Tenecteplase vs. alteplase for acute ischemic stroke: a systematic review

Introduction Thrombolysis for acute ischemic stroke (AIS) with alteplase is the currently approved therapy for patients who present within 4.5 h of symptom onset and meet criteria. Recently, there has been interest in the thrombolytic tenecteplase, a modified version of alteplase, due to its lower cost, ease of administration, and studies reporting better outcomes when compared to alteplase. This systematic review compares the efficacy of tenecteplase vs. alteplase with regard to three outcomes: (1) rate of symptomatic hemorrhage, (2) functional outcome at 90 days, and (3) reperfusion grade after thrombectomy to compare the efficacy of both thrombolytics in AIS Methods The search was conducted in August 2021 in PubMed, filtered for randomized controlled trials, and studies in English. The main search term was “tenecteplase for acute stroke.” Results A total of 6 randomized clinical trials including 1675 patients with AIS was included. No one’s study compared alteplase to tenecteplase with all three outcomes after acute ischemic stroke; however, by using a combination of the results, this systematic review summarizes whether tenecteplase outperforms alteplase. Conclusions The available evidence suggests that tenecteplase appears to be a better thrombolytic agent for acute ischemic stroke when compared to alteplase.

Microlyse; a thrombolytic agent that targets VWF for clearance of microvascular thrombosis

Thrombotic microangiopathies are hallmarked by attacks of disseminated microvascular thrombosis. In thrombotic thrombocytopenic purpura (TTP), this is caused by a rise in thrombogenic ultra-large von Willebrand factor (VWF) multimers because of ADAMTS13 deficiency. We previously reported that systemic plasminogen activation is therapeutic in a TTP mouse model. In contrast to its natural activators (i.e. tPA and uPA), plasminogen can directly bind to VWF. For optimal efficacy and safety, we aimed to focus and accelerate plasminogen activation at sites of microvascular occlusion. We here describe the development and characterization of Microlyse, a fusion protein consisting of a high-affinity VHH targeting the CT/CK domain of VWF and the protease domain of uPA, for localized plasminogen activation on microthrombi. Microlyse triggers targeted destruction of platelet-VWF complexes by plasmin on activated endothelial cells and in agglutination studies. At equal molar concentrations, Microlyse degrades microthrombi 7-fold more rapidly than blockade of platelet-VWF interactions with a bivalent humanized VHH (caplacizumab*). Finally, Microlyse attenuates thrombocytopenia and tissue damage (reflected by increased plasma lactate dehydrogenase activity, as well as PAI-1 and fibrinogen levels) more efficiently than caplacizumab* in an ADAMTS13-/- mouse model of TTP, without affecting hemostasis in a tail-clip bleeding model. These findings show that targeted thrombolysis of VWF by Microlyse is an effective strategy for the treatment of TTP and might hold value for other forms of VWF-driven thrombotic disease.

Effectiveness of mechanical recanalization for intraluminal occlusion of totally implantable venous access ports

Purpose: To evaluate if the mechanical injection of saline is effective in restoring patency of a totally implantable venous access port (TIVAP) with an intraluminal occlusion. Materials and methods: From January 2017 to June 2019, 64 cases of dysfunction of a TIVAP were referred to interventional radiology. Among these, 16 cases showed normal function of the TIVAP, 19 cases the showed the appearance of a fibroblastic sheath, and 29 cases showed intraluminal occlusion. Mechanical recanalization was performed for intraluminal occlusion of the TIVAP with an indeflator and a 20G non-coring needle. Linograms were performed in all recanalized cases. The success or failure of recanalization and the pressure of the indeflator were recorded. Linograms were evaluated for breakage or migration of catheters. Medical records were retrospectively reviewed. Results: Among the 29 intraluminal occlusion cases, 24 cases (82.7%) were recanalized by mechanical recanalization via an indeflator. The pressure of the indeflator ranged from 29 to 220 psi (median: 118 psi). Linograms revealed breakage of the catheter of the TIVAP in two failed cases. The median interval from implantation to dysfunction was 405 days (range: 43–1723 days). The median interval from last use to dysfunction was 8 days (mean: 15.4 days; range: 1–119 days). The median re-occlusion free period after successful mechanical recanalization was 100.5 days (range: 6–859 days). Conclusion: In the absence of an available thrombolytic agent, mechanical injection of saline was a tolerable alternative method for restoring occluded catheters and sustaining the function of catheters. Because breakage of the catheter can occur during mechanical recanalization of a TIVAP, a linogram should follow the procedure.

Recombinant Expression of Thrombolytic Agent Reteplase in Marine Microalga Tetraselmis subcordiformis (Chlorodendrales, Chlorophyta)

Tetraselmis subcordiformis, a unicellular marine green alga, is used widely in aquaculture as an initial feeding for fish, bivalve mollusks, penaeid shrimp larvae, and rotifers because of its rich content of amino acids and fatty acids. A stable nuclear transformation system using the herbicide phosphinothricin (PPT) as a selective reagent was established previously. In this research, the recombinant expression in T. subcordiformis was investigated by particle bombardment with the rt-PA gene that encodes the recombinant human tissue-type plasminogen activator (Reteplase), which is a thrombolytic agent for acute myocardial infarction treatment. Transgenic algal strains were selected by their resistance to PPT, and expression of rt-PA was validated by PCR, Southern blotting, and Western blotting, and bioactivity of rt-PA was confirmed by the fibrin agarose plate assay for bioactivity. The results showed that rt-PA was integrated into the genome of T. subcordiformis, and the expression product was bioactive, indicating proper post-transcriptional modification of rt-PA in T. subcordiformis. This report contributes to efforts that take advantage of marine microalgae as cell factories to prepare recombinant drugs and in establishing a characteristic pathway of oral administration in aquaculture.

A novel and potent thrombolytic fusion protein consisting of anti-insoluble fibrin antibody and mutated urokinase

Tissue plasminogen activator (tPA) is used clinically because it has higher binding specificity for insoluble fibrin (IF) than urokinase (UK), but even pro-tPA has catalytic activity in places other than IF. UK has the advantage that it is specifically activated on IF, but it binds IF weakly. Previously, we established a monoclonal antibody (mAb) that recognizes a pit structure formed only in IF. Here, we developed a new mAb against the pit, 1101, that does not affect coagulation or fibrinolysis, and prepared a fusion protein of UK with humanized 1101 Fab to transport UK selectively to IF. In IF-containing lesions, UK is cleaved by plasmin at two sites, Lys158/Ile159 and Lys135/Lys136. Cleavage of the former leads to activation of UK; however, because activated UK is linked by S-S bonds before and after cleavage, it is not released from the fusion. Cleavage at the latter site causes UK to leave the fusion protein; hence, we mutated Lys135/Lys136 to Gly135/Gly136 to prevent release of UK. This engineered UK-antibody fusion, AMU1114, significantly decreased the reduction of plasma plasminogen levels in vivo as compared to UK. In the photo-chemically induced thrombus mouse model, the vascular patency rate was 0% (0/10) in the control, 50% (5/10) in the tPA, and 90% (9/10) in the AMU1114 treatment group. Although no death was observed 1 hour after administration of each thrombolytic agent, some dead mice were identified within 24 hours in all treatment groups including control. These data indicate the need for further basic studies of AMU1114.

Early Experience With Tenecteplase at a Comprehensive Stroke Center

Purposeof review: Tenecteplase has been studied and recommended as an alternative thrombolytic agent in acute stroke patients. A brief review of clinical trials and guidelines pertinent to our clinical decision algorithm is described. This is followed by operational steps that were made to create and implement a clinical pathway based on available evidence in which tenecteplase is used in select stroke patients at our comprehensive stroke center.Recent findings:A number of patients have been treated at our center with IV tenecteplase. A case is presented to illustrate the successful implementation of this new process.Summary:Development of our protocol is discussed in detail in order to enable other centers to create their own clinical pathways for thrombolytic treatment of acute ischemic stroke using tenecteplase.

Lysis of arterial thrombi by perfusion of N,N’-Diacetyl-L-cystine (DiNAC)

The search persists for a safe and effective agent to lyse arterial thrombi in the event of acute heart attacks or strokes due to thrombotic occlusion. The culpable thrombi are composed either primarily of platelets and von Willebrand Factor (VWF), or polymerized fibrin, depending on the mechanism of formation. Current thrombolytics were designed to target red fibrin-rich clots, but may be not be efficacious on white VWF-platelet-rich arterial thrombi. We have developed an in vitro system to study the efficacy of known and proposed thrombolytic agents on white clots formed from whole blood in a stenosis with arterial conditions. The agents and adjuncts tested were tPA, ADAMTS-13, abciximab, N-acetyl cysteine, and N,N’-Diacetyl-L-cystine (DiNAC). Most of the agents, including tPA, had little thrombolytic effect on the white clots. In contrast, perfusion of DiNAC lysed thrombi as quickly as 1.5 min, which ranged up to 30 min at lower concentrations, and resulted in an average reduction in surface area of 71 ± 20%. The clot burden was significantly reduced compared to both tPA and a saline control (p<0.0001). We also tested the efficacy of all agents on red fibrinous clots formed in stagnant conditions. DiNAC did not lyse red clots, whereas tPA significantly lysed red clot over 48 h (p<0.01). These results lead to a novel use for DiNAC as a possible thrombolytic agent against acute arterial occlusions that could mitigate the risk of hyper-fibrinolytic bleeding.

Development and Testing of Thrombolytics in Stroke

Despite recent advances in recanalization therapy, mechanical thrombectomy will never be a treatment for every ischemic stroke because access to mechanical thrombectomy is still limited in many countries. Moreover, many ischemic strokes are caused by occlusion of cerebral arteries that cannot be reached by intra-arterial catheters. Reperfusion using thrombolytic agents will therefore remain an important therapy for hyperacute ischemic stroke. However, thrombolytic drugs have shown limited efficacy and notable hemorrhagic complication rates, leaving room for improvement. A comprehensive understanding of basic and clinical research pipelines as well as the current status of thrombolytic therapy will help facilitate the development of new thrombolytics. Compared with alteplase, an ideal thrombolytic agent is expected to provide faster reperfusion in more patients; prevent re-occlusions; have higher fibrin specificity for selective activation of clot-bound plasminogen to decrease bleeding complications; be retained in the blood for a longer time to minimize dosage and allow administration as a single bolus; be more resistant to inhibitors; and be less antigenic for repetitive usage. Here, we review the currently available thrombolytics, strategies for the development of new clot-dissolving substances, and the assessment of thrombolytic efficacies <i>in vitro</i> and <i>in vivo</i>.