General Child Neurology
Cerebral venous thrombosis in infants and children
Nov. 21, 2022
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Tissue plasminogen activator is an enzyme that catalyzes the conversion of plasminogen to plasmin for clot breakdown. Therefore, it is approved for the treatment of embolic or thrombotic stroke, but use is contraindicated in hemorrhagic stroke. Several clinical trials have shown that intravenous thrombolytic therapy for ischemic stroke using tissue plasminogen activator within a "therapeutic window" treatment time of 3 hours is the best available approach to improve the clinical outcome safely. Tissue plasminogen activator has been administered effectively as late as 6 hours after the onset of stroke. There is still some concern about hemorrhagic complications.
• Tissue plasminogen activator is approved for thrombolytic therapy of acute ischemic stroke.
• Two decades of clinical use, including numerous clinical trials, show that it is the first-line treatment of acute ischemic stroke due to thrombosis or embolism.
• A recognized complication is intracerebral hemorrhage.
Although the potential of thrombolytic agents for treating ischemic stroke was recognized in the 1950s, further development was held back because of the fear of high risk of death from intracranial hemorrhage. Streptokinase and urokinase have been commercially available since 1978 and are referred to as first generation thrombolytics. Thrombolytic therapy in acute stroke patients has been studied extensively during the past 10 years, and second generation thrombolytics have evolved. One of these second generation thrombolytics is tissue plasminogen activator (tPA), which received approval from the United States Food and Drug Administration in 1996 and has become part of emergency care of patients with stroke. The approval of tissue plasminogen activator for treatment of patients with ischemic stroke in the United States marked the first therapy proven to reverse or limit the effects of acute stroke. Alteplase is a tissue plasminogen activator produced by recombinant DNA technology.
North American perspectives on the use of tissue plasminogen activator in acute ischemic stroke are based on early pilot studies and phase 3 trials conducted by the National Institutes of Neurological Disorders and Stroke in the United States in 1995; these were the basis for Food and Drug Administration approval. Tissue plasminogen activator was approved for the treatment of patients within 3 hours of onset of stroke.
Pharmacodynamics. Tissue plasminogen activator is an enzyme that has the property of conversion of plasminogen to plasmin. When introduced into the circulation as a drug, it binds to fibrin in a thrombus to convert entrapped plasminogen into plasmin, leading to fibrinolysis. A decrease in circulating fibrinogen can be demonstrated after injection of tissue plasminogen activator.
The effect of tissue plasminogen activator on recanalization of a thrombosed artery may decrease over time. A study showed that time to treatment of over 270 minutes predicted lack of recanalization, especially in distal occlusions (31). When injected into aged animal models of stroke, tissue plasminogen activator rescues white matter from ischemia although it is toxic to the gray matter. The overall effect of tissue plasminogen activator is as a neuroprotectant of white matter from stroke-induced lesions, which may contribute to its global benefit as a stroke treatment (11).
Patients with ischemic stroke who have a high body temperature may benefit more from treatment with tissue plasminogen activator than those with lower body temperatures because lowering temperature decreased the fibrinolytic activity of tissue plasminogen activator (12). This interaction indicates that trials of therapeutic hypothermia for acute ischemic stroke should be controlled if combination with thrombolytics is used.
Pharmacokinetics. The important features are as follows:
• Tissue plasminogen activator is rapidly cleared from the plasma with a half-life of less than 5 minutes.
The pharmacokinetic profile of tissue plasminogen activator is based on studies in patients with acute myocardial infarction; one cannot assume that this would be similar in patients with acute ischemic stroke because of differences in the pathophysiology of the 2 conditions. Clearance of tissue plasminogen activator may be impaired due to impairment of cardiac function and hepatic perfusion in myocardial infarction whereas impaired metabolic clearance in elderly stroke patients may increase plasma concentrations (01). There is need for pharmacokinetic studies of tissue plasminogen activator in stroke patients.
Pharmacogenetics. Tissue plasminogen activator is encoded by the PLAT gene, which is located on chromosome 8. A study has identified 3 loci associated with circulating tissue plasminogen activator levels, the PLAT region, STXBP5, and STX2, which indicates a novel role for these in regulating tissue plasminogen activator release (19).
Related drugs. Two of the several third-generation thrombolytic agents have been investigated for the treatment of acute ischemic stroke; these are tenecteplase (a tissue plasminogen activator produced by recombinant DNA technology) and reteplase (mimics endogenous tissue plasminogen activator). By virtue of structural modifications, third generation thrombolytics have longer half-lives and greater penetration into the thrombus matrix. Microplasmin, a truncated form of plasmin, is a direct-acting thrombolytic with neuroprotective activities.
Alteplase versus tenecteplase. Alteplase is the cornerstone of acute ischemic stroke pharmacological treatment, either alone or prior to mechanical thrombectomy according to the guidelines of the American Stroke Association (34). A limitation of alteplase is the early recanalization rate of less than 50%, and efforts are being made to find a better substitute.
Tenecteplase is a genetically engineered molecule of alteplase, but it has higher fibrin affinity, greater resistance to plasminogen activator inhibitor-1, and longer half-life, enabling a single intravenous bolus instead of 1-hour infusion, with less effect on general hemostasis. Currently, tenecteplase is the drug of choice for systemic fibrinolysis in myocardial infarction, but head-to-head clinical trials are comparing it with alteplase for acute ischemic stroke. Information is available on only one of these, as an ongoing trial in Norway with an expected completion date in 2023 (NCT03854500).
In the early phase of development of tissue plasminogen activator for stroke in the United States, there were 9 placebo-controlled trials. Functional recovery was more frequent in the tissue plasminogen activator group than in the placebo group when treatment was started within the first 3 hours, but there was no survival benefit. The positive effects of tissue plasminogen activator on all outcome measures were not affected by age, severity of stroke, use of aspirin before onset of stroke, or baseline classification of stroke type. The National Institutes of Neurological Disorders and Stroke trial showed statistically significant results in combined 4 end points: National Institute of Health Stroke Scale, Modified Rankin Scale, Barthel Index, and Glasgow Outcome Scale; and mortality was lower in the tissue plasminogen activator-treated group (04). There was a higher incidence of intracerebral hemorrhage in patients treated with tissue plasminogen activator, but there was improvement in clinical outcome at 3 months in patients treated with a dose of 0.9 mg/kg within 3 hours of onset of stroke.
The European perspective is based on the results of the intent-to-treat analysis of the European Cooperative Acute Stroke Study trial in which tissue plasminogen activator was used within a 6-hour time window and no statistically significant benefit for tissue plasminogen activator-treated patients was seen in the primary end points: Modified Rankin Scale and the Barthel Index (14). However, in the target population analysis 1 primary end point (Modified Rankin Scale) and all secondary end points, except for mortality, were statistically significantly better for the tissue plasminogen activator-treated patients. This led to the reluctance of European neurologists to support broader use of tissue plasminogen activator, but for a subset of patients without early signs of infarction on CT scan. In a reassessment of tissue plasminogen activator in acute ischemic stroke (European Cooperative Acute Stroke Study II), the European investigators did not confirm a statistical benefit for thrombolysis within 6 hours of stroke onset, although it was felt that there was a clinically relevant improvement in selected patients (16). Secondary analysis of European Cooperative Acute Stroke Study data by time stratification, however, support the efficacy of early thrombolytic therapy in acute hemispheric stroke (40).
A prospective, multicenter, single-arm, open-label trial was conducted in Japanese patients using different doses of tissue plasminogen activator (51). Results showed that tissue plasminogen activator, when administered at 0.6 mg/kg to Japanese patients, provides clinical efficacy and safety comparable to that reported in patients in North America and the European Union for a 0.9 mg/kg dose.
Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) has shown that intravenous tissue plasminogen activator is safe and effective in routine clinical use when used within 3 hours of stroke onset, even by centers with little previous experience of thrombolytic therapy for acute stroke (45). In a randomized, double-blind study, intravenous tissue plasminogen activator administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke as compared to placebo, but it was more frequently associated with symptomatic intracranial hemorrhage (15).
Results of the RECANALISE study--a prospective cohort study in patients with stroke and confirmed arterial occlusion--showed that a combined intravenous-endovascular approach is associated with higher recanalization rates than is intravenous tissue plasminogen activator in patients with stroke and confirmed arterial occlusion (29).
Results of the European Cooperative Acute Stroke Study III (ECASS III) support the use of tissue plasminogen activator up to 4.5 hours after the onset of stroke symptoms across a broad range of subgroups of patients who meet the requirements of the European product label but miss the approved treatment window of 0 to 3 hours (06).
An updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials show that patients with ischemic stroke benefit from intravenous tissue plasminogen activator when treated up to 4.5 hours from onset (24).
An exploratory analysis of patients enrolled in the Japan Alteplase Clinical Trial II (J-ACT II) with unilateral occlusion of the middle cerebral artery showed that a residual vessel length less than 5 mm on magnetic resonance angiography can identify poor responders to tissue plasminogen activator (18).
A randomized open-label trial showed that early administration of intravenous aspirin in patients with acute ischemic stroke treated with tissue plasminogen activator does not improve outcome at 3 months and increases the risk of intracerebral hemorrhage (52). These results do not support a change of the current guidelines for starting antiplatelet therapy 24 hours after administration of tissue plasminogen activator.
In an open-label, international, multicenter, randomized trial, patients with ischemic stroke were randomly allocated within 6 hours of onset to either intravenous tissue plasminogen activator plus standard care or standard care alone (20). Results showed that intravenous tissue plasminogen activator did not affect survival in acute ischemic stroke but did lead to statistically significant and clinically relevant improvements in functional outcome that were sustained for at least 18 months. A randomized clinical trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous tissue plasminogen activator, as compared with intravenous tissue plasminogen activator alone (08).
A randomized trial has shown that tenecteplase is associated with significantly better reperfusion and clinical outcomes than alteplase in patients with stroke who were selected on the basis of CT perfusion imaging (33). In a phase 2 randomized trial, administration of tenecteplase prior to thrombectomy was associated with a higher incidence of reperfusion and better functional outcome than alteplase in patients with ischemic stroke treated within 4.5 hours after symptom onset (10). In a phase 3 trial that enrolled mainly patients with mild stroke who were not expected to have thrombectomy, the superiority of tenecteplase was not shown at a dose of 0.4 mg per kilogram, as compared with conventional doses of alteplase (25). Ongoing trials involving patients with stroke who are not expected to proceed to thrombectomy include TASTE (Tenecteplase vs. Alteplase for Stroke Thrombolysis Evaluation; Australian New Zealand Clinical Trials Registry number, ACTRN12613000243718) and ATTEST2 (Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis; ClinicalTrials.gov number, NCT02814409).
Concluding remarks on clinical trials. A review of various trials of thrombolytic therapy shows that intravenous thrombolytic therapy for ischemic stroke using tissue plasminogen activator and a "therapeutic window" treatment time of 3 hours is still the best available approach to improve the clinical outcome safely as there is still some concern about hemorrhagic complications beyond the 3-hour window. However, a European study has shown that there was no increase in hemorrhagic complications when the window was extended to 4.5 hours, and in 1 trial even to 6 hours.
More than 2 decades since the publication of the landmark National Institute of Neurological Disorders and Stroke trials, the efficacy as well as safety of intravenous tissue plasminogen activator has been consistently verified in international real-world clinical practice (13). Although tissue plasminogen activator has considerably improved stroke outcomes, skeptics still challenge the reliability of the evidence, and it is not a universal therapy as only to 5% to 10% of patients with acute stroke receive it (37). A meta-analysis of clinical trials in patients receiving intravenous tissue plasminogen activator shows that thrombectomy with a stent retriever versus tissue plasminogen activator alone is associated with significant improvement of functional independence 90 days after for acute ischemic stroke (43). The study “Perfusion Imaging Selection of Ischemic Stroke Patients for Endovascular Therapy (POSITIVE) Stroke Trial” started to investigate thrombectomy versus best medical treatment (in patients ineligible for thrombolysis) for stroke within 6 to 12 hours of onset but was stopped because of the clearly better results with thrombectomy in this as well as other similar trials (NCT01852201). Trial recruitment is currently suspended. Published results of the POSITIVE trial support the already established practice of delayed thrombectomy for appropriately selected patients presenting within 0 to 12 hours selected by perfusion imaging from any vendor (30).
Results of the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) trial, in which patients with specific imaging features were randomly assigned to receive standard doses of intravenous alteplase or placebo between 4.5 and 9 hours after the onset of stroke, revealed the likelihood of a good outcome (a score of 0 or 1 on the modified Rankin scale at 90 days) was 44% higher in the alteplase group than in the placebo group, although the study was terminated after only two thirds of the intended population were enrolled (27). The success of this trial is attributable to an image-guided approach to patient selection that had already brought success to mechanical thrombectomy performed many hours after the onset of stroke symptoms. Patients were eligible for the EXTEND trial if they had a mismatch between the core volume of infarction and the volume of potentially salvageable brain tissue in the ischemic penumbra. This trial represents a major successful step in using an image-guided approach to extend the seemingly immutable time limit for pharmacologic thrombolysis in patients with acute stroke (28).
As of March 2021, 162 clinical trials mentioning tissue plasminogen activator are listed on the U.S. Government web site for clinical trials:https://clinicaltrials.gov/ct2/results?cond=Acute+Stroke%2C+Ischemic&term=tissue+plasminogen+activator&cntry=&state=&city=&dist=&Search=Search.
These included completed and discontinued trials including combination of other treatments with tissue plasminogen activator.
The following are indications for tissue plasminogen activator use approved by the United States Food and Drug Administration:
• Acute myocardial infarction
• Use of tissue plasminogen activator beyond the 3-hour time window
• Intraventricular hemorrhage due to re-ruptured arteriovenous malformation has been reported to clear following administration of tissue plasminogen activator through a preexisting ventriculoperitoneal shunt placed for hydrocephalus resulting from a previous rupture of the malformation (39).
• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (21).
• Experimental studies in mice show that both endogenous and exogenous tPA protect against white matter injury after traumatic brain injury without increasing intracerebral hemorrhage volumes (49).
• tPA stimulates axonal regeneration and facilitates functional regeneration in a murine model of stroke, which is independent of its proteolytic activity and tPA-S478A, a mutant, protease-inactive form of tPA and is as effective as regular tPA without the risk of inducing intracerebral hemorrhage (35).
• Subdural injection of tissue plasminogen activator via catheter for residual subdural hematoma facilitates drainage by minimally invasive methods such as a twist-drill hole in the skull (23).
• In patients with severe COVID-19 respiratory failure, treatment with tissue plasminogen activator improved the respiratory status (48).
• In patients who have had a stroke with unknown time of onset with a diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care (42). A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial hemorrhage.
The contraindications of tissue plasminogen activator use are as follows:
• If the onset of stroke is more than 3 hours prior to arrival at the hospital
The aim of tissue plasminogen activator treatment is dissolution of the thrombus obstructing the artery. This is a 1-time treatment in the acute phase. Treatment must be administered in an acute care or intensive care setting and directed by physicians with expertise in diagnosing and managing stroke. Early administration of tissue-plasminogen activator improves the long-term clinical outcome at 5 years after onset (05). Lack of improvement in 24 hours in patients with acute stroke treated with thrombolytic therapy is associated with poor outcome.
Despite various controversies about thrombolytic therapy, there is consensus on the following points:
• American Heart Association/American Stroke Association (AHA/ASA) acute ischemic stroke guidelines support the use of tissue plasminogen activator in selected patients up to 4.5 hours after symptom onset (17).
• Thrombolytic therapy should be restricted to patients with evidence of an arterial occlusion.
• Thrombolytic therapy should be limited to patients with severe neurologic deficits such as hemiplegia. Pure sensory strokes and minor hemiparesis may recover spontaneously without treatment.
• Presence of infarction on CT scan is not necessarily a contraindication for thrombolytic treatment, but patients with large hemorrhagic infarcts should be excluded.
Because the narrow time window currently approved for the use of 3 hours excludes many patients, various possibilities are still being explored to extend this time window. Use of thrombolysis from a 3 to 4.5 hour window is still controversial, and a thorough review has concluded that until there are data showing benefits to outweigh known harms, use of tissue plasminogen activator beyond 3 hours after stroke should not be strongly recommended or encouraged (02).
Intravenous tissue plasminogen activator (0.9 mg/kg, maximum 90 mg) with 10% of the dose given as bolus, followed by an infusion lasting 60 minutes, is recommended within 3 hours of onset of stroke.
Anesthesia. No special precautions.
Surgery. Carotid endarterectomy (CEA) should be pursued cautiously in patients who recently received intravenous tissue plasminogen activator as it may be associated with an increased risk for intracerebral hemorrhage (44).
Pregnancy. No animal reproductive studies have been done; therefore, it is not known if tissue plasminogen activator can cause fetal harm if given during pregnancy. Activase should be used only if it is absolutely indicated. It is not known if tissue plasminogen activator is excreted in human milk. Caution should be exercised if tissue plasminogen activator is given to a nursing mother.
Pediatric. Clinical trials are needed to evaluate the dose and the safety as well as efficacy of tissue plasminogen activator in childhood stroke. Results of a clinical study suggest that the overall risk of symptomatic intracranial hemorrhage after intravenous tissue plasminogen activator in children with acute arterial ischemic stroke, when given within 4.5 hours after symptom onset, is low (03).
Geriatric. There is some concern that use of tissue plasminogen activator in patients 80 years or older is more likely to be associated with intracranial bleeds, but a review has shown the risk of symptomatic intracranial hemorrhage does not appear to be significantly higher in the elderly group, and intracranial bleeding complications are unlikely to outweigh the potential benefit in this age group (36). Based on current evidence, patients over the age of 80 should not be excluded from intravenous thrombolysis based on the criterion of older age (26). Alteplase for acute ischemic stroke has a positive benefit-risk profile among patients aged greater than 80 years when administered according to other regulatory criteria and on an individual benefit-risk basis (07).
The following drugs increase the risk of bleeding if given concomitantly with tissue plasminogen activator: heparin, vitamin K antagonists, and platelet inhibitors like aspirin. Tissue plasminogen activator is well tolerated in selected patients with acute ischemic stroke treated with nonvitamin K antagonist oral anticoagulants (50). Interactions with other central nervous system drugs have not been studied.
Experimental evidence suggests that some of the antihypertensive drugs (diuretics, beta-blockers, and calcium antagonists) may alter the activity of the fibrinolytic system. Antihypertensive drugs acting within the renin angiotensin system should also exert effects within the fibrinolytic system, but results from clinical studies with angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists do not unequivocally support such a concept.
Concurrent therapy with nitroglycerin reduces plasma tissue plasminogen activator concentrations and its clinical efficacy.
• Hypersensitivity reactions rarely occur, but orolingual angioedema has been reported in 1 of 5 patients treated with tissue plasminogen activator and is attributed to increased levels of bradykinin and histamine. Angiotensin-converting enzyme inhibitors, used for the treatment of hypertension, can increase levels of bradykinin and are a risk factor for tissue plasminogen activator—associated angioedema; therefore, concomitant use should be avoided (09). Treatment of angioedema usually requires a combination of corticosteroids, antihistamines, and epinephrine.
• Cholesterol embolization has been reported rarely in patients treated with thrombolytic agents and may cause infarction of various organs.
• Intracerebral hemorrhage. In a 4-year study, use of intravenous tissue plasminogen activator therapy was associated with symptomatic intracranial hemorrhage rate of 2.2% (32). Despite this complication, treatment offered significantly better odds of achieving a favorable functional outcome compared to no therapy. The hemorrhagic complication of tissue plasminogen activator may be due to impairment of blood-brain barrier integrity resulting from activation of latent platelet-derived growth factor-CC. Treatment of mice with the platelet-derived growth factor antagonist imatinib, an approved drug for leukemia, reduces both cerebrovascular permeability and hemorrhagic complications associated with late administration of thrombolytic plasminogen activator following ischemic stroke (41). Imatinib may, thus, have potential clinical application in prevention of hemorrhagic complications associated with tissue plasminogen activator. A phase 2 randomized trial has shown that imatinib is safe and tolerable and may reduce neurologic disability in patients treated with intravenous thrombolysis after ischemic stroke (46). Prolongation of activated partial thromboplastin time, low fibrinogen levels, and low platelet counts are associated with the risk of hemorrhagic transformation of stroke, and their correction may help patients to prevent cerebral hemorrhage (47).
• Cerebral edema. Cerebral edema associated with stroke may also be aggravated by thrombolysis. Forced reperfusion of already irreversibly damaged tissue increases edema formation and enlarges developing infarcts with an increase of intracranial pressure.
• Animal studies have reported neurotoxicity after tissue plasminogen activator thrombolysis but there is no evidence that tissue plasminogen activator administration can increase ischemic injury in human patients.
• Post-stroke seizures occur in 1 out of 10 patients. However, clinical studies have not shown that incidence of seizures is higher in those treated with tissue plasminogen activator than treatment-naive patients.
Current noninvasive vascular imaging tests such as CT angiography and MRI angiography can diagnose vascular occlusions safely, quickly, accurately, and specifically. At centers with facilities for MRI, fluid-attenuating inversion recovery scans, T2-weighted MRI, and multivariate regression analysis, exclusion brain hemorrhage, definition of ischemic areas, and identification of occluded arteries can all be performed prior to thrombolysis to reduce hemorrhagic complications. The likelihood of a poor outcome after thrombolysis is proportional to the extent of hemorrhage seen on pretreatment CT scans. Despite an increased risk of symptomatic intracranial hemorrhage, tissue plasminogen activator has not been reported to increase mortality.
Important steps in post-tissue plasminogen activator management are:
• The avoidance of antithrombotic or antiplatelet aggregating drugs within 24 hours of treatment.
• The performance of a brain imaging study (MRI or CT) 24 hours following the procedure.
• Tissue plasminogen activator should be stopped if intracerebral hemorrhage is suspected and other appropriate steps should be taken for further management, including neurosurgical consultation.
• Hyperbaric oxygen therapy may be considered for patients with neurologic deficits, intracerebral hemorrhage, and cerebral edema; however, this is still an investigative procedure.
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.See Profile
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