Tissue Plasminogen Activator Thrombolysis Research Articles

Histotripsy and Catheter-Directed Lytic: Efficacy in Highly Retracted Porcine Clots In Vitro

ObjectiveStandard treatment for deep vein thrombosis (DVT) involves catheter-directed anticoagulants or thrombolytics, but the chronic thrombi present in many DVT cases are often resistant to this therapy. Histotripsy has been found to be a promising adjuvant treatment, using the mechanical action of cavitating bubble clouds to enhance thrombolytic activity. The objective of this study was to determine if histotripsy enhanced recombinant tissue plasminogen activator (rt-PA) thrombolysis in highly retracted porcine clots in vitro in a flow model of occlusive DVT. MethodsHighly retracted porcine whole blood clots were treated for 1 h with either catheter-directed saline (negative control), rt-PA (lytic control), histotripsy, DEFINITY and histotripsy or the combination of rt-PA and histotripsy with or without DEFINITY. Five-cycle, 1.5 MHz histotripsy pulses with a peak negative pressure of 33.2 MPa and pulse repetition frequency of 40 Hz were applied along the clot. B-Mode and passive cavitation images were acquired during histotripsy insonation to monitor bubble activity. ResultsClots subjected to histotripsy with and without rt-PA exhibited greater thrombolytic efficacy than controls (7.0% flow recovery or lower), and histotripsy with rt-PA was more efficacious than histotripsy with saline (86.1 ± 10.2% compared with 61.7 ± 19.8% flow recovery). The addition of DEFINITY to histotripsy with or without rt-PA did not enhance either thrombolytic efficacy or cavitation dose. Cavitation dose generally did not correlate with thrombolytic efficacy. ConclusionEnhancement of thrombolytic efficacy was achieved using histotripsy, with and without catheter-directed rt-PA, in the presence of physiologic flow. This suggests these treatments may be effective as therapy for DVT.

Left ventricular systolic dysfunction predicts clinical prognosis in patients with acute ischemic stroke after intravenous thrombolysis.

Although intravenous recombinant tissue plasminogen activator (rt-PA) thrombolysis is the most effective early treatment for acute ischemic stroke (AIS), outcomes vary greatly among patients. Left ventricular systolic dysfunction (LVSD) is prone to distant organ ischemia and may be a predictor for poor prognosis in AIS patients undergoing intravenous thrombolysis (IVT). Our aim was to investigate the predictivity of LVSD diagnosis (as measured by left ventricular ejection fraction (LVEF)) on 90-day clinical outcomes in AIS patients undergoing thrombolysis. The current prospective cohort study continuously enrolled 273 AIS patients from the National Stroke Prevention and Treatment Engineering Management Special Database who underwent IVT and completed echocardiography within 24 h of admission between 2021 and 2023. LVSD was examined by evaluation of the echocardiographic LVEF values using Simpson's biplane method of discs in line with international guidelines, and defined as a LVEF value < 50%. Multivariable ordinal logistic regression model was performed to analyze the association between LVEF and functional outcome at 3 months. Restricted cubic spline (RCS) was used to examine the shape of the dose-response association between reduced LVEF and poor functional outcomes. Subgroup analysis was also employed to further verify the reliability and practicability of the results. Baseline data analysis showed LVSD patients had more comorbidities including on multivariate analyses, LVSD (OR 2.78, 95% CI 1.23 to 6.24, P=0.014), pre-existing diabetes mellitus (OR 2.08, 95% CI 1.11 to 3.90, P=0.023) and NIHSS on arrival (OR 1.31, 95% CI 1.21 to 1.49, P<0.001) were independent predictors of poor functional outcomes (mRS ≥ 3) at 3 months. Multivariable-adjusted spline regression indicated a linear dose-response association between LVEF after IVT and poor functional outcomes (p for linearity < 0.001), with the optimal cutoff values of LVEF being 0.48. Our finding indicated that AIS patients with LVSD after IVT had poorer outcomes, suggesting the need to monitor and optimize LVEF in stroke management.

Mediation of long-pulsed ultrasound enhanced microbubble recombinant tissue plasminogen activator thrombolysis in a rat model of platelet-rich thrombus.

Ultrasound (US)-enhanced microbubble (MB) therapy has been investigated as a therapeutic technique to facilitate the thrombolysis for the treatment of pericardial and microvascular obstruction. This study sought to assess the therapeutic effects of long-pulsed US-assisted MB-mediated recombinant tissue plasminogen activator (rt-PA) thrombolysis in a rat model of platelet-rich thrombus. Ferric chloride (10%) was used to induce total arterial occlusion before formation of platelet-rich thrombi. Therapeutic long-tone-burst US (1 MHz, 0.6 MPa, 1,000-µs pulse length) was used, and 2.9×109/mL of lipid MBs and 1 mg/mL of rt-PA were infused. Subsequently, 42 Sprague-Dawley (SD) male rats were randomly divided into seven groups: (I) control; (II) rt-PA; (III) high duty cycle US + MB; (IV) low duty cycle US + rt-PA; (V) high duty cycle US + rt-PA; (VI) low duty cycle US + rt-PA + MB; and (VII) high duty cycle US + rt-PA + MB. The recanalization grades were evaluated after 20 minutes' treatment. Compared to the control, there was significant improvement in recanalization in the US + rt-PA groups (P=0.01 vs. control), US (low duty cycle) + rt-PA + MB (P=0.003 vs. control) and US (high duty cycle) + rt-PA + MB (P<0.001 vs. control) groups, in which recanalization was successfully achieved in all rats. Long-pulsed US-enhanced MB-mediated rt-PA thrombolysis offered a powerful approach in the treatment of platelet-rich thrombus.

Real-Time Ultrasound Doppler Tracking and Autonomous Navigation of a Miniature Helical Robot for Accelerating Thrombolysis in Dynamic Blood Flow.

Untethered small-scale robots offer great promise for medical applications in complex biological environments. However, challenges remain in the control and medical imaging of a robot for targeted delivery inside a living body, especially in flowing conditions (e.g., blood vessels). In this work, we report a strategy to autonomously navigate a miniature helical robot in dynamic blood flow under ultrasound Doppler imaging guidance. A magnetic torque and force-hybrid control approach is implemented, enabling the actuation of a millimeter-scale helical robot against blood flow under a rotating magnetic field with a controllable field gradient. Experimental results demonstrate that the robot (length 7.30 mm; diameter 2.15 mm) exhibits controlled navigation in vascular environments, including upstream and downstream navigation in flowing and pulsatile flowing blood with flow rates up to 24 mL/min (mean flow velocity: 14.15 mm/s). During navigation, the rotating robot-induced Doppler signals enable real-time localization and tracking in flowing and pulsatile flowing blood environments. Moreover, the robot can be selectively navigated along different paths by actively controlling the robot's orientation. We apply this autonomous strategy for localizing thrombus and accelerating thrombolysis rate. Compared with conventional tissue plasminogen activator (tPA) thrombolysis, the robot-enhanced shear stress and tPA convection near the clot-blood interface increase the unblocking and thrombolysis efficiency up to 4.8- and 3.5-fold, respectively. Such a medical imaging-guided navigation strategy provides simultaneous robot navigation and localization in complex dynamic biological environments, providing an intelligent approach toward real-time targeted delivery and diagnostic applications in vivo.

Ischemic post-conditioning is neuroprotective even at delayed tPA administration after embolic stroke in female rats.

Objective(s):Delayed tissue plasminogen activator (tPA) thrombolysis is accompanied by different complications in stroke patients. Studies reported sex differences in stroke therapy. Ischemic postconditioning (PC) unveils neuroprotection in stroke models. In this study, we investigate the combined effect of delayed tPA therapy and PC procedure during an embolic stroke experimental model in female rats. Materials and Methods:Female Wistar rats were randomly divided into control (saline), tPA, PC, and tPA+PC groups after stroke induction via clot injection to the middle cerebral artery. tPA treatment was initiated 6 hr after stroke, and PC procedure was performed 6.5 hr post-ischemia induction (occlusion: 10 sec; reopening: 30 sec; 5 cycles). The cerebral blood flow (CBF) was recorded up to 60 min from IV tPA injection time. The parameters of brain edema, infarct volume, disruption of the blood-brain barrier (BBB), behavioral tests, and matrix metalloproteinases-9 (MMP-9) were evaluated.Results: This study revealed that PC conduction prevents excessive CBF increase by tPA and played a protective role in infarct volume reduction (P<0.05). The combination of PC and tPA reduced the infarct volume, brain edema, and protected BBB. tPA+PC could alleviate neurobehavioral disorders compared with control or tPA. Moreover, PC had the capability of MMP-9 reduction when combined with delayed tPA (P<0.05).Conclusion: Conduction of PC not only alleviated some stroke complications but also enhanced the therapeutic time window of tPA in female rats under embolic stroke.

Prognostic analysis of different therapeutic regimens in patients with acute cardiogenic cerebral embolism

BackgroundFew studies focused on the functional outcomes of patients at 3 months after receiving intravenous thrombolysis, anticoagulation, or antiplatelet therapy within 4.5 h of onset of the cardiogenic cerebral embolism (CCE) subtype.MethodsThe purpose of this retrospective study was to analyse the clinical data of patients with acute CCE and compare the 3-month functional prognoses of patients after administration of different antithrombotic therapies within 4.5 h of stroke onset. A total of 335 patients with CCE hospitalized in our institution were included in this study. The patients were stratified according to the hyperacute treatment received, and baseline clinical and laboratory data were analysed. A 3-month modified Rankin scale (mRS) score of 0–2 was defined as an excellent functional outcome.ResultsA total of 335 patients were divided into thrombolytic (n = 78), anticoagulant (n = 88), and antiplatelet therapy groups (n = 169). A total of 164 patients had a good prognosis at 3 months (mRS ≤ 2). After adjustments were made for age and National Institute of Health Stroke Scale (NIHSS) score, each group comprised 38 patients, and there were no significant differences in sex composition, complications, lesion characteristics, or Oxfordshire Community Stroke Project (OSCP) classification among the three groups. The plasma D-dimer level (µg/ml) in the thrombolytic group was significantly higher than those in the anticoagulant and antiplatelet groups [3.07 (1.50,5.62), 1.33 (0.95,1.89), 1.61 (0.76,2.96), P < 0.001]. After one week of treatment, the reduction in NIHSS in the thrombolytic group was significantly greater than those in the other two groups [3.00 (1.00, 8.00), 1.00 (0.00, 5.00), 1.00 (0.00, 2.00), P = 0.025]. A total of 47 patients (41.2 %) had an mRS score of ≤ 2 at 3 months, and 23 patients died (20.2 %). There was no significant difference in the proportion of patients with a good prognosis or the mortality rate among the three groups (P = 0.363, P = 0.683).ConclusionsThrombolytic therapy is effective at improving short-term and 3-month prognoses. Anticoagulant therapy may be a safe and effective treatment option for patients with the cardiac stroke subtype who fail to receive intravenous recombinant tissue plasminogen activator (r-tPA) thrombolysis within 4.5 h in addition to antiplatelet therapy, as recommended by the guidelines.

Application of quantitative electroencephalogram monitoring in evaluating thrombolytic effect of acute cerebral infarction

To investigate the value of quantitative electroencephalography (qEEG) in the evaluation of thrombolytic efficacy in acute cerebral infarction. A prospective cohort study was conducted. Ninety-four patients with acute cerebral infarction who received intravenous thrombolysis admitted to the department of emergency of Qinhuangdao First Hospital from October 2019 to September 2020 were enrolled. The relative energy values of δ, θ, α and β waves in qEEG before and 2 hours, 24 hours and 7 days after intravenous recombinant tissue plasminogen activator (rt-PA) thrombolysis were dynamically monitored, and the power ratio index [DTABR, DTABR = (δ+θ)/(α+β)] was calculated. The National Institutes of Health stroke scale (NIHSS) score was also recorded. The reduction of NIHSS score ≥ 3 or the disappearance of neurological symptoms were regarded as effective thrombolytic therapy. The changes of DTABR before and after thrombolysis in patients with effective and ineffective thrombolysis were analyzed, and the correlation between DTABR and NIHSS score was analyzed by Pearson method. A total of 94 patients were enrolled, including 64 males and 30 females. The average age was (61.71±10.11) years from 36 to 89 years old. Thrombolysis was effective in 57 cases and ineffective in 37 cases. Compared with before thrombolysis, DTABR of the effective group was significantly decreased at 2 hours, 24 hours and 7 days after thrombolysis (left cerebral infarction: 1.87±1.45, 1.59±0.88, 1.58±0.90 vs. 3.82±2.60; right cerebral infarction: 1.55±0.57, 1.41±0.50, 1.35±0.44 vs. 3.20±1.63, all P < 0.05). DTABR did not change or increase significantly at 2 hours, 24 hours and 7 days after thrombolysis compared with before thrombolysis (left cerebral infarction: 3.56±2.57, 3.48±2.19, 3.54±2.50 vs. 3.11±1.62; right cerebral infarction: 5.29±3.93, 5.33±3.94, 5.19±4.52 vs. 4.73±2.43, all P > 0.05). Pearson correlation analysis showed a significant positive correlation between DTABR and NIHSS score in patients with acute cerebral infarction (r = 0.691, P < 0.01). The quantitative index of qEEG, DTABR, can accurately and quickly monitor the process of thrombolysis in acute cerebral infarction, and can effectively evaluate the effect of thrombolysis in patients.

Association Between the Change of Coagulation Parameters and Clinical Prognosis in Acute Ischemic Stroke Patients After Intravenous Thrombolysis With rt-PA

Acute ischemic stroke patients with intravenous (IV) recombinant tissue plasminogen activator (rt-PA) thrombolysis have different outcomes. The degree of thrombolysis depends largely on the delicate balance of coagulation and fibrinolysis. Thus, our study aimed to investigate the prognostic value of routine coagulation parameters in acute stroke patients treated with rt-PA. From December 2016 to October 2018, consecutive patients treated with standard-dose IV rt-PA within 4.5 h of stroke onset were collected in Beijing Tiantan Hospital. Routine coagulation parameters, including platelet count, mean platelet volume, platelet distribution width, prothrombin time (PT), activated partial thromboplastin time, thrombin time, and fibrinogen, were measured at baseline (h0) and 24 h (h24) after thrombolysis. The change of coagulation parameters was defined as the (h24-h0)/h0 ratio. The prognosis included short-term outcome at 24 h and functional outcome at 3 months. A total of 267 patients were investigated (188 men and 79 women) with a mean age of 60.88 ± 12.31 years. In total, 9 patients had early neurological deterioration within 24 h, and 99 patients had an unfavorable outcome at the 3-month visit. In multivariate logistic regression, the (h24-h0)/h0 of PT was associated with unfavorable functional outcomes at 3 months (odds ratio: 1.42, 95% confidence interval: 1.02-2.28). While the change of other coagulation parameters failed to show any correlation with short-term or long-term prognosis. In conclusion, the prolongation of PT from baseline to 24 h after IV rt-PA increases the risk of 3-month unfavorable outcomes in acute stroke patients.

Association Between Plasma Total Homocysteine Levels and Risk of Early Hemorrhagic Transformation in Patients with Acute Ischemic Stroke: A Hospital-Based Study

ObjectsIn this study, we investigated the association between plasma total homocysteine(tHcy) levels and the risk of early hemorrhagic transformation(HT) in patients with acute ischemic stroke(AIS). MethodsConsecutive hospitalized participants who met the inclusion criteria were enrolled and grouped according to plasma tHcy levels. Participants were divided into a low homocysteine level(L-tHcy) group (<12 µmol/L) and a high homocysteine level group(H-tHcy) (≥ 12 µmol/L). Baseline computed tomography (CT) examination was performed. HT was determined via CT or magnetic resonance imaging within 1 to 3 days after admission. ResultsA total of 1858 patients were screened and 1378 patients completed the this study(797 patients in the H-tHcy group and 581 patients in the L-tHcy group). HT incidence was 5.2% (30/581,) in the L-tHcy group and 11.2% (90/797) in the H-tHcy group(P<0.05). Binary logistic regression analysis showed that initial NIHSS score, tHcy levels, treatment with recombinant tissue plasminogen activator thrombolysis, systolic blood pressure on admission, glucose level on admission, smoking status and estimated glomerular filtration rate were independent risk factors for HT. Receiver operating characteristic analysis showed that tHcy level was a moderately sensitive and specific index to predict the incidence of HT, and the optimal cutoff was 16.56 μmol/L (sensitivity 63.3%, specificity 41.3%). ConclusionOur study findings reveal that high plasma tHcy level is one independent risk factor associated with increased risk of early HT in patients with AIS.

Assessing the Clinical Efficacy of Recombinant Tissue Plasminogen Activator on Acute Cerebral Infarction.

To assess the efficacy of intravenous recombinant tissue plasminogen activator (rt-PA) thrombolysis on clinical outcomes and risk of death in patients with acute cerebral infarction. Patients (n = 258) with acute cerebral infarction, treated within 4-5 h of the episode, were grouped according to whether intravenous thrombolysis was performed using rt-PA or not. Both groups received routine treatment for cerebral infarction, but the former received rt-PA intravenously at a dosage of 0.9 mg/kg. The National Institutes of Health Stroke Scale (NIHSS) score, clinical efficacy, and risk of bleeding and death were compared between the two groups. The NIHSS score and clinical effects for the rt-PA group were more favorable than those of its counterpart (P < 0.05), though there was no significant difference in risk of an intracranial hemorrhage. The mortality rate for the rt-PA group was lower than that of the control group (P < 0.05). Administration of intravenous rt-PA thrombolysis within 4.5 h of an acute cerebral infarction had a significant impact and did not increase risk of intracranial hemorrhage or death.

Review Cerebral Ischemic Tolerance and Preconditioning: Methods, Mechanisms, Clinical Applications, and Challenges.

Stroke is one of the leading causes of morbidity and mortality worldwide, and it is increasing in prevalence. The limited therapeutic window and potential severe side effects prevent the widespread clinical application of the venous injection of thrombolytic tissue plasminogen activator and thrombectomy, which are regarded as the only approved treatments for acute ischemic stroke. Triggered by various types of mild stressors or stimuli, ischemic preconditioning (IPreC) induces adaptive endogenous tolerance to ischemia/reperfusion (I/R) injury by activating a multitude cascade of biomolecules, for example, proteins, enzymes, receptors, transcription factors, and others, which eventually lead to transcriptional regulation and epigenetic and genomic reprogramming. During the past 30 years, IPreC has been widely studied to confirm its neuroprotection against subsequent I/R injury, mainly including local ischemic preconditioning (LIPreC), remote ischemic preconditioning (RIPreC), and cross preconditioning. Although LIPreC has a strong neuroprotective effect, the clinical application of IPreC for subsequent cerebral ischemia is difficult. There are two main reasons for the above result: Cerebral ischemia is unpredictable, and LIPreC is also capable of inducing unexpected injury with only minor differences to durations or intensity. RIPreC and pharmacological preconditioning, an easy-to-use and non-invasive therapy, can be performed in a variety of clinical settings and appear to be more suitable for the clinical management of ischemic stroke. Hoping to advance our understanding of IPreC, this review mainly focuses on recent advances in IPreC in stroke management, its challenges, and the potential study directions.

Improving timely treatment with a stroke emergency map: The case of northern China.

ObjectiveThe Chinese stroke emergency map (SEM) was implemented in 2017 to reduce prehospital and hospital delays for acute ischemic stroke (AIS) patients suitable for intravenous recombinant tissue plasminogen activator (rt‐PA) thrombolysis. However, data on the time delay following the implementation of an SEM in China are limited.MethodsData for suspected stroke patients from the SEM registry center of Taiyuan, Shanxi Province, from August 2017 to July 2019, patients’ characteristics, thrombolysis rate, and functional outcome at 90 days were analyzed.ResultsOne thousand seven hundred and eighty six patients who arrived at hospitals within 4.5 hr of onset were included; 35.9% arrived by emergency medical services (EMSs), and 1,207 (67.6%) of the population received intravenous rt‐PA. As a result of the SEM, the number of patients treated with rt‐PA increased from 63.9% in phase 1 (August 2017 to July 2018) to 70.5% in phase 2 (August 2018 to July 2019). The median onset‐to‐door and onset‐to‐needle times decreased by five minutes (100 [IQR: 62–135] vs. 105 [IQR: 70–145], p = .005) and nine minutes (158 [IQR: 124–197] vs. 167 [IQR: 132–214], p = .001), respectively. Patients in phase 2 achieved greater independent function outcome at 90 days (79.9% vs. 72.1%; adjusted odds ratio, 2.010; 95% confidence interval, 1.444–2.798). The binary logistic regression models revealed that shorter onset‐to‐needle time (OR: 0.994; 95% CI: 0.992–0.997; p < .001) and lower baseline NIHSS scores (OR: 39.120; 95% CI: 23.477–65.188; p < .001 and OR: 18.324; 95% CI: 11.425–29.388; p < .001 and OR: 3.123; 95% CI: 2.044–4.773; p < .001) were significant predictors for the independent function outcome.ConclusionThe implementation of a stroke emergency map is more likely to reduce prehospital delays and improve function outcomes. Future efforts should attempt to increase EMS usage.

Perioperative and long-term outcomes after percutaneous thrombectomy of arteriovenous dialysis access grafts

ObjectiveMaintenance of functional arteriovenous grafts (AVGs) for dialysis is difficult secondary to low primary patency, need for reinterventions, and limited alternative dialysis access options. We assessed our experience with percutaneous thrombectomy for treatment of occluded AVGs. MethodsWe performed a retrospective analysis of all percutaneous thrombectomies for AVGs from 2015 to 2017. These were generally performed using mechanical thrombectomy and occasional chemical tissue plasminogen activator thrombolysis, over-the-wire balloon embolectomy for inflow, and adjunctive inflow and outflow interventions as necessary. Perioperative outcomes, long-term patency, reinterventions, and need for new permanent access placement were analyzed. ResultsThere were 218 percutaneous thrombectomies performed on 86 AVGs in 77 patients. Approximately half (53.2%) of the patients were male and 68.8% were black. Mean age was 61.1 ± 13.0 years. At the time of thrombectomy, 73.8% underwent venous outflow interventions and 4.5% underwent arterial inflow interventions. Within 30 days, 24.8% of declotted grafts underwent repeated percutaneous thrombectomy, 14.3% required tunneled dialysis catheter placement, 4% developed minor access site or graft infections, and one patient underwent surgical arterial thrombectomy for arm ischemia. There were no venous thromboembolic, cardiopulmonary, or cerebrovascular complications or clinically significant pulmonary embolism. At 1 year and 3 years after percutaneous thrombectomy, freedom from repeated thrombosis was 37% and 18%, respectively, and freedom from new dialysis access placement was 66% and 51%, respectively. Overall patient survival was 82% at 3 years. ConclusionsPercutaneous thrombectomy of AVGs is safe and is associated with acceptable patency rates. This minimally invasive method extends AVG use for these high-risk patients with limited dialysis access options.

Dl-NBP (Dl-3-N-Butylphthalide) Treatment Promotes Neurological Functional Recovery Accompanied by the Upregulation of White Matter Integrity and HIF-1α/VEGF/Notch/Dll4 Expression.

Dl-3-n-butylphthalide (dl-NBP) was approved by the FDA of China for the treatment of acute ischemic stroke. Dl-NBP has been shown to promote neurological functional recovery and enhance white matter integrity using an endothelin-1-induced focal permanent cerebral ischemia model, which could mimic those patients who have no opportunity to receive either tissue plasminogen activator (tPA) thrombolysis or endovascular therapy. However, it is not clear whether dl-NBP could promote neurological functional recovery in a focal transient cerebral ischemia model, which could mimic those patients who have the opportunity to receive either tPA thrombolysis or endovascular therapy. In this study, using a model of middle cerebral artery occlusion in mice, we aim to explore the effect of two-week dl-NBP treatment on neurological functional recovery after ischemic stroke as well as its underlying mechanism. Our results showed that dl-NBP treatment promoted functional recovery assessed by neurological scores and an adhesive remove test, and this improved the integrity of white matter after 60-min ischemia and 14-day reperfusion. In addition, dl-NBP increased the number of RECA-1 positive vessels and enhanced the expression of the tight junction protein occludin. More importantly, dl-NBP also promoted the expression of hypoxia-induced factor-1α, the vascular endothelial growth factor, Notch, and delta-like ligand 4. In conclusion, our study provides evidence that dl-NBP treatment could also promote functional recovery after focal transient ischemia stroke, and this recovery is associated with upregulated white matter integrity, microvessels, and the tight junction protein occludin. Our results suggested that, in future, dl-NBP may also be applied in clinic to promote functional recovery during the later phase of focal transient ischemic stroke.

Protocoled thrombolytic therapy for frostbite improves phalangeal salvage rates.

BackgroundFrostbite is a cold injury that has the potential to cause considerable morbidity and long-term disability. Despite the complexity of these patients, diagnostic and treatment practices lack standardization. Thrombolytic therapy has emerged as a promising treatment modality, demonstrating impressive digit salvage rates. We review our experience with thrombolytic therapy for severe upper extremity frostbite.MethodsRetrospective data on all frostbite patients evaluated at our institution from December 2017 to March 2018 was collected. A subgroup of patients with severe frostbite treated with intra-arterial thrombolytic therapy (IATT) were analysed.ResultsOf the 17 frostbite patients treated at our institution, 14 (82%) were male and the median age was 31 (range: 19–73). Substance misuse was involved in a majority of the cases (58.8%). Five (29.4%) patients with severe frostbite met inclusion criteria for IATT and the remaining patients were treated conservatively. Angiography demonstrated a 74.5% improvement in perfusion after tissue plasminogen activator thrombolysis. When comparing phalanges at risk on initial angiography to phalanges undergoing amputation, the phalangeal salvage rate was 83.3% and the digit salvage rate was 80%. Complications associated with IATT included groin hematoma, pseudoaneurysm and retroperitoneal hematoma.ConclusionsThrombolytic therapy has the potential to greatly improve limb salvage and functional recovery after severe frostbite when treated at an institution that can offer comprehensive, protocoled thrombolytic therapy. A multi-center prospective study is warranted to elucidate the optimal treatment strategy in severe frostbite.

Early prediction of the 3-month outcome for individual acute ischemic stroke patients who received intravenous thrombolysis using the N2H3 nomogram model.

Background:The aim of this study was to establish a nomogram model for individualized early prediction of the 3-month prognosis in patients with acute ischemic stroke (AIS) who were treated with intravenous recombinant tissue plasminogen activator (rt-PA) thrombolysis.Methods:A total of 691 patients were included in this study; 564 patients were included in the training cohort, while 127 patients were included in the test cohort. The main outcome measure was a 3-month unfavorable outcome (modified Rankin Scale 3–6). To construct the nomogram model, stepwise logistic regression analysis was applied to select the significant predictors of the outcome. The discriminative performance of the model was assessed by calculating the area under the receiver operating characteristic curve (AUC-ROC). A decision curve analysis was used to evaluate prognostic value of the model.Results:The initial National Institutes of Health Stroke Scale [NIHSS, odds ratio (OR), 1.35; 95% confidence interval (CI), 1.28–1.44; p < 0.001], delta NIHSS (changes in the NIHSS score from baseline to 24 h, OR, 0.75; 95% CI, 0.70–0.79; p < 0.001), hypertension (OR, 2.07; 95% CI, 1.32–3.31; p = 0.002), hyperhomocysteinemia (Hhcy, OR, 2.18; 95% CI, 1.20–4.11; p = 0.013), and the ratio of high-density lipoprotein cholesterol (HDL-C) to low-density lipoprotein cholesterol (LDL-C) (HDL-C/LDL-C, OR, 3.29; 95% CI, 1.00–10.89; p = 0.049) (N2H3) were found to be independent predictors of a 3-month unfavorable outcome from multivariate logistic regression analysis and were incorporated in the N2H3 nomogram model. The AUC-ROC of the training cohort was 0.872 (95% CI, 0.841–0.902), and the AUC-ROC of the test cohort was 0.900 (95% CI, 0.848–0.953).Conclusion:The study presented the N2H3 nomogram model, with initial NIHSS score, delta NIHSS, hypertension, Hhcy, and HDL-C/LDL-C as predictors. It therefore provides an individualized early prediction of the 3-month unfavorable outcome in AIS patients treated with intravenous rt-PA thrombolysis.

P5592Thrombolysis with tissue plasminogen activator for patients with acute pulmonary embolisms in the real world: from the COMMAND VTE Registry

Abstract Background/Introduction There is still uncertainty about the optimal usage of thrombolysis for acute pulmonary embolisms (PEs), leading to widely varying usage of thrombolysis in the real world. However, these have not been fully evaluated yet. Purpose We sought to evaluate the management strategies and clinical outcomes of thrombolysis for acute PEs in the real world. Methods The COMMAND VTE Registry is a multicenter registry enrolling 3,027 consecutive patients with acute symptomatic venous thromboembolisms in Japan between January 2010 and August 2014. The present study population consisted of 1,549 patients with PEs who received tissue plasminogen activator (t-PA) thrombolysis (N=180, 12%), or those who did not (N=1,369). The effectiveness outcome was all-cause death. The safety outcome was major bleeding. We used a multivariable logistic regression analysis to estimate the odds ratio (OR) and 95% confidence intervals (CI), to adjust clinically relevant confounders (age, sex, history of major bleeding, active cancer, and anemia). Additionally, we conducted stratified analysis by clinical severity, and we also evaluated clinical outcomes according to dosages of t-PA. Results Patients with t-PA thrombolysis were younger, and more frequently had higher body weight, but less frequently had active cancer, history of major bleeding, and anemia. More than half of patients with t-PA thrombolysis were patients with mild PEs, and the proportions of t-PA thrombolysis varied widely across the participating centers. More than half of patients received low-dose of t-PA (&lt;20,000 IU/kg). As for the effectiveness, 9 (5.0%) patients in the t-PA thrombolysis group and 95 (6.9%) patients in the non t-PA thrombolysis group died at 30 days (Crude OR, 0.71; 95% CI 0.35–1.42, P=0.33). As for the safety, 7 (3.9%) patients in the t-PA thrombolysis group and 22 (1.6%) patients in the non t-PA thrombolysis group experienced major bleeding events at 10 days (Crude OR, 2.48; 95% CI 1.04–5.88, P=0.04). T-PA thrombolysis group had a significantly higher risk for 10-day major bleeding (Adjusted OR, 4.01; 95% CI 1.57–10.2, P=0.004), but not a lower risk for 30-day mortality (Adjusted OR, 1.10; 95% CI 0.53–2.28, P=0.79), although the risk for 30-day mortality was significantly lower in those with severe PEs (Adjusted OR, 0.36; 95% CI 0.15–0.88, P=0.02). After adjusting confounders, the 10-day major bleeding risk of the low-dose of t-PA group relative to the standard-dose of t-PA group tended to be lower (Adjusted OR, 0.07; 95% CI 0.004–1.05, P=0.05). Conclusions In the present real-world registry, relatively large number of patients received t-PA thrombolysis with wide variation across the participating centers. T-PA thrombolysis was significantly associated with a higher risk for major bleeding, but not a lower risk for mortality, although there appeared to be a benefit of t-PA thrombolysis in decreasing the risk for mortality in patients with severe PEs. Acknowledgement/Funding Research Institute for Production Development, Mitsubishi Tanabe Pharma Corporation

Peripheral Monocyte Count Predicts Outcomes in Patients with Acute Ischemic Stroke Treated with rtPA Thrombolysis.

The aim of this study was to investigate the predictive value of the monocyte count as a prognostic biomarker on 90days in patients with acute ischemic stroke (AIS) treated with recombinant tissue plasminogen activator (rtPA) thrombolysis. In total, 206 patients with AIS treated in our institute between 2013 and 2018 were retrospectively enrolled. All patients received rtPA thrombolytic therapy within 4.5h of AIS onset. Using receiver operating characteristic (ROC) curve analysis, patients were divided into two groups according to monocyte count: a low monocyte count (LMC) group (monocytes < 0.53 × 109/L) and a high monocyte count (HMC) group (monocytes ≥ 0.53 × 109/L). Patients' functional outcomes 90days after AIS were assessed using the modified Rankin Scale. More patients had a poor outcome in the HMC group than in the LMC group (49.32% vs.31.58%, p = 0.012). Multivariate logistic regression analysis revealed that infarct volume (odds ratio = 1.03, 95% confidence interval 1.01-1.04, p < 0.001), systolic pressure at admission (odds ratio = 1.02, 95% confidence interval 1.00-1.04, p = 0.016), fasting blood glucose at admission (odds ratio = 1.41, 95% confidence interval 1.18-1.67, p < 0.001), and monocyte count ≥ 0.53 × 109/L (odds ratio = 2.25, 95% confidence interval 1.09-4.62, p = 0.028) were independently associated with a poor outcome in AIS patients treated with rtPA thrombolysis. A peripheral monocyte count ≥ 0.53 × 109/L is an independent prognostic marker on 90-days in patients with AIS treated with rtPA thrombolysis.

The effect of 220 kHz insonation scheme on rt-PA thrombolytic efficacy in vitro

Ultrasound-enhanced recombinant tissue plasminogen activator (rt-PA) thrombolysis is under development as an adjuvant to ischemic stroke therapy. The goal of this study was to design a pulsed ultrasound (US) exposure scheme that reduced intracranial constructive interference and tissue heating, and maintained thrombolytic efficacy relative to continuous wave (CW) insonation. Three 220 kHz US schemes were evaluated, two pulsed insonation schemes (15 cycles, 68 µs pulse duration, 33% or 62.5% duty cycle) and an intermittent CW insonation scheme (50 s active, 30 s quiescent) over a 30-min treatment period. An in silico study using a finite-difference model of transcranial US propagation was performed to estimate the intracranial acoustic field and temperature rise in the skull for each insonation scheme. In vitro measurements with flow were performed to assess thrombolysis using time-lapse microscopy. Intracranial constructive interference was not reduced with pulsed US using a pulse length of 15 cycles compared to intermittent CW US. The 33.3% duty cycle pulsed US scheme reduced heating in the temporal bone as much as 60% relative to the intermittent CW scheme. All insonation schemes promoted sustained stable cavitation in vitro and augmented thrombolysis compared to rt-PA alone (p < 0.05). Ultraharmonic (UH) and harmonic cumulative energy over a 30 min treatment period was significantly higher (p < 0.05) for the intermittent CW US scheme compared to either pulsed US scheme. Despite the difference in cavitation emissions, no difference was observed in the clot lysis between the three US schemes. These findings demonstrate that a 33.3% duty cycle pulsed US scheme with a 15-cycle burst can reduce bone heating and achieve equivalent thrombolytic efficacy as an intermittent CW scheme.

Thrombolysis with tissue plasminogen activator in patients with acute pulmonary embolisms in the real world: from the COMMAND VTE registry.

There is still uncertainty about the optimal usage of thrombolysis for acute pulmonary embolisms (PEs), leading to a widely varying usage in the real world. The COMMAND VTE Registry is a multicenter retrospective registry enrolling consecutive patients with acute symptomatic venous thromboembolisms (VTEs) in Japan. The present study population consisted of 1549 patients with PEs treated with tissue plasminogen activator (t-PA) thrombolysis (N = 180, 12%) or without thrombolysis (N = 1369). Thrombolysis with t-PA was implemented in 33% of patients with severe PEs, and 9.2% of patients with mild PEs with a wide variation across the participating centers. Patients with t-PA thrombolysis were younger, and less frequently had active cancer, history of major bleeding, and anemia. At 30days, t-PA thrombolysis as compared to no thrombolysis was associated with similar mortality rates (5.0% vs. 6.9%, P = 0.33), but a lower adjusted mortality risk (OR 0.41; 95% CI 0.18-0.90, P = 0.03), while it was associated with a trend for higher rates of major bleeding (5.6% vs. 2.9%, P = 0.06) and a significantly higher adjusted risk for major bleeding (OR 2.39; 95% CI 1.06-5.36, P = 0.03). In patients with severe PEs, the mortality rates at 30days were significantly lower in the t-PA thrombolysis group than no thrombolysis group (15% vs. 37%, P = 0.006). In the present real-world VTE registry in Japan, t-PA thrombolysis was not infrequently implemented, not only in patients with severe PEs, but also in patients with mild PEs. A substantial mortality risk reduction might be suggested with t-PA thrombolysis in patients with severe PEs.