delivery regimen is still unknown. The aim of this survey was to identify the current practice of tPA/DNase use by physicians with published interests in pleural infection, and their opinions on dose de-escalation of tPA/DNase therapy.MethodsPotential participants were identified using four search strategies. Only practising physicians who were managing patients with pleural infections and either actively involved in pleural research and publications, or were members of relevant pleural disease guideline panels at the time of survey were included.ResultsAn invitation email with the questionnaire was sent to 102 participants, of whom 49 (48%) responded. Most respondents (90%, n=44) have used tPA/DNase to manage pleural infection, but the dosing and delivery regimens employed varied. Many (86%, 38 out of 44) respondents have used 10 mg tPA, while 73% (n=32), 16% (n=7) and 9% (n=4) have used 5 mg, 2.5 mg and 1 mg doses, respectively. Most respondents instilled tPA/DNase concurrently (61%, n=27) and routinely administered six doses of tPA/DNase (52%, n=23) twice daily (82%, n=36). Respondents would consider using a lower starting dose of tPA (with the possibility of escalation if clinically needed) if a median 80% (interquartile range 50–80%) of patients could be successfully treated at that dose.ConclusionThis survey observed a large variation in the current treatment protocol of intrapleural tPA/DNase therapy worldwide and the need for more data on this subject.

Metal ion chelation enhances tissue plasminogen activator (tPA)-induced thrombolysis: an in vitro and in vivo study.

Stroke is the third leading cause of death in the United States and the leading cause of adult disability. Despite enormous research efforts including many clinical trials, tissue plasminogen activator (tPA) remains the only FDA-approved treatment for acute ischemic stroke. Unfortunately, only 1-3% of stroke patients in the US receive this therapy because of the narrow time window and severe side effects for using tPA. The most deadly and damaging side effect is the risk of intracranial bleeding or hemorrhage. For that reason, the dose of tPA and its overall administration are under tight control, which may compromise the effect of thrombolysis. Studies have been focused on improving the effectiveness of tPA for higher rate of reperfusion, and the safety for less adverse bleeding episode. We studied how metal ions (zinc & iron) affect tPA-induced thrombolysis in vitro and in vivo, and proposed a method to improve the rate of thrombolysis. The amount of hemoglobin in the blood clot lysis was measured by a spectrophotometer. The tPA-induced thrombolysis was measured in vivo in femoral artery. Our results showed that Zn2+, Fe3+ and Fe2+ inhibited tPA-induced thrombolysis, with Zn2+ and Fe2+ being the most effective. Metal ion chelating agent EDTA when it was co-applied with tPA significantly enhanced the tPA-induced thrombolysis. The chelation alone did not have noticeable thrombolytic effect. In in vivo study of tPA-induced thrombosis following femoral artery thrombosis, the co-application of tPA and EDTA achieved significant higher rate of reperfusion than that by tPA treatment alone, suggesting that ion chelation facilitates tPA-induced thrombolysis and potentially improves the safety of tPA application by reducing the necessary dose of tPA application. Our results suggest that the co-application of a chelator and tPA improves the efficacy and, potentially, safety of tPA application, by reducing the necessary dose of tPA for thrombolysis.

Novel Pharmacomechanical Thrombolysis for Treating Intermediate-Risk Acute Pulmonary Embolism: The Bashir Endovascular Catheter.

Novel Pharmacomechanical Thrombolysis for Treating Intermediate-Risk Acute Pulmonary Embolism: The Bashir Endovascular Catheter.

THIRD TIME'S A CHARM: TREATING PULMONARY EMBOLISM WITH MECHANICAL THROMBECTOMY AFTER TWO FAILED ATTEMPTS WITH THROMBOLYTIC THERAPY

TOPIC: Procedures TYPE: Medical Student/Resident Case Reports INTRODUCTION: Pulmonary embolism (PE) can be a life-threatening condition. Massive PE, characterized by hemodynamic instability with signs of shock, comprises 4.5%-10% of all PE cases and has over 50% mortality rate. When medical therapy fails, aspiration thrombectomy is a treatment option for acute massive or submassive PE in patients with hemodynamic compromise or right ventricular (RV) dysfunction (Dopazo et al, 2018). CASE PRESENTATION: A 61-year-old male presented after an episode of syncope, chest pain, and dyspnea. Due to profound hypoxia, he was intubated. ECG as seen in figure 1 was changed from prior. Troponin was 0.80. In the ED, he was placed on norepinephrine and epinephrine due to hypotension. Bedside echocardiogram (ECHO) showed enlarged RV with severely reduced RV systolic function, hypokinetic RV free wall, and apex. The patient subsequently developed pulseless electrical activity (PEA) arrest. Two cycles of CPR were performed to achieve the return of spontaneous circulation. Due to the possibility of PE, weight-based tPA was administered. He had PEA arrest a second time and CPR was done for 9 minutes. A second dose of weight-based tPA was given after which his hemodynamics transiently improved. Epinephrine drip was discontinued, but norepinephrine drip was continued. He was transferred to ICU for monitoring and was placed on a heparin drip. Over the next 12 hours, despite multiple tPA doses, he progressively decompensated with systolic blood pressure to 40mmHg while on norepinephrine. Vasopressin drip was initiated. Lactic acidosis increased from 3.8 to 6.6 mmol/L, creatinine worsened from 1.6 to 4.0 mg/dL, and Hb 12.2 to 8.5 g/dL. CTA for PE confirmed saddle pulmonary embolism with evidence of RV strain with RV/LV ratio 1.1. He was taken emergently for cardiac catheterization on multiple vasopressors. A bilateral pulmonary artery thrombectomy with a T24 Inari catheter was done successfully, with subsequent improvement in hemodynamics. ECHO after the procedure showed improved RV function and RV size reduction. Within 24 hours of the thrombectomy, vasopressors were titrated off and the patient remained hemodynamically stable. DISCUSSION: Though systemic thrombolytic therapy is typically indicated for hemodynamically unstable patients with suspected pulmonary emboli, it was not effective in our patient, despite multiple doses. Catheter-directed therapies for PE can remove obstructive emboli directly, allowing for rapid patient improvement as seen in our case. Furthermore, though it is an invasive strategy, catheter-directed thrombectomy has the potential to offer both short- and long-term benefits over systemic thrombolysis including early recovery, reduced risk of bleeding, pulmonary hypertension, and reversal of RV failure. CONCLUSIONS: Catheter-directed techniques should be considered on a case-by-case basis, especially in patients who do not improve with thrombolysis. REFERENCE #1: 1.Ciampi-Dopazo, Juan José et al. "Aspiration Thrombectomy for Treatment of Acute Massive and Submassive Pulmonary Embolism: Initial Single-Center Prospective Experience.” Journal of vascular and interventional radiology : JVIR vol. 29,1 (2018): 101-106. doi:10.1016/j.jvir.2017.08.010 REFERENCE #2: 2.Tu, Thomas et al. "A Prospective, Single-Arm, Multicenter Trial of Catheter-Directed Mechanical Thrombectomy for Intermediate-Risk Acute Pulmonary Embolism: The FLARE Study.” JACC. Cardiovascular interventions vol. 12,9 (2019): 859-869. doi:10.1016/j.jcin.2018.12.022 DISCLOSURES: No relevant relationships by Mukul Bhattarai, source=Web Response No relevant relationships by radhika deshpande, source=Web Response no disclosure on file for Abdul Hafiz; No relevant relationships by Cameron Koester, source=Web Response No relevant relationships by Abhishek Kalidas Kulkarni, source=Web Response no disclosure on file for Mohsin Salih; No relevant relationships by Omar Siddiqui, source=Web Response