Unexpected results identify new cardiovascular risk factor, spur development of novel diagnostic
The protein fibrinogen is an essential factor in the body’s ability to properly form blood clots.
For more than four decades, scientists have been studying the biochemical properties of a variant of fibrinogen called γ’ fibrinogen.
“This alternatively-spliced fibrinogen variant displays different coagulation parameters in vitro than the major form of fibrinogen,” said David H. Farrell, Ph.D., FAHA, professor of surgery, Division of Trauma, Critical Care and Acute Care, OHSU School of Medicine.
Results from the Farrell lab and others have shown that γ’ fibrinogen is a risk factor for death by cardiovascular disease, development of heart failure and the development of peripheral artery disease. Paradoxically, though, purified γ’ fibrinogen also has slower clotting kinetics than unfractionated fibrinogen in vitro, which would normally be protective against these diseases.
γ’ fibrinogen also forms clots that are stronger and resistant to fibrinolysis, an enzymatic process that breaks down clots.
“The conflicting in vitro properties of γ’ fibrinogen made it unclear which, if any, of these properties may contribute to cardiovascular disease,” said Dr. Farrell.
To better understand that, Dr. Farrell collaborated with Susan Rowell, M.D., now at Duke School of Medicine, and Martin Schreiber, M.D., professor of surgery, OHSU School of Medicine, and others to investigate the associations between γ’ fibrinogen and traditional clinical coagulation measures.
Their study, “γ’ fibrinogen levels are associated with blood clot strength in traumatic brain injury patients,” published in the American Journal of Surgery is OHSU School of Medicine’s Paper of the Month.
Because the properties have only been investigated in human populations in a limited number of studies, the team performed a retrospective analysis to test the hypothesis that γ’ fibrinogen levels influence coagulation in vivo.
The results demonstrated that γ’ fibrinogen levels were associated with stronger clots, as revealed by thrombelastography (TEG), a method of testing blood coagulation, consistent with previous biochemical results.
“Unexpectedly, however, γ’ fibrinogen levels were associated with more rapid clotting, as indicated by a shortened international normalized ratio or INR,” said Dr. Farrell. “This is the opposite of the properties of γ’ fibrinogen in vitro. These results may explain why γ’ fibrinogen is a risk factor for cardiovascular disease, since it is associated with both more rapid blood coagulation and stronger clots.”
Dr. Farrell and team saw an opportunity for that knowledge to benefit patients. They’ve now developed an assay for γ’ fibrinogen with an OHSU spinoff company called Gamma Therapeutics and are pursuing FDA clearance for the assay as a clinical diagnostic test for cardiovascular disease risk.
“This paper really highlights the importance of communication between ‘bench’ and ‘bedside,’ and the value of that conversation for a strong clinical department like OHSU’s Department of Surgery,” said Mary Heinricher, Ph.D., associate dean of research, OHSU School of Medicine.
Learn more! Dr. Farrell discusses his findings in this TEDxMcMinnville talk.
Am J Surg. 2019 Dec 28. pii: S0002-9610(19)31583-1. doi: 10.1016/j.amjsurg.2019.12.028. [Epub ahead of print] γ’ fibrinogen levels are associated with blood clot strength in traumatic brain injury patients. Farrell DH, Rick EA, Dewey EN, Schreiber MA, Rowell SE.