October 12, 2017

Story and photo by Nadir Balba

The Paper of the Month for September 2017 is "Differential Roles for the Coagulation Factors XI and XII in Regulating the Physical Biology of Fibrin" published in the Annals of Biomedical Engineering. This project was led by Drs. Joanna Sylman and Owen McCarty, Ph.D., professor and interim chair of biomedical engineering, OHSU School of Medicine.

The project is the culmination of an extremely successful multi-site collaboration between several departments and universities, as well as the OHSU biopharmaceutical start-up company Aronora Inc. Its authors, in descending order, are Dr. Joanna Sylman; Dr. Uranbileg Daalkhaijav from Oregon State University's School of Chemical, Biological, and Environmental Engineering; Ying Zhang, Elliot Gray Parsa Farhang, Tiffany Chu, Jevgenia Zilberman-Rudenko, Drs. Christina Puy, and Erik Tucker from the school's Department of Biomedical Engineering; Stephanie Smith and Dr. James Morrissey from the Department of Biochemistry at University of Illinois at Urbana-Champaign; Dr. Travis Walker from Oregon State University's School of Chemical, Biological, and Environmental Engineering; and Drs. Xiaolin Nan , András Gruber, and Owen McCarty, also from the school's Department of Biomedical Engineering.

When clotting goes wrong

Coagulation, or more commonly called clotting, is a process where blood plasma changes from a liquid to a gel preventing sustained bleeding after a vascular injury. This process is accomplished using a fibrous protein aptly name fibrin, which "glues" together blood cells forming a fibrin clot. Without this essential biological reaction, even a slight cut or injury to a blood vessel can lead to severe blood loss, a common condition in patients with hemophilia and von Willebrand disease. However, in diseased blood vessels this process can go awry and contribute to pathological thrombosis, a medical condition where a blood clot is formed inside a blood vessel and can potentially cause stroke and heart attack.

There are two different pathways of coagulation, an "intrinsic" and an "extrinsic" pathway. It is not yet understood how to safely prevent the formation of harmful blood clots in diseased vessels, so Dr. McCarty's team decided to examine how clots initiated by either the intrinsic or extrinsic coagulation pathways differed in their physical biology, and to see if inhibition of specific enzymes involved in the coagulation cascade were more likely to prevent pathological thrombus formation.

The "factors" of blood clotting

There are several enzymes involved in the coagulation process, with factors (F) XI and FXII being two of the most vital. Previous work has demonstrated that congenital FXI deficiency can protect patients from stroke and thrombosis without damaging the body's natural hemostatic response that stops bleeding.

Based on the hypothesis that inhibiting FXI or FXII activation could prevent thrombosis without comprising hemostasis, the team lead by Drs. Gruber, Tucker and McCarty began developing FXI inhibitors to test their ability to treat or prevent thrombosis. Earlier studies demonstrated that FXI activation provided benefits in models of several cardiovascular diseases including thrombosis, heart attack and stroke. But further work was needed to examine differences between fibrin clots that were initiated by either the intrinsic or the extrinsic pathway, and how inhibiting FXI and FXII activation would affect the formation of these clots.

The present study discovered that the physical biology of fibrin-rich clots substantially differed when thrombin generation is initiated by the intrinsic pathway. Activation of this pathway by bacterial components promoted distinct fibrin clot formation and kinetics, which suggested that inhibition of FXII may provide a therapeutic benefit.

Dr. Sylman and colleagues decided to take this a step further, manipulating this system firsthand by impeding enzyme activation. They found that, by inhibiting FXI and FXII, they could decrease total fibrin density and the rate of fibrin formation, while also increasing clot digestion and gel strength. This was a monumental step in understanding how individual enzymes impact the clotting process and provided a basis for preventing harmful blood clots.

Mary Heinricher, Ph.D., associate dean for basic research at OHSU's School of Medicine, was especially impressed by the team's meticulous characterization of how different pathways and enzymes affected the biology of blood clots. "I was fascinated by the differential contributions of these factors depending on how coagulation is triggered. It certainly speaks to the ability to "fine tune" the system depending on physiological challenges."

Preventing and treating cardiovascular disease

This research has helped identify potential pharmacological targets to prevent clot formation in diseased blood vessels and could hopefully prevent potential stroke and heart attack. The research team has already created a series of agents that can inhibit the activation of the intrinsic pathway of coagulation. This work has spanned single cell assays to rodent and even non-human primate models and have been tested on models of thrombosis, heart attack, stroke, infectious disease and cardiac bypass surgery.

That has led to the advancement of targeted pharmacology interventions to inhibit FXI and safely treat cardiovascular disease without causing bleeding. Currently, the safety of the FXI inhibitor developed by the team is already being evaluated in a Phase I clinical trial. This marks one of the first instances of a drug being brought from invention to development at OHSU. It is important to note that this development relied on the collective work of the cardiovascular group within the Department of Biomedical Engineering, the founding and partnering with the OHSU start-up company Aronora, and the collaboration between researchers from Oregon State University, Oregon National Primate Research Center and OHSU's Technology Transfer and Business Development Office.

Together, this research has led to the advancement of a promising new approach to safely treat cardiovascular disease.

Resources

• Read the paper 

Citation

Sylman JL, Daalkhaijav U, Zhang Y, Gray E, Farhang P, Chu TT, Zilberman-Rudenko J, Puy C, Tucker EI, Smith SA, Morrissey JH, Walker TW, Nan X, Gruber A, McCarty OJ. Differential roles for the coagulation factors XI and XII in regulating the physical biology of fibrin. Annals of Biomedical Engineering May 2017, Volume 45, Issue 5, pp 1328–1340

More Published Papers

• Previous School of Medicine Papers of the Month
• Recent OHSU published papers

Pictured above: Members of the McCarty lab.