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Student Perspective
ULTRASOUND-ASSISTED TISSUE PLASMINOGEN ACTIVATOR DELIVERY TO ISCHEMIC
STROKES
Abeyat Zaman1, BHSc, MD candidate 2012*, Ajit Thakur2, BSc, MASc, MD
candidate 2014 and Iran Rashedi2, MD, PhD candidate 2013
1Pediatric
Laboratory Medicine, Hospital for Sick Children, 555 University
Avenue, Toronto, Ontario
2Institute
of Biomaterials and Biomedical Engineering, Rosebrugh Building, 164
College Street, Room 407, University of Toronto, Toronto, Canada
*Corresponding Author contact: [email protected]
Keywords:
ultrasound
assisted
thrombolysis,
sonothrombolysis,
tissue
plasminogen activator , stroke
The World Health Organization defines stroke as ‘rapidly developing clinical
signs of focal (or global) disturbance of cerebral function, with symptoms lasting
24 h or longer or leading to death, with no apparent cause other than that of
vascular origin’1. In adults, strokes, or ischemic cerebrovascular accidents, is the
third major cause of morbidity and mortality, surpassed only by heart disease and
cancer1, 2. With increasing longevity and increasing proportion of people aged
over 65 in North America, death and disability from strokes can be expected to
increase2. Current therapies for strokes, while effective, have significant
hemorrhagic risks to the patient and must be administered within a very narrow
timeframe, Therefore, there is a need to investigate novel therapeutic agents as
well as improve drug administration techniques to acutely decrease the injury
caused to the brain in the event of a stroke, while minimizing the potential for
hemorrhages and reperfusion injuries.
Strokes can be broadly classified into two categories: ischemic and hemorrhagic.
The former category comprises 80% of all strokes1, 2. Ischemic strokes are
caused by occlusion of the arteries of the brain, which can be caused by a
thrombus in situ, or by an emboli, a clot formed elsewhere that migrates to the
brain1. Within the brain vasculature, blood clots form when activated platelets
aggregate and inactive fibrinogen forms a fibrin meshwork, thus blocking blood
flow and depriving neurons of oxygen and nutrients. Therefore, the current
standard for treatment in strokes is thrombolysis, in which thrombolytic agents
dissolve the occluding fibrin meshwork that causes the clot1. The thrombolytic
agent of choice is tissue plasminogen activator (tPA). Fibrinolysis occurs when
tissue plasminogen activator, which is a serine protease, cleaves the zymogen
plasminogen to produce the active serine protease plasmin1. Tissue plasminogen
activator has been shown to be more specific to fibrin at the site of adherence
than other thrombolytic agents and can thus degrade the fibrin clot more
efficiently2. Therefore, it is the agent of choice in an emergency thrombolytic
setting.
Despite its efficacy in an acute setting, there are several conditions associated
with tissue plasminogen activator use. The administration of tPA within three
hours of the onset of a stroke is associated with an increased proportion of
patients with a positive outcome, such as improvement in neurological function.
Tissue plasminogen activator use is also associated with a simultaneous
decrease in the proportion of patients suffering from permanent disabilities 1, 3.
However, it is not always possible to administer this agent within such a narrow
time window for several reasons. Firstly, patients often may not recognize the
symptoms of a stroke, and may not seek medical attention immediately.
Secondly, there may be delays in transporting the patient to an appropriate care
facility. As well, administration of tissue plasminogen activator can significantly
increase the risk of intracranial hemorrhage, which itself may be quite
devastating1, 2. In order to decrease the risk of reperfusion injury or hemorrhages,
there has been a drive to investigate combination therapies that may improve the
efficacy of tPA as a therapeutic agent. Specifically, there has been research into
the application of existing biomedical technologies in combination with tPA to
improve patient outcomes.
Sonothrombolysis is one such technique that uses ultrasound waves on the skull
to dislodge thrombi from its interface with a vessel. The ultrasound delivers
momentum to areas of stagnant blood flow, which causes agitation and
dissolution of the thrombus and also increases the penetration of tPA into the
thrombus4. Experimental evidence has suggested that the use of ultrasound
waves may accelerate enzymatic fibrinolysis of tPA as well. This results in a
greater infiltration of drugs into the clot and a bigger area of thrombolysis3. One
study has shown that rats treated with low-frequency, pulsed ultrasound
combined with systemic tPA have shown a smaller area of infarcts compared to
untreated controls as well as rats receiving only the drug3. Clinical trials have
also shown optimistic results of using sonothrombolysis in combination with
systemic tPA. For example, a study by Alexandrov et. al. showed that 83% of
patients receiving tPA and transcranial Doppler achieved recanalization at two
hours (as shown by ultrasound or CT or MR angiography), versus 50% of
patients receiving tPA only. This study also found that 38% of patients that had
received tPA and sonothrombolysis were functionally independent at 3 months,
versus 22% of patients who had only received tPA5. Therefore, combining tPA
with sonothrombolysis may significantly increase the efficacy of tPA, and have a
positive biological effect.
Considering the enormous familial, societal and financial burden faced by those
affected by strokes, there is a need to investigate more efficacious methods that
can be used in combination with current therapies for strokes. The rigid criteria
for tPA administration as well as the time restriction of three hours limits the
number of patients that may receive this treatment. We believe that the most
exciting option appears to be the augmentation of tPA use with procedures such
as sonothrombolysis. The ultrasound mechanically agitates the area of the
thrombus, thus increasing the amount of residual blood flow and augments the
delivery of tissue plasminogen activator to the thrombus. Results of the animal
studies3 and clinical trials4 have shown favourable results, and the low cost and
ease of using ultrasound treatment make it feasible for routine use in hospitals.
We believe that sonothrombolysis may supplement tissue plasminogen activator
infusion in patients to reduce long-term morbidity and mortality. Considering the
extended length of time it takes to license a new drug approved by the FDA, this
trend towards the combination of biomedical technologies with existing FDAapproved drugs might be a fast way forward that allows for significant
improvements in the efficacy of drug treatments for a wide variety of diseases.
Combination therapies could not only serve to reduce the burden on the
Canadian healthcare system, but also promote and accelerate the integration of
biomedical technologies in mainstream medicine.
REFERENCES
1. Armstead, WM, Ganguly K, Kiessling JW, Riley J, Chen XH, Smith DH, Stein
SC, Higazi AA, Cines DB, Bdeir K, Zaitsev S, Muzykantov VR. Signaling,
delivery and age as emerging issues in the benefit/risk ratio outcome of tPA
For treatment of CNS ischemic disorders, J Neurochem 2010; 113 (2): 303 –
312.
2. Murray V, Norrving B, Sandercock PA, Terént A, Wardlaw JM, Wester P. The
molecular basis of thrombolysis and its clinical application in stroke, J Intern
Med 2009; 267: 191 – 208.
3. Daffertshofer, M, Huang Z, Fatar M, Popolo M, Schroeck H, Kuschinsky W,
Moskowitz MA, Hennerici MG. Efficacy of sonothrombolysis in a rat model of
embolic ischemic stroke. Neurosci Lett 2004; 361: 115 – 119.
4. Alexandrov, A.V. Current and future recanalization strategies for acute
ischemic stroke. J Intern Med 2010; 267: 209 – 219.
5. Tsivgoulis, G, Eggers J, Ribo M, Perren F, Saqqur M, Rubiera M, Sergentanis
TN, Vadikolias K, Larrue V, Molina CA, Alexandrov AV. Safety and efficacy of
ultrasound-enhanced thrombolysis: a meta-analysis of randomized and nonrandomized studies. Stroke 2008; 39: 593 – 594.