Michael Clements

Time-Dependent Analysis of Thrombolytic Delivery for Stroke Treatment

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Image of a thrombus

Stroke is the third leading cause of death in the United States accounting for approximately one out of every eighteen fatalities each year. Stroke has a mortality rate of over 17 percent, and the survivors have over a 71 Image of a thrombuspercent chance of moderate to severe disability.  Eighty-seven percent of all strokes are ischemic, caused by a blockage of blood flow and starvation of oxygen to the brain due to a thrombus (blood clot). Strokes can be treated with thrombolytics such as streptokinase and tissue plasminogen activator (tPA) that aim to dissolve the blood clot and restore blood flow to the oxygen deprived region of the brain. These fibrinolytic proteins activate plasminogen to plasmin which cleaves the fibrin mesh that holds a thrombus together.

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Typical concentration profiles of tPA (a) and plasminogen (b) one hour after the start of intravenous tPA administration

Unfortunately, the standard one hour long intravenous administration of these thrombolytics is still rather ineffective.  Intravenous administration results in the thrombolytic being diluted throughout the body’s entire blood supply which can result in systemic over-elevation of plasmin levels leading to hemorrhaging or bleeding complications.  This prevents the administration of large doses of thrombolytic.  If an artery is fully occluded, convection can only transport the drug a short distance into the blocked vessel and transport through the remaining vessel length is diffusion-limited.  The slow speed of this process can prove fatal especially since the vast majority of the thrombolytic will flow past the occluded vessel rather than entering it.  Also, thrombolytics react in the bulk bloodstream so as time passes less thrombolytic is available to dissolve the thrombus.  tPA has fibrin specificity and reacts faster at the clot, but streptokinase reacts slower in the bloodstream.  While a great deal of research is being done to develop an ideal thrombolytic, the many issues that arise between injection and delivery to the clot suggest that the mechanism of delivery should be radically altered.  My research aims to design and analyze such new and more rapid mechanisms for thrombolytic delivery like administering it with a magneto-rheological fluid in the presence of a rotating magnetic field with a gradient.

 

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from www.mayoclinic.com; Image of a possible cause of an ischemic stroke

 

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Transient plots of the local concentrations of streptokinase (a) and tPA (b) at the clot and the cumulative amount of streptokinase (c) and tPA (d) delivered to the thrombus