In a report published in February 2008, researchers from Oregon Health and Science University (OHSU) in Portland, OR, and Washington University in St. Louis, MO, explain how a genetically engineered version of the enzyme thrombin has the potential to become a new clotting therapy. The modified enzyme, known as WE-thrombin, could provide a viable treatment alternative to prevent excessive clots that can lead to strokes and heart attacks. The principal investigator of the study was András Gruber, MD, PhD, associate professor of biomedical engineering and medicine in the division of hematology and medical oncology, OHSU School of Medicine.
Normally, thrombin promotes coagulation by cutting the protein fibrinogen into fibrin strands that interlock to form a platelet plug, which stems bleeding. It then stimulates activated protein C (APC) inside the blood vessel to break up the clot. APC ensures that clots do not linger long enough to risk triggering a heart attack or stroke. WE-thrombin, on the other hand, forgoes its clot-forming role while still initiating APC, making it an effective local anticoagulant. The enzyme is particularly effective at busting clots because it latches onto glycoprotein Ib on the platelet membrane, inhibiting von Willebrand factor (VWF) from contributing to coagulation. Typically, glycoprotein Ib binds VWF, allowing it to secure platelets to the injured blood vessel cell wall.
“The process parallels that of targeted drug delivery. It’s effective inside a blood vessel, but not at all effective outside the blood stream, which is exactly what you want from an antithrombotic agent,” said Gruber. He and his colleagues have already conducted efficacy and safety tests on primates.
One of the primary advantages of WE-thrombin is that it could prevent or break up dangerous clots without causing bleeding, a common risk for patients undergoing treatment with currently available anticoagulant therapies such as heparin and tissue plasminogen activator. A person showing signs of a possible heart attack or stroke could conceivably be treated with such a therapy at the onset of symptoms without the concern about additional bleeding complications. The therapy would also allow emergency medical personnel to use a precautionary approach in treating potential heart attack or strokes victims, when time is of the essence.
“The successful development of WE-thrombin would be a major medical breakthrough in antithrombotic therapy, ultimately saving thousands of lives worldwide each year,” said Gruber.
Gruber, his fellow researchers and others have partnered to create Aronora LLC, a startup biotechnology company, to seek financial support for preclinical and early clinical development of WE-thrombin. The patents on WE-thrombin are currently co-owned by OHSU, Washington University and Emory University.
The study, “Thrombin Mutant W215A/E217A Acts as a Platelet GPIb Antagonist,” was published in the February 2008 issue of Arteriosclerosis, Thrombosis, and Vascular Biology, a peer-reviewed journal of the American Heart Association.
Source: Science Daily, March 11, 2008; OHSU Press Release, dated March 10, 2008