Thrombolytic Science International (TSI)
Strokes and heart attacks together kill 15 million people per year . The occlusion of blood vessels by blood clots, thromboembolism, is the major factor in the etiology of both conditions. Aside from its potentially fatal effects in the brain and heart, thrombosis may also be dangerous when it occurs in the limbs or in other organs, such as the liver or lungs. In addition, it is a common side effect of surgery.
In general, blood clots serve an important haemostatic function in the body: they block the flow of blood from damaged capillaries and vessels. Blood vessels can easily become damaged in everyday life, and blood clots help prevent small cuts to vessels in the skin, gastrointestinal tract, brain, or any other part of the body from becoming big problems.
Helpful hemostatic clots and harmful occlusive clots are structurally similar. This is a problem for thrombosis therapy because most thrombolytic agents treat all clots alike, making hemorrhage a major side effect of treatment. The foundation of a blood clot is polymerized protein fibrin, and its degradation can be triggered by a complex of several protein factors. One of the factors is the tissue plasminogen activator (tPA), which is normally released from the blood vessel walls in case of occlusion. Protein factors such as tPA have been adopted by modern medicine for thrombosis therapy. This enzyme begins the process of the thrombus degradation, making fibrin change its structure. This in turn makes other activators capable to join the process. Single chain pro-urokinase and the mature two-chain enzyme urokinase are among those activators.
The mature form of plasminogen, the enzyme plasmin, begins degradation of a thrombus. Plasminogen is released from the liver into the bloodstream, where it maintains an activation-resistant conformation until binding. After binding to fibrin inside a thrombus , plasminogen converts to a form that can be activated by tPA . Plasmin cleaves single fibrin molecules into two kinds of fragments — fibrin fragmentD (FFD) and E (FFE). FFE carries additional plasminogen binding sites, and plasminogen bound to this substrate undergoes a conformational change that allows it to be activated by pro-urokinase (proUK) . The molecule of proUK is turn activated by the plasmin and becomes the mature urokinase, which can activate not only FFE-bound plasminogen but also the plasminogen bound to intact fibrin . ProUK loses its specificity after activation and becomes capable of destroying both occlusive and hemostatic clots.
In case of serious pathology the described pathway may not be enough to destroy the thrombus. In this case, several variants of the therapy may be used, most involving higher doses of plasmin activators. The main problems, however, remain the same — side effects, such as intra-cranial hemorrhage or severe bleeding elsewhere.
Now, TSI company has introduced the TS01 — a thrombolytic treatment of a single-site mutant of native pro-urokinase (proUK) preceded by administration of the natural plasma inhibitor, C1 esterase inhibitor. The scientific group of Dr. Victor Gurewich discovered this single amino-acid mutant of proUK, which is not converted to urokinase in the presence of C1 inhibitor. As a result, the mutant proUK retains the ideal thrombolytic properties of native proUK at higher, therapeutic, plasma concentrations. Its most important property is its specificity for partially degraded fibrin, which is found only on occlusive clots. In other words, treatment with TS01 will ensure the degradation of harmful blood clots, only, thereby avoiding the side effects common with other therapies. TS01 will complete Phase 1 clinical studies in healthy adults in 2012.
The mutant proUK (m-proUK or M5) is distinguished by its 300th amino acid residue, where lysine has been substituted for histidine. Due to this substitution the C1 inhibitor, which is also a part of a treatment, can make a covalent bond with the active site of the mature mutant UK after it is activated by plasmin. The mutant UK therefore becomes inactive .
Visual Science created the illustrations in an interactive, scrollable strip to demonstrate the mechanism of TS01 to specialists in medicine and pharmacology. These illustrations depict the crucial stages of TS01 action on both occlusive and hemostatic clots. They are adapted for use on the TSI website, on iOS and Android devices, in presentations, at conferences, and in talks.
We want to thank TSI Chief Scientific Officer Dr. Victor Gurewich, TSI CEO Alexis Wallace and Matt Middleman from Russo Partners.
Molecular modelling through computer graphics permits plenty of latitude for exercising artistic talent to inform, explain and instruct. Visual Science shows the way with its high quality, accurate, informative graphics that explain even the most complex processes of life.